Cognitive Impairment in children with Acute Lymphoblastic Leukemia and its relationship with Chemotherapy
Idham Jaya Ganda1,2*, Urfianty1,2, Hadia Angriani2,3, Rinvil Renaldi3, Nadirah Rasyid Ridha1,2 Pujihastuti4, Sherly Sumartiya4, Khadijah A. Mansur4, Vawella Febria4, Ansar5, Asty Almaida6, Muhammad Nasrum Massi7
1Department of Pediatrics, Faculty of Medicine Hasanuddin University, Makassar, 90245, Indonesia.
2Child Health Department, DR Wahiddin Sudirohusodo Hospital, Makassar, 90245, Indonesia.
3Department of Child and Adolescent Psychiatry, Faculty of Medicine,
Hasanuddin University, Makassar, 90245, Indonesia.
4Pediatrics Study Program, Faculty of Medicine Hasanuddin University, Makassar, 90245, Indonesia.
5Communication Faculty of Pejuang Republik Indonesia University, Makassar, 90234, Indonesia.
6Management Department, Faculty of Economics and Bussiness,
Hasanuddin University, Makassar, 90245, Indonesia.
7Department of Microbiology, Faculty of Medicine Hasanuddin University, Makassar, 90245, Indonesia.
*Corresponding Author E-mail: dhamjaya_spa@yahoo.co.id
ABSTRACT:
Objective: This study assessed cognitive impairment using the school-year screening test of mental status-revised (SYSTEMS-R) and intelligence quotient (IQ) level using Raven Progressive Matrices in children with acute lymphoblastic leukemia (ALL) who received chemotherapy. Materials and Methods: This cross-sectional study was conducted at the Mother and Child Outpatient Clinic and the child psychiatric outpatient clinic from April to July 2023. The population was ALL patients collected by consecutive sampling with a total of 150 subjects. Results: The prevalence of cognitive impairment was 24.7%, and the low IQ level was 24.7%. There was a correlation between cognitive impairment and the chemotherapy phase, with the frequency in each phase being 10.4%, 23.4%, and 38.2%. There was a relationship between low IQ level and chemotherapy phase, with the frequency at each phase being 12.5%, 21.3%, and 38.2%. There was a significant relationship between cognitive impairment and low IQ level, with an OR of 5.017 (95% CI 2.892 - 8.705). ALL chemotherapy patients with cognitive impairment had an 83.3% chance of having a low IQ. Conclusion: There was a correlation between the chemotherapy phase, cognitive impairment, and low IQ level. ALL chemotherapy patients are more likely to have a low IQ level.
KEYWORDS: Cognitive Impairment, Acute Lymphoblastic Leukemia, Children, Chemotherapy.
INTRODUCTION:
This development is influenced by various factors, including natural factors, such as genetic inheritance from parents as well as family socioeconomic status, parental education level, parenting, nutrition, and physical health as nurture factors, both of which play a significant role. Many factors affect cognitive function, such as socioeconomic status, and ecological factors, such as health, dietary consumption, and mother's education level. Children with physical health problems not only have an impact on their physical, but also can affect their cognitive development.1–5
Acute Lymphoblastic Leukemia (ALL) is a pediatric cancer that is estimated to reach 19% of the total incidence of cancer in children.2,6 The prevalence of cancer in Indonesia in children aged 0-14 years is around 16,291 cases per year.2,6 At Dr. Wahidin Sudirohusodo Hospital Makassar, the prevalence of ALL over the past three years tends to increase. It is the disease with the highest number of cases in the pediatric care department.2,6-8 Acute leukemia in children accounts for 97% of all leukemia in children, and consists of 2 types, namely ALL 82% and acute myeloblastic leukemia (AML) 18%. ALL is a malignancy characterized by proliferation of immature lymphoblastic cells and is indicated by an excessive number of lymphoblasts in the bone marrow, lymph nodes, and blood. Clinical symptoms are pallor, fatigue, anorexia, fever, spontaneous or traumatic bleeding, bone pain (25%), hepatosplenomegaly (60-70%), enlarged lymph nodes (50%), and symptoms of CNS infiltration (10-50%) (headache, vomiting, papillary edema, N VI paralysis). Laboratory examination showed anemia, low, normal or increased leukocytes, thrombocytopenia, and blast cell count > 5%.9-14
