|Year : 2021 | Volume
| Issue : 3 | Page : 144-150
Study of exposure to dexamethasone among children with acute lymphoblastic leukemia and effect on intellectual function – A pilot study
Shumraa Aminath1, Gurpreet Kaur Dhillon2, Shifla Abdul Latheef1, Harpreet Singh Dhillon3, Shibu Sasidharan4, Babitha Manalikuzhiyil5, Suneeta Singh6
1 Department of Pediatrics, MNDF Senahiya Militrary Hospital, Moonlight Hingun, Malé, Maldives
2 Department of Paediatrics, 166 Military Hospital, Jammu, Jammu and Kashmir, India
3 Department of Psychiatry, 166 Military Hospital, Jammu, Jammu and Kashmir, India
4 Department of Anaesthesiology and Critical Care, Level III Hospital, Goma, Democratic Republic of the Congo
5 Department of Radiodiagnosis, Ojas Hospital, Panchkula, Haryana, India
6 Department of Obstetrics and Gynaecology, Level III Hospital, Goma, Democratic Republic of the Congo
|Date of Submission||20-Feb-2021|
|Date of Decision||16-Mar-2021|
|Date of Acceptance||05-Apr-2021|
|Date of Web Publication||05-Jul-2021|
Harpreet Singh Dhillon
Department of Psychiatry, 166 Military Hospital, Jammu, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: There has been significant increase in the remission rates for childhood acute lymphoblastic leukemia (ALL) with addition of corticosteroids to chemotherapy regimens. However, with increase in survivors, there has been increase in the incidence of neurocognitive dysfunction as a 'long term sequelae. The present study was undertaken with the aim to study the effect of a chemotherapy regimen with dexamethasone on intellectual abilities in children with ALL. Methodology: This was a prospective, observational, and descriptive study conducted at a tertiary care hospital over a period of 18 months. Sixty children aged between 6 and 12 years diagnosed with B cell ALL and belonging to the standard risk ALL group on treatment protocol Pediatric Berlin-Frankfurt-Munster (1–10 years) (standard risk), initiated and maintained on oral dexamethasone as part of their chemotherapy regimen were recruited. All the patients were followed up for 6 months and assessed for intellectual ability using Raven's standard progressive matrices (SPM), which was carried out before starting oral dexamethasone, at 3 months and after 6 months of starting oral dexamethasone. Results: The scores obtained at three intervals were compared by one-way repeated analysis of variance and the results showed a significant increase in raw scores of SPM. The difference between the mean scores at the three specified intervals was statistically significant (P < 0.001). The overall maximum improvement (mean raw scores of 5.5) was seen over 6 months period in older age group (12 years). Gender-wise comparison of performance revealed an overall better scores in males, though the differences were not significant. Conclusion: The current study revealed a significant increase in raw scores of SPM in children with standard risk B cell ALL undergoing chemotherapy along with dexamethasone. However, randomized control studies with larger sample size followed up longitudinally for a longer period of time are needed for specific recommendations of using dexamethasone over other corticosteroids.
Keywords: Acute lymphoblastic leukemia, dexamethasone, intelligence, Raven progressive matrices
|How to cite this article:|
Aminath S, Dhillon GK, Latheef SA, Dhillon HS, Sasidharan S, Manalikuzhiyil B, Singh S. Study of exposure to dexamethasone among children with acute lymphoblastic leukemia and effect on intellectual function – A pilot study. Curr Med Issues 2021;19:144-50
|How to cite this URL:|
Aminath S, Dhillon GK, Latheef SA, Dhillon HS, Sasidharan S, Manalikuzhiyil B, Singh S. Study of exposure to dexamethasone among children with acute lymphoblastic leukemia and effect on intellectual function – A pilot study. Curr Med Issues [serial online] 2021 [cited 2021 Dec 4];19:144-50. Available from: https://www.cmijournal.org/text.asp?2021/19/3/144/320644
| Introduction|| |
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and represents approximately 25% of cancer diagnoses in childhood. The development of a cure for ALL is one of the most successful stories in the treatment of cancer. Vincristine use in 1960's brought about remission of ALL in 60% of children which increased significantly to 90% with addition of corticosteroids. However, with increase in survivors, there has been increase in the incidence of long-term sequelae of the chemotherapy agents.
