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July2005 Vol.42 Issue:      2 Table of Contents
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Electroencephalographic Changes with Methotrexate in Childhood Acute Lymphoblastic Leukemia and Lymphoma

Mona H. El-Samahy1, M.A. Abo-El-Asrar1, Nahad Salah2
Departments of Pediatrics1, Neuropsychiatry2, Ain Shams University

ABSTRACT

The neurological side effects of high dose methotrexate (HD-MTX) and intrathecal MTX in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) patients through the use of EEG recording was investigated in this study. Eighteen patients with ALL and 7 patients with NHL were studied for their EEG changes after each I.V. HD-MTX (2 gm / m²). Focal and generalized EEG changes in both groups of patients after each MTX administration either as systemic high-dose or as intrathecal dose were observed. However, in many of the patients, these findings were transient and disappeared by the time of next HD-MTX. These findings indicate that although HD-MTX and/or intrathecal MTX may occasionally be associated with EEG changes, most of the time these changes are transient and no cumulative EEG changes have to be expected. It is thus suggested that the risk of an acute or sub acute encephalopathy with cortical dysfunction is low. However, subtle sub cortical damage in the deep white matter cannot be ruled out by the EEG alone, and no conclusions on the long-term toxicity can be drawn. If acute neuropsychiatry symptoms or EEG slowing occurs, delayed methotrexate clearance has to be suspected.

(Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2): 537-543).

 





INTRODUCTION

 

Prophylactic treatment of occult central nervous system involvement is one of the most important principles for successful therapy of acute lymphoblastic leukemia (ALL) in children. However after the knowledge emerged that cranial radiotherapy in young children can give rise to a decline in neuropsychologic and cognitive function radiotherapy in children with a tolerable risk of relapse has been replaced by intensified chemotherapy including intrathecal and high dose intravenous methotrexate. In retrospective follow-up studies, this regimen has been shown to carry fewer side effects than radiotherapy.1  

However, methotrexate is also well known to be potentially neurotoxic drug. Chemical meningitis; stroke-like episodes, subacute encephalomyelopathy and chronic lukoencephalopathies have been reported in patients with and without concomitant radiotherapy2.

Aim of the work

The aim of this study was to investigate whether acute or subacute electroencephalo-graphic (EEG) disturbances occur in children undergoing central nervous system prophylaxis with intrathecal and high-dose intravenous methotrexate.

    

SUBJECTS AND METHODS

 

The study was conducted on 25 patients. Their ages ranged 1 6/12 to 14 years with a mean of 6 6/12±4 1/12 years. These patients attending the Hematology/Oncology Clinic, Children's Hospital Shams University in the period from May 2003 to March 2004.

Patients of this study were subdivided into two groups:

*      Group A: Eighteen of them were diagnosed as acute lymphoblastic leukemia standard and intermediate risk, 9 were males and 9 were females with a mean age of 7 1/12 ± 4 2/12 years. Treated according to ALL-BFM90 protocol.

*      Group B: Seven patients were diagnosed as non-Hodgkin's lymphoma stage I, II, (28%). Five (71%) were males and 2 (29%) were females with a mean age of 6 1/12 ± 3 11/12 years. They treated according to NHL-BFM90 protocol.

 

All patients with CNS clinical manifestation and high risk ALL were excluded.

The children's parents and as far as possible, the patients themselves gave their informed consent to participate in the study.

 

All patients were subjected to the following:

I.      Complete history taking with particular stress on: headache, convulsions, neurological deficit, psychological troubles.

II.     Thorough clinical and neurological examination. 

III.           Laboratory investigation:

1.      Complete hemogram and blood film examination along with peripheral blast count.

2.      Blood chemistry: before each high dose MTX: renal function tests (BUN, S. creatinine), liver function tests (ALT, AST), serum uric acid, serum electrolytes, Ca+2, Ph, Na+, K+.

3.      CSF examination for: cytology (blasts) using cytospin.

4.      Conventional EEG was recorded using 12 channel machine; Electrodes were placed according to 10/20 international system of electrode placement. Bipolar as well as monopolar montages were applied. Provocation techniques, hyperventilation and intermittent photic stimulation, were done for children over 3 years old. For children under 3 years of age sleep was induced by using chloral hydrate. EEG examination were done on the day before and on the third day after every dose.

5.      Methotrexate serum level after 48 hours of methotrexate administration.

 

RESULTS

 

A total of 18 patients with ALL were examined, male to female ratio 1:1. The highest TLC was 189 x 10³/L. Only in one patient, there was no peripheral blasts detected (Aleukemic leukemia). All liver and renal function tests were within normal.

