EuropeanJoumalof

Eur. J. Pediatr. 127, 255--262 (1978)

PediatMcs
9 by Springer-Verlag1978

Cranial Computerized Tomography in Children
with Lymphoid Malignancy and Seizures
H. U. Schwenk ~, G. Neuh~tuser 1, and W. Huk 2
University Children's Hospital, Erlangen-Ntirnberg (Director: Prof. Dr. K. Stehr),
Loschgestr. 15, D-8520 Erlangen
2Department of Neurological Surgery, University Erlangen-Ntirnberg
(Director: Prof. Dr. W. Schiefer), D-8520 Erlangen, Federal Republic of Germany

Abstract. Focal and generalized seizures occurred in 4 patients with acute
lymphoblastic leukemia and non-Hodgkin-Iymphoma. The etiology of the
neurological complications could be established by cranial computerized
tomography (CT): i.e., 1_ localized metastasis with calcification and 2. acute
intracerebral hemorrhage during induction therapy in two patients with
malignant lymphomas; 3. diffuse cerebral infiltration with blast cells and 4.
cerebral atrophy in two children with acute lymphoblastic leukemia who were
in relapse.
Accurate diagnosis of cerebra/compIications in hemobIastoses is essential
for appropriate therapy and CT may lead to more effective treatment in
patients with lymphoid malignancy and seizures.
Key words: Lymphoid malignancy - Seizures - Cranial computerized tomography.

Introduction
The increasing survival of children with leukemia and related diseases is accompanied by a higher frequency of neurological complications [8]. Seizures may
be induced in these patients by different causes: i.e., side effects of anti-neoplastic
drugs; infiltration of the CNS by blast cells; encephalitis due to various agents;
intracranial bleeding or chronic subdural hematoma [1, 7, 10, 11].
Whatever the cause, specific therapeutic measures according to the etiology
are necessary in each patient, in addition to symptomatic anticonvulsant treatment. An accurate diagnosis is therefore required and this is usually based on
historical data, a detailed neurological examination, fundoscopy, lumbar puncture with cytocentrifuge preparation of CSF-cells, electroencephalogram, echoencephalogram or brain scan. After more than two years experience, we believe
that cranial computerized tomography (CT) represents another reliable, noninvasive method for evaluating patients with neurological disorders caused by

0340-6199/78/0127/0255/$ 01.60

256

H.U. Schwenk et al.

h a e m o b l a s t o s e s . C o m p a r e d to o t h e r n o n - i n v a s i v e m e t h o d s , C T h a s t h e a d v a n t a g e
t h a t it c a n l o c a l i z e a n d d e t e r m i n e t h e e x t e n t o f a c e r e b r a l l e s i o n precisely. In
s o m e c a s e s t h i s is e s s e n t i a l f o r e f f e c t i v e t h e r a p y .

Method
The CT examinations were done with a prototype of the Siemens head scanner (Siretom), which
flas a matrix of 80 x 80 pictures points and a slice thickness of 10 millimeters, the volume element
measuring 3 x 3 x 10 millimeters. To reveal small areas of pathological density, overlapping
horizontal sections parallel to the 25 ~ standard plane were performed. When areas of abnormal
density were found, identical cuts were repeated after Contrast enhancement with ! ml/kg Ur0grafin 60%.

