|Year : 2021 | Volume
| Issue : 1 | Page : 19-28
Neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia: A prospective cross-sectional study
Jisha Abraham1, Surendran Veeraiah1, Venkatraman Radhakrishnan2
1 Department of Psycho-Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Medical Oncology and Pediatric Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Submission||14-Sep-2020|
|Date of Decision||17-Dec-2020|
|Date of Acceptance||04-Feb-2021|
|Date of Web Publication||26-Mar-2021|
Department of Psycho Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Given the improvement in the survival of patients with ALL over the last few decades, the adverse effects of treatment and disease on survivors have become a major concern. Neuropsychological functioning has been reported to be affected in long-term survivors of ALL and can impact their quality of life.
Objective: The objective of the study was to assess the neuropsychological functioning of long-term survivors of pediatric ALL.
Materials and Methods: This prospective cross-sectional study was conducted at the Cancer Institute, Chennai, India, between March and August 2014. Pediatric patients with ALL who had survived at least 2 years after treatment and were in remission were included in the study. Various neuropsychological domains such as sustained attention, focused attention, verbal working memory, immediate memory, verbal learning, immediate recall, delayed recall, visuoconstructive ability, and visuomotor speed were assessed using age-appropriate tests. Data were analyzed using descriptive statistics and nonparametric tests such as the Mann–Whitney U and Kruskal–Wallis H-tests. P < 0.05 was considered statistically significant.
Results: Of the 51 participants, there were 30 male and 21 female survivors. Their median ages at diagnosis and assessment were 8.6 years and 18.3 years, respectively. Adult survivors (n = 31) were found to have deficits in immediate memory, verbal learning, immediate recall, visuoconstructive ability, and visuomotor speed. Adolescent survivors (n = 20) were found to have deficits in immediate memory and verbal working memory. Survivors aged 8 years or more at diagnosis had better focused attention and verbal working memory, while those diagnosed at age <8 years had better visuoconstructive ability. Those with longer survival had better verbal working memory.
Conclusions: Long-term survivors of pediatric ALL experience deficits in various neuropsychological functions. Adult survivors have deficits in immediate memory, visuoconstructive ability, verbal learning, immediate recall, and visuomotor speed, whereas adolescent survivors have deficits in immediate memory and verbal working memory.
Keywords: Leukemia, neurology, psycho-oncology, survivorship
|How to cite this article:|
Abraham J, Veeraiah S, Radhakrishnan V. Neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia: A prospective cross-sectional study. Cancer Res Stat Treat 2021;4:19-28
|How to cite this URL:|
Abraham J, Veeraiah S, Radhakrishnan V. Neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia: A prospective cross-sectional study. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Oct 18];4:19-28. Available from: https://www.crstonline.com/text.asp?2021/4/1/19/312074
| Introduction|| |
Cure rates for pediatric acute lymphoblastic leukemia (ALL) have increased over the past few decades, and currently, most developed countries report a 5-year survival of more than 80%. However, the outcomes in low- and middle-income countries like India are comparatively inferior. Survivors of pediatric ALL, due to their disease and the treatment received, experience long-term adverse effects which can be physical, emotional, and psychological.,
Central nervous system (CNS)-directed therapy is an important part of ALL management. CNS serves as a disease sanctuary site, and thus omitting CNS-directed therapy can lead to relapses in the CNS. CNS-directed therapies can be administered in several ways. These include prophylactic cranial radiotherapy (CRT), intrathecal methotrexate (IT MTX), and high-dose intravenous methotrexate (HDMTX). Over the years, prophylactic CRT has been omitted from CNS-directed therapy as data suggest that IT MTX and HDMTX can produce similar outcomes with lesser long-term toxicities, particularly neurocognitive deficits. At our center, all pediatric ALL patients received prophylactic CRT until 2016, after which this practice was discontinued. However, patients with CNS disease at presentation continue to receive therapeutic CRT.
