Leukemia & Lymphoma

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Coexistence of Life Threatening Chemotherapy
Related Leukoencephalopathy, Saggital Sinus
Thrombosis and Multiple Organ Failure in a Child
with Acute Lymphoblastic Leukemia: An Unusual
Case with Clinical Recovery
Feride Duru, Ulya Ertem, Ayhan Dagdemir, Benal Kunak, Tülay Keskin, Işil
Saatci, Sadi Gündğdu & Ayşenur Cila
To cite this article: Feride Duru, Ulya Ertem, Ayhan Dagdemir, Benal Kunak, Tülay Keskin, Işil
Saatci, Sadi Gündğdu & Ayşenur Cila (1997) Coexistence of Life Threatening Chemotherapy
Related Leukoencephalopathy, Saggital Sinus Thrombosis and Multiple Organ Failure in a
Child with Acute Lymphoblastic Leukemia: An Unusual Case with Clinical Recovery, Leukemia &
Lymphoma, 26:3-4, 377-385, DOI: 10.3109/10428199709051788
To link to this article: http://dx.doi.org/10.3109/10428199709051788

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0 1997 OPA (Overseas Publishers Association) Amsterdam B.V.
Published in the Netherlands by Harwood Academic Publishers

Leukemia and Lymphoma, Vol. 26, pp. 377-385

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Printed in Malaysia

Coexistence of Life Threatening Chemotherapy Related
Leukoencephalopathy, Saggital Sinus Thrombosis
and Multiple Organ Failure in a Child
with Acute Lymphoblastic Leukemia:
An Unusual Case with Clinical Recovery
FERIDE DURU', ULYA ERTEM".*.+,AYHAN DAGDEMIR", BENAL KUNAK", TULAY KESKIN',
ISIL SAATCI', SAD1 GUND06DUd and AYSENUR CILA'
"Dr. Sami Ulus Children's Hospital Department of Pediatric Oncology and Neurology, bBetemar Radiodiagnostic Center,
'Hacattepe University Faculty of Medicine, Deparmtent of Radiology, dBayindir Medical Center, Ankara, Turkey
(Infinal form 09 September 1996)

A nine-year old girl with T cell acute lymphoblastic leukemia (ALL) had acute severe neurologic complications at the end of the remission-induction chemotherapy course. Thirty-six
hours following triple intrathecal (IT) therapy and intravenous (IV) administration of
L-asparaginase (L-asp), tetraplegia developed and she became unconscious. She had bouts of
hypertension and persistent tachycardia unresponsive to digitalis therapy. Magnetic resonance
imaging (MRI) showed multiple brain white matter hyperintensities and filling defects in the
saggital sinus, suggesting thrombosis. Over the 40 days, in addition to her neurologic compromise she also had transient diabetes mellitus, severe hyperlipidemia, hypoproteinemia and
edema, liver and heart failure and staphylococcus aureus sepsis with prolonged bone marrow
depression. Despite, coexistence of all these chemotherapy related complications, her neurologic functions and multiple organ failure improved gradually. After a 70 days' period of interruption, chemotherapy was resumed and continued without any further complications.
Although, the etiology of her extensive sensitivity to some drugs remains unclear, we believe
that it is important to document these unusual events in this child.
Keywords: Acute lymphoblastic leukemia, central nervous system complications, methotrexate,
L-asparaginase

*Corresponding author.
+Presentaddress: A&i Ayranci Ye$lyurt Sok No:25/14,Ankara, Turkey.
311

378

F. DURU e? al.

INTRODUCTION
The prognosis of ALL has improved due to the
intensification of chemotherapy regimens and central nervous system (CNS) prophylaxis. However,
chemotherapy related complications are also well
described today[',']. Radiotherapy and intrathecal
chemotherapy with methotrexate (MTX) and cytosine
arabinoside (AM-C) may result in acute or chronic
CNS disturbances; Vincristine (VCR) may also cause
peripheral neuropathy;While, L-Asparaginase(L-asp)
may lead to coagulation abnormalities, and transient
diabetes mellitus especially when used together with
corticosteroids; anthracyclines are known to produce
cardiotoxicity and most of the chemotherapeutic
agents are hepatotoxic and obviously cause bone marrow depression.['-"]
Here we describe an unusual case of childhood
ALL in whom most of the above complications developed together with severe leukoencephalopathyat the
end of remission-induction chemotherapy course.
Despite her severely compromised state, all symptoms resolved gradually. Fortunately, chemotherapy
was resumed and has been continued without further
complications in this child.