In the NHL group, 7 patients were examined, the male to female ratio was 2.5 : 1. All liver and renal function tests were within normal. The highest platelet count was 592 x 109/L. More than half of the patients were of the B-cell immunophenotype.

In the present study, a baseline EEG as shown in table (1) was done to all patients before starting the 1st HD-MTX in which it was normal in 17 of the all patients (94.44 %). Only one child (5.56 %) showed focal abnormality in EEG before 1st HD-MTX.

Trying to compare between the EEG's before and after each HD-MTX as shown in table (2), in which there was a significant correlation regarding focal changes in EEG, but there was no significant correlation regarding generalized EEG changes.

In fact, many of the observed EEG abnormalities were transient and tend to disappear by the beginning of next HD-MTX. The focal changes were more common than the generalized one. Yet definitely there is cumulative increase in the percentage of generalized EEG discharges with the repetition of high dose MTX as shown in tables (1 & 2).

The results of EEG recording in the NHL group are in table (3). All the 7 NHL patients showed normal EEG recording, before a random HD-MTX. Two of them (28.57%) developed generalized changes after the HD-MTX. In NHL patients, the observed EEG changes after HD-MTX were generalized and it was statistically significant when compared with EEG before HD-MTX.

There was no correlation between the number of HD-MTX and occurrence of EEG changes. Comparison between B-cell and T-cell, ALL revealed no significant difference regarding EEG changes.

On comparing group of patients with EEG changes and no detectable MTX level in blood and group of patients with EEG changes and detectable MTX level in blood as shown in table (4), no significant correlation was found between them.

Comparison between 1st, 2nd, 3rd and 4th HD-MTX in ALL patients regarding EEG's with focal and generalized discharges as shown in table (5 & 6) showing no significant difference.

Comparison between ALL and NHL patients regarding EEG after each HD-MTX as shown in table (7) shows significant difference between ALL and NHL patient regarding EEG results after 1st and 2nd dose, but no significant difference after 3rd and 4th.

In the present study, comparison between the initial BUN and BUN after each HD-MTX showed no significant difference in ALL and NHL patients.

Also, the comparison between the initial S-creatinine and S-creatinine after 1st and 2nd HD-MTX in ALL patients and after  random HD-MTX in NHL showed no significant difference in both groups. Although there was statistical significance regarding 3rd and 4th HD-MTX, still it was within normal range.

Liver functions was evaluated in the 18 patients before and after each HD-MTX. Both ALT and AST showed highly significant increase after each HD-MTX. But, the increase of liver functions after each HD-MTX was transient and usually it returns to normal level by the start of next HD-MTX.


 

 

Table 1. EEG results in all patients before and after each DH-MTX.

 

Dose

Result

1st

2nd

3rd

4th

B

A

B

A

B

A

B

A

Normal EEG

94.44%

66.67%

88.89%

61.11%

88.88%

50%

77.77%

50%

Focal Discharge

5.56%

27.78%

11.11%

38.89%

5.56%

38.89%

5.56%

27.78%

Generalized

Discharge

0%

5.56%

0%

0%

5.56%

11.11%

16.67%

22.22%

B = Before, A = After

 

Table 2. Abnormal EEG findings among ALL patients before and after HD-MTX.

 

 

Type of EEG abnormality

 

No. of Patients with EEG abnormality

before HD-MTX

No. of Patients with EEG abnormality

after HD-MTX

Z

P

Focal changes in EEG

 

 

 

 

(1st) dose

1

5

1.79**

< 0.05

(2nd) dose

2

7

1.92**

< 0.05

(3rd) dose

1

7

2.41***

< 0.01

(4th) dose

1

5

1.79**

< 0.05

Generalized changes in EEG

 

 

 

 

(1st) dose

0

1

1.01

> 0.05

(2nd) dose

0

0

Missing

-

(3rd) dose

1

2

0.6*

> 0.05

(4th) dose

3

4

0.42

> 0.05

*p>0.05 = not-significant, **p<0.05 = significant, ***p<0.01 = highly significant

Table 3. EEG results in NHL patients before and after a random HD-MTX.

 

                        Dose

Results

Random HD-MTX

B

A

Normal EEG

100%

71.43%

Focal discharge

0%

0%

Generalized discharge

0%

28.57%

 

B = Before, A = After

 

 

Fig. (1) : Normal EEG.

 

 

Fig. (2) : EG showing generalized changes.

 

Fig. (3) : EEG showing focal changes.