Studies have shown that administering chemotherapy and radiotherapy to the brain can affect various domains of neuropsychological functioning such as attention, memory, processing speed, and verbal learning in adult survivors of pediatric ALL.,,,, A meta-analysis of 28 studies reported a decline in the overall intellectual functioning and specific cognitive areas such as attention, speed of information processing, and executive functions in survivors of pediatric ALL compared to the healthy controls. A recent study with a large cohort also reported deficits in the areas of verbal intelligence, focused attention, verbal fluency, working memory, dominant/non-dominant motor speed, visuomotor speed, memory span, and reading and math measures. Conversely, there have been studies that have reported no significant alterations in the neuropsychological functioning of adult survivors of pediatric ALL., This disparity in the results could be due to the use of different treatment protocols, assessment parameters, and tools for assessment.
There is a paucity of data on neuropsychological outcomes of pediatric ALL survivors in the Indian setting.,, Therefore, we conducted this study to understand the neuropsychological functioning of long-term survivors of pediatric ALL treated with CRT and chemotherapy. Understanding the neuropsychological functions of long-term survivors of pediatric ALL in India can help the professionals to tailor the treatment with minimal late effects, take adequate steps to prevent deficits, and design cognitive retraining methods to enhance the cognitive abilities.
| Materials and Methods|| |
General study details
This prospective, cross-sectional study was performed at the Cancer Institute (W.I.A) in Chennai, India, between March 1, 2014, and August 30, 2014. We included survivors of pediatric ALL who had completed treatment at least 2 years ago and were in remission. The study was approved by the Institutional Thesis Review Committee (ITRC/04/14) [Supplementary Appendix 1]. Informed consent was obtained from the participants or caregivers (for participants aged below 18 years) before enrollment in the study. The study was not registered with a public clinical trials registry, like the Clinical Trials Registry-India. No funding was obtained for conducting this research. The study was conducted according to the ethical guidelines outlined in the Declaration of Helsinki and the Indian Council of Medical Research guidelines for ethical research.
We included long-term survivors of pediatric ALL (CNS negative) who were diagnosed before 18 years of age; were disease-free for a minimum of 2 years after completion of treatment; aged between 8 and 50 years at the time of enrollment; and able to read, write, and comprehend Tamil/Telugu/Malayalam/English, with at least fourth-grade education. Study participants consisted of both childhood (age at assessment 15 years and below) and adult survivors (age at assessment 16 years and above). We excluded persons with any evidence of relapse at the time of enrollment in the study and persons with a history of mental retardation or neurological disease or psychiatric conditions.
The primary endpoint of the study was to assess the neuropsychological functioning of long-term survivors of pediatric ALL. The secondary endpoint was to evaluate the difference in the neuropsychological functioning based on the age at diagnosis and the number of years of survival.
The neuropsychological domains assessed included sustained attention, focused attention, verbal learning, immediate recall, delayed recall, verbal working memory, immediate memory span, visuoconstructive ability, and visuomotor speed.
These functions were assessed using two separate sets of tools for adults and children. For adults the Digit Vigilance Test, Color Trails Test (CTT), Rey's Auditory Verbal Learning Test (AVLT), Verbal Working Memory N-Back Test (part 1 and 2) from NIMHANS Neuropsychological Battery for Adults and Digit Span Test, Digit Symbol Substitution Test, and Block Design Test from Wechsler Adult Intelligence Scale-III (WAIS-III) were used. For children, the Color Cancellation Test, CTT, Rey's AVLT, Verbal N-Back Test (part 1 and 2) from NIMHANS Neuropsychological Battery for Children and Digit Span Test, Coding, and Block Design Test from Malin's Intelligence Scale for Indian Children were used.,,, All the tests were administered individually to the participant by a psycho-oncologist.
The study participants were treated with MCP 841, Berlin Frankfurt Munster 86 (BFM 86), BFM 95, or INCTR protocols.,,, All the pediatric patients with ALL had received prophylactic CRT as they underwent treatment before 2016.
