Clinical Neurology and Neurosurgery 112 (2010) 575577

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Case report

Diagnosis of acute lymphoblastic leukemia from intracerebral hemorrhage and

blast crisis. A case report and review of the literature
Matthew R. Naunheim a , Brian V. Nahed a , Brian P. Walcott a , Kristopher T. Kahle a , Chad P. Soupir b ,
Daniel P. Cahill a , Lawrence F. Borges a,
a
b

Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States
Department of Hematopathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States

a r t i c l e

i n f o

Article history:
Received 28 May 2009
Received in revised form
18 November 2009
Accepted 3 April 2010
Available online 20 May 2010
Keywords:
Acute leukemia
ALL
Blast crisis
Intracerebral hemorrhage
Leukocytosis

a b s t r a c t
Intracerebral hemorrhage (ICH) contributes signicantly to the morbidity and mortality of patients suffering from acute leukemia. While ICH is often identied in autopsy studies of leukemic patients, it is rare
for ICH to be the presenting sign that ultimately leads to the diagnosis of leukemia. We report a patient
with previously undiagnosed acute precursor B-cell lymphoblastic leukemia (ALL) who presented with
diffuse encephalopathy due to ICH in the setting of an acute blast crisis. The diagnosis of ALL was initially suspected, because of the hyperleukocytosis observed on presentation, then conrmed with a bone
marrow biopsy and ow cytometry study of the peripheral blood. Furthermore, detection of the BCR/ABL
Philadelphia translocation t(9:22)(q34:q11) in this leukemic patient by uorescent in situ hybridization
permitted targeted therapy of the blast crisis with imatinib (Gleevec). Understanding the underlying etiology of ICH is pivotal in its management. This case demonstrates that the presence of hyperleukocytosis
in a patient with intracerebral hemorrhage should raise clinical suspicion for acute leukemia as the cause
of the ICH.
2010 Elsevier B.V. All rights reserved.

1. Introduction
Intracerebral hemorrhage (ICH) is common in patients diagnosed with acute leukemia, accounting for approximately 20%
of the mortality associated with this disease [13]. Despite
advancements in chemotherapeutic dosing regimens, targeted
pharmacotherapy, and close monitoring of associated coagulation
abnormalities, ICH continues to be a signicant cause of morbidity and mortality in leukemic patients [4]. Management for ICH in
general remains controversial, while evidence-based recommendations for ICH in the setting of leukemia are lacking [512]. Risk
factors associated with ICH include the presence of a blast crisis (i.e., greater than 30% of WBC in the circulating blood are
immature blast forms), leukocytosis, and other coagulopathies
[11,13,14]. While there are several post-mortem studies identifying
ICH in patients previously diagnosed with leukemia, it is unusual
to encounter ICH as the initial presenting sign that reveals a new
diagnosis of acute leukemia [15,16,3]. Since the management of ICH
in the setting of newly diagnosed acute leukemia with blast crisis

Corresponding author at: Department of Neurosurgery, Massachusetts General

Hospital, 55 Fruit Street, Boston, MA 02114, United States. Tel.: +1 617 726 6156;
fax: +1 617 724 7407.
E-mail address: lborges@partners.org (L.F. Borges).
0303-8467/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.clineuro.2010.04.001

is very uncommon and may need to focus on the management of

the leukemia as well as the hemorrhage, we present such a patient
who was managed without surgery and with an excellent outcome.
2. Case report
A 55-year-old male with a history of myocardial infarction, coronary artery bypass graft, and no prior blood dyscrasias presented
in June 2007 with a chief complaint of dizziness after sustaining an unwitnessed syncopal fall in his kitchen. The patients wife
stated that she found her husband lying on the oor, complaining of back pain. Initial physical examination in the emergency
department revealed him to be stable; he was alert, oriented,
and neurologically intact. Probing further into his medical history, it was learned that he complained of mid-scapular pain over
the previous two weeks. He also had a severe occipital headache
over the previous two days. Given the patients scapular pain
and known aortic root dilatation, attention was turned to investigation of his aortic vasculature with a concern for dissection.
A contrast-enhanced computerized tomography (CT) of the chest
demonstrated a 4.7 cm undissected ascending aortic aneurysm
without evidence of acute pathology. While awaiting further evaluation by cardiothoracic surgery, the patient developed acute mental
status changes and became unresponsive. He was emergently intubated and underwent a non-contrast head CT which revealed many