Studies on human tissue culture cells have confirmed that glucocorticoids have a preferential cytotoxic effect on lymphoblasts by inducing cell cycle arrest, particularly at G1 phase of cell cycle with subsequent apoptosis. However, corticosteroids do exert adverse effects with prolonged use including gastritis, abnormal fat deposition, myopathy, obesity, diabetes mellitus, hypertension, osteopenia, avascular necrosis of joints, and immune suppression. In addition to these, long-term use of corticosteroids have been linked to impairment in memory and other neurocognitive domains such as recall, abstraction, analysis and concentration, especially with dexamethasone due to its better central nervous system (CNS) penetration.,
Prolonged glucocorticoid use has been found to cause brain atrophy with prefrontal cortex and hippocampal volume shrinkage. The exact mechanism is unclear, however, various proposed hypotheses are reduced glucose uptake in the brain leading to decreased glucose-dependent metabolism in brain, increase in excitatory amino acids (Glutamate), decrease in brain-derived neurotrophic factor.,
The glucocorticoids, prednisone, and dexamethasone have been used in varying intensities in different treatment protocols of ALL. Recent studies have established a therapeutic benefit of dexamethasone over prednisone in ALL with lower rates of CNS and bone marrow relapses attributed mainly due to its better CNS penetration. However, the use of dexamethasone is associated with poor neurocognitive outcomes as compared with prednisone in both non cancer as well as ALL populations. The risk factors identified for impairment of neurocognitive functioning in survivors of childhood ALL are an early age at diagnosis, female gender, treatment intensity as well as duration.
Democratic Republic of the Congo is one of the worst hit countries in Africa with poverty, infectious diseases, war, insufficient resources, and hence, no such study was conducted in the past, thus making it a pilot study on this population. Hence, the present study was undertaken with the aim to study the impact of a chemotherapy regimen with dexamethasone on intellectual abilities in children with ALL.
| Methodology|| |
This was a prospective, observational, and descriptive study conducted at a tertiary care hospital over a period of 18 months from November 1, 2017 till August 30, 2019, after obtaining clearance from institution's research ethical committee. The ethical committee approval number for this project no: 211/14 was approved on June 5, 2018. The study population included children aged between 6 and 12 years, diagnosed with standard risk ALL and initiated and maintained on oral dexamethasone as part of their chemotherapy regimen. The children with CNS leukemia, leukoencephalopathy or who received cranial radiotherapy or any child who could not participate in standard progressive matrices (SPM)/color progressive matrices were excluded from the study. Furthermore, children with preexisting mental sub normality/neurological disability before onset of malignancy and those who developed any other neurological complication during treatment were excluded. The tertiary care center managing pediatric ALL is a specialized malignant diseases treatment center along with facilities for assessing intellectual ability with standardized neuropsychological expertise and tools. Patients attending this treatment center belonged to different geographical areas and ethnicities within the country. The age group selection was dependent on the validated range of the intellectual ability tool used, the SPM. Informed consent was taken from the parents. All the patients were followed up for 6 months where intellectual ability testing with SPM was carried out before starting oral dexamethasone, at 3 months after starting and after 6 months of starting oral dexamethasone.
The chemotherapy regimen for pediatric age group was adapted from Berlin-Frankfurt-Munster (BFM) study group which use oral dexamethasone as a component in reinduction and maintenance phases of treatment [Table 1].
|Table 1: Pediatric Berlin-Frankfurt-Munster (1-10 years), chemotherapy regimen|
Click here to view
Children newly diagnosed with ALL were considered to be standard risk if at the time of diagnosis, the child was aged more than 1 year and <10 years of age; total leukocyte count at the time of diagnosis < 20,000/cmm, showed good response to prednisolone, B cell precursor, cALLa-positive immunophenotype, no CNS disease, normal cytogenetics, hyperdiploidy., All patients were treated with same regimen pediatric BFM (1–10 years) (standard risk) [Table 1].