CASE REPORT
A 9-year old girl was presented in June, 1995 with
bilaterally enlarged parotid glands and cervical, jugular, post auricular lymphadenopathy. Mediastinal
enlargement was also seen on the chest-X-ray.
Hepato-splenomegaly was not present. Abdominal
ultrasonography, bone radiographs, echo and electrocardio-graphy revealed no abnormality. Her Hb was
15.5 g/dl, WBC count was 26 x 109/1with 33% blasts
and platelet count was 50 x 109/l.Bone marrow aspirate showed 90% lymphoblasts of L1 morphology
according to the French-American-British(FAB) classification. The immunocytochemistry of the blasts
was consistent with T cell ALL: CD3, CD5, CD7 were
35%, 77%, 80% respectively, PAS and Tdt were positive. No cytogenetic abnormality was found. Except
for elevated level of uric acid (9.5 mg/dl), blood

biochemistry, including liver and renal function tests
were all normal.
Following oral allopurinol and IV hydration therapy, she was placed on the protocol 'total therapy X',
used at by St. Judes Children Research Hospital.['*]A
lumbar puncture was performed for IT administration
of the first dose of MTX (12mg/m2).Examination of
cerebrospinal fluid (CSF) showed no evidence of
meningeal leukemia. Until July 10, 1995, 4 doses of
VCR and daunorubicin (DRB), 5 doses of L-asp along
with daily oral corticosteroids were given without any
complication. She seemed to have achieved complete
remission with disappearance of the blasts in a moderately depressed bone marrow aspirate preparation.
On July 10, 1995, she received a second IT therapy
with a triple injection, containing MTX (12mg/m2).
ARA-C (30mg/m2) and hydrocortisone (30mg/m2).
The protein level of CSF was normal (15mg/dl) and 3
lymphocytes were seen in the cytocentrifuged preparation. MTX was diluted appropriately and drugs were
administered slowly in separate injections. On the
same day she also received the 6th dose of L-asp
(6 OOOU/m2) intravenously. She was in a completely
normal condition, before, during and after these procedures. The next day, she had moderate pancytopenia
with a Hb level of 9g/dl, WBC count of 1.5 x 109/1and
platelet count of 40 x 109/l.Thirty-six hours following
IT therapy, she complained of headache, visual disturbances and a feeling of lack of the extremities with
slurred speech. Shortly afterwards she became completely unconscious. Both pupils were dilated and
unresponsive to light. Neither papilledema nor retinal
hemorrhage were present and deep tendon reflexes
were all lost. She had tachycardia with a heart apex
beats of 150/per minute. She experienced an abrupt
onset of hypertension, her blood pressure increased to
150/90 mm Hg, which was controlled with sublingual
0.25mg/kg of nifedipine. As well, IV furosemide
(lmgkg) was injected and she was digitalized. In an
attempt to minimize presumed MTX induced chemical
arachnoiditis, dexamethasone (4mg/m2 every 6 hour)
was started. Blood biochemistry, chest X-ray, echo
and electrocardiography showed no abnormalities.
Within the following 6 hours, hypertension recurred
and she was placed on regular captopril therapy.

COEXISTENTCHEMOTHERAPY TOXICITY IN ALL

Electroencephalograph revealed diffuse slow and
sharp waves and a few spikes on the occipito-parietal
regions. Brain MRI showed bilaterally multifocal
periventricular, frontal, parietal and occipital white
matter hyperintensities, extending into the subcortical regions, more pronounced in the right cerebral
hemisphere (Fig. 1,2). Spinal MRI showed no abnormality. During the following 12 hours, her blood
pressure remained stable, but tachycardia persisted
despite the digitalis therapy. No remarkable finding
was seen in echo and electrocardiography. Her neurologic state remained stable and did not change during
the following hours.
Although, IT MTX or/and ARA-C induced leukoencephalopathy was the most likely diagnosis, the
presence of an underlying meningeal leukemia, could
not be completely excluded. The child was in an
extremely critical state and CNS leukemia would have
been the only treatable option at the time, as a result of
this hypothesis we administered IV infusion of MTX
( 1g/m2) over 24 hours with appropriate leucovorin
rescue. Following systemic MTX therapy no change
was detected in her neurologic state, but her hepatic
transaminases increased and jaundice appeared. She

