Ischemic stroke

Case Report

Tyrosine kinase inhibitor induced rapidly progressive
vasculopathy after intracranial stent placement
Ching-Jen Chen,1 Brian J Sorace,2 Aria Shakeri,2 Min S Park,1 Andrew M Southerland,2
Bradford B Worrall,2 M Yashar S Kalani1
1

Department of Neurological
Surgery, University of Virginia,
Charlottesville, Virginia, US
2
Department of Neurology,
University of Virginia,
Charlottesville, Virginia, US
Correspondence to
Dr M Yashar S Kalani,
​YK6Z@​hscmail.​mcc.​virginia.​edu
Accepted 15 March 2018

Summary
Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid
leukemia (CML) has been associated with progressive
peripheral arterial disease and, more recently, rare cases
of intracranial vascular stenosis have been reported.
We report the fourth case of TKI treatment associated
intracranial vasculopathy and rapid progression of
intracranial vascular stenosis following intracranial
stent placement. This was a 49-year-old woman
who developed right-sided weakness, paresthesias,
numbness, and speech difficulties 7 years following
TKI treatment for CML. Cerebral catheter angiography
demonstrated 90% stenosis of the left supraclinoid
internal carotid artery, for which the patient underwent
intracranial stent placement with no residual stenosis
and improved distal blood flow. Approximately 1 month
following the procedure, the patient returned with similar
symptoms. Catheter angiography demonstrated 70%
and 50% stenosis just distal and proximal to the stent
construct, respectively. Rapid disease progression and
non-atherosclerotic vasculopathy may argue against
endovascular therapy.

Background

Tyrosine kinase inhibitors (TKIs), such as Imatinib,
Nilotinib, and Bosutinib, have become the mainstay
therapy in preventing the progression of chronic
myeloid leukemia (CML) in its chronic phase. TKI
therapy for CML has been associated with progressive peripheral arterial disease and, more recently,
rare cases of intracranial vascular stenosis have been
reported.1–4 Successful cases of intracranial stent
placement and surgical revascularization have been

Figure 2 (A, B) Cerebral catheter angiograms in
anteroposterior (AP) and lateral views, demonstrating
improved left supraclinoid internal carotid artery segment
with no residual stenosis after stent placement. (C, D)
Cerebral catheter angiogram in AP and lateral views,
demonstrating 70% and 50% stenosis just distal and
proximal to the stent construct (red arrowheads),
respectively.
reported.2 3 However, due to the paucity of these
cases, the efficacy and safety of these interventions
cannot be evaluated.
Here, we report the fourth case of TKI treatment associated intracranial vasculopathy, and
rapidly progressive intracranial vascular stenosis
following intracranial stent placement. This patient
is also the first case of TKI induced concurrent transient ischemic attack (TIA) and myocardial infarction in the medical literature.

Case presentation

To cite: Chen C-J, Sorace BJ,
Shakeri A, et al. BMJ Case
Rep Published Online First:
[please include Day Month
Year]. doi:10.1136/bcr-2018013777

Figure 1 (A) Axial MRI in diffusion weighted imaging
sequence, demonstrating multifocal acute infarcts
(red arrowheads) within the left cerebral hemisphere
in a watershed distribution. (B, C) Cerebral catheter
angiograms in anteroposterior and lateral views,
demonstrating findings suggestive of moyamoya
syndrome, with 80% and 90% stenosis of the left
cavernous internal carotid artery (ICA) and left
supraclinoid ICA segments (red arrowheads), respectively.

This was a 49-year-old woman with known type
2 diabetes mellitus and hyperlipidemia who was
diagnosed with CML in 2010. She was initially
treated with Imatinib but there was a slow increase
in her BCR-ABL expression by 2016. Therefore,
she was transitioned from Imatinib to Nilotinib,
resulting in her BCR-ABL oncogene level becoming
undetectable. In 2017, the patient presented to
several emergency departments with episodes of
transient right-sided weakness, paresthesias, numbness, and speech difficulties. She later presented

Chen C-J, et al. BMJ Case Rep 2018. doi:10.1136/bcr-2018-013777

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Ischemic stroke
(figure 1B and C). Her Nilotinib was switched to Bosutinib due
to concerns for progressive Nilotinib vasculopathy.

