neuropsychological abnormalities following cns prophylaxis in children with acute lymphatic leukemia

Indian J Pediatr 1993; 60 : 675-681

Neuropsychological Abnormalities Following CNS Prophylaxis in Children with Acute Lymphatic Leukemia

Yogesh Jain, V.P. Choudhry*, L.S. Arya and M. Mehta**

Departments of Pediatrics, *Hematology and **Psychiatry, All India Institute of Medical Sciences, New Delhi

Abstract. The pattern and prevalence of neuropsychological abnormalities in children receiving combination CNS prophylaxis (2000 rads cranial irradiation and intrathecal methotrexate) during therapy for acute lymphoblastic leukemia (ALL) were studied. Thirty five children (25 boys) in the age group 5-15 years (mean 9.3) with no evidence of CNS leukemia were included and 20 age matched normal siblings served as controls. Neuropsychological parameters of general intelligence (Malin's modification of WlSC test); attention and concentration(colour cancellation test); memory (modified PGI memory test) and visuomotor perception (Bender Gestalt test) were evaluated at least 6 months after CNS prophylaxis. Six (17.1%) patients had mean intelligence quotients (IQ) tess than 85, while all controls had IQ > 85 (p < 0.05). The mean IQ of the patient population (93.4 • 11.9) was significantly lower than the control group (107 • 8.4) (p < 0.001). Scores on the colour cancellation test were lower in the patients as compared to controls (148.7 • 27.7 versus 184.9 • 23.9; p < 0.01). The mean memory quotient in the patient population was also lower than in controls (74.5 • 12 versus 93.6 • 9.2; p < 0.001). Scores on the Bender-Gestalt test did not show a significant difference. The presence of significant neuropsychological abnormalities in patients of ALL indicates the need for modification of the schedule of CNS prophylaxis. A comprehensive psychometric evaluation at regular intervals is essential for Iongterm rehabilitation. (Indian J Pediatr 1993; 60 : 675-681)

Key words: Acute leukemia; CNS prophylaxis; Cranial irradiation; Neuropsychological abnormalities.

Advances in therapy of acute lymphoblastic leukemia (ALL) including use of sys- temic combination chemotherapy along with central nervous system (CNS) prophylaxis have led to event-free survival of over more 5 years, in more than 70% children. 1 However, delayed CNS sequelae as evidenced by histopathological, compu- terized tomographic, neuroendocrine & neuropsychological abnormalities related to therapy have been seen in children with

Reprint requests: Dr. L.S. Arya, Additional Pro- lessor, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi-ll0 029.

ALL. 2 The impact of CNS prophylaxis on cognitive functions such as intelligence, attention, concentration, memory and per- ceptual abilities has not been studied in Indian children. As the number of long term survivors is increasing, many educational and vocational problems are likely to be experienced secondary to these abnormalities. The purpose of this study was to evaluate the prevalence and patten of neuropsychological abnormalities in children with ALL.

MATERIAL AND METHODS

Thirty-five children diagnosed as ALL at

676 THE INDIAN JOURNAL OF PEDIATRICS 1993; Vol. 60. No. 5

the All India Institute of Medical Sciences, New Delhi and attending the Pediatric Hematology/Oncology Clinic were sub- jected to this study. All patients bad re- ceived CNS prophylaxis in the form of cranial irradiation (2000 rads over 10 sittings) and intrathecal methotrexate (12 rag/m2 BSA, 5 doses) at least six months prior to entry into the study. Patients showing presence of leukemic blasts in cerebrospi- nal fluid were excluded. Twenty normal age-matched siblings served as controls. The neuropsychological test battery aimed to evaluate, (i) general intelligence; (ii) attention and concentration; (iii) memory; and (iv) visuomotor perception. General intelligence was assessed according to Malin's Intelligence Scale for Indian Chil- dren (MISIC), a verbal test which is an ad- aptation of Weschler's Intelligence Scale for Children (WISC). 3 The test includes assessment under the subclasses oL (i) information; (ii) comprehension; (iii) analogies

& similarities; and (iv) digit spanforward and backward. Intelligence quotients (IQ) were computed and value of less than 85 was considered subnormal. Attention and concentration were evaluated by the use of modified colour cancellation test. 4 Chil- dren were given a sheet with a number and circles of four different colours (red, green, yellow and blue). They were then asked to cancel the maximum number of circles of two specified colours in a fixed period of five minutes. They were then scored for the total number of correct circles and the number of errors committed. The PGI scale for memory testing was adapted to test memory function. Verbal memory test of irm-nediate and delayed recall, as well as nonverbal memory tests of visual retention and recognition were ad- ministered. A mean memory quotient av- eraging the four test scores was calculated. Visuomotor perception was tested by the Bender-Gestalt Test 6 and the responses

TABLE 1. IQ Scores in the Various Subgroups of Intelligence

Subjects

Patients Controls (n=35) (n=20)