The definitions of the various domains used in the neuropsychological assessments are as follows:
- Sustained attention: The ability of an individual to maintain attention for a long period of time
- Focused attention: The ability of an individual to attend to or focus on a particular stimulus among a group of stimuli
- Immediate memory span: The ability of an individual to attend immediately to the stimulus and verbally recall it immediately after auditory attention
- Verbal learning: The process of learning about verbal stimuli and responses, such as letters, digits, nonsense syllables, or words
- Immediate recall: The ability to recall (reproduce) the stimuli immediately after they are presented
- Delayed recall: The ability of an individual to recollect information acquired earlier
- Verbal working memory: This refers to the temporary maintenance and manipulation of verbal information. It is responsible for temporarily storing verbalizable information, such as letters, words, numbers, or nameable objects
- Visuoconstructive ability: It is the ability to draw or construct two- or three-dimensional figures or shapes by the spatial manipulation of objects, such as arranging, building, or drawing. It involves the coordination of fine motor skills with spatial abilities, usually in the reproduction of geometric figures. Individuals who have difficulties with visuoconstruction and spatial abilities often struggle with daily tasks such as arithmetic, driving, and writing
- Visuomotor speed: The ability of an individual to efficiently integrate eyes and hands to complete a task.
A formal sample size calculation was not performed, as this was a cross-sectional study limited to a specific time frame. All consecutive participants fulfilling the eligibility criteria who visited the medical oncology outpatient department for follow-up during the study period were enrolled. The raw scores for the tests were calculated, and the corresponding percentile or cutoff scores were obtained from the manuals. Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS Inc. Released 2006. SPSS for Windows, Version 15.0. Chicago, SPSS Inc.). Descriptive statistics and nonparametric tests such as the Mann-Whitney U and Kruskal–Wallis tests were used to analyze the data. Descriptive statistics were used to determine the frequency, mean, and standard deviation of different demographic variables and the proportion of long-term adult and childhood survivors with and without a deficit. P < 0.05 was considered statistically significant.
| Results|| |
Fifty-four participants meeting the eligibility criteria and willing to participate in the study were recruited. Three participants, two with relapsed ALL and one who could not complete the test due to fatigue, were excluded [Figure 1]. Among the survivors of pediatric ALL, there were 20 children (aged 15 years or less at assessment) and 31 adults (aged 16 years and above at assessment). The median ages of the survivors at diagnosis and assessment were 8.6 years and 18.3 years, respectively. The median survival after completion of treatment was 9.2 years. The demographic details of the long-term survivors of pediatric ALL are reported in [Table 1].
|Table 1: Demographic characteristics of the long-term adolescent and adult survivors of pediatric acute lymphoblastic leukemia|
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The various neuropsychological functions of long-term adult survivors of pediatric ALL are described in [Table 2]. Majority (71%) of the survivors showed deficits in the immediate memory span (71%) and visuoconstructive ability (74.2%). About 58.1% of the survivors showed no deficits in verbal learning. Deficits in immediate recall and visuomotor speed were observed in 45.2% and 41.9% of the survivors, respectively.
|Table 2: Neuropsychological functions of long-term adult survivors of pediatric acute lymphoblastic leukemia|
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The neuropsychological functions of long-term adolescent survivors of pediatric ALL are described in [Table 3]. Half of the survivors showed deficits in the first test for verbal working memory, and 95% showed deficits in the second test with an increasingly difficult level; 40% of the survivors showed deficits in immediate memory span.
|Table 3: Neuropsychological functions of long-term adolescent survivors of pediatric acute lymphoblastic leukemia|
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The neuropsychological functions of long-term survivors of pediatric ALL based on the age at diagnosis and survival are shown in [Table 4].
