Novel treatment (new drug/intervention; established drug/procedure in new situation)

Neurosurgical management of L-asparaginase induced
haemorrhagic stroke
Elisha Ogbodo, Chandrasekaran Kaliaperumal, Michael O’Sullivan
Department of Neurosurgery, Cork University Hospital, Cork, Ireland
Correspondence to Mr Chandrasekaran Kaliaperumal, ckaliaperumal@gmail.com

Summary
The authors describe a case of L-asparaginase induced intracranial thrombosis and subsequent haemorrhage in a newly diagnosed 30-yearold man with acute lymphoblastic leukaemia who was successfully managed by surgical intervention. At presentation, he had a Glasgow
Coma Score of 7/15, was aphasic and had dense right hemiplegia. Neuroimaging revealed an acute anterior left middle cerebral artery infarct
with parenchymal haemorrhagic conversion, mass effect and subfalcine herniation. He subsequently underwent left frontal craniotomy and
evacuation of large frontal haematoma and decompressive craniectomy for cerebral oedema. Six months postoperatively he underwent
titanium cranioplasty. He had made good clinical recovery and is currently mobilising independently with mild occasional episodes of
expressive dysphasia, difficulty with fine motor movement on the right side, and has remained seizure free. This is the first documented case
of L-asparaginase induced haemorrhagic stroke managed by neurosurgical intervention. The authors emphasise the possible role of surgery in
managing chemotherapy induced intracranial complications.

BACKGROUND
The association between malignancy and thromboembolic
disease has long been established in medical literature.1
The release of procoagulant factors by tumour cells, the
interaction with cells of the macrophage lineage and the
subsequent release of tumour necrosis factor, interleukin-1
(IL-1) and IL-6, which are potent activators of the coagulation cascade, form the basis for this association. However,
antineoplastic agents have been associated with cerebral
haemorrhage, infarction and cerebral venous thrombosis. The mechanisms by which antineoplastic agents may
lead to stroke include endothelium toxicity, abnormalities
of coagulation factors and depletion of plasma proteins
involved in coagulation and fibrinolysis. Medical management of these vascular complications have largely been
described in literature.2–5
We describe a case of cerebrovascular complication arising from L-asparaginase based chemotherapy, and surgical management of the same. We emphasise the possible
role of surgery along with medical management of this
condition.

CASE PRESENTATION
A 30-year-old man presented to us after an episode of collapse. At presentation, his Glasgow Coma Score was 7/15;
he was aphasic and had a dense right hemiplegia. He was
intubated and ventilated and transferred to the intensive
care unit. He was on day 19 of induction phase I LKALL
14 protocol (daunorubicin D 1, 8, 15, 22; vincristine D1,
8, 15, 22; dexamethasone D1-5, 8–11, 15–18; polyethylene
glycol-asparaginase D4, 18; and intrathecal methotrexate
D14). He was a non-smoker and had no co-morbidities
associated with acute lymphoblastic leukaemia (ALL). He
had no predisposing factors to provoke thrombosis and
was not on any medication which induces thrombosis.

BMJ Case Reports 2012; doi:10.1136/bcr.11.2011.5240

There was no history of thrombotic episodes before the
diagnosis of leukaemia, and he had no family history of
the same.

INVESTIGATIONS
Coagulation profile revealed an international normalised
ratio within the first 2 weeks of admission ranging between
1.2 and 3.4. Prothrombin time during this period ranged
between 12.9 and 34.5 s while activated partial thromboplastin time was between 22 and 33 s. He had been on
prophylactic low-molecular weight (LMW) heparin before
this presentation. Other laboratory investigations were
within normal limits.
Thrombophilia screen was negative for Factor V Leiden,
anticardiolipin and lupus anticoagulant. Antithrombin was
slightly reduced at 65% (normal is >80), and protein S at
52%. Protein C level was normal. However, prothrombin
gene analysis did not reveal any abnormality. Non-contrast
CT brain (figure 1) revealed an acute anterior left middle
cerebral artery infarct with parenchymal haemorrhagic
conversion, mass effect and subfalcine herniation.

DIFFERENTIAL DIAGNOSIS
▶
▶

Ischaemic stroke with haemorrhagic transformation
L-asparaginase induced thrombosis and secondary
intracerebral haemorrhage.

TREATMENT
With this background, the patient was offered surgical
intervention, and he subsequently underwent left frontal
craniotomy and evacuation of large frontal haematoma.
Postevacuation of the haematoma there was significant
cerebral oedema and because of this the decompressive craniectomy was performed in the same setting.

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Figure 1 CT brain demonstrating left frontal MCA territory
ischaemic stroke with haemorrhagic transformation.

Figure 2 CT brain postdecompressive craniectomy and
evacuation of the frontal haemorrhage.

