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P300 as indicator of effects of prophylactic cranial radiation
P300 as Indicator of Effects of Prophylactic Cranial Radiation T a k a m i Sato, M D , M a s u t o m o M i y a o , M D , H i r o m u M u c h i , M D , Yuji Gunji, M D , A t s u o Iizuka, M D , a n d M a s a y o s h i Y a n a g i s a w a , M D
In order to assess the late adverse effects of cranial radiation on the central nervous system, 33 children with acute lymphocytic leukemia were examined through event-related potential P300, brain response analysis. P300 latency was significantly prolonged in children who received both prophylactic cranial radiation and intrathecal methotrexate. Although a longitudinal study is necessary, we believe that P300 is useful in the assessment of the adverse effects of cranial radiation in children with acute lymphocytic leukemia. Sato T, Miyao M, Muchi H, Gunji Y, Iizuka A, Yanagisawa M. P300 as indicator of effects of prophylactic cranial radiation. Pediatr Neurol 1992;8:130-2.
Introduction Although treatment for children with cancer has improved significantly in the last 10 years, central nervous system (CNS) side effects continue to be assessed. Children with acute lymphocytic leukemia (ALL) are particularly at risk due to the need for CNS prophylaxis. In this study, we evaluated the effects of prophylactic cranial radiation to the CNS using the event-related potential (ERP) P300 brain wave tracing method. P300 wave response is considered to be an objective electrophysiologic evaluator of cognitive dysfunction [ 1] and therefore a possible monitoring tool for CNS damage due to prophylactic cranial radiation.
Methods Thirty-three children with ALL were divided into 2 groups according to the use or nonuse of CNS radiation. None had experienced neurologic problems at the time of diagnosis or was receiving antiepileptic drugs, which affect P300 latency, at the time of examination. The CNS-radiated group consisted of 13 patients. They had been enrolled in a high-risk chemotherapy protocol [2] that included the administration of intrathecal methotrexate (MTX), intermediate dose (500 mg/m2) intravenous MTX, and CNS radiation (1,800 cGy). The nonradiated group consisted of 20 patients treated under standard risk chemotherapy protocol which included intrathecal MTX and intermediate do~ intravenous MTX, but no CNS radiation. At each evaluation, none of the patients had any signs of CNS or bone marrow relapse. Side effects
From the Depa~ment of Pediatrics; Jichi Medical School; 3311- I ; Yakushiji, Tochigi, Japan.
130
PEDIATRIC NEUROLOGY
Vol. 8 No. 2
due to treatment were evaluated by a P300 response more than 2 years after diagnosis.
P300 The ERP P300 was elicited using the auditory "odd ball" paradigm. A single run consisted of a sequence of 200 tone bursts of which 85% were 2,000 Hz (nontarget tone) and 15% were 1,000 Hz (target tone). Interstimulus of presentation was pseudorandom. The patients were instructed to listen to the target tones, to count the number of the target tones, and to press a key when a target tone was detected. Electroencephalographic (EEG) activity was recorded at the F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4 electrode sites in accordance with the International 10/20 System, using linked earlobes as the reference. Additional electrodes were placed at the outer canthus and supraorbital region for electrooculogram (EOG). Wave forms were averaged on-line by a 7T-18-S analyzer (NipponKoden). Trials in which EEG or EOG activity exceeded _+50 ~tV were rejected automatically. Peak latencies and amplitudes of NI, P2, N2, and P300 components were measured by computer algorithm. Each amplitude was measured relative to the prestimulus baseline. P300 latency was defined as the point of time of maximum amplitude between 250-500 ms. The prolongation of P300 latency was estimated from the data of our normal subjects I3,4]. The children whose P300 latencies were between 1-2 S.D. above the mean of age-matched normal subjects were categorized as manifesting moderate prolongation. The children whose P300 latencies were longer than 2 S.D. above the mean of age-matched normal subjects were categorized as manifesting severe prolongation. In this study, we evaluated the ERPs elicited from the Cz site in the "count" paradigm for 2 reasons: (1) The stability and reproducibility of the wave in children is very clear; and, (2) Our previous data on normal subjects were collected from the Cz site in the "count" paradigm [3,4].