379

then also had a bloody stool. Her PT and PTT were
slightly increased (I4sec. and 48sec respectively) and
the platelet count was now 38 x 109/l. She was now
treated with a plasma infusion, vitamin K and thrombocyte replacement therapy. Repeated MRI showed
neither extension nor regression in the white matter
abnormalities, but a significant filling defect was seen
in the saggital sinus, suggesting thrombosis (Fig. 3).
The latter pathology was suspected in the previous
MR images by some specialists, but it was definitively
diagnosed within a week after repeated images were
taken. Although, saggital sinus thrombosis was proven
with the repeated MRI, since she had a bleeding tendency, antithrombotic therapy was discouraged.
During the following days, liver transaminases,
blood triglycerides and cholesterol continued to
increase with progressive enlargement of her liver.
Hypertension was under control, but tachycardia persisted. On August 1, 1995 her laboratory findings were
as follows: Hb 10g/dl, WBC count 0.9 x 109/1without
blasts, platelet count 42 x 109/1,ALT 596 U/1, AST
274 U/1, alkaline phosphatase 538U/1, glucose 180
mg/dl, cholesterol 778 mg/dl, triglycerides 875 mg/dl,
total biluribin 13.4 mg/dl with a direct bilirubin of

FIGURE 1 T2 weighted, proton density MR images, showing periventricular, frontal and occipital white matter hyperintensities areas.

380

F. DURU et al.

FIGURE 2 T1 weighted contrast enhanced MR images, showing pathologic signal areas in the white matter of the occipital lobes and
enhanced pial contrast uptake.

FIGURE 3 T1 weighted contrast enhanced MR images, showing a filling defect in the posterior superior saggital sinus and sinus rectus, suggesting thrombosis.

COEXISTENTCHEMOTHERAPY TOXICITY IN ALL

9.5 mg/dl, albumin 3 g/dl, globulin 2g/dl. Electrolytes,
BUN and creatinine were within normal levels. She
was now somnolent. Occasionally when more awake,
she was able to speak a few words. Deep sensitivity
was, in part, still present in upper extremities and she
was able to move her right fingers slowly, however,
paraplegia was still present in both lower extremities
with coexistent bladder and stool dysfunction.
On August 8, 1995, she was taken to another medical center in Switzerland on of her parents' demands
and stayed there for a week. We were informed that
her state worsened during that week. Transient diabetes mellitus had disappeared after discontinuationof
steroids but she had became progressively dyspneic,
needing more and more oxygen and sedation.
Pancytopenia also continued and staphylococcus
aureus sepsis developed. She had bloody stools several
times and severe edema developed with hypoalbuminemia. While the tachycardia persisted. Finally
echocardiography showed poor contractility of the
myocardium. She had been treated with albumin and
thrombocyte substitutions, vancomycin, ceftazidime
and amikacin were started. When she returned home,
her cardiorespiratory functions were severely compromised and she was strictly dependent on oxygen.
There was bilateral disseminated infiltration in the
lungs on the chest X-ray, however, despite the fact that
pneumocytis carinii was not proven microbiologically,
trimethoprim-sulphamethaksazol(20mg/kg/day) was
added to the antimicrobial therapy previously started.
Surprisingly, over the next few days, a progressive
improvement occurred in her state. Her cardiorespiratory, neurologic and liver functions gradually
improved, pancytopenia resolved and bone marrow
aspirate recovered without blasts. She slowly started
to speak consciously,her extremities became sensitive
and moved. With a trial of rehabilitation therapy, she
gradually started to walk step by step. On October 21,
1995, chemotherapy resumed. She completed consolidation chemotherapy without complications and for
the time being, she is doing well under the ongoing
maintenance chemotherapy in which MTX is being
omitted. However, since we are afraid to cause a similar catastrophe, we have not dared to administer any
more MTX by any rout and have not given any other

381

modalities for CNS prophylaxis. A recent MRI
showed a remarkable regression in the white matter
hyperintensities (Figs. 4,5)while the cerebrovascular
flow seems to be normal.