Mean (SD) Mean (SD) (%) (%)

Statistical significance

Information 90.4 104.3 (14.3) (12.9)

Comprehension 100.9 110.3 (18.2) (10.8)

Similarities 90.9 107.2 (13.7) (9.4)

Arithmetic 96.7 107 (17.0) (9.5)

Digit span 89.1 106.5 (12.8) (ll.6)

p < 0.001

p < 0.05

p < 0.001

p < 0.01

p < 0.001

Mean IQ 93.4 107 (11.9) (8.4)

p < 0.001

1993; Vol. 60. No. 5 THE INDIAN JOURNAL OF PEDIATRICS

TABLE 2. Comparison of Memory Subsets in Patients and Controls

677

Subjects

Patients Controls Statistical (n=35) (n=20) significance

Mean (SD) Mean (SD) (%) (%)

Verbal immediate recall 6.2 7.7 p < 0.001 (1.65) (0.65)

Delayed recall 6.9 9.0 p < 0.001 (1.5) (1.16)

Non verbal visual recall 7.34 9.3 p < 0.001 (1.37) (1.08)

Visual recognition 5.7 6.75 p < 0.001 (1.1) (0.71)

Mean 74.5 93.6 p < 0.001

were scored according to the system de- vised by Koppitz. 7

The statistical analysis was done using Student's 't' test and the chi-square test.

RESULTS

Thirty-five children between the ages 5 and 15 years (mean 9.3 years) were studied; 25 (71.4%) were boys. Twenty normal siblings between the ages 6 and 14 years (mean 9.3 years) served as controls; 13 (65%) were boys. Neuropsychological evaluation was done 6-24 months after CNS prophylaxis in 18 (51.5%) patients. In 17 (48.5%) patients it was done following 24 months; 10 of these 17 were off all an- tileukemic therapy.

The mean IQ of patients was 93.4 (range 57-131) and in controls was 107 (range 86- 122) (p < 0.001). Six patients (17.1%) had Subnormal IQ; of these one had an IQ of below 70. None of the controls had a subnormal IQ. The difference in IQ between

the two groups was statistically significant (p < 0.05). IQ scores on the various subgroups of intelligence were also significantly lower in the patients as compared to controls (Table 1). The mean IQ of 19 patients (54.8%) whose age at diagnosis of ALL was < 6 years was 91.7 as compared to 95.4 in 16 (45.2%) whose age at diagnosis of ALL was --. 6 years; this difference was, however, not statistically significant. There was also no significant difference in IQ of 18 patients whose assessment was done within 24 months after CNS prophylaxis (mean IQ = 95.7), when compared to 17 patients (90.9) who were assessed 24 months after treatment.

Scores on colour cancellation test ranged from 96 to 203 (mean 148.1) in the patients, while in the controls it varied from 133 to 217 (mean 184.9). This difference was statistically significant (p < 0.001). Patients committed more errors (mean 2.1) than did the controls (mean 1.3) (p < 0.01). There was no correlation be-


2 0 0

I

150~-

I !

100~ ~

5~ 0 - - - -

mean IQ CCT

CCT �9 Color Cancel lat ion Test Score BG - Normal Bender Gestal t Score

M e m o r y BG

~ l l Pa t i en t s ~ S ib l i ngs (n-35) (n--20)

Fig. 1. Comparative performance of CNS treated patients and their siblings onneuropsychological test battery.

tween the scores on colour cancellation test, and duration elapsed since CNS prophylaxis. Memory quotient in patients ranged from 57.1 to 97.4 (mean 74.5) as compared to controls (range 60-100; mean 93.6) (p < 0.001). A significant difference was also observed when the mean scores of all the four memory substests were compared in the two groups (Table 2). Scores on Bender-Gestalt test for visuomotor perception did not show a significant difference in two groups. However, 4 (11.2%) of 35 patients had scores more than 2. SD from the mean, whereas all controls had values within the normal range.

DISCUSSION

The findings of the present study suggest that significant neuropsychological abnormalities occur following combination CNS

prophylaxis in children with acute lymphoblastic leukemia (Figure 1).

In the present study, patients mean had a mean IQ deficit of 13.6 in comparison to their siblings (p < 0.001). Though the mean IQ was within the normal range, this deficit is sufficiently large to have a significant bearing on the potential of these patients for academic achievement. The IQ for a group of people is based on their genetic and /o r environmental background rather than on a hypothetical average of 100, and the mean IQ of different groups of children have been shown to vary according to the educational and occupational back- grounds. Siblings with same genetic and environmental background performed significantly better than the patients in the present study. Moss et al s also found a 13 point difference in verbal and pe;formance IQ levels of CNS treated patients. Eiser

1993; Vol. 60. No. 5 THE INDIAN JOURNAL OF PEDIATRICS 679

and Lansdown, 9'~~ found poorer performance on quantitative tasks and motor skills, especially in younger patients. farnaroff tl has also reported similar findings.