Statistical Analysis of Results All group means were reported as mean + I S.D. and significance was expressed as a P value. To account for age in P300 latency, all P300 values were converted to Z scores. The scores were calculated a~s (observed value - mean)/S.D., in which mean and S.D. were derived from data of age-matched normal controls. Statistical evaluation was made using the unpaired Student t test for the average. The chi-square test (with Yates' continuity correction when necessary) was used for tables to compare unmatched groups (significance P < .05).
Results The P300 peak was detected in 12 of 13 patients in the CNS-radiated group and in 16 of 20 in the nonradiated
Communications should be addressed to: Dr. Sato; Noguchi Medical Research Institute; 3600 Market Street; Suite 350; Philadelphia, PA 19104-2644. Received August 14, 1991; accepted January 13, 1992.
Table 1. Demographic characteristics CNS-radiated
Group
Nonradiated Group
12
16
7/5
9/7
Age at Diagnosis (yrs)
8.3 _+4.3*
5.2 + 2.5
Age at Examination (yrs)
13.2 + 4.3
10.4 _+3.0
3 / 12 (25.0%)
1/16 (6.3%)
Number of Patients Sex (M/F)
Neuroiogic Complica-
tions*
* P < .05, 2-tailed value used. Convulsion, gait disturbance, involuntary movement,mental deficits.
Discussion
group. All patients who did not have the obvious P300 peak were younger than 10 years of age. The demographic characteristics of 28 patients whose P300 peaks were detected are listed in Table 1. At diagnosis, the CNS-radiated group of children were older than the nonradiated group, mainly because age is one of the major factors in deciding the indication of cranial radiation. The average age at P300 wave response evaluation was slightly higher in the CNS-radiated group than in the nonradiated group. Three of 12 patients in the CNS-radiated group and 1 of 16 patients in the nonradiated group manifested the neurologic abnormalities, such as convulsion and gait disturbance, during the course of therapy. The scattergram of P300 latency is illustrated in Figure 1. A significant nega-
5001 o
[]
~ 400~.~o °
,,z,
3oo-
20C- o Ioo 5
~ o
.O.o
;
80
O
O O
Dol
o ?.-vq.: ° •
o.
o Y-457.0-9.7X
I
10 15 AGE(Years)
tive correlation was observed between P300 latency and age in the data of normal subjects: latency (ms) = -9.81 x age (yr) + 457.0, r = 0.75, P < .01 [4]. The CNS-radiated group of children, especially older than 15 years of age, had a tendency to demonstrate the prolongation of P300 latency. In contrast, the nonradiated group of children had a tendency to have a shortening of P300 latency. The children who had neurologic symptoms during the course of therapy demonstrated the prolongation of P300 latency. The number of children who had the prolongation in P300 latency is larger in the CNS-radiated group than in the nonradiated group (P < .05; Table 2). The average Z score of the CNS-radiated group was larger than that of the nonradiated group (1.62 + 1.57 vs. -1.1 + 2.21; P < .05).
20
Figure 1. Scattergram of P300 latency. CNS-radiated group of children demonstrates the prolongation of 1'300 latency, compared with nonradiated group. Children who had had neurologic symptoms during the course of therapy had a tendency to have prolongation of P300 latency. C]: cranial radiation (+); O: cranial radiation (-); 0 : data of normal subjects; *: subjects who had neurologic abnormalities during the course of therapy.