|Table 4: Neuropsychological functions of long-term survivors of pediatric acute lymphoblastic leukemia based on age at diagnosis and survival|
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Neuropsychological functions based on the age at diagnosis
Long-term ALL survivors aged 8 years or above (median2) at diagnosis performed better than those aged <8 years (median1) at diagnosis on the focused attention test 2 (median2 = 86.73 > median1 = 42.50) (U = 196.00, P = 0.015), verbal working memory part 1 (median2 = 71.66 > median1 = 28.33) (U = 120.00, P = 0.000), and verbal working memory part 2 (median2 = 27.50 > median1 = 5.00) (U = 124.00, P = 0.000). On the other hand, those aged <8 years at diagnosis had better visuoconstructive ability than who aged 8 years or above at diagnosis (median1 = 12.00 > median2 = 7.00) (U = 181.00, P = 0.006). The performance on the focused attention test 1 (P = 0.090), the verbal learning (P = 0.654), and delayed recall (P = 0.127) did not significantly differ depending on the age at diagnosis.
Neuropsychological functioning based on the survival
Participants with survival longer than 9 years (median2) performed better than those with a survival of 8 years or less (median1) on verbal working memory part 1 (median2 = 67.50 > median1 = 37.50) (U = 207.50, P = 0.038). However, the performance on the focused attention test 1 (P = 0.259) and test 2 (P = 0.085) and verbal working memory part 2 (0.353), the verbal learning (P = 0.090), delayed recall (P = 0.985), and visuoconstructive ability (P = 0.065) did not significantly differ depending on the survival.
| Discussion|| |
To the best of our knowledge, this study is the first from India to assess the neuropsychological functioning of long-term survivors of pediatric ALL. We found that both adult and childhood survivors of pediatric ALL have deficits in various neuropsychological functions. Deficits in immediate memory and verbal memory were observed in long-term childhood survivors, whereas deficits in immediate memory, verbal learning and immediate recall, visuoconstructive ability, and visuomotor speed were observed in long-term adult survivors.
The Digit Span test showed impairment in the immediate memory in long-term ALL survivors. Most adult survivors and nearly half of the children who survived showed deficits in immediate memory. This could be due to the damage to the areas of the left hemisphere which are responsible for the immediate memory function. This finding is in line with those of many other studies that reported a deficit in the immediate memory of long-term survivors treated with CRT and chemotherapy.,,,,,,,,
In our study, the adolescent survivors of pediatric ALL showed a deficit in the verbal working memory. This could be attributed to the damage to the central executive area which is controlled by the prefrontal cortex and anterior cingulate cortex of the frontal lobe. Consistent with this finding, different studies have reported deficits in the working memory and verbal immediate memory among childhood survivors., The adult survivors in our cohort showed no impairment in the verbal working memory. This result is supported by the findings from Conklin et al.'s study that reported no deficit in the verbal memory among adult survivors and Chidambaram et al.'s study that reported no deficit in this domain in pediatric patients with ALL in India. Furthermore, in our study, the AVLT revealed impairment in the verbal learning and immediate recall in half of the adult survivors. This is similar to the findings of a study on 112 adult survivors of pediatric ALL.
However, we did not observe any deficits in delayed recall among both adult and adolescent survivors. Other studies on ALL survivors also reported no deficits in delayed recall in adult, and verbal learning, immediate recall, and delayed recall in childhood survivors.,,
A large proportion of the adult survivors of pediatric ALL showed deficits in visuoconstructive ability; a minimal deficit in this domain was also observed in childhood survivors. However, only a few studies have documented specific deficits in the visuoconstructive ability, namely lower spatial ability specifically among adult survivors and low performance on various visuospatial skills, such as visuomotor coordination, visuomotor integration, visuospatial task, and perceptual organization among adult and childhood survivors.,,,,,,, Our finding of minimal deficit could be attributed to the small sample size of our study.
The Digit-symbol test revealed impaired visuomotor speed among half of the adult survivors and no impairment in the childhood survivors in our study. As visuomotor speed requires the integration of different functions, it is not associated with a specific area in the brain, rather the co-ordination between the different areas of the brain. The Digit-symbol test or coding test is also sensitive to the progressive nature of any damage. Damage to any area that contributes to the performance of this task may affect the function. Our observation of a deficit in the visuomotor speed among adult survivors of pediatric ALL is in line with the findings of various other studies., The results of the visuomotor speed of the adolescent survivors in our study are consistent with those of several other studies that have reported no deficit in the visuomotor speed.,, However, one study reported a deficit in the processing speed among pediatric patients with ALL.