Case Reports
Patient 1. M.F. was a 97/lz year old girl, who presented with a mass in the left side of the neck
above the clavicle. There was no evidence of other enlarged lymph nodes. Her liver and spleen
were normal. No blasts could be detected in peripheral blood (Hb 13.6mg/dt, RBC 4.10 • 106/
mm ~. WBC 6000/ram 3 and thrombocytes 160000/ram ~) and bone marrow. The cerebrospinal
fluid contained 3 cells/ram3; their morphology was not documented.
Radiology of the chest showed symmetrical enlargement of the upper mediastinum. Histologicai examination of the cervical mass revealed a T-lymphoblastic malignant non-Hodgkinlymphoma (convoluted type). Because of the frequent leukemic transformation of this type of
lymphoid malignancy--as demonstrated during the course of the disease--cytostatic therapy
was initiated during irradiation of the turnout, using 6 • 2.0 m g / m 2 vincristine, 2 x 20 m g / m 2
adriamycin, and 60 m g / m 2 prednisolone. After induction therapy over six weeks, additional
prophylactic irradiation of the CNS and 50mg/m 2 mercaptopurine was started. During this
irradiation (2200 fads) 5 • 12mg/m 2 methotrexate was administered intrathecally.
During maintenance therapy with mercaptopurine, cyclophosphamide and methotrexate,
bone marrow punctures were done at intervals of 3--4 months and at the same time cerebrospinal fluid was examined for blasts. Eight months after diagnosis, incipient generalisation of
the disease was suspected from bone marrow studies, since 3% temperature-resistant E37rosettes could be detected [12]. Eleven months after diagnosis, the girl suddenly complained of
dizziness, double vision, and stomach ache. She was immediately admitted to the hospital when
a possible seizure was observed. During the following physical examination, she developed a
tonic-clonic attack, spreading from the right forearm and involving the entire body. The seizure
was controlled by diazepam (8 nag i.v.). Over the next few days, several brief, focal seizures
affecting the right arm and face were observed, despite treatment With hydantoin. No blasts
were detectable in the cerebrospinal fluid by cytocentrifuge preparation, and there was no
increase in the lumbar pressure. The electroencephalogram showed some focal slowing over the
left hemispher e and the echoencephalogram was normal. However, slight displacement to the
right of the midline structures was detected by CT which als showed compression of the left
lateral ventricle and an area of low density in the left parietal white matter (Fig. 1a).
In addition to anticonvulsant treatment, chemotherapy with L-asparaginase, vincristine
and prednisolone was commenced. At the same time, the solid metastasis shown by CT was
given further irradiation (4400 R over an area of 6 • 6cm). Seven weeks after the initial
examination, a second scan confirmed the effectiveness of these measures. There was no displacement of midline structures, and the area of low density was hardly seen (Fig. lb). Since
then, no seizures have occurred with continuing anticonvulsant therapy and the neurological
findings are normal. Another CT scan 7 months after the initial observation showed a Small area
of calcification around the presumed metastasis which had not increased in size (Fig. 1c).

Cranial Computerized Tomography in Children

257

Fig. 1. a Patient F.M., C T - N o . 1965. Irregular, ring-shaped mass in the supraventricular
sections of the left parietal white matter after contrast enhancement. Clearly diminished density
extending over the entire left hemisphere at this level indicating wide-spread secondary edema.
Shift of the media/ brain structures to the right, b Patient F.M., CT-No. 2342. Control scan
after 6 weeks of therapy: Only a poorly defined, comparatively small area of slightly diminished
density in place of the pervious tumor. The midline shift has returned to normal, e Patient F. M.,
CT-No. 1060. Control CT about 8 months later: Irregular, comparatively dense (+95 Hounsfield units) structure measuring about 2.5 x 2.5 x 2.5cm in the left parietal, supraventricular
white matter in the place of the previous ring-shaped tumor. Small, poorly defined surrounding
area of edema. The shape of the structure strongly suggests a calcifying process

Patient 2_ E, U., a 15Y~2year old gift admitted to hospital with the diagnosis of delayed puberty.

However, she was jaundiced, extremely emaciated, and had bean-sized lymph nodes in the
inguinal and cervical region. A large tumour could be felt in the middle of the abdomen, close to
the liver. The differential blood count and bone marrow cytology were normal. The bilirubin
was 8.5 mg%, lactate dehydrogenase 970U/L, and alkaline phosphatase 1089 U / L with other
biochemical signs of liver damage and reduced liver-dependent clotting factors.
Histological examination of a cervical lymph node revealed an immunoblastic nonHodgkin-lymphoma (Stage III). Since the abdominal tumour was already interfering with

258

H.U. Schwenk et al.

Fig. 2. a Patient E.U., CT-No. 622. Normal ventricular system. In the right supraventricular
parietal white matter small (1.5 x 2 em) dense area (+ 80 Hounsfield units) without surrounding
edema. The lesion is very suggestive of a small hemorrhage, b Patient E.U., CT-No.659.
Control scan three days later: The structure in the right parietal white matter has enlarged and
changed into a horseshoe-shaped lesion with a marrow margin. Density again + 80 Hounsfield
units, e Patient E.U., CT-No. 729. Control scan 10 days after the initial examination: Poorly
defined area of low density occupying the right parietal white matter and compressing the
trigone and posterior horn of the right lateral ventricle. The small hematoma has Changed its
density and induced a moderate swelling of the surrounding brain tissue