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M.R. Naunheim et al. / Clinical Neurology and Neurosurgery 112 (2010) 575577

Fig. 1. (A) A non-contrast head CT taken at the time of initial presentation demonstrates a 0.9 cm left cerebral convexity subdural hematoma with left-to-right midline shift
measuring 1.1 cm at its greatest dimension. There are also two parenchymal hemorrhages, measuring 4.3 cm 1.6 cm and 2.9 cm 2.7 cm. There is extensive subarachnoid
hemorrhage. (B) A non-contrast head CT scan taken three weeks after patients initial presentation demonstrating evolution of the previously seen hemorrhage with midline
shift now measuring 9 mm (previously 1.1 cm).

intracranial lesions: a 9 mm left subdural hematoma, two noncontiguous left frontal parenchymal hemorrhages (4.3 cm 1.6 cm
and 2.9 cm 2.7 cm), and extensive left subarachnoid hemorrhage.
The mass effect exerted from this hemorrhage resulted in a 1.1 cm
left-to-right midline shift.
The patient was then transferred to the Massachusetts General
Hospital where he arrived intubated and sedated. His pupils were
equal, round, and reactive to light. His bilateral upper extremities
exed to stimuli and his bilateral lower extremities withdrew to
stimuli. The neurosurgical service was consulted for the evaluation of ICH, which was initially thought to be related to the fall
he sustained from his syncopal episode. However, the neurosurgical impression was that it seemed that the pattern of hemorrhage
was more extensive than would be expected from the minor head
trauma associated with a syncopal episode. The patient underwent an interval non-contrast head CT which demonstrated stable
ICH (Fig. 1a). CT angiography revealed no evidence of aneurysm
or vascular malformation to account for the hemorrhage. Laboratory tests obtained concurrent to the radiological workup were
notable for marked thrombocytopenia (30,000/L) and leukocytosis (92,000/L), with 86% blasts (Table 1). A presumptive diagnosis
of acute leukemia was made following review of the laboratory

Table 1
Results of laboratory tests on presentation.
Variable

Value

Reference range

White blood cell count (per mm3 )

Hemoglobin (g/dl)
Hematocrit (%)
Platelet count (per mm3 )

92
12.3
36.5
30

4.511.0 th/cmm
13.517.5 g/dl
41.053.0%
150350 th/cumm

Differential count (%)

Blasts
Band forms
Lymphocytes
Monocytes
Eosinophils
Basophils
Poly

86
2
5
1
0
0
6

0%
010%
2244%
411%
08%
03%
4070%

Prothrombin time (s)

Partial thromboplastin time (s)
International normalized ratio

12.6
21.6
1.1

10.313.2 s
22.134.0 s

Sodium
Potassium
Chloride
CO2
BUN
Creatinine
Glucose

135
5.5
106
22.9
45
1
220

135145 mmol/L
3.44.8 mmol/L
100108 mmol/L
23.031.9 mmol/L
825 mmol/L
0.61.5 mg/dl
70110 mg/dl

data and the peripheral blood smear. The patients neurological

exam improved as sedation was held; he opened his eyes to voice
and spontaneously moved all four extremities. The patient was
admitted to the Intensive Care Unit where his neurological exam
was closely monitored. Exogenous platelets were administered to
correct his thrombocytopenia. To manage his robust leukocytosis, he underwent leukophoresis and a course of hydroxyurea (2 g
BID), allopurinol (300 mg BID) and dexamethasone (4 m Q6 hours).
His platelet count increased to 70,000/L after his platelet transfusion. After leukopheresis and pharmacological treatment of his
leukocytosis, the patients neurological exam improved such that
eye opening became spontaneous and he followed commands.
Interval head CT scans revealed stable hemorrhages, and he was
soon extubated. Following review of the bone marrow aspirate,
biopsy, and peripheral blood ow cytometry, a diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) was made by
the hematopathology service. Fluorescence in situ hybridization
(FISH) analysis identied a BCR/ABL Philadelphia translocation
t(9;22)(q34;q11), which is characteristic of CML but can also be
found in a subset of ALL. The patient started chemotherapy (imatinib) to inhibit the exuberant tyrosine kinase of the BCR/ABL
fusion product. He was discharged to home in complete remission.
Follow-up in one month revealed improved cognitive function and
ambulation. His white blood cell count and platelet count improved
(13,000/L and 326,000/L, respectively). A head CT demonstrated
interval resolution of the original hemorrhage with no sign of further hemorrhage (Fig. 1b). Two months after discharge, the patient
underwent successful allogenic stem cell transplantation, with his
brother as a donor.
3. Discussion
Approximately 37,000 people develop an ICH each year [17].
Multiple pathological processes can cause ICH, including trauma,
cerebrovascular disease, and coagulation disorders [18,19]. A careful medical history and non-contrast head CT often leads to a
diagnosis of ICH, as was the case with our patient. Presenting
signs of ICH are headache, fatigue, mental status changes and
focal neurological decits [15,16]. Once identied, ICH necessitates investigation to elucidate contributing factors. Hematoma
growth is associated with increased mortality and poor outcome in
ICH; correctable factors must therefore be treated expeditiously, as
approximately 30% of patients with ICH presenting to an emergency
department have ongoing intracerebral bleeding [20,21]. One such
etiologic factor is leukemic blast crisis, which should be suspected
in the setting of ICH with marked leukocytosis. Thus, signs and
symptoms of ICH should be monitored closely in leukemic patients,