OUTCOME AND FOLLOW-UP
An intracranial pressure (ICP) monitor was inserted
and was managed in the intensive care unit for 4 days
postevacuation of haematoma. CT brain 2 days postsurgery demonstrated satisfactory reduction of mass effect
and resolution of haematoma (figure 2). Half the usual
dose of tinzaparin was administered to our patient on
the morning before surgery with no additional heparin.
Postoperatively, we re-introduced the prophylactic dose
of LMW heparin for 6 weeks, and then increased to therapeutic dose. Our aim was to discontinue long-term anticoagulation once his mobility improved. As the ICP was
well controlled at that stage, he was successfully extubated and was left with a mild right-sided hemiparesis.
Few days later, he had worsening headaches, and a repeat
CT brain raised the possibility of an intracranial collection suggestive of an abscess. He underwent a wound
re-exploration and aspiration of residual haematoma. No
evidence of infection was noted from microscopic analysis of the aspirated fluid and culture and sensitivity were
normal.
During the recovery phase, he also developed a left
above-knee deep vein thrombosis. A Greenfield filter
was inserted, and was subsequently removed in 3 weeks
time, when the patient was more ambulant and was commenced on LMW heparin treatment. Both thrombotic
events were considered to have been provoked by the
L-asparaginase treatment. He also developed one episode
of grand mal seizures for which he was commenced on
sodium valproate.
He received cyclophosphamide – total body irradiation
allogeneic bone marrow transplant resulting in complete
remission, but this was complicated by graft-versus-hostdisease, which later resolved.
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Six months later, he underwent titanium cranioplasty for
the cranial defect and made a significant symptomatic
recovery. He is currently mobilising independently with
mild occasional expressive dysphasia, difficulty with fine
motor movement on the right side and has remained seizure free.

DISCUSSION
L-Asparaginase is a well-known component of combination chemotherapy for ALL. There is a variety of complications arising from the use of L-asparginase including
thrombotic and/or haemorrhagic ones. The majority of
these thrombotic and/or haemorrhagic complications
occur in the central nervous system. The incidence of this
occurrence is approximately 1–2%.4
L-asparaginase hydrolyses asparagine to aspartic acid,
depleting asparagine and inhibiting protein synthesis.
This inhibition is thought to be the basis of its antineoplastic effect, but it also leads to the depletion of other
plasma proteins including those involved in coagulation
and fibrinolysis. Decreased levels of fibrinogen, factor
IX, factor XI, plasminogen, antithrombin III, protein C,
protein S, α2-antiplasmin, histidine-rich glycoprotein and
α2-macroglobulin have been reported.5–7 Deficiencies
become progressively more severe with repeated doses
of L-asparaginase, in protocols with two or three doses
per week, and in daily regimens. L-asparaginase is also
known to affect fibrinolysis. Plasma from patients during
L-asparaginase therapy shows reduced inhibition of the
fibrinolytic activities of plasmin, urokinase and human tissue plasminogen activator.8 A change occurs in the relative
concentrations of the two forms of α2-antiplasmin, with
a decrease in the ratio of the plasminogen-binding form
BMJ Case Reports 2012; doi:10.1136/bcr.11.2011.5240

Table 1

Cerebrovascular complications from L-asparaginase chemotherapy

Author/Year

Age/Sex

Symptoms*

Diagnosis

Therapy

Outcome

Ganick et al11
Priest et al3 4
Cairo et al12/
Priest et al4

6/M
6/F
2/F

MS, HA, SZ, HP
SZ, MS
SZ, HP

SSS thrombosis, haemorrhagic infarct
R frontal haemorrhage, haemorrhagic infarct
L frontal haemorrhage, haemorrhagic infarct

NR
None
FFP, cryoprecipitate

Died
Complete recovery
Complete recovery

5/M
NR/NR

HA, SZ, HP
Weakness, MS

None
FFP

Complete recovery
Complete recovery

NR/NR
NR/NR
NR/NR
NR/NR
NR/NR

HA, SZ, V, MS
HA, SZ, V, MS
HP, MS SZ, HA
SZ, HA, MS
HA, MS, SZ, HP

FFP, cryoprecipitate
FFP, cryoprecipitate, platelets
FFP, cryoprecipitate
None
FFP, craniotomy

Complete recovery
Complete recovery
Mild hemiparesis
Complete recovery
Occipital seizure

13/M
NR/F
10/M
5/M
44/F
13/NR
NR/NR
NR/NR
NR/NR
13/F
30/M

SZ, HP
Confusion, memory loss
HA, HP, focal SZ, aphasia
Focal SZ, HP
MS, aphasia
SZ, HP, MS
NR
NR
NR
HA, MS, HP, CrN III
HA, SZ, HP

L frontal haemorrhage, haemorrhagic infarct
Bilateral thalamic haemorrhages, haemorrhagic
infarcts
R frontal and L parietal haemorrhages
R parieto-occipital haemorrhage
Bilateral frontoparietal haemorrhages
L frontal haemorrhage
R frontal haemorrhage, L iliofem venous
thrombosis
R frontoparietal haemorrhage, SSS thrombosis
Bilateral thalamic haemorrhages
L parietal haemorrhage
L parietal haemorrhage
L intracerebral haemorrhage
SSS thrombosis, cortical haemorrhage
R parital haemorrhagic infarct, SSS thrombosis
L frontoparietal haemorrhagic infarct
R basal ganglia haemorrhagic infarct
R parietal haemorrhagic infarct
L frontal haemorrhagic infarct

