Comparison of intelligence quotient in children surviving leukemia who received different prophylactic central nervous system treatments
Reisi Nahid1, Khalilian Leila2
1 Pediatric Hematologist and Oncologist, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
2 Resident of Pediatrics, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||11-Apr-2012|
|Date of Acceptance||10-Jun-2012|
|Date of Web Publication||31-Oct-2012|
Department of Pediatric Hematology and Oncology, AlzahraHospital, Isfahan University of Medical Sciences
Source of Support: None, Conflict of Interest: None
Background: Neurocognitive deficits and decrease in intelligence quotient (IQ) is one of the complication of prophylactic central nervous system (CNS) treatment in acute lymphoblastic leukemia (ALL) patients. In this study, we compare the IQ in survivors of ALL that were treated with different prophylactic CNS treatments.
Materials and Methods : We compared 43 long-term survivors of ALL: 21 survivors with intrathecal methotrexate (IT MTX) as CNS prophylaxis, 22 with IT MTX+1800-2400 rads cranial irradiation and 20 healthy controls. The IQ was measured using the Raven's test in these patients.
Results: Raven's test revealed significant differences in IQ between the survivors of ALL that were treated with IT MTX, IT MTX plus cranial irradiation and control group. There was no significant difference in the IQ with respect to sex, age and irradiation dose.
Conclusion: We can that reveal that CNS prophylaxis treatment, especially the combined treatment, is associated with IQ score decline in ALL survivors. Therefore,a baseline and an annual assessment of their educational progress are suggested.
Keywords: Acute lymphoblastic leukemia, chemotherapy, intelligence quotient, radiotherapy
|How to cite this article:|
Nahid R, Leila K. Comparison of intelligence quotient in children surviving leukemia who received different prophylactic central nervous system treatments. Adv Biomed Res 2012;1:83
|How to cite this URL:|
Nahid R, Leila K. Comparison of intelligence quotient in children surviving leukemia who received different prophylactic central nervous system treatments. Adv Biomed Res [serial online] 2012 [cited 2020 Feb 18];1:83. Available from: http://www.advbiores.net/text.asp?2012/1/1/83/103005
| Introduction|| |
Acute lymphoblastic leukemia (ALL) is the most common cause of malignancy in children.  The average life expectancy of patients in 1950 was approximately 3 months.  With the advent of systemic chemotherapy, the remission rate increased from less than 5% to 90%, but a substantial number of the patients sustained relapse at central nervous system (CNS) after their remission.  Prophylactic CNS treatment includes intrathecal methotrexate (IT MTX) alone or in combination with cranial irradiation (1800-2400 rads), which can prevent CNS relapse, increasing the 5-year survival rate of patients to more than 80%, but is not without disadvantages. ,
Radiation, vincristine, prednisolone, methotrexate and high-dose cytarabine are medications that might have adverse effects on cognitive function. , Neurocognitive deficits usually become evident 1-2 years after radiation, and are progressive. The patients have difficulties in reading, languages and mathematics and younger age in intelligence quotient (IQ). 
The exact pathogenesis of CNS damage is not clear. Cranial irradiation and IT MTX can both cause significant microangiopathy, demyelination and cerebral necrosis. 
Imaging findings show that white matter tracts and right frontal white mater loss may be the cause of cognitive difficulties observed in survivors, , and Mulhern et al. have shown an association between volume of white mater loss and full-scale IQ. ,
Young age at the time of treatment, treatment with irradiation and chemotherapy, increasing radiation dose and female gender are risk factors for neurocognitive sequelae. 
Many studies have been conducted to assess these effects but, unfortunately, the results are not clear-cut. Some studies found intellectual deficit and others did not, and those that found deficits are not consistent with each other.
In this study, we compared theIQ in survivors of ALL that were treated with different prophylactic CNS treatments: IT MTX alone and IT MTX plus cranial irradiation.
| Materials and Methods|| |
This study was carried out at the Al-Zahra Hospital of Isfahan (central area of Iran) from May 2010 to February 2011.
All survivors of ALL who were between 5 and 15 years of age and at least 6 months past from the end of treatment were recruited to participate in this study. They were informed of the study by phone. None of the children enrolled in this study had a mental delay and chronic disease predating the diagnosis of leukemia and none of the survivors had a history of recurrence and bone marrow transplant. Specific treatment protocols varied, but all survivors received CNS prophylaxis with IT chemotherapy (MTX) or IT chemotherapy combined with cranial radiation (1800-2400 rads). Mental retardation, neurologic disorder and traumatic brain injury associated with alteration of consciousness were exclusionary criteria. Potential healthy siblings of participating survivors of ALL were recruited as the control group.