The discovery that leukemia cells penetrate the blood-brain barrier into the central nervous system (CNS) with a 30%-70% frequency necessitates intensive treatment in that area. Several studies of pediatric ALL patients have found that chemotherapy has a negative impact on several neurocognitive domains (intelligence, attention and concentration, executive function, memory and learning, information processing speed, psychomotor function, and visuospatial skills), as it can prevent normal brain maturation and myelination. Even in the absence of radiation therapy, intrathecal methotrexate has been linked to white matter alterations in the brain, leukoencephalopathy, cortical atrophy, calcification, and seizures. Chemotherapy treatment for leukemia is divided into three phases: induction, consolidation, and maintenance. Children with ALL are vulnerable to neurotoxicity due to intensive chemotherapy and radiation treatment, which causes white matter damage in the brain, resulting in neurocognitive problems.15-19
The School Years Screening Test for Evaluation of Mental Status-Revised (SYSTEMS-R) instrument is designed to be used by neurologists, consultant pediatricians and other health professionals to assess children with cognitive impairment. The sensitivities of the instrument are 83% and 92% and the specificity values are 76% and 95%. In 2010,Bornholt and Fisher developed the SYSTEMS for wider use in children aged 4 to 15 years. This instrument is currently known as SYSTEMS-Revised (SYSTEMS-R).20-22
The examination to assess IQ level is the Raven Progressive Matrices Test. This examination is conducted by a pediatric psychiatrist consultant. The RAVEN test is a non-verbal test designed to measure a child's IQ ability.21,23 In this study, the Colored Progressive Matrices (CPM) Test was used which is suitable for children aged 5 - 11 years and Advanced Progressive Matrices (APM) for children over 11 years.21,23,24 Based on the description above, this study aimed to analyze cognitive function impairment and IQ level in children with ALL who received chemotherapy at Dr. Wahidin Sudirohusodo Hospital, Makassar.
MATERIAL AND METHODS:
This study was conducted by the principles of the Declaration of Helsinki and research permission was obtained from Wahidin Sudirohusodo Hospital and Ethical Clearance from the Research Ethics Committee of the Faculty of Medicine, Hasanuddin University with approval number 187/UN.4.6.4.5.31/PP36/2023. Written Inform consents have been obtained from the patients parents/guardian.
This cross-sectional study was conducted at the Mother and Child outpatient clinic and pediatric psychiatric outpatient clinic at Wahidin Sudirohusodo Hospital, from April to July 2023. The population of this study was children aged 5 to 15 years who were diagnosed with ALL and had received chemotherapy. Sampling was done by consecutive sampling. The sample size was calculated using the formula with a minimum sample size of 75 people. Inclusion criteria were children aged 5 - 15 years, diagnosed with ALL, and parents/patients agreed to participate in the study. Exclusion criterias were uncooperative children, impaired vision and/or hearing, and other central nervous system diseases (head trauma, infection, tumor, and epilepsy). Dropout criteria were patients who did not complete the SYSTEM R and/or Raven test.
Study procedure:
At the beginning of the study, demographic data, including age, gender, nutritional status, comorbid diseases, Hb and platelet levels were recorded. The study samples were patients undergoing chemotherapy in 3 phases: induction, consolidation, and maintenance. Induction is the first chemotherapy phase that lasts 4 to 6 weeks. The goal of this phase of therapy is to induce a complete remission, with approximately 95% of all patients achieving this benchmark. This is followed by the consolidation phase, which aims to eradicate any residual submicroscopic disease that remains after complete remission has been obtained. Maintenance phase chemotherapy is the final, and longest, stage of ALL treatment in children. As a much more intensive regimen than previous chemotherapy.