Soni et al. reported that there may be neuropsychologic damage to long-term ALL survivors treated with CNS prophylaxis [5]. Since their report, many studies have been published concerning impaired memory and learning performance [6-8]. The majority of studies have demonstrated at least some neuropsychologic deficiencies and have implicated radiation in the genesis of these changes. In this study, the CNS-irradiated patients, especially those older than 15 years of age, exhibited significant prolongation of P300 latency. Although an age-matched study is necessary, these data suggest the possibility that cranial radiation has an unfavorable late effect on the developing brain during childhood. The patients who had experienced neurologic complications demonstrated significant prolongation of P300 latency. The CNS-irradiated group included 3 of 4 patients who had neurologic abnormalities during the course of therapy. The increase in severity of the brain damage may be the possible explanation for the prolonged P300 latency in the CNS-irradiated group. It is unknown why the nonradiated group of children had a tendency to have a shorter P300 latency. Because the nonradiated group consisted of younger children, this shorter latency may be due to the instability of P300 at a younger age. Further study is necessary to clarify the relationship between age at which examination is performed and the time when the prolongation of P300 latency appears. The P300 latency response, discovered by Sutton et al. [9], has been demonstrated to reflect fundamental cognitive processes among normal case studies [ 10,11 ]. Because it increases systematically with increases in cognitive dysfunction, P300 latency has been employed as an objective electrophysiologic index for assessing the degree of dementia [1]. In children, P300 latency decreases with age and is supposed to be a useful indicator for evaluating age-related development of cognitive function [3,4,12]. Brouwers and Polack reported that memory impairment, particularly short-term, was an underlying neuropsychologic dysfunction in ALL children treated with a CNS prophylaxis [8]. Although a longitudinal study is neces-
Sato et al: Cranial Radiation and P300 131
Table 2.
17300 latency CNS-radiated G roup *
Nonradiated Grou p
Normal Range (< mean + 1 S.D.)
4
13
Moderate Prolongation (1-2 S.D. above mean)
4
I
Severe Prolongation (> mean + 2 S.D.)
4
2
* P < .05, chi-~uare analysis; CNS-radiated group had the prolongation of P300 latency, compaired with the nonradiated group.
s a r y , t h e E R P P 3 0 0 , w h i c h is c l o s e l y r e l a t e d to m e m o r y p r o c e s s i n g , a p p e a r s to b e a n i n d i c a t o r o f t h e a d v e r s e e f fects of prophylactic cranial radiation.
We are indebted to Kazuo Nihei and Yoshiki Fujimoto for their technical assistance.
References
[1] Douglas S, Goodin DS. Clinical utility of long latency 'cognitive' event-related potentials (P3): The pros. Electroencephalogr Clin Neurophysiol 1990;76:2-5.
132
PEDIATRIC NEUROLOGY
Vol. 8 No. 2
[2] Muchi H, Sato T, Taniguchi Y. The treatment and neurological complication in the children with acute lymphoblastic leukemia. Jpn J Clin Hematol 1987;28:1941-7. [3] Sato T. Sawa R, Miyao M, Shimizu N, Nihei K, Kalnoshita S. Age-related changes of P30(/ in children. No To Hattatsu 1986;18: 373-9. [4] Ezoe T, Sato T. Miyao M, Yanagisawa M. Event related potential P300: Age-related change in adolescence. No To Hattatsu 1989;21: 581-3. [5] Soni SS, Marten GW, Pitner SE, Duenas DA, Powazek M. Effects of central nervous irradiation on neuropsychological functioning of children with acute lymphocytic leukemia. N Engl J Med 1975;293: 113-8. [6] Eiser C. Intellectual abilities among survivors of childhood leukemia as a function of CNS irradiation. Arch Dis Child 1978;53:391-5. [7] Muchi H, Sato T, Yamamcto K, Karube T, Miyao M. Studies on the assessment of neurotoxicity in children with acute lymphoblastic leukemia. Cancer 1987;59:891-5. [8] Bronwers R Polack D. Memory and learning sequelae in longterm survivors of acute lymphoblastic leukemia: Association with attention deficits. Am J Pediatr Hematol Oncol 1990;12:174-81. [9] Sutton S, Brarun M, Zubin J, John ER. Evoked-potential correlates of stimulus uncertainty. Science 1965;I 50: I 187-8. [10] Johnson R, Pfefferbaum A, Kopell BS. P300 and long-term memory: Latency predicts recognition performance. Psychophysiology 1985;22:497-507. [ll] Fabiani M, Karis D, Donchin E. P300 and recall in an incidental memory paradigm. Psychophysiology 1986;23:298-314. [12] Finley WW, Fanx SF. Hutcheson J, Anstutz L. Long-latency event-related potentials in the evaluation of cognitive function in children. Neurology 1985;35:323-7.