The tests for sustained and focused attention revealed no deficit in most of the long-term adult and childhood survivors of pediatric ALL; this has been corroborated by many other studies on long-term adult and childhood survivors.,,,,
In long-term survivors, focused attention, verbal working memory, and visuoconstructive ability differed significantly based on the age at diagnosis. Those who were diagnosed with ALL after 8 years of age performed better on focused attention and verbal working memory. This could be due to the delayed development or damage to the brain areas associated with both attention and verbal working memory functions for those treated at an early age. Our findings are in line with those of Krull et al., who reported that younger age at diagnosis and CRT were associated with impairment in attention, memory, and learning.,
Patients diagnosed before 8 years of age had better visuoconstructive ability. This could be due to the lateralization of function or due to the repair of the damaged areas of the brain after the completion of therapy. There was no statistically significant difference in verbal learning and delayed recall based on the age at diagnosis.
Analysis of neuropsychological functions in the long-term survivors in our cohort showed that those who survived longer differed significantly in verbal working memory from those who survived for a shorter duration. Those who survived for 9 years and more performed better on verbal working memory. This could have been due to skill acquisition in the disease-free period through education and learning. However, there are no studies to support or contradict this finding. In addition, there was no statistically significant difference reported in focused attention, verbal learning, delayed recall, and visuoconstructive ability of long-term survivors based on the duration of survival. [Table 5] provides a comparison of important neuropsychological assessment studies on pediatric ALL survivors with our study.
|Table 5: Comparison of studies on neuropsychological functioning in survivors of pediatric acute lymphoblastic leukemia|
Click here to view
Our study is limited by its cross-sectional design which did not allow longitudinal neuropsychological assessment or comparison to baseline data or a healthy control group. The sample size was small, and the study was restricted to a single institution. There was heterogeneity in the treatment protocols received by the survivors. Moreover, the differences based on the demographic factors for all variables have not been reported due to the lack of similar norms for adults and children. Neuroimaging was not used to correlate neuropsychological functional deficit with brain damage.
Therefore, future research could focus on carrying out multicenter, longitudinal, prospective assessments with randomized control designs.
| Conclusions|| |
Long-term survivors of pediatric ALL develop neuropsychological deficits. Adult survivors have deficits in immediate memory, visuoconstructive ability, verbal learning, immediate recall, and visuomotor speed, whereas childhood survivors have deficits in immediate memory and verbal working memory. Younger age at diagnosis is associated with reduced focused attention and verbal working memory, while older age at diagnosis is associated with poor visuoconstructive ability. Verbal working memory was found to be better in those with a longer duration of survival.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Supplementary Appendix 1|| |
Neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia
Ms. Jisha Abraham
M. Phil Research Scholar
Department of Psycho-oncology, Cancer Institute (WIA)
Dr. Surendran Veeriah
Department of Psycho-Oncology
1. Dr. Venkatraman Radhakrishnan
Department of Medical Oncology
| Background|| |
Acute Lymphoblastic leukemia (ALL) is the most common cancer seen in children. Due to the advancements in treatment protocols, a 5-year survival rate of these children has increased up to 80%. However, with improvements in long-term survival, treatment-induced morbidity has become a major concern. One of the major long-term morbidities associated with ALL treatment is a decline in neuropsychological function.,,,,,, The available literature on short-term and long-term neuropsychological effects of ALL treatment is sparse and inconclusive.
| Review of Literature|| |
Brown et al. reported the impact of systemic chemotherapy and prophylactic central nervous system (CNS) chemotherapy on the cognitive functioning of 46 children with ALL. They found that the deficits were more pronounced in patients who had completed treatment than in those who were undergoing treatment. Krappman et al. found a significant decline in neuropsychological functioning in younger patients compared to older patients and in female patients in comparison to male patients.