NR
NR
None
None
Craniotomy
NR
FFP
FFP
FFP
Dexamethasone
Craniotomy

Died
Complete recovery
Mild residual
Recovery
Nearly complete recovery
Died
Died
NR
NR
Mild hemiparesis, CrN III
Mild residual

Priest et al4

White et al13
Urban et al14
Lederman et al15
Packer et al16
Pui et al7

Feinberg et al17
Index case/2011

*The initial symptom is listed first.
CrN, cranial nerve palsy; FFP, fresh frozen plasma; HA, headache; HP, hemiparesis; L, left; MS, alteration in mental status; NR, not reported; R, right; SSS, superior sagittal
sinus; SZ, seizure; V, vomiting.

to the non-plasminogen-binding form. A rebound effect
occurs after stopping therapy.8 This may lead to alteration
of the free fraction of plasminogen and affect fibrinolysis.
Fibrin degradation products however, do not increase during L-asparaginase therapy.6 8
The timing of vascular events (VE) suggests a strict relation with the administration of chemotherapy. In our case,
our patient’s VE occurred after day 19 of chemotherapy. In
the series by Weijl et al, the timing of the VE was similar:
They reported that VEs occurred a median of 50 days after
the start of chemotherapy and approximately 1 week after
the last cisplatin administration.9 The incidence of VEs
were noted to suddenly decrease after the completion of
chemotherapy.
Weijl et al also demonstrated that arterial and venous
events share the same risk factors, and both can occur in
the same patient in their study.9 In our case, the patient
suffered a cerebrovascular accident and a deep vein thrombosis. He also had a second transient VE after continuing
the treatment. It may be of benefit to discontinue chemotherapy once a VE is detected, but this is again debatable.
A review of existing literature suggests most chemotherapy-induced stroke events have been managed either
by administration of fresh frozen plasma, cryoprecipitate,
platelets, anticoagulant therapy, or steroidal agents, in various combinations (table 1).
Some studies have shown that the patients with intracranial complications from L-asparaginase were managed
conservatively and various degrees of outcome measures ranging from complete recovery to death have been
reported.

BMJ Case Reports 2012; doi:10.1136/bcr.11.2011.5240

This complication induced by L-asparaginase is considered an adverse drug reaction (ADR). Analysing
L-asparaginase induced ADR according to Naranjo algorithm score10 yields a score of 5, suggesting a probable relation of this drug causing the intracranial complication.
To summarise and to ascertain the temporal association
of L-asparginase with the hemorrhagic stroke, we reiterate
three important aspects, which were analysed. The first
point was to rule out all other possible causes which may
lead to stroke including thrombophilia screen, absence of
co-morbidities, smoking, medications and other factors
including prolonged bed rest and recumbency.
The second point is regarding temporal relationship and
pharmacological time plausibility, which was addressed.
The third point is the positive dechallenge/rechallenge
response. Dechallenge was demonstrated by discontinuing L-asparginase and because of the seriousness of this
adverse drug reaction, rechallenge was not attempted.
We report the first documented case of L-asparaginaseinduced stroke that made good recovery after decompressive craniectomy. The place of accurate diagnostic
neuroimaging, good ICP monitoring and adequate anticoagulation peri-operatively, as adjuncts to successful surgical outcomes cannot be overemphasised. We also conclude
that surgical management may prove beneficial in selected
group of patients with CVA from chemotherapy considering the following factors: age of the patient, type of tumour,
location of the haematoma, co-morbidities and overall
clinical condition of the patient. This may also improve
the quality of life of patients with cancer in selected group
of patients based on all the above-mentioned factors.

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Learning points
L-asparaginase induced thrombosis and stroke is
known and must be anticipated when combination
chemotherapy is planned.
▶ Naranjo algorithm score for L-asparaginase induced
thrombosis and stroke suggests a probable relation of
L-asparaginase causing this ADR.
▶ Different factors like patients age, type of tumour and
location of the intracerebral hematoma, co-morbidities
and overall clinical condition of the patient should be
taken into account before considering surgery.
▶ Though neurosurgical intervention is fraught with
morbidity and mortality, it should be considered an
option and this may potentially improve the quality of
life and outcome in patients with cancer.
▶

Competing interests None.
Patient consent Obtained.

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Ogbodo E, Kaliaperumal C, O’Sullivan M. Neurosurgical management of L-asparaginase induced haemorrhagic stroke. BMJ Case Reports 2012;
10.1136/bcr.11.2011.5240, Published XXX
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BMJ Case Reports 2012; doi:10.1136/bcr.11.2011.5240