The study was then continued after obtaining informed consent from the patient's parents, by taking a history, general physical examination and neurological examination and there were no significant emotional and behavioral problems. Assessment of cognitive function with the SYSTEM-R was conducted by 2 pediatric neurologist consultants. The first assessment was done by the first pediatrician and the second pediatrician will validate the results. The SYSTEM-R instrument uses a checklist containing 40 questions. If the research subject answers 1 question correctly, it will be given a score of 1. If the research subject answers 1 question incorrectly, it will be given a score of 0. A cut-off point is used to determine the presence/absence of impaired cognitive function based on age group. Cognitive function is impaired if the cut-off point score is < 13 for children aged 5 years, < 18 for children aged 6 years, < 19 for children aged 7 years, < 22 for children aged 8 years, < 27 for children aged 9 years, < 28 for children aged 10 years, < 29 for children aged 11 years, < 30 for children aged 12 years, < 30 for children aged 13 years, < 31 for children aged 14 years, < 33 for children aged 15 years (13). IQ level examination using Raven Progressive Matrices was conducted by a child and adolescent psychiatrist. IQ levels consist of Superior (percentile >95), Above Average (percentile 75), Average (Percentile 25-75), Below Average (percentile 25) and Mentally Defective (percentile <5). IQ levels are divided into two groups. First, it is said to be unimpaired if there are Superior (percentile>95), Above Average (percentile 75), Average (Percentile 25-75), and impaired if there are Below Average (percentile 25) and Mental Defective (percentile<5).21,22
Statistical Analysis:
Data was entered into Microsoft Excel 2021 and analyzed using SPSS version 26. Univariate analysis was used for data description in the form of frequency distribution. Bivariate analysis using chi-square test, determining odd ratio, 95% confidence interval and calculating probability. The results were considered to be significant if p < 0.05.
RESULTS:
There were 174 ALL patients aged 5-15 years who were treated at Dr Wahidin Sudirohusodo General Hospital. Of 174 patients, there were 154 patients who met the inclusion criteria and 20 patients who were excluded. Of the 154 patients who received chemotherapy, there were 49 in the induction phase, 47 in the consolidation phase and 55 in the maintenance phase. There were 154 patients who underwent the SYSTEM-R examination, but only 150 people were able to undergo the Raven Progressive Matrices Test (4 people dropout). (Figure 1)
The study subjects consisted of 62% male and 38% female, 76% in the age group of 5 - ≤ 11 years and 24% in the age group of >11-15 years. 52% of subjects experiencing malnutrition. 55.3% of subjects had comorbid diseases, 26% had anemia, and 56% had thrombocytopenia. As many as 24.7% of subjects experienced impaired cognitive function. As many as 24.7% of subjects experienced impaired IQ levels. In this study, 32% of the subjects underwent induction phase, 31% underwent consolidation phase, and 37% underwent maintenance phase. (Table 1)
Figure 1: Study’s Flowchart
Table 1: Characteristics of the Study Subjects
|
Characteristics |
N % (n=150) |
|
Gender |
|
|
Male |
93 (62%) |
|
Female |
57 (38%) |
|
Age Group |
|
|
5 - ≤11 years |
114 (76%) |
|
>11 - 15 years |
36 (24%) |
|
Nutrition Stats |
|
|
Malnourished |
78 (52%) |
|
Normal |
72 (48%) |
|
Comorbid |
|
|
Yes |
83 (55.3%) |
|
No |
67 (44.7%) |
|
Hemoglobin Level |
|
|
Anemic |
39 (26%) |
|
Normal |
111 (74%) |
|
Thrombocyte Level |
|
|
Thrombocytopenia |
84 (56%) |
|
Normal |
66 (44%) |
|
Cognitive Impairment |
|
|
Yes |
37 (24.7%) |
|
No |