This study was approved by the institutional review board committee and informed consent was obtained from the parents.
A total of 43 ALL survivors [21 survivors with IT MTX as CNS prophylaxis (group1), 22 with IT MTX+1800-2400 rads cranial radiation (group2) and 20 healthy controls (group3)]were enrolled in the study, and all of them completed the study.
Mean of age±SDof the three groups in order was 9±2.6 years in group 1, 12.2±4.2 years in group 2 and 8.6±3.1 years in the healthy control group (P=0.002). The male/female ratio was 1.5, 1.9 and 2.3, respectively (P=0.8).
Themean age at diagnosis of ALL was 4.4 years (SD=2.6, range=1.5-13 years)in group1 and 6.8 years (SD=3.7, range=2.9-13.3 years) in group 2 (P=0.8). The mean time since end of treatment was 22 months (SD=15.2, range=6-58 months) in group 1 and 18 months (SD=15, range 6-60 months)in group2. Survivors of group 1 were given 14-16-times IT MTX and group 2 14-18-times IT MTX, and cranial radiation was given at 1800 rads in 13 patients (59%) and 2400 rads in nine patients (41%).
IQ was measured using Raven's test,which is a non-verbal IQ test and it doesnot rely on language to determine cognitive abilities. This test included multiple choice questions of abstract understandings. It allowed children to show pattern-recognition, attention to details, memory and spatial reasoning. This test is close to the functioning scales on a WISC-III (Wechsler Intelligence Scale-3 rd Edition).
Raven's test is very easy to use and the cost is low.It has the highest predictive validity and with SD=16,IQ<76 is very low, 7690 is low, 90110 isnormal, 110132 is high and>132 is the Mensa level. ,,
Data obtained were analyzed through SPSS 18 software using the ANOVA test.
| Results|| |
There were significant differences in IQ between the survivors of ALL that were treated with IT MTX (group1), IT MTX plus cranial radiation (group2) and control group (group3). The mean±SD was101.3±13.8, 94.8±14, 105±9.4, respectively, in group 1, group 2 and group 3; P=0.027 [Figure 1].
The LFD (least significant difference) test revealed significant differences in IQ between the group 2 survivors and the control group (P=0.008), but there was no significant difference between the ALL survivors who received IT MTX alone in comparison with the two other groups (P=0.11 and P=0.26, respectively).
There was no significant difference in IQ with respect to sex(mean±SD: Female=101±13.3, male=100.4±13.3; P=0.89).
The Pearson correlation test revealed a weak relationship (7%) between the age at diagnosis and IQ scores, and this relationship was not significant, P=0.6 [Figure 2].
|Figure 2: Correlation between the age at diagnosis and intelligence quotient scores|
Click here to view
There was no difference between IQ scores and irradiation dose between group 1 and group 2 (97.1±10.1 and 92.3±16.3, respectively).
| Discussion|| |
Consistent with some previous researches, ,,,,,, the results of this study indicate adverse effects of prophylactic CNS treatment, especially irradiation, on intelligence.
The first study about the effects of CNS irradiation on neuropsychologic functioning of children with ALL was done in 1975,  and then many studies were done about the effects of different forms of CNS prophylaxis on neuropsychological function, especially IQ of children with ALL. ,,,,,,,,,
Most studies performed on leukemic children who received only IT MTX prophylaxis showed mild intellectual deficit with mean IQ scores in the average range, ,,,, but otherstudies such as the study by Proulx et al. reported significant adverse effects of cumulative dosage of IT MTX on performance IQ in 24 children (13 boys, 11 girls) that received IT MTX (17±2-4 times) without cranial irradiation (42-45% of the IQs for this group fell>1SD below the normative mean) and the study by Raymond-Spenden et al. on survivors of ALL treated with CNS chemotherapy (n=21), CNS chemotherapy plus 1800 rads cranial irradiation (n=20) and healthy children (n=21) showed "CNS chemotherapy, with and without cranial irradiation was associated with significantly lower levels of intellectual and academic functioning".
Our study showed that the mean IQ scores of long-term survivors of ALL that were treated with IT MTX was lower than their healthy siblings. Although this decrease is subtle, it is consistent with the previous reports and shows the toxic effects of CNS chemotherapy.