DISCUSSION
Complications involving the CNS in ALL, may be due
to the disease process itself or may occur as a result of
chemotherapy. Only fewer than 5% of children with
ALL, initially present with CNS leukemia, but CNS
still remains the most common extramedullary
involvement site in ALL during the treatment of the
disease.[''21Although, with the institution of CNS preventive therapy, the incidence of CNS relapse has
considerably decreased, meningeal leukemia however, still remains an important cause of neurologic
dysfunction. In particular, the risk for CNS involvement increases when the disease occurs with a high
initial leukocyte count and when there is a T cell
immtuio-phenotype.[21
Intrathecal MTX therapy is one
of the cornerstones of CNS prophylaxis, however, it
may cause acute or chronic neurologic complications.
The most common MTX induced toxic reaction is
chemical arachnoiditis, in which the symptoms range
from a mild pleocytosis to meningismus, fever and
h e a d a ~ h e . ~ ' , ~ , Furthermore,
~,'~,'~]
leukoencephalopathy with transient or permanent paraplegia, paresis
and even death has also been clearly described following IT administration of MTX.[',4*5,'3-'71
In most of the
events of this type, MRI showed pathologic hypo- or
hyperintense signals in the white matter of the
brain.['"''] Cytosine arabinoside also may cause acute
cerebral or cerebellar dysfunction, but ARA-C associated neurotoxicity has frequently been described with
high doses of the drug given systemically.
Neurotoxicity is rare with ARA-C when it is used
intrathecally as a single agent.[',4.51In practice, most
protocols, use IT ARA-C in combination with MTX.
Thus, there is little data available related to ARA-C
induced neurotoxicity alone after IT administration.
L-asparaginase (L-asp) is another chemotherapeutic
agent that may also cause CNS complications with
cerebrovascular events. It has been shown that, L-asp

382

F. DURU et al.

FIGURE 4 MR images, showing regression of the white matter abnormalities compared with the initial MRI.

FIGURE 5 MR images, showing regression of the white matter abnormalities compared with the initial MRI.

