Chronic Myeloid Leukemia (CML)
presenting with isolated central nervous system (CNS) blast crisis is uncommon.
A 22 years male, with chronic phase CML was in hematological and cytogenetic
remission till July 2016, had acute onset headache and vomiting with
meningeal signs and was admitted elsewhere, investigated by brain imaging and
CSF analysis, and suspected to have tubercular meningitis, for which steroids
and anti tubercular medications were started. Patient continued to be
deteriorated, and VP shunt surgery was done for hydrocephalus by
neurosurgeon. After 2 months of the illness he was admitted with persistent
headache and vomiting, recurrent seizures, altered sensorium and on
examination had meningeal signs. CSF showed lymphocytic pleocytosis with
positive cytospin for myeloid blasts on Myeloperoxidase (MPO) staining. He was
still in hematological remission. A diagnosis of isolated CNS blast crisis
was made and he was transferred to hemato-oncology department, where
chemotherapy was started and he had improvement.

BACKGROUND

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Isolated blast crisis involving CNS
without haematological relapse is rare entity, clinically characterized by headache, seizures, signs of meningeal irritation and/or focal
neurological deficits.1 These features may have a resemblance to chronic tubercular
meningitis and as tuberculosis being endemic in India, tubercular meningitis
can be diagnosed as a primary disease. However by the CSF cytospin, CNS blast
disease can be diagnosed easily.
Imatinib mesylate, used in
treatment of CML, has poor CNS penetration; hence CNS may serve as a
reservoir site for CML. Therefore patients on long term
imatinib therapy with haematological and cytogenetic remission may rarely
present with CNS blast crisis.2

CASE PRESENTATION

We present a case of 22 years male,
diagnosed as a case of CML in 2011, and was on Imatinib 400 mg twice daily
and had complete hematological and cytogenetic remission till July 2016. He
developed fever, headache, nausea, vomiting and was admitted elsewhere,
diagnosed as having Tubercular Meningitis on basis of CSF analysis, MRI brain
and received Anti Tubercular Treatment with steroids. Initially for few days,
he had transient relief in symptoms, but gradually deteriorated for which
Right MPVP shunt was done in September 2016. Even then he continued to have
headache, nausea, vomiting & gradual decline in sensorium, and was admitted
at our hospital, which is a tertiary care hospital of North India. On General
physical examination vital signs were normal. He had no organomegaly and
there was no evidence of skin or mucosal bleeding. On neurological
examination he was drowsy, had signs of meningeal irritation and bilateral
papilloedema with restricted abduction in both eyes. A possibility of CNS
blast crisis was kept. 

INVESTIGATIONS

Investigations revealed normal
hemoglobin (13.2 g/dl), white blood cell count (5.40×1000 /cumm) and platelet
counts (1.43lakh/ml). Peripheral smear was also normal with differential
count showed 70% neutrophils, 25% lymphocytes, 2% eosinophils and no atypical
cells. Lactate dehydrogenase was mildly raised (565 U/l). Serum electrolytes,
liver and renal function tests were normal. CSF analysis revealed total 75
cells (80% lymphocytes, 20% polymorphs), sugar-19.4mg/dl (corresponding blood
sugar was 77 mg/dl), and protein-340.29 mg/dl. CSF for malignant cytology was
suggestive of CNS infiltration by immature myeloid cells including
leucoblasts. Blast cells showed positivity for MPO stains, suggestive of
myeloblasts (Figure 1). MRI Brain was suggestive of ill defined foci of
altered signal intensity, hyperintense on T2/FLAIR and DWI noted in bilateral
capsuloganglionic region, bilateral thalamus, mid brain and bilateral
periventricular region and post contrast meningeal enhancement (Figure 2).
So, A diagnosis of CNS blast crisis was kept. 

TREATMENT

Anti tubercular treatment was
stopped and patient was shifted to hemato-oncology department where intra
thecal chemotherapy was given.

OUTCOME AND
FOLLOW-UP  

Patient gradually improved in 6 months follow up.
 

DISCUSSION

CML is a clonal malignancy,
characterised by the presence of Philadelphia chromosome, which is formed due
to a reciprocal translocation between the long arms of chromosomes 9 and 22.3
Disease
course of CML is triphasic with a chronic phase and accelerated phase,
followed by blastic phase after 3-5 years. In cases of blastic transformation,
blast cells are increased in bone marrow and blood. However, few cases of CML
develop extramedullary disease due to infiltration by blast cells.4
Extramedullary
blast crisis usually involves lymph nodes, bone, gastrointestinal tract,
skin, and soft tissues. In rare situations extramedullary blast crisis can
involve CNS.5
CNS blast
crisis clinically and radiologically resembles meningitis or encephalitis,
symptoms of which are headache, seizures, signs of meningeal irritation, and
focal neurological deficits with lymphoid or myeloid blast positivity on CSF
examination. BCR-ABL oncogene may be detected on molecular testing of CSF.6
Imatinib is
actively transported out of the CNS by P-glycoprotein, which is a membrane
bound transport protein, so that reducing bioavailability of Imatinib in CSF.
Concentration of Imatinib in CSF has been found to be about 175 times
lower than in plasma by Takayama et al.7
Therefore, in
patients of CML treated with Imatinib, CNS acts as a reservoir site for
malignant cells.
Our patient’s initial
presentation resembled to that of meningitis with clinical features including
headache, vomiting, altered mental status, signs of meningeal irritation and
CSF picture of lymphocytic pleocytosis and raised proteins, which led to
previous misdiagnosis as Tubercular meningitis. CSF cytology for malignant
cells was not done previously. Presence of the BCR ABL oncogene was confirmed
in leucocytes. Our patient had myeloid blasts in his CSF confirmed on MPO
staining.

LEARNING
POINTS/TAKE HOME MESSAGES

·       
Patients of CML, who are being treated with
Imatinib, may develop CNS blast crisis despite being in hematological and
cytogenetic remission.
·       
A high suspicion for CNS leukemia should be thought
in a patient of CML who present with neurological complaints.
·       
CSF examination for atypical/blast cells by cytospin
is essential in CML patients who present with fever, headache, altered mental
status and signs of meningeal irritation to start appropriate  treatment to prevent permanent neurological
deficits.
 

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