113 (75.3%) |
|
IQ Level |
|
|
Impairment |
37 (24.7%) |
|
No Impairment |
113 (75.3%) |
|
Chemotherapy Phase |
|
|
Induction Phase |
48 (32%) |
|
Consolidation Phase |
47 (31%) |
|
Maintenance Phase |
55 (37%) |
There was a significant relationship between cognitive impairment and IQ level (p<0.05). The parameter of the strength of the relationship between cognitive impairment and IQ impairment in ALL patients receiving chemotherapy is an odds ratio of 5.017 (95% CI 2.892 – 8.705), meaning that ALL patients receiving chemotherapy who experience cognitive impairment have 5.017 times more likely to experience an impaired IQ level compared to those without cognitive impairment. The probability that ALL patients who receive chemotherapy experience cognitive impairment to cause IQ disturbances is 83.3%. (Table 3)
DISCUSSION:
The characteristics of the research subjects were found to be mostly male and aged 5-11 years. Based on the data cited from the National Cancer Institute, in 2021, around 58% of leukemia cases were found in boys. From 2017 to 2021, many cases of children with leukemia were found in children under the age of 15, with an estimated 3,715 and 2,751 diagnosed with ALL.2,15Another study conducted by Ardanta et al. found that the prevalence of ALL in children at Sanglah General Hospital was 87%, and it occurred more frequently in boys aged 18 months-10 years with the most common type being L2.15,25
Table 2: Relationship between demographics, nutritional status, comorbid diseases, anemia, platelets, cognitive impairment, and IQ level with the chemotherapy phase of ALL in children
|
Characteristic |
Chemotherapy Phase |
P Value |
|||
|
Induction (%) |
Consolidation (%) |
Maintenance (%) |
|||
|
Gender |
|||||
|
Male |
30 (62.5%) |
32 (68.1%) |
31 (65.4%) |
0.476 |
|
|
Female |
18 (37.5%) |
15 (31.9%) |
24 (43.6%) |
||
|
Age Group |
|||||
|
5 - ≤11 years |
37 (77.1%) |
32 (68.1%) |
45 (81.8%) |
0.264 |
|
|
>11 - 15 years |
11 (22.9%) |
15 (31.9%) |
10 (18.2%) |
||
|
Nutrition Stats |
|||||
|
Malnourished |
25 (52.1%) |
26 (55.3%) |
27 (49.1%) |
0.821 |
|
|
Normal |
23 (47.9%) |
21 (44.7%) |
28 (50.9%) |
||
|
Comorbid |
|||||
|
Yes |
29 (60.4%) |
22 (46.8%) |
32 (58.2%) |
0.356 |
|
|
No |
19 (39.6%) |
25 (53.2%) |
23 (41.8%) |
||
|
Hemoglobin Level |
|||||
|
Anemic |
12 (25%) |
13 (27.7%) |
14 (25.5%) |
0.951 |
|
|
Normal |
17 (35.4%) |
34 (72.3%) |
41 (74.5%) |
||
|
Thrombocyte Level |
|||||
|
Thrombocytopenia |
31 (64.6%) |
26 (55.3%) |
27 (49.1%) |
0.285 |
|
|
Normal |
17 (35.4%) |
21 (44.7%) |
28 (50.9%) |
||
|
Cognitive Impairment |
|||||
|
Yes |
5 (10.4%) |
11 (23.4%) |
21 (38.2%) |
0.005 |
|
|
No |
43 (89.6%) |
36 (76.6%) |
34 (61.8%) |
||
|
IQ Level |
|||||
|
Impairment |
6 (12.5%) |
10 (21.3%) |
21 (38.2%) |
0.009 |
|
|
No Impairment |
42 (87.5%) |
37 (78.7%) |
34 (61.8%) |
||
*Chi Square Test
|
Cognitive Impairment |
IQ Stats |
OR (95% CI) |
P Value |
|
|
Impairment |
No Impairment |
|||
|
Yes |
23 |
14 |
5.017 |
0.000* |
|
No |
14 |
99 |
(2.982-8.705) |
|
*Chi Square Test; OR: Odd Ratio; 95% CI: 95% Confidence Interval
In this study, more subjects were found to have cognitive impairments, namely 113 (75.3%) people and those whose IQ levels were disturbed, namely 113 (75.3%) subjects. In a study by Miranda Pereira et al.26 The prevalence of IQ scores with the Raven Test was below the average of 5.6% in ALL children who were undergoing therapy. In this study, short-term chemotherapy treatment had no impact on language development and cognitive ability. Meanwhile, long-term therapy will affect the cognition of ALL children who have undergone long-term chemotherapy treatment, as found by two other studies.24,27 In this study, the impaired cognitive abnormalities were the ability to remember and the inhibitory response.