The Ravens' SPM is a widely used nonverbal test which is independent of education attained and hence can be applied to a wide range of population. Broadly, it is a test of general intelligence that assesses observational skills and clear thinking. The influence of culture is minimized in this test as it relies on nonverbal problems which require abstract reasoning and do not depend on knowledge of a particular culture or linguistic abilities. While doing the test the child apprehends meaningless figures presented, which tests his observational skills and abstract thinking. Following this, an answer is searched for testing his ability for clear thinking, visuospatial, and deductive reasoning. With each following problem his working memory, recall and reproducibility is assessed.
It can be used as an untimed test of intellectual ability or a timed “speed” or “efficiency” test. In this study, we have used it as an untimed test of capacity. The results are evaluated by comparing with norms expected as per age group printed on tables of percentile norms which are provided in the manual for Raven's Progressive Matrices. In this study, 1986 National US Norms, from research supplement number 3 of the manual were used. Participants were classified according to their scores and the matching percentile on the percentile charts of norms and were graded as shown in [Table 2].
The SPM test was administered before child was started on oral dexamethasone in the reinduction phase. The test was administered as an untimed individual test and an initial score was recorded for each participant, along with the corresponding percentile (from the norms table) and grade of intellectual ability. Similarly, this test was administered at 3 months after and at 6 months after starting on oral dexamethasone. Scores were recorded and charts were plotted at each interval. The intravenous dose of dexamethasone received at day 1 and 2 of Preinduction phase of treatment was not considered in the total cumulative dose, as an initial score was not taken before this dose considering the physical and psychological impact of a malignancy on children as well as the parents.
The results were analyzed using one-way Analysis of variance (ANOVA) test and paired Student's t-test for univariate analysis Statistical Package for Social Sciences for Windows (SPSS Inc. Released 20017, version 23.0. Armonk, New York, USA).
| Results|| |
All the children were diagnosed with standard risk ALL and were tested for their intellectual ability with the Ravens' SPM over a 6 months' period. Sixty children fulfilling the inclusion criteria were selected for the study after informed consent. All these children had B cell ALL and belonged to the standard risk ALL group and were on protocol Pediatric BFM (1–10 years) (standard risk). Majority (n = 28, 46.7%) of the children were aged ≤6 years with a mean age of 8.33 years. The study population had equal gender distribution i.e., 30 were females and 30 males [Table 3].
Comparison of intelligence score at subsequent assessments
The raw scores obtained at three intervals were compared by one-way repeated ANOVA test. The difference between the mean scores at the three specified intervals was statistically significant (P < 0.001) [Table 4].
Distribution of the subjects by standard progressive matrices grading
The study participants were also graded into various grades of intelligence defined by SPM [Table 5].
|Table 5: Distribution of the subjects by standard progressive matrices grading|
Click here to view
Gender wise performance of intelligence assessment
Gender wise performance and the mean raw scores were compared at each of three intervals. Overall males were found to have better scores than the female participants. However, the differences were not significant [Table 6].
Side effects during chemotherapy
Majority of patients reported mood changes during the re-induction phase and pulse dexamethasone therapy of 5 days during maintenance phase. The side-effects of 'mood changes' was assessed as per history from the parents only. They were mainly episodes of mood swings. There was no objective evaluation done for the same considering the young age of the participants. We provided general supportive psychotherapy to parents regarding the management of the same without any other specific intervention. Other side effects were change in appetite; sleep disorders, infections and behavior changes. Out of 60 patients, 6 attributed no side effects to dexamethasone therapy [Table 7].
| Discussion|| |
Dexamethasone is widely used in comparison to prednisolone in various chemotherapy protocols for childhood ALL due to its established therapeutic benefit. Research on effect of dexamethasone on neurocognitive outcome in children with ALL is limited.