In order to assess the late adverse effects of cranial radiation on the central nervous system, 33 children with acute lymphocytic leukemia were examined through event-related potential P300, brain response analysis. P300 latency was significantly prolonged in children who received both prophylactic cranial radiation and intrathecal methotrexate. Although a longitudinal study is necessary, we believe that P300 is useful in the assessment of the adverse effects of cranial radiation in children with acute lymphocytic leukemia. Sato T, Miyao M, Muchi H, Gunji Y, Iizuka A, Yanagisawa M. P300 as indicator of effects of prophylactic cranial radiation. Pediatr Neurol 1992;8:130-2.
Introduction Although treatment for children with cancer has improved significantly in the last 10 years, central nervous system (CNS) side effects continue to be assessed. Children with acute lymphocytic leukemia (ALL) are particularly at risk due to the need for CNS prophylaxis. In this study, we evaluated the effects of prophylactic cranial radiation to the CNS using the event-related potential (ERP) P300 brain wave tracing method. P300 wave response is considered to be an objective electrophysiologic evaluator of cognitive dysfunction [ 1] and therefore a possible monitoring tool for CNS damage due to prophylactic cranial radiation.
Methods Thirty-three children with ALL were divided into 2 groups according to the use or nonuse of CNS radiation. None had experienced neurologic problems at the time of diagnosis or was receiving antiepileptic drugs, which affect P300 latency, at the time of examination. The CNS-radiated group consisted of 13 patients. They had been enrolled in a high-risk chemotherapy protocol [2] that included the administration of intrathecal methotrexate (MTX), intermediate dose (500 mg/m2) intravenous MTX, and CNS radiation (1,800 cGy). The nonradiated group consisted of 20 patients treated under standard risk chemotherapy protocol which included intrathecal MTX and intermediate do~ intravenous MTX, but no CNS radiation. At each evaluation, none of the patients had any signs of CNS or bone marrow relapse. Side effects
From the Depa~ment of Pediatrics; Jichi Medical School; 3311- I ; Yakushiji, Tochigi, Japan.
130
PEDIATRIC NEUROLOGY
Vol. 8 No. 2
due to treatment were evaluated by a P300 response more than 2 years after diagnosis.
P300 The ERP P300 was elicited using the auditory "odd ball" paradigm. A single run consisted of a sequence of 200 tone bursts of which 85% were 2,000 Hz (nontarget tone) and 15% were 1,000 Hz (target tone). Interstimulus of presentation was pseudorandom. The patients were instructed to listen to the target tones, to count the number of the target tones, and to press a key when a target tone was detected. Electroencephalographic (EEG) activity was recorded at the F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4 electrode sites in accordance with the International 10/20 System, using linked earlobes as the reference. Additional electrodes were placed at the outer canthus and supraorbital region for electrooculogram (EOG). Wave forms were averaged on-line by a 7T-18-S analyzer (NipponKoden). Trials in which EEG or EOG activity exceeded _+50 ~tV were rejected automatically. Peak latencies and amplitudes of NI, P2, N2, and P300 components were measured by computer algorithm. Each amplitude was measured relative to the prestimulus baseline. P300 latency was defined as the point of time of maximum amplitude between 250-500 ms. The prolongation of P300 latency was estimated from the data of our normal subjects I3,4]. The children whose P300 latencies were between 1-2 S.D. above the mean of age-matched normal subjects were categorized as manifesting moderate prolongation. The children whose P300 latencies were longer than 2 S.D. above the mean of age-matched normal subjects were categorized as manifesting severe prolongation. In this study, we evaluated the ERPs elicited from the Cz site in the "count" paradigm for 2 reasons: (1) The stability and reproducibility of the wave in children is very clear; and, (2) Our previous data on normal subjects were collected from the Cz site in the "count" paradigm [3,4].