intestinal transit and the girl was vomiting frequently, cytostatic treatment in accordance with
LSA2L2protocol of the Sloan Kettering Cancer Center was commenced as quickly as possible
[ 16]. On the 9th day of treatment--4 days after intrathecal injection of 6.25 m g / m 2 methotrexate
and 6 days after administration of 1.5 m g / m 2 vincristine--left sided seizures occurred and were
followed by a flaccid left hemiplegia with central paresis of the facial nerve.
Using CT, there was evidence of a 1.5 x 2cm area of increased density in the right parietal
supraventrieular area (Fig. 2 a). Follow-up CT studies within the next 10 days demonstrated that
the findings were probably caused by slight hemorrhage (Figs. 2b and c). Seizures recurred
3 days later, despite anticonvulsant therapy. Cytostatic treatment was discontinued and the

Cranial Computerized Tomography in Children

259

4

Fig. 3. Patient E. U., CT-No. 296. Large, poorly defined area of low density covering the white
matter of almost the entire right hemisphere, including the putamen and extending from the
Sylvian fissure to the apex. Compression of the right lateral ventricle; small midline shift to the
left
Fig. 4. Patient O.T., CT-No. 1052. Slightly enlarged ventricular system; dilatation of Sylvian
fissures and of the callosal cistern, suggestive of cerebral atrophy

hemiplegia quickly resolved after physiotherapy. Since hemorrhage was supposedly the cause of
the fits, injections of vincristine and methotrexate were continued after correction of deficient
clotting factors. No further seizures were observed although the anticonvulsant treatment was
terminated after 4 weeks. Eight weeks later the abdominal tumor recurred, despite previous
abdominal radiation. During maintenance chemotherapy with cyclical oral thioguanine 300mg/
m 2 for 4 consecutive days, the patient lost vision within two days. No blasts were demonstrable
in the spinal fluid. The girl died from heart failure caused by a left sided pleural effusion
secondary to trans-diaphragmatic spread of the tumour. Postmortem findings (brain): Both
optic nerves were enlarged from lymphoblastic infiltrations. There was a slit like cavity 3 cm
long within the right cerebral white matter as a result of an old hemorrhage. Histological
examination showed cyst formation and glial-mesenchymal organization in this area, but also
showed sequelae of circulatory disturbance in the corresponding cortical regions where
lymphoblastic infiltration of the arachnoid was found.

Patient 3. E.U., a 96/~zyear old boy, presented with acute lymphoblastic leukemia. He had been
in complete remission for 21/2years and combination ct~emott~erapy was therefore discontinued.
However, 3 months later a relapse in bone marrow, testis and cerebrospinat fluid was diagnosed. Following elimination of the meningeal involvement by high-dose induction therapy, a
second course of CNS radiation was performed in an attempt to induce a second long remission.
However, 9 months later meningeal involvement recurred. This again responded to steroids, Lasparaginase, intrathecal cytosine-arabinoside and methotrexate therapy and blasts could no
longer be detected any more in the cerebrospinal fluid. About 6 months later, the boy
complained of deteriorating vision and weakness of the left arm. Soon he could not elevate his
arm, he became very clumsy with his left hand and was unable to stretch the fingers. At his next
admission, there was a facial paralysis and spasticity of the left arm with paresis of arm and
shoulder elevation. The deep tendon reflexes were exaggerated, compared to the right. His gait
was unsteady, the left arm showing uncoordinated associated movements. Speech was impaired

260

H.U. Schwenk et al.

and mental reactions markedly slow. The blood count showed thrombocytopenia and the
cerebrospinal fluid was again free of blast cells. The EEG revealed generalised slowing.
Papilledema was not present. CT showed that the midline structures were displaced to the left
(Fig. 3). An area of lower density was seen between trigonum and anterior horn. This extended
to the ventricular roof and was interpreted as being due to diffuse infiltration of brain tissue
with blast cells. Following rapid mental deterioration and generalized seizure, therapy was
stopped and the patient died after a 3-week period of unconsciousness. Even after death, there
was no indication of blasts in the cerebrospinal fluid. An autopsy was not permitted.
Patient 4. O. T., a boy who was 5 years old when ALL was diagnosed. Although still on therapy

two years later, meningeal relapse occurred with 300 blasts/mm 3 in the cerebrospinal fluid.
Despite vigorous systemic and intrathecal chemotherapy, the meningeal disease recurred. Four
weeks after an intrathecal cytosine-arabinoside injection, he suddenly had a seizure at home,
which lasted for more than 6 minutes. Generalized brain atrophy was diagnosed by CT on the
same day (Fig. 4). The patient had received a cumulative intrathecal dose of 174rag methotrexate and 65 mg cytosine-arabinoside.