Although the addition of cranial irradiation, especially 2400 rads, to CNS prophylaxis treatment in childhood ALL has been very effective in the reduction of CNS relapse from 75% to 80% to less than 10%,is associated with structural abnormalities and white matter changes and, finally,long-term difficulties in cognitive and academic functions. ,
The oldest studies by Ivnik et al., Meadows et al.(1981),Pfefferbaum-Levine et al. and Rowand et al.(1984) indicated IQ differences between irradiated and non-irradiated patients.Mulhern et al.(1991), in a prospective comparison of neuropsychologic performance of children surviving leukemia who received IT MTX plus 1800 rads cranial irradiation (n=23) and 2400 rads (n=23) or no cranial irradiation (n=26) showed that 22-30% of the children exhibited a clinically significant deterioration greater than or equal to 15 points in uncorrected IQ value. 
Cetingul et al.(1999) also compared 19 children (15 male, four female) with ALL who were all given cranial irradiation (12-18 Gy, n=15, 73.6%) or (24 Gy,n=4, 21.1%) with 17 healthy siblings as the control group, and showed significantly low performance and total IQ scores; P=0.007 and P=0.02. 
Our results are consistent with these findings, and irradiated patients had lower mean IQ scores in comparison with the control group (P=0.008).
The mean age of diagnosis for ALL is 5 years, and age lower than 5 years is a risk factor for the neurotoxic effects of CNS prophylaxis.  Brain myelination in children occurs in an inferior-to-superior and posterior-to-anterior fashion, and continues through adolescence.  For these reasons, any toxic agent as chemotherapy drugs and irradiation, especially in early age, may disrupt development of the white matter and cause regional white matter volume reduction,and these abnormalities are associated with impairment in cognitive functions. ,
In the current study, there was a weak relationship between the age of diagnosis and IQ scores,which was in accordance with the findings of Cetingul, Mulhern and Kolotas, ,, and show the role of other factors except age.
One of the other risk factors is female gender, and the sensitivity of girls to neurotoxic effect of chemotherapy and irradiation is due to delay in brain maturation in this gender. 
In this study, there was no significant difference between sex and IQ scores probably due to the greater number of males in comparison with females.
Irradiation dose has been reported as another risk factor for neurotoxic sequelaes of CNS treatment in ALL patients,  but Kolotas reported that irradiation does not predict a decrease in IQ, and the only predictor is time lapse between irradiation and IQ measurement.  Mulhern also didnot show any significant decline in IQ in 23 survivors who received 2400 rads versus 23 patients who were treated with 1800 rads irradiation.  Against these studies, Halberg and Cetingulrevealed the neurotoxic effect of 2400 rads irradiation versus 1800 rads on IQ scores of ALL survivors. ,
In our study no significant differences was observed between the two radiation groups and larger samples are recommended for further research in this area.
Although this study was limited by small size. But, despite this limitation, the results revealed neurotoxic effect of CNS treatment on IQ scores survivors of ALL.
| Conclusion|| |
We can reveal that CNS prophylaxis treatment, especially combined treatment, is associated with a decline in IQ scores in ALL survivors. Therefore, a baseline and an annual assessment of their educational progress should be monitored and, if needed, use special educational services.
| Acknowledgments|| |
The authors wish to thank Isfahan University of medical sciences for support this reaserch and Dr.Arman S., Mr.Farshidnejad A. and Mr. Mehrabi A. for their kind assistance.