 

 

 

Table 4. Comparing EEG findings in ALL patients with detectable blood MTX to findings seen in patients with detectable blood MTX.

 

 

 

Dose

 

 

Total number of patients with detectable MTX in blood

number of patients with detectable MTX in blood and focal discharge in EEG

Total number of patients with no detectable MTX in blood

number of patients with no detectable MTX in blood and focal discharge in EEG

Z

P

A1

2

1

16

4

0.74*

>0.05

A2

4

2

14

5

0.52*

>0.05

A3

3

1

15

6

0.22*

>0.05

A4

3

1

15

5

1.18*

>0.05

Dose

Total number of patients with detectable MTX in blood

number of patients with detectable MTX in blood and generalized discharge in EEG

Total number of patients with no detectable MTX in blood

number of patients with no detectable MTX in blood and generalized discharge in EEG

Z

P

A1

2

0

16

1

0.36*

>0.05

A2

4

0

14

0

Missing

-

A3

3

1

15

1

1.34*

>0.05

A4

3

1

15

3

0.51*

>0.05

A1, A2. A3 and A4 = after 1st , 2nd , 3rd and 4th HD-MTX respectively.

*p>0.05 = not-significant, **p<0.05 = significant, ***p<0.01 = highly significant

 

Table 5. Comparison between 1st, 2nd, 3rd and 4th HD-MTX in all patients regarding EEG's with focal discharges.

 

Dose

Timing

1st

2nd

3rd

4th

Total

Number of EEG's showing focal discharges before HD-MTX

1

2

1

1

5

Number of EEG's showing focal discharges after HD-MTX

5

7

7

5

24

Total

6

9

8

6

29

Chi-square = 0.285, p> 0.05 = not significant

 

Table 6. Comparison between 1st, 2nd, 3rd and 4th HD-MTX in all patients regarding EEG's with generalized discharges.

 

Dose

Timing

1st

2nd

3rd

4th

Total

Number of EEG's showing generalized discharges before HD-MTX

0

0

1

3

4

Number of EEG's showing generalized discharges after HD-MTX

1

0

2

4

7

Total

1

0

3

7

11

Chi-square = 0.711, p> 0.05 = not significant

 

Table 7. Comparison between ALL and NHL patients regarding EEG after each  HD-MTX.

 

 

ALL

NHL

Z

P

Number of EEG showing generalized discharges after 1st  dose

1

2

1.59 **

< 0.05

Number of EEG's showing generalized discharges after 2nd   dose

0

2

2.36 **

< 0.05

Number of EEG showing generalized discharges after 3rd   dose

2

2

1.07 *

> 0.05

Number of EEG showing generalized discharges after 4th   dose

4

2

0.33

> 0.05

*P > 0.05 = not-significant, **p<0.05 = significant, ***p<0.01 = highly significant

 

 


DISCUSSION

                                                 

Five pathogenetic pathways that could give rise to an impaired brain function after MTX are under discussion: inhibition of dihyrofolate reductase giving rise to (1) decreased thymidylate synthesis, (2) decreased synthesis of S-adenosylmethionine and demyelination. (3) increased homocysteine concentration with resulting vasculopathy, (4) increased adenosine concentration, and (5) decreased neurotransmitter synthesis along several pathways3.

In this study, it was tried to investigate whether acute or subacute electroencephalographic disturbances occur in children undergoing central nervous system prophlaxis with intrathecal and high-dose intravenous methotrexate.

                In fact, many of the observed EEG abnormalities were transient and tend to disappear by the beginning of next HD-MTX This is in consistency with Rudolf et al.4, who studied 21 patients with ALL regarding their EEG changes before and after each HD-MTXD.

Other authors also reported a low risk of neurologic complications in children with ALL. Rubnitz et al.5, investigating 259 children with ALL who were treated with 10 courses of methotrexate 2 g/m2 intravenously, observed transient focal central nervous symptoms in eight patients only. One of them showed changes of white matter in the MRI.

It was observed that there is no correlation between the number of HD-MTX and occurrence of EEG changes. But there is cumulative increase in the percentage of generalized EEG discharges with the repetition of high dose MTX Also, comparison between B-cell and T-cell, ALL revealed no significant difference EEG changes.

On comparing patients with EEG changes and no detectable MTX level in blood to those patients with EEG changes and detectable MTX level in blood, no significant correlation was founded between them.

Both, intrathecal and high-dose systemic MTX therapy, although occasionally, are associated with neurotoxicity, in the form of acute chemical arachnoididtis, motor paralysis, cranial nerve palsies, seizures, coma, chronic demyelinating encephalopathy or transient cerebral dysfunction with symptoms of paresis, aphasia and behavioral abnormalities6,7.