Discussion
The neurotoxic effects of anti-neoplastic agents, such as vinca alkaloids, Lasparaginase, procarbazine, nitrogen m u s t a r d and methotrexate etc., are frequently t h o u g h t to be responsible for seizures in children with leukemia [15].
Moreover, if these substances are administered intrathecally, their ionic content,
osmolarity, unphysiological p H or the preservatives m a y be responsible for
neurotoxicity. A l t h o u g h reliable determination o f methotrexate in cerebrospinal
fluid is possible [2] and neurotoxicity is supposedly correlated to concentration
[13], the pathogenetic effects o f intrathecal methotrexate remain unclear. There
are no clinical, biochemical or histological methods available which permit an
u n a m b i g u o u s diagnosis o f cerebral d a m a g e induced by methotrexate. The frequency of methotrexate neurotoxicity is unusually variable, and has been reported
in 4% to o v e r 60% of cases by different authors [3, 9]. This discrepancy m a y
be caused b y different neurological documentation. On the other hand, neurological disturbances m a y be falsely ascribed to methotrexate therapy. CT examination is o f little help in proving the neurotoxic effects of anti-neoplastic agents.
However, it m a y show other causes o f seizures which occur during intrathecal
methotrexate or vincristine therapy. Thus, it should be performed even if the side
effects of therapy are suspected to be the cause of seizures. D u r i n g the initial
phase o f treatment in patient 2 who had a coagulation disorder, slight intracerebral bleeding was demonstrable by CT. This occurred 6 days after methotrexate and vincristine was administered. Since a definite diagnosis o f h e m o r rhage was possible, intrathecal methotrexate therapy and weekly vincristine could
be continued without further complications, as soon as i m p r o v e m e n t of neurological signs was observed. Therefore, effective medication was possible and
interruption o f therapy and treatment with folinic acid were avoided.
While the frequency o f intracerebral bleeding is p r o b a b l y decreasing as a
result o f to i m p r o v e d c h e m o t h e r a p y in acute leukemia, there is evidence that
chronic subdural h e m a t o m a s are being diagnosed more frequently. Pitner and
J o h n s o n [11] f o u n d subdural h e m a t o m a s in 13 out o f 126 autopsies on children

Cranial Computerized Tomography in Children

261

with acute lymphocytic leukemia. Five of these thirteen patients had focal or
generalized seizures. Diagnosis by echoencephalogram or electroencephalogram
is only possible in cases with large hematomas. Cerebral angiography is often
dangerous, especially in patients with hemorrhagic disorders. Therefore, in
children with leukemia, chronic subdural hematomas will be diagnosed more
frequently by routine CT examinations as we have already observed in nonmalignant subdural effusion in infants [5].
Routine CT could also establish an early and objective diagnosis of cerebral
atrophy induced by anti-leukemic treatment and radiotherapy (Fig. 4). Follow-up
studies, using cranial CT annually in all patients with a high risk of cerebral
involvement, would be necessary to get more information about these sequels of
therapy.
In patient 1, CT showed an isolated area of low density in the left parietal
white matter fourteen months after diagnosis of a mediastinal T-cell lymphoma
and following several predominantly right sided seizures. Since this type of
lymphoma often causes metastatic tumours (abdomen, CNS), a solid metastasis
was suspected. Because it could be localized precisely, repeat CNS irradiation was
given over a small area even though prophylactic CNS irradiation had been
discontinued only 12 months before. The success of this therapy was obvious
from the following CT examinations and no further seizures occurred.
In the same patient, blast cells were never demonstrated by cytocentrifuge
preparation. This is not surprising since the metastasis was located deep in the
cerebral white matter, without contact with the cerebral or ventricular surfaces.
Again, in patient 3 no definite blasts could be detected in the CSF, although
diffuse infiltration of the right hemisphere had penetrated to the ventricular wall.
The value of the highly-recommended and widely-used spinal fluid cell concentration method [6] should not be over-estimated with regard to its use in
excluding CNS infiltration. In our experience, morphological examination of the
cytocentrifuge preparation is not effective if the cell count is less than one cell per
mm 3, which may yet indicate up to 1000 blasts per ml cerebrospinal fluid.
CT examination can also demonstrate cerebral changes in encephalitis [14].
This may occur in children with leukemia during the course of immunosuppressive therapy [1]. Therefore, CT may be important in planning the treatment of
children with seizures: If neurotoxic effects are the cause, withdrawal of the drug
is necessary, together with administration of folinic acid. Infiltration with blasts
requires intrathecal and systematic cytostatic drugs followed by further irradiation. In encephalitis, adenosine-arabinoside and improvement of the body's
natural immunity is indicated, in addition to relief of increased intracranial
pressure. Surgery may be necessary in subdural hematomas. Because there are
many different therapeutic possibilities, reliable diagnosis is of great importance.
For example, radiation for a presumed metastasis in a patient with encephalitis
may be fatal.
Improvement in the resolution of CT in the future will probably permit
analysis of the fine tissue structures in the brain. Even extensive fibrillary gliosis
[4], a probable consequence of antileukemic treatment which is frequently seen,
will be diagnosed by CT. The CT examination will therefore help to ensure that
children with lymphoid malignancy, who have overcome their serious disease as a