The results of this study showed a significant increase in raw scores of SPM. The difference in raw scores obtained at three intervals was statistically significant (P < 0.001). In the above average group, the percentage of children increased from 3.3% to 13.3% over the subsequent 6 months. Furthermore, in the below average group, there was reduction in percentage of children from 10% to zero over following 6 months [Table 5]. The overall maximum improvement (mean raw scores of 5.5) was seen in age 12 years over 6 months' period. The results of the current study are noteworthy as they are not in agreement with a previous meta-analysis by Warris et al. and Nina et al. which did not show any significant differences between dexamethasone and prednisone on cognition. The results of the current study are in fact opposite to a study by Eddelman et al. in which survivors of ALL who received dexamethasone had increased risk for impaired memory and word recognition.
The gender distribution of the participants of current study was equivalent. The current study revealed greater improvement in scores by the male participants at each of the 3 intervals, though the differences were not statistically significant. Also, improvement in mean raw score at 3 months and 6 months were observed to be higher at older age group (12 years) in the study. This concurs with most previous studies which have shown worse outcomes in the younger age groups and female gender., This association of poor neurocognitive outcome with younger age can be attributed to the significantly more deleterious effect of chemotherapy in a maturing brain in early childhood., The comparatively poorer neurocognitive outcome in female children also is in agreement with Ellenberg et al.
Diagnosable impairments in neurocognitive function has been demonstrated to appear years after completion of treatment in ALL. Limited data is available on neurocognitive functioning in children with ALL immediately after remission is achieved and during treatment. The current study has compared the neurocognitive functioning before start of chemotherapy with the neurocognitive function in the ensuing period immediately after remission. This can aid in early focused diagnostic tests and counseling of parents along with early rehabilitation for these children.
The major advantage of our study was that all patients were similar in terms of the National Cancer Index risk category having standard risk B cell ALL. The patients were also similar in terms of race and gender distribution was equal. The chemotherapy protocol was same and thus the dosage of dexamethasone and other chemotherapy drugs including 6-mercaptopurine received was similar in all patients. The test used for assessment, Ravens SPM is a nonverbal test independent of language differences and previous academic achievement of the child. In addition, the test was administered in a standardized manner when children were not acutely ill in an untimed version so as to avoid the pressure of completing the test in given time. The difference in nutrition can be an important confounder, but it was not so in our study because all the participants were children of serving military personnel with almost similar socio-economic status.
However, the results of this study should be interpreted with attention as we could enroll only 60 patients into the study who were similar in terms of ALL risk category and availability of prescribed age group. Second, there was no comparison group, in ascertaining the effect of dexamethasone exposure on intellectual ability. Third, a single assessment tool which measures the analytic intelligence or educative capacity was used. Finally, although there were no major CNS infections and tests were administered when the children were not acutely ill (febrile/symptomatic), it might have affected the performance of children.
Our future endeavor based on the results of this pilot study is to study the effect of dexamethasone in long-term neurocognitive outcome using multiple tools such as combinations of Wechsler Intelligence Scale for Children–Fourth Edition, Beery Developmental Test of Visual Motor Integration, the Conner's Continuous Performance Test II, Children's Memory Scale.
There were few challenges which we encountered during this study, such as selection of appropriate domains of intelligence and control groups, differences in intelligence scales defining impairment and methods of repeated testing.
| Conclusion|| |
The aim of the current study was to assess the effects of a chemotherapy regimen with dexamethasone on intellectual abilities in children with ALL. The results have shown statistically significant improvement in performance in children with standard risk B cell ALL undergoing chemotherapy. Individual variations in performances have been observed, though not statistically significant in different gender and age groups. Nevertheless randomized control studies with larger sample size followed up longitudinally for a longer period of time are mandatory to distinctly define the cause of these variations.