Conclusion, focal and generalized EEG changes was observed in both group of patients after each MTX administration either as systemic high-dose or as intrathecal dose. But, in many of the patients, these findings were transient and disappeared by the time of next HD-MTX.

These findings indicate that although HD-MTX and/or intrathecal MTX may occasionally be associated with EEG changes. Most of the time these changes are transient especially focal changes and cumulative EEG changes have to be expected for generalized EEG changes which needs further follow up.

It was suggested that the risk of an acute or subacute encephalopathy with cortical dysfunction is low. However, subtle subcortical damage in the deep whit matter cannot be ruled out by the EEG alone, and no conclusions on the long-term toxicity can be drawn.

 

REFERENCES

 

1.      Uberall MA, Skirl G and strassburg HM (1997): Neuro-physiological findings in long term survivors of acute lymphoblastic leukemia in childhood treatment with the BFM protocol 81 SR-A/B . Eur J pediatr ; 156 : 727 - 733 .

2.      Och JJ (1989): Neurotoxicity due to central nervous system therapy for childhood leukemia . Am J pediatr Hematology Oncology; 4: 93-105.

3.      Shuper A, Stark B, Kornreich L, et al. (2000): Methotrexate treatment protocols and the central nervous system : significant cure with significant neurotoxicity . J Child Neurol ; 15: 573-580.

4.      Rudolf K, Annette S and Charlotte N (2002): Central nervous system prophylaxis with high-dose methotrexate dose not give rise to signicant electroencephalographic changes in children with acute lymphoblastic leukemia . J Child Neurol ; 17: 409- 412.

5.      Rubnitz JE and look AT (1998): Molecular genetics of childhood leukemias . J Pediatr Hematol Oncol; 20: 1.

6.      Wu XP and Dolnick BJ (1993): 5-Fluorouracil alters dihydrofolate reductase pre-mRNA splicing as determined by quantitative polymerase chain reaction . Mol Pharmacol ; 44: 22.

7.      Chu E and Allegra CJ (1996): Antifolates in :Chabner BA, Longo Dl, eds. Cancer Chemotherapy and Biotherapy : Principles and Practica . Philadelphia : Lippincott-Raven, 109-148.


 

الملخص العربى

 

تغيرات رسم المخ الكهربى المصاحبة للعلاج بعقار الميثوزكسيت فى الأطفال

 المصابين باللوكيميا الليمفاوية الحادة والليمفوما

 

فى هذا البحث دراسة الأعراض الجانبية لعقار الميثوزكسيت متضمناً أسلوب حقن حول النخاع الشوكى فى مرضى اللوكيميا الليمفاوية الحادة والليمفوما خلاف الهورجكين، وذلك عبر التباينات الحادثة فى رسم المخ الكهربى.

وتضمنت الدراسة 18 مريض باللوكيميا الليمفاوية الحادة و 7 مرضى بالليمفوما خلاف الهورجكين وتم فحصهم برسم المخ الكهربى عقب كل مرة من الحقن بعقار الميثوزكسيت الوريدى بجرعة (2 جم/م2)، وأسفر رسم المخ عن وجود تغيرات موضعية وعامة فى كلا المجموعتين عقب كل مرة تم حقنهم فيها سواء بجرعة وريدية عالية أو بأسلوب الحقن حول النخاع الشوكى ولكن ظلت هذه التغيرات فى العديد من المرضى ذات طبيعة مؤقتة تختفى عند الموعد التالى للحقن بالعقار.

وتشير هذه النتائج إلى الطبيعة المؤقتة لتغيرات رسم المخ الكهربى والتى قد تحدث بصورة عرضية فى المرضى المعالجين بهذا العقار بأسلوبين الوريدى وحول النخاع الشوكى، وذلك دون أثار تراكمية يمكن توقعها.

ولهذا يمكننا افتراض أن مخاطر تدهور الوظائف المخية الحادة ودون الحادة والناتج عن الاختلال الوظيفى للقشرة المخية ذات احتمالية الأعتلالات الطفيفة فى المادة البيضاء فيما دون القشرة المخية، وذلك باقتصارنا على الفحص برسم المخ الكهربى بالإضافة لغياب دراسة الآثار السامة طويلة الأمر لهذا العقار.

أما فى حالات ظهور أعراض نفسية أو عصبية حادة أو تباطؤ خلقية الموجات برسم المخ الكهربى فيجب الألتفات لاحتمالية تأخر التخلص الأيضى فى العقار الميثوزكسيت.



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