262

H.U. Schwenk et al.

result o f highly effective c h e m o t h e r a p y , are n o t left with p e r m a n e n t n e u r o l o g i c a l
abnormalities.

Acknowledgement. The examination of the brain in patient 2 was done by Prof. Dr. H. Schmidt.
We appreciate his permission to publish the findings.

References
1. Aicardi, J., Goutieres, F., Arsenio-Nunes, M. L., Lebon, R.: Acute measles encephalitis in
children with immunosuppression. Pediatrics 59, 232--239 (1977)
2. Bleyer, W. A., Drake, J. C., Chabner, B. C.: Neurotoxicity and elevated cerebrospinal fluid
methotrexate concentration in meningeal leukemia. N. Engl. J. Med. 289,770--773 (1973)
3. Gagliano, R. G., Costanzi, J. J.: Paraplegia following intrathecal methotrexate. Cancer 37,
1663--1668 (1976)
4. Hendin, B., Devivo, D. C., Torack, R., Lell, M.-E., Ragab, A. H., Vietti, T. J.: Parenchymatous degeneration of the central nervous system in childhood leukemia. Cancer 33,
486--492 (1974)
5. Huk, W.: Unpublished
6. Komp, D. M.: Cytocentrifugation in the management of central nervous system leukemia.
J. Pediat. 81,992--993 (1972)
7. Law, J. P., Dick, F. R., Blom, J., Bergevin, P. R.: Involvement of the central nervous system
in Non-Hodgkin's lymphoma. Cancer 36, 225--231 (1975)
8. Mclntosh, S., Klatskin, E., O'Brien, R., Aspnes, G., Kammerer, B., Snead, C., Kalavsky, S.,
Pearson, M.: Chronic neurologic disturbance in childhood leukemia. Cancer 37, 853--857
(1976)
9. Meadows, A. T., Evans, A. E.: Effects of chemotherapy on the central nervous system.
Cancer 37, 1079--1085 (1976)
10. Phair, J. P., Anderson, R. E., Namiki, H.: The central nervous system in leukemia. Annales
Int. IVied. 61, 863--875 (1964)
11. Pitner, S. E., Johnson, W. W.: Chronic subdural hematoma in childhood acute leukemia.
Cancer 32, 185--190 (1973)
12. Schwenk, H. U., Willital, G.: Frtiherkennung der leuk~imischen Transformation maligner
Nicht-Hodgkin-Lymphome im Kindesalter. Dtsch. med. Wschr. 101,450--454 (1976)
13. Tatersall, M. H. N., Pitman, S. W., Parker, L. M.: Clinical pharmacology of high dose
methotrexate (HDMTX) with citrovorin (CF) rescue. Proc. Am. Assoc. Cancer Res. 16,
161 (1975)
14. Thomson, J. L. G.: The computed axial tomograph in acute herpes simplex encephalitis.
Br. J. Radiol. 49, 86--93 (1976)
15. Weiss, H. D., Walker, M. P., Wiernik, P. H.: Neurotoxicity of commonly used antineoplastic
agents. N. Engl. J. Med. 291, 75--81 (1974)
16. Wollner, N., Burchenal, J. H., Liebermann, P. H., Exelby, P., D'Angio, G., Murphy, M. L.:
Non-Hodgkin's lymphoma in children. Cancer 37, 123--134 (1976)
Received August 23, 1977