COEXISTENTCHEMOTHERAPY TOXICITY IN ALL

383

inhibits synthesis of plasma hemostatic proteins, such
who receive intermediate or high doses of IV MTX
as fibrinogen, antithrombin I11 and plasminogen. As a
with leucovorin rescue, neurotoxicity is rare and tranresult, CNS hemorrhagic or thrombotic complications
sient. Clinically significant neurotoxicity due to sysmay develop in the course of L-asp therapy.['~3~5~7~20~211
temic MTX therapy does occur, generally with the
Finally, the neurotoxicity encountered in childhood
administration of very high doses of the drug, as used
ALL is a complex phenomenon arising from the comin osteosarcoma or alternatively in the absence of
bined effects of CNS prophylaxis, systematic
sufficient leucovorin r e s ~ u e . [ ' ~ ~ J ~ ]
chemotherapy and meningeal leukemia. Thus, in some
It is conceivable that, saggital sinus thrombosis may
cases, it should be stressed that it may be difficult to
in part have been, responsible for the neurologic
identify the clear etiology of the exact neurologic
symptoms seen in the patient. It has been reported that,
complication in this disease.
2-3% of children will ALL, treated with L-asp may
In the case presented here, we experienced this difhave a thrombotic stroke with the symptoms of
ficulty. Although, IT MTX or/and ARA-C induced
headache, visual disturbances and hemiparesi~.['*~*~*~I
leukoencephalopathy seemed to be the most likely
In some of those children, although initial computed
cause, we could not exclude an underlying CNS
tomography (CT) scans were normal, when repeated
leukemia with certainty. It has been reported earlier
several days later, they disclosed high density lesions
that, in children treated for CNS leukemia, the CNS
in the sinus, as occurred in our patient.[51Coagulation
toxicity of the IT therapy was frequent and more
screening in this patient was not done at the time of the
neurologic event. However, after recovery, we detersevere than those of children without CNS leukemia
treated with a similar regimen.[4*5s221
Leukemic blasts
mined her protein-C, protein-S and antithrombin I11
damage endothelial cells which may cause increased
levels, in order to understand if she had a congenital
permeability of MTX to the CNS, hence, increased
deficiency of any of these proteins, that may have predisposed her to thrombosis, but these were normal.
concentration of the drug can lead to severe leukoenNonetheless, even if there was no congenital propencephal~pathy.[~,~,'~,~~~
Although, examination of the
sity. L-asp induced transient deficiency of antithromCSF in our patient, did not show any evidence of
bin 111,protein C or/and plasminogen and its activators
meningeal leukemia, this may still sometimes be
may have caused saggital sinus t h r o r n b o ~ i s . [ ' ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
insufficient to exclude specific CNS involvement.
When the saggital sinus thrombosis was proven
Leukemic infiltration of the CNS may be difficult to
clearly in this patient, antithrombotic therapy was not
identify, because cytologic examination of the CSF is
given because she had a bleeding tendency. However,
not always d i ag n o ~ t i c . [ ~Meningeal
.~~]
leukemia was
plasma
infusions, may have substituted anticoagulant
the only treatable condition in this patient and in our
proteins (protein-C, antithrombin 111, etc) which were
previous experience, IV infusion of intermediate or
deficient due to the L-asp therapy, accordingly spontahigh dose MTX frequently produced a dramatic
neous recanalization of the thrombosis might have
improvement in the neurologic symptoms if in fact
taken place.
CNS involvement, was present, in children with ALL.
Unfortunately for this girl, she was not restricted
Because of this, we infused 1 g/m2 of MTX over 24
only to neurologic complications. As defined above,
hours. However, no improvement occurred in the neushe also had some metabolic complications and multirologic status of this patient following IV infusion of
ple
organ failure. Transient diabetes mellitus seemed
MTX. Lack of response to systemic MTX therapy,
to be associated with corticosteroids, but L-asp also
made the possibility of specific CNS involvement less
known to lead to such a transient metabolic disturlikely in this patient. Although, her clinical and MRI
b a n ~ e . [ ' ~ ~Hypertension
~~~']
was also probably related
findings did not worsen following systemic MTX
to the corticosteroids, but it may have been a compotherapy, we are not sure however, whether it did in
nent of the cerebral event.['] Liver failure presumably
fact not play a role in the prolongation of her neurowas the result of systemic MTX i n f ~ s i o n . [ ~ * ' ~ ]
logic dysfunction. Nonetheless, in children with ALL

384

F. DURU et al.

Although, there was no clear explanation for severe
hyperlipidemia and hypercholesterolemia, it has been
reported that, significant hyperlipidemia does develope in some patients with ALL at the end of the remission-induction chemotherapy course and is attributed
to corticosteroids and L - a ~ p . [ ~In~ ]this patient,
hepatosplenomegaly was most likely due to steatosis.
Among other complicationsin this case, the persistent
tachycardia and subsequent weakness of myocardial
contractility was difficult to explain. Although,
anthracyclines do induce cardiotoxicity, this side
effect is known to appear in a dose dependent manner
and cardiotoxicity is rare below a total dose of 350
even 400 mg/m2.[2~3,'o~''1
Our patient had received only
4 doses (25 mg/m2) of DNR with a total dose of 120
mg. So, in this respect, the etiology of the heart failure
still remains unclear during this event.
Since the patient seemed to be widely sensitive to
various drugs, we suspected that, she may have had a
subtle, undefined metabolic defect involving the
metabolism of some drugs. For this reason, it was difficult to decide whether to continue chemotherapy
even when her clinical state improved. However,
consolidation and maintenance chemotherapy regimens of the initiated protocol, do not include the
agents which seemed to be the most likely to be
responsible for the complications which developed.
Since the resumption of chemotherapy, she has not
received any more MTX via any route nor anthracyclines or L-asp therapy. In addition, we have been
discouraged to administer any therapy for CNS prophylaxis. For this reason, we are still concerned about
whether she remains at great risk for the development
of CNS leukemia. Nevertheless, we are still afraid
that administration of IT chemotherapy or/and radiotherapy may cause similar complications and have as
yet not done so.
Although, we are unable to explain her extreme
sensitivity to some drugs, which resulted in her very
severe compromised state, we believe it is worthwhile
to report this case. We would also like to stress that, to
the best of our knowledge, there has been no clear MR
images data reported in the literature related to the
appearance of CNS leukemia and if there is any difference in the MRI findings of MTX induced neurotoxi-

city between the children with and without CNS
leukemia. It is clear to us that this subject still needs
careful investigation in the future.

Acknowledgements
We are thankful to Dr. HJ Ploss and his colleagues
from Eleonorenstiftung Universitats-Kinderling,
Kinderspital-Zurich, for their kind connection and
participation in follow-up of the patient.

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