Statistical Analysis of Results All group means were reported as mean + I S.D. and significance was expressed as a P value. To account for age in P300 latency, all P300 values were converted to Z scores. The scores were calculated a~s (observed value - mean)/S.D., in which mean and S.D. were derived from data of age-matched normal controls. Statistical evaluation was made using the unpaired Student t test for the average. The chi-square test (with Yates' continuity correction when necessary) was used for tables to compare unmatched groups (significance P < .05).
Results The P300 peak was detected in 12 of 13 patients in the CNS-radiated group and in 16 of 20 in the nonradiated
Communications should be addressed to: Dr. Sato; Noguchi Medical Research Institute; 3600 Market Street; Suite 350; Philadelphia, PA 19104-2644. Received August 14, 1991; accepted January 13, 1992.
Table 1. Demographic characteristics CNS-radiated
Group
Nonradiated Group
12
16
7/5
9/7
Age at Diagnosis (yrs)
8.3 _+4.3*
5.2 + 2.5
Age at Examination (yrs)
13.2 + 4.3
10.4 _+3.0
3 / 12 (25.0%)
1/16 (6.3%)
Number of Patients Sex (M/F)
Neuroiogic Complica-
tions*
* P < .05, 2-tailed value used. Convulsion, gait disturbance, involuntary movement,mental deficits.
Discussion
group. All patients who did not have the obvious P300 peak were younger than 10 years of age. The demographic characteristics of 28 patients whose P300 peaks were detected are listed in Table 1. At diagnosis, the CNS-radiated group of children were older than the nonradiated group, mainly because age is one of the major factors in deciding the indication of cranial radiation. The average age at P300 wave response evaluation was slightly higher in the CNS-radiated group than in the nonradiated group. Three of 12 patients in the CNS-radiated group and 1 of 16 patients in the nonradiated group manifested the neurologic abnormalities, such as convulsion and gait disturbance, during the course of therapy. The scattergram of P300 latency is illustrated in Figure 1. A significant nega-
5001 o
[]
~ 400~.~o °
,,z,
3oo-
20C- o Ioo 5
~ o
.O.o
;
80
O
O O
Dol
o ?.-vq.: ° •
o.
o Y-457.0-9.7X
I
10 15 AGE(Years)
tive correlation was observed between P300 latency and age in the data of normal subjects: latency (ms) = -9.81 x age (yr) + 457.0, r = 0.75, P < .01 [4]. The CNS-radiated group of children, especially older than 15 years of age, had a tendency to demonstrate the prolongation of P300 latency. In contrast, the nonradiated group of children had a tendency to have a shortening of P300 latency. The children who had neurologic symptoms during the course of therapy demonstrated the prolongation of P300 latency. The number of children who had the prolongation in P300 latency is larger in the CNS-radiated group than in the nonradiated group (P < .05; Table 2). The average Z score of the CNS-radiated group was larger than that of the nonradiated group (1.62 + 1.57 vs. -1.1 + 2.21; P < .05).
20
Figure 1. Scattergram of P300 latency. CNS-radiated group of children demonstrates the prolongation of 1'300 latency, compared with nonradiated group. Children who had had neurologic symptoms during the course of therapy had a tendency to have prolongation of P300 latency. C]: cranial radiation (+); O: cranial radiation (-); 0 : data of normal subjects; *: subjects who had neurologic abnormalities during the course of therapy.