| References|| |
|1.||Carey ME, Haut MW, Reminger SL, Hutter JJ, Theilmann R, Kaemingk KL, et al. Reducedfrontal white matter volume in long-term childhood leukemiasurvivors: Avoxel-based morphometrystudy.AJNR Am J Neuroradiol2008;29:792-97. |
|2.||WilliamsJ, Michael, Davis Kelli S. Central nervous system prophylactic treatment for childhood leukemia: neuropsychological outcome studies. Cancer Treat Rev 1986;13:113-27. |
|3.||Allen JC. The effects of cancer therapy on the nervous system. JPediatr1978;93:903-9. |
|4.||Montour-Proulx I, Kuehn SM, Keene DL,Barrowman NJ, Hsu E, Matzinger MA, et al. Cognitive changes in children treated for acute lymphoblastic leukemia with chemotherapy only according to the Pediatric Oncology Group 9605 Protocol. J Child Neurol 2005;20:129-33. |
|5.||Saro H, Armenian, Anna T.Medows and Smita Bhatia. Late effects of childhood cancer and its treatment. (Neurocongnitive Sequelae) in Pizzo, Philip A,Poplack David G. Principles and Practice of Pediatric Oncology,6th edition. 2011. p. 137-4. |
|6.||Mulhern RK, Reddick WE, Palmer SL, Glass JO, Elkin TD, Kun LE, et al. Neurocognitive deficits in medulloblastoma survivors and white matter loss. Ann Neurol 1999;46:834-41. |
|7.||Reddick WE, WhiteHA, Class JO, Wheeler GC, Thompson SJ, Gajjar A, et al. Developmental model relating whitematter volume to neurocognitive deficits in pediatric brain tumor survivors. Cancer 2003;97:2512-9. |
|8.||Reddick WE, Shan ZY, Glass JO, Helton S, Xiong X, Wu S,et al. Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia. Cancer 2006;106:941-9. |
|9.||Brown RT,Sawyer MB, Antoniou G, Toogood I, Rice M, Thompson N, et al. A 3-year follow-up of the intellectual and academic functioning of children receiving central nervous system prophylactic chemotherapy for leukemia. J DevBehavPediatr 1996;17:392-8. |
|10.||http://www.greatschools.org/california/los-angeles/community/discussion.gs?content=4119(What is the Raven Test for gifted child all about?) |
|11.||http://ww http://www.iqtest.dk/main.SWF. |
|13.||Halberg FE, Kramer JH, Moore IM,Wara WM, Matthay KK, Ablin AR. Prophylactic cranial irradiation dose effects on late congnitive function in children treated for acute lymphoblastic leukemia.Int J RadiatOncol Bio Phys 1992;22:13-6. |
|14.||Cetingül N,Aydinok Y, Kantar M, Oniz H, Kavakli K, Yalman O, et al.Neuropsychologicsequelae in the long-term survivors of childhood acutelymphoblastic leukemia.PediatrHemtol Oncol1999;16:213-20. |
|15.||Ramond-Speden E, Tripp G, Lawrence B, Holdaway D . Intellectual, neuropsychological and academic functioning in long-term survivors of leukemia.JPediatrPsychol 2000;25:59-68. |
|16.||Duffner PK. Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist 2004;10:293-310. |
|17.||Soni SS, Marten GW,Pitner SE, Duenas DA, Powazek M. Effects of CNS irradiation on neuropsychologic functioning of children with acute lymphoblastic leukemia. NEngl J Med1975;293:113-8. |
|18.||Mulhern PK,Fairclough D, Ochus J. A prospective comparison of neuropyschologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation. J ClinOncol1991;9:1348-56 |
|19.||Liu HC, Liang DC, Chen SH, Lo CY, Tseng KP, Kuo TB, et al. Intelligence quotient in childhood acute lymphoblastic leukemia afterprophylactic treatment in central nervous system with 18 Gy cranial irradiation and intrathecal methotrexate.Zhonghua Min Guo Xiao ErKe Yi XueHuiZaZhi1996;37:107-10[Abstract/PMID:8935408]. |
|20.||Kolotas C, Daniel M,Demetriou L,Martin T, Kurek R, Tonus C, et al. Long-term effects on the intelligence of children treated for acute lymphoblastic leukemia. Cancer Invest 2001;19:581-7. |
|21.||Krappmann P, Paulides M, Stöhr W, Ittner E, Plattig B, Nickel P, et al. Almost normal cognitive function in patients during therapy for childhood acute lymphoblastic leukemia without cranial irradiation according to ALL-BFM 95 and COALL 06-97 protocols: Results of an Austrian-German multicenter longitudinal study and implication for follow-up. Pediatric HematolOncol 2007;24:101-9. |
|22.||Brown RT, Madam-Swain A, WalcoGA, Cherrick I, Ievers CE, Conte PM,et al.Congnitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. J PediatrPsychol 1998;23:333-40. |
|23.||Fossen A, Abrahamsen TG, Storm-Mathisen I. Psychological outcome in children treated for brain tumor.PediatrHematolOncol 1998;15:479-88. |
|24.||Lesnik PG,Ciesieiski KT, Hart BL, Benzel EC, Sanders JA.Evidence for cerebellar-frontal subsystemchanges in children treated with intrathecal chemotherapy for leukemia: enhanced data analysis using an effect size model. Arch Neurol1998;55:1561-8. |
[Figure 1], [Figure 2]