The IQ scores on various subsets of intelligence also show a significant difference between the patients and the siblings. Dif- ference is more significant in the information, arithmetic, analogies and similarities and digit span subsets (p<0.001) than in the comprehension subset (Table 1). Com- prehension test scores are a good index of premorbid intellectual achievement of brain damaged patients generally. Thus, when damage is diffuse or bilateral, the comprehension subtest score is likely to be a useful indicator of premorbid ability. lherefore, the fact that comprehension subtest has shown less significant deficits in patients as compared to controls is a strong pointer to possible CNS dysfunc- tion due to medical intervention.

As skills accrue with age, the abilities of younger children given CNS prophylaxis could get arrested at more elementary levels because of the early disruption in their brain development. Although our data did not show statistically significant incidence of abnormalities in children, others 8,9,,12'14 have shown higher incidence of abnormalities in younger children.

Significant deficits in attention and con- Centration were also seen. Brouwers ~5 found similar abnormalities in his ALL Survivors, particularly in those patients With intracranial calcifications. This is im- POrtant because it compounds the severity of other observed neuropsychological de- fects, since intact attentional processing is required for subsequent steps in cognitive PrOcess. The present study also revealed that not only the number of correct an-

swers marked were significantly lower in the patients, the number of errors committed in the patient and control group dif- fered significantly.

The mean memory quotient of patients of 74.5% (SD=12) was significantly poorer than that of controls; memory deficits were noticed in both verbal and nonverbal memory test (Table 2). Both, immediate and delayed recall were poorer in the patient group. Impaired memory and learn- ing performance on tasks requiring inten- tional remembering of facts and events have been noticed by many workers. 9,1~ Other workers, 1,1s have observed that immediate recall is less affected than delayed recall.

Bender Gestalt test for visual-motor perception is an indicator of diffuse brain damage. 17 Although the patients in the present study committed more errors than their siblings, this difference was not statistically significant possibly due to a small sample size.

The findings in this study emphasize the need for comprehensive psychometric evaluation of patients with ALL undergo- ing prophylactic CNS therapy. Though earlier studies have shown abnormalities with the 'standard" 2400 rads, they have been reported with 1800 rads alsoJ 3 Since the risk of developing subacute leu- koencephalopathy is related to the total irradiation dose, 18 decreasing the dose further may be associated with fewer sequelae. The second approach to decrease sequelae is to eliminate cranial irradiation, since irradiation has been found to be re- sponsible for significantly higher incidence of neuropsychological abnormalities in various studies23,~9 Standard risk ALL can be managed without cranial irradiation if the intrathecal methotrexate therapy is


supplemented with int ravenous methotrexate intensification. 2~ Moe et a121 have even shown the efficacy of high dose intra- venous methotrexate in high risk ALL. The toxicity of such chemotherapy is lessen than any regime which includes cranial ir- radiat ion} 3

In India, the propor t ion of acute leukemia patients having high risk factors is significantly higher than in the West, which necessitates a more intensive regime. In a s tudy repor ted from this centre, 22 the patients having high risk features was above 60%, similar figures are also reported f rom other parts of the country. 23

The presence of neuropsychological ab- normalit ies necessitates a further evaluation of a protocol for CNS prophylaxis which produces least neuropsychological abnormalities with best CNS disease pre- vent ion . This could be done by ei ther elimination, or reduct ion of cranial irradiation, at least in s tandard risk patients.

Further studies of similar nature on a larger number of cases, and for a longer dura t ion are necessary to enable oncolo- gists to educate parents regarding the long te rm effects of therapy. It wou ld also pro- v ide guidelines for planning education, as well as a vocational career of long term survivors whose number is growing with i m p r o v e d modes of t he r apy for this c o m m o n malignancy.

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Gilbert AD, Kagan AR, eds. Radiation Damage to the Nervous System. New York : Raven Press, 1989 : pp. 155-174.

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F A O / W H O E N D O R S E IODATE A N D IODIDE FOR I O D I Z A T I O N OF SALT

The Joint FAO/WHO Expert Committee on Food Additives, in its 37th report concluded that "potasium iodate and potassium iodide should continue to be used for fortification of salt for correction of iodine deficiency". This statement should dispel concerns expressed by some governments about the safety of salt iodization with either potassium iodide or potassium iodate.

From all the evidence that is available, it appears that iodate taken in quantities present in iodated salt is quite safe by a factor of at least a thousand. This, in addition to its favorable Stability under storage conditions, indicates that it is a reliable and entirely acceptable agent for fortification of salt in the prevention of the iodine deficiency disorders.

Abstracted From: IDD Newsletter~1991; Vol 7 : No. 3, 22-23.

neuropsychological abnormalities following cns prophylaxis in children with acute lymphatic leukemia

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