In this study, the number of children with cognitive impairment was 37 subjects (24.7%) with almost the same proportion of subjects between the induction (10.4%), consolidation (23.4%) and maintenance (38.2%) phases. The presence of cognitive impairment in the subject increased with the duration of therapy. A recent meta-analysis byPeterson et al.28 (10 studies reporting comparison group data from 18 studies) reported no reduction in intelligence, such as the use of 6-Mercaptopurine in the consolidation phase, but the time of initiation of treatment was a significant predictor. In addition, age at diagnosis was not significant.29,30
Several meta-analysis studieshave been reported regarding IQ outcomes in childhood ALL. Peterson et al. and Iyer et al. found a significant reduction in the intellectual function of ALL survivors as a result of systemic chemotherapy treatment compared to the control group. Peterson et al. suggest that the female sex may be at greater risk for neuropsychological effects.28,31
SYSTEMS-R is a cognitive examination used by pediatric neurologists, pediatricians, and other health workers to assess the cognitive function of children aged 6 to 15 years. SYSTEMS had 83% and 92% sensitivity and 76% and 95% specificity. In Harsono et al.'s study, the Indonesian version of System R is a valid screening tool and has good internal consistency (α=0.936−0.941) for children aged 4-15 years.23,32,33 In the initial phase of chemotherapy, there may be no cognitive function disorder, but the longer the chemotherapy is taken, cognitive disorders can develop, such as language disorders, memory skills, which are examined including the cognitive domains of orientation, registration, attention, recall, repetition, orders, reading, writing, calculations, and abstraction or interpretation of proverbs. Examination of cognitive function in ALL patients during chemotherapy (every phase of treatment) is an early detection measure in treating cognitive disorders. Preventive interventions such as cognitive training and maintenance of academic growth are the managements with the best outcome measures to prevent the occurrence of long-term effects.23,34-36
The strength of this study that it conducted at the first time on a population of children suffering from ALL. The ALL patients received chemotherapy using a standardized and same protocol for each study group. An assessment of cognitive dysfunction was carried out by a pediatrician or other health worker who has been trained and then validated by a child neurology consultant and IQ level assessment is carried out by a child and adolescent psychiatrist.The limitations of this study including no assessment of cognitive function and IQ level before undergoing chemotherapy but we collected children who were attending school, so that abilities were commensurate, the sample limited to age of 5-15 years, and did not cover the entire age group in children because the SYSTEMS-R cut off has been carried out in Indonesia only up to that age, difference in the course of disease of ALL in each study sample, not all of the factors that affect cognitive function disorders have been studied in research and assessment of cognitive function with (SYSTEMS-R) with an assessment of the level of IQ (Raven test) is not possible to be carried out simultaneously because of the less optimal conditions of the study sample.
CONCLUSION:
SYSTEM-R can be used as an instrument to assess the presence or absence of cognitive impairment in children with ALL. There is an effect of chemotherapy phase with the onset of cognitive function impairment and low IQ level. Impairment due to chemotherapy can be cognitive impairment only, low IQ level, or both.
CONFLICT OF INTEREST:
The authors have no conflicts of interest regarding this investigation.
ACKNOWLEDGMENT:
We would like to thank Ms. HestianiSaharuddin for her assistance with manuscript editing and language proof. This study received grant from the Institute for Research and Community Services (LPPM), Hasanuddin University.
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Received on 23.04.2024 Revised on 17.09.2024 Accepted on 06.11.2024 Published on 10.04.2025 Available online from April 12, 2025 Research J. Pharmacy and Technology. 2025;18(4):1809-1814. DOI: 10.52711/0974-360X.2025.00259 © RJPT All right reserved
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