A recent study conducted in St. Jude hospital by Krull et al. also showed significant neurocognitive deficits in adult long-term survivors who were treated for ALL in childhood. Of the 567 survivors evaluated, significant deficits were reported in the neurocognitive functioning in those who were diagnosed at a younger age. They also reported impairment in attention and executive function with an increase in the duration of survival period. Abraham et al. also reported deficits in intellectual functioning and analytical reasoning in a study conducted among 19 pediatric ALL patients after completion of therapy. A study conducted by Veeriah et al. on 26 pediatric ALL patients at a tertiary center in South India reported a cognitive decline in different neuropsychological aspects such as attention, memory, and visuospatial abilities. Further, Sechalam and Sundaramoorthy also found that pediatric ALL patients had deficits in various areas of neuropsychological functioning such as performance intelligence, visuospatial, processing speed, planning, immediate verbal memory, attention, and verbal fluency during the maintenance phase when compared to the baseline assessment in the induction phase.
| Aim of The Study|| |
This study aimed to study the neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia.
| Study Rationale|| |
The survival rates of childhood ALL have increased to about 80% due to the advancements in treatment procedures. Therefore, the long-term consequence of treatment has become a major concern.
ALL protocols include drugs such as high-dose methotrexate and cranial radiation therapy. These modalities of treatment can affect brain growth and development, which, in turn, can result in neuropsychological deficits.
Data from India on long-term neuropsychological late effects of pediatric ALL survivors are sparse. This study seeks to look at the neuropsychological effects of ALL treatment in Indian children. It is important to know the adverse effects of treatment on neuropsychological functioning to design interventions, which can mitigate the long-term consequences of treatment. Therefore, the current study aims to find out the neuropsychological effects of ALL treatment in children and assess the impact of age, gender, age at diagnosis, year of survival, and treatment protocol on neuropsychological functioning.
| Objectives|| |
- To study find out the neuropsychological long-term effects in children treated for acute lymphoblastic leukemia
- To compare the neuropsychological functions of ALL long-term survivors based on gender, age, age at diagnosis, years of survival, and protocol.
| Methods|| |
The study is a cross-sectional study. The study will be conducted on long-term survivors of pediatric ALL reporting to the Medical Oncology Out Patient Department at Cancer Institute, Adyar, Chennai. Study participants will be assessed for neuropsychological functioning in the psycho-oncology department by a qualified psycho-oncologist. Oral and written informed consent will be taken from the patient above 18 years of age. For patients between the age of 8 years to 18 years, consent to participate in the study will be obtained from the patient and the consent will be obtained from the parent or guardian. Enrollment in the study will begin after obtaining approval from the institute ethics committee.
It is planned to enroll 100 survivors in the study. The enrollment period will be from January 1, 2014, to October 30, 2014.
- Minimum 5 years from the date of diagnosis and 2 years of survival after treatment.
- Age between 8 years and 50 years at the time of enrollment
- Able to read, write, and comprehend Tamil/Telugu/English, with a minimum education of Grade III.
- Evidence of relapse at enrollment
- Known case of mental retardation/Neurological diseases/psychiatric conditions
- Prior diagnosis of attention deficit hyperactivity disorder
- Part of any other psychological intervention study.
The following neuropsychological tests will be performed on the study patients.
- Digit vigilance test
- Color trails test
- Verbal N-back test
- Memory span for digits
- Rey's auditory verbal learning test
- FAS phonemic fluency test
- Child: Coding (Malin's Intelligence Scale for Indian Children [MISIC]); Adult: digit symbol test (Wechsler Adult Performance Intelligence Scale [WAPIS])
- Child: Block design test (MISIC); Adult: block design test (WAPIS).
The above tests have been adapted from NIMHANS battery of neuropsychological assessment (child and adult), WAPIS, and MISIC. These tests have been validated in Indian patients.
Data analysis will be performed using statistical software.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]