Research quality and ethics statement
All authors of this manuscript declare that this scientific study is in compliance with standard reporting guidelines set forth by the EQUATOR Network. The authors ratify that this study required Institutional Review Board/Ethics Committee review, and hence prior approval was obtained (IRB Min. No 211/14 dated June 5, 2018). We also declare that we did not plagiarize the contents of this manuscript and have performed a Plagiarism Check.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Seibel NL. Acute lymphoblastic leukemia: an historical perspective. Hematology Am Soc Hematol Educ Program. 2008;365. doi:10.1182/asheducation-2008.1.365.
Pui CH, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 2013;50:185-96.
Baxter GD, Collins RJ, Harmon BV, Kumar S, Prentice RL, Smith PJ, et al
. Cell death by apoptosis in acute leukaemia. J Pathol 1989;158:123-9.
Edelmann MN, Ogg RJ, Scoggins MA, Brinkman TM, Sabin ND, Pui CH, et al
. Dexamethasone exposure and memory function in adult survivors of childhood acute lymphoblastic leukemia: A report from the SJLIFE cohort. Pediatr Blood Cancer 2013;60:1778-84.
Buizer AI, de Sonneville LM, Veerman AJ. Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: A critical review of the literature. Pediatr Blood Cancer 2009;52:447-54.
Bentson J, Reza M, Winter J, Wilson G. Steroids and apparent cerebral atrophy on computed tomography scans. J Comput Assist Tomogr 1978;2:16-23.
Zhou J, Zhang F, Zhang Y. Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: Involvement of brain-derived neurotrophic factor. Brain Res 2000;885:182-91.
Coluccia D, Wolf OT, Kollias S, Roozendaal B, Forster A, de Quervain DJ. Glucocorticoid therapy-induced memory deficits: Acute versus chronic effects. J Neurosci 2008;28:3474-8.
Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al
. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: A report from the children's cancer group. Blood 2003;101:3809-17.
Waber DP, Carpentieri SC, Klar N, Silverman LB, Schwenn M, Hurwitz CA, et al
. Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 2000;22:206-13.
Essig S, Li Q, Chen Y, Hitzler J, Leisenring W, Greenberg M, et al
. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: A report from the childhood cancer survivor study cohort. Lancet Oncol 2014;15:841-51.
Sasidharan S, Dhillon HS. Ebola, COVID-19 and Africa: What we expected and what we got. Dev World Bioeth 2021;21:51-4.
Greenstein S, Ghias K, Krett NL, Rosen ST. Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin Cancer Res 2002;8:1681-94.
Raven J. The Raven's progressive matrices: Change and stability over culture and time. Cogn Psychol 2000;41:1-48.
Warris LT, van den Heuvel-Eibrink MM, den Hoed MA, Aarsen FK, Pieters R, van den Akker EL. Does dexamethasone induce more neuropsychological side effects than prednisone in pediatric acute lymphoblastic leukemia? A systematic review. Pediatr Blood Cancer 2014;61:1313-8.
Kadan-Lottick NS, Brouwers P, Breiger D, Kaleita T, Dziura J, Liu H, et al
. A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 2009;114:1746-52.
Jansen NC, Kingma A, Schuitema A, Bouma A, Huisman J, Veerman AJ, et al
. Post-treatment intellectual functioning in children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only: A prospective, sibling-controlled study. Eur J Cancer 2006;42:2765-72.
von der Weid N, Mosimann I, Hirt A, Wacker P, Nenadov Beck M, Imbach P, et al
. Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: Age- and sex-related differences. Eur J Cancer 2003;39:359-65.
Krull KR, Brinkman TM, Li C, Armstrong GT, Ness KK, Srivastava DK, et al
. Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: A report from the St Jude lifetime cohort study. J Clin Oncol 2013;31:4407-15.
Ellenberg L, Liu Q, Gioia G, Yasui Y, Packer RJ, Mertens A, et al
. Neurocognitive status in long-term survivors of childhood CNS malignancies: A report from the childhood cancer survivor study. Neuropsychology 2009;23:705-17.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]