M.R. Naunheim et al. / Clinical Neurology and Neurosurgery 112 (2010) 575577

as fatal ICH is most likely to occur within the rst ten days following
the initial blast crisis [22]. This case presents a unique situation in
which ICH was detected prior to the diagnosis of B-cell ALL, demonstrating that leukemia should be on the differential diagnosis for
ICH of unknown etiology, particularly in the setting of hyperleukocytosis, and a characteristically abnormal peripheral blood
smear.
The underlying pathophysiology of ICH in ALL is likely multifactorial. Graus et al. [13] report that while hypertension is the most
commonly associated risk factor for ICH in the general population,
in leukemic patients other causes such as hyperleukocytosis, coagulopathy, or emboli from infection are more likely to cause ICH. The
exact pathogenesis of ICH in leukemia is unknown, but components
of leukostasis (i.e., stagnation of small cerebral vessel blood ow
due to increased blood viscosity from high numbers of circulating
leukocytes) and/or coagulopathy (i.e., due to severe thrombocytopenia) likely contribute. In an autopsy study of patients with
acute leukemia and ICH, 19 of 69 demonstrated severe leukostasis,
while 50 had no leukemic inltration, likely indicating coagulopathy as the primary etiology in this group [13]. Regardless of its
exact pathogenesis, ICH is a grave prognostic indicator in ALL and
is second only to infection as the most common cause of death in
patients with either acute myelogenous or lymphoblastic leukemia
[2,1,16].
Surgery has little role in the management of ICH in cases with
an extant coagulopathy such as leukemic blast crisis. Management
of ICH is largely medical as a result of ndings generated from
the International Surgical Treatment in Intracerebral Hemorrhage
(STICH) trial. This study demonstrated no benet to early surgical
evacuation of ICH [23]. However, subgroup analysis demonstrated
advantage to early surgical evacuation of hemorrhages located
within 1 cm of the cortical surface. Current recommendations
from the American Heart Association parallel these ndings, only
giving consideration to surgical evacuation of hemorrhage that
is located within 1 cm of the cortical surface and those lesions
associated with marked mass effect, edema, or midline shift [7].
Although not completed, an ongoing trial may show benet for
minimally invasive surgery for ICH in the absence of coagulopathy
[24].
Treatment in this case was immediately aimed at addressing
the underlying pathophysiology; platelets were administered to
correct the thrombocytopenia, and leukophoresis was performed
to reverse leukostasis. These initial treatments were essential to
his recovery. This patient is fairly unique, as he survived with
excellent neurological outcome; most patients with blast crisis
ICH have a high rate of mortality. In addition, patients with subdural hematoma and ICH fare considerably worse, likely due to
the parenchymal injury caused by the hematoma and brainstem
compression [25]. Cases of ICH with associated hematological
abnormalities such as hyperleukocytosis, especially if associated
with thrombocytopenia, particularly those with an unusual pattern of hemorrhage, should raise clinical suspicion of uncommon
etiologies such as leukemic blast crisis. Accurate and rapid diagnosis drastically impacts both the choice of treatment and patient
outcome.
Competing interests
The authors do not have any conicts or competing interests.
Our paper has not been previously published and is not under consideration elsewhere for publication.

577

Funding
None.
Acknowledgements
None.
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