Soni et al. reported that there may be neuropsychologic damage to long-term ALL survivors treated with CNS prophylaxis [5]. Since their report, many studies have been published concerning impaired memory and learning performance [6-8]. The majority of studies have demonstrated at least some neuropsychologic deficiencies and have implicated radiation in the genesis of these changes. In this study, the CNS-irradiated patients, especially those older than 15 years of age, exhibited significant prolongation of P300 latency. Although an age-matched study is necessary, these data suggest the possibility that cranial radiation has an unfavorable late effect on the developing brain during childhood. The patients who had experienced neurologic complications demonstrated significant prolongation of P300 latency. The CNS-irradiated group included 3 of 4 patients who had neurologic abnormalities during the course of therapy. The increase in severity of the brain damage may be the possible explanation for the prolonged P300 latency in the CNS-irradiated group. It is unknown why the nonradiated group of children had a tendency to have a shorter P300 latency. Because the nonradiated group consisted of younger children, this shorter latency may be due to the instability of P300 at a younger age. Further study is necessary to clarify the relationship between age at which examination is performed and the time when the prolongation of P300 latency appears. The P300 latency response, discovered by Sutton et al. [9], has been demonstrated to reflect fundamental cognitive processes among normal case studies [ 10,11 ]. Because it increases systematically with increases in cognitive dysfunction, P300 latency has been employed as an objective electrophysiologic index for assessing the degree of dementia [1]. In children, P300 latency decreases with age and is supposed to be a useful indicator for evaluating age-related development of cognitive function [3,4,12]. Brouwers and Polack reported that memory impairment, particularly short-term, was an underlying neuropsychologic dysfunction in ALL children treated with a CNS prophylaxis [8]. Although a longitudinal study is neces-
Sato et al: Cranial Radiation and P300 131
Table 2.
17300 latency CNS-radiated G roup *
Nonradiated Grou p
Normal Range (< mean + 1 S.D.)
4
13
Moderate Prolongation (1-2 S.D. above mean)
4
I
Severe Prolongation (> mean + 2 S.D.)
4
2
* P < .05, chi-~uare analysis; CNS-radiated group had the prolongation of P300 latency, compaired with the nonradiated group.
s a r y , t h e E R P P 3 0 0 , w h i c h is c l o s e l y r e l a t e d to m e m o r y p r o c e s s i n g , a p p e a r s to b e a n i n d i c a t o r o f t h e a d v e r s e e f fects of prophylactic cranial radiation.
We are indebted to Kazuo Nihei and Yoshiki Fujimoto for their technical assistance.
References
[1] Douglas S, Goodin DS. Clinical utility of long latency 'cognitive' event-related potentials (P3): The pros. Electroencephalogr Clin Neurophysiol 1990;76:2-5.
132
PEDIATRIC NEUROLOGY
Vol. 8 No. 2
[2] Muchi H, Sato T, Taniguchi Y. The treatment and neurological complication in the children with acute lymphoblastic leukemia. Jpn J Clin Hematol 1987;28:1941-7. [3] Sato T. Sawa R, Miyao M, Shimizu N, Nihei K, Kalnoshita S. Age-related changes of P30(/ in children. No To Hattatsu 1986;18: 373-9. [4] Ezoe T, Sato T. Miyao M, Yanagisawa M. Event related potential P300: Age-related change in adolescence. No To Hattatsu 1989;21: 581-3. [5] Soni SS, Marten GW, Pitner SE, Duenas DA, Powazek M. Effects of central nervous irradiation on neuropsychological functioning of children with acute lymphocytic leukemia. N Engl J Med 1975;293: 113-8. [6] Eiser C. Intellectual abilities among survivors of childhood leukemia as a function of CNS irradiation. Arch Dis Child 1978;53:391-5. [7] Muchi H, Sato T, Yamamcto K, Karube T, Miyao M. Studies on the assessment of neurotoxicity in children with acute lymphoblastic leukemia. Cancer 1987;59:891-5. [8] Bronwers R Polack D. Memory and learning sequelae in longterm survivors of acute lymphoblastic leukemia: Association with attention deficits. Am J Pediatr Hematol Oncol 1990;12:174-81. [9] Sutton S, Brarun M, Zubin J, John ER. Evoked-potential correlates of stimulus uncertainty. Science 1965;I 50: I 187-8. [10] Johnson R, Pfefferbaum A, Kopell BS. P300 and long-term memory: Latency predicts recognition performance. Psychophysiology 1985;22:497-507. [ll] Fabiani M, Karis D, Donchin E. P300 and recall in an incidental memory paradigm. Psychophysiology 1986;23:298-314. [12] Finley WW, Fanx SF. Hutcheson J, Anstutz L. Long-latency event-related potentials in the evaluation of cognitive function in children. Neurology 1985;35:323-7.