Treatment
The patient underwent intracranial stent placement (2.25 mm
× 8 mm; Multi-link Vision, Abbott, Illinois, USA) over the
stenotic left supraclinoid ICA segment with no residual stenosis
(figure 2A, B), resulting in improved distal blood flow. There
was also interval resolution of the previously noted narrowing
of the left cavernous ICA, representing slow flow rather than
true stenosis.

Outcome and follow-up

Figure 3 (A,B) Cerebral catheter angiograms in anteroposterior and
lateral views, demonstrating interval near occlusion of the intracranial
segments of the left internal carotid artery (ICA). (C) Cerebral catheter
angiograms in lateral view in the early arterial phase, demonstrating
contrast filling of the left ICA to the level of the petrous segment
(black arrowhead), and external carotid artery (ECA) to pial collaterals
via branches of the occipital artery (red arrowheads) and parietal
branch of the superficial temporal artery (yellow arrowhead). There is
retrograde filling of the distal left MCA branches via the ECA to pial
collaterals (green arrowheads) and filling of the left MCA candelabra
(blue circle) via collaterals. (D) Cerebral catheter angiograms in lateral
view in the late arterial phase, demonstrating contrast filling of the left
ICA to the level of the cavernous segment (black arrowhead), ECA to
pial collaterals (blue circles), and retrograde filling of distal left MCA
branches (green arrowhead).

with recurrent TIA symptoms and was found to be in the midst
of a non-ST elevation myocardial infarction. This is believed to
be the first report of concurrent TIA and myocardial infarction
in TKI induced vasculopathy.

Investigations
CT angiography of her head demonstrated severe multifocal
vascular irregularity and stenoses, most significant in the left
anterior intracranial circulation. MRI of her brain demonstrated
chronic hypoperfusion ischemic changes in the left centrum
semiovale and posterior periventricular region, without evidence
of acute infarct. The patient subsequently underwent coronary
catheter angiography with a drug eluting stent placed in her right
coronary artery for severe stenosis. The patient was subsequently
discharged on a high intensity statin (atorvastatin 80 mg daily)
and dual antiplatelet therapy (aspirin 325 mg daily and clopidogrel 75 mg daily).
Within a month she represented to the emergency department
with similar symptoms. MRI demonstrated multifocal acute
infarcts within the left cerebral hemisphere in a watershed distribution (figure 1A). Subsequent cerebral catheter angiography
demonstrated 80% and 90% stenosis of the left cavernous internal
carotid artery (ICA) and left supraclinoid ICA, respectively
2

Approximately 1 month following placement of the intracranial stent, the patient returned to the emergency department
with a transient episode of right-sided numbness. Cerebral
catheter angiography demonstrated 70% and 50% stenosis
just distal and proximal to the stent construct, respectively
(figure 2C, D). Aspirin and P2Y assays demonstrated therapeutic levels. The risk of further endovascular or surgical
intervention was deemed high due to the progressive vasculopathy and inability to withhold dual antiplatelet therapy. Hence
the patient was maintained on dual antiplatelet therapy with
permissive blood pressure parameters. Follow-up angiogram
at 3 months demonstrated interval near occlusion of the intracranial segments of the left ICA (figure 3A, B), both within and
outside of the stented segment, with development of extensive
external carotid artery to pial collaterals (figure 3C, D).

Discussion
Growing evidence suggests that TKIs may be associated with
an increased risk of vasculopathy causing peripheral arterial
disease, stroke, and ischemic heart disease.5 However, intracranial vascular stenosis is an extremely rare adverse effect associated with TKI treatment for CML. This was first described
by Coon et al.4 They reported a 70-year-old woman who
after approximately 11 years of starting treatment with TKIs for
CML presented with left-sided weakness and dysarthria, with
MR angiography demonstrating multifocal narrowing of the
anterior and posterior circulations, and >95% narrowing of the
right ICA on cerebral catheter angiography.4 That patient was
managed conservatively due to the risks associated with endovascular or surgical intervention. More recently, Alshiekh-Nasany et
al reported a case of bilateral middle cerebral artery narrowing
in a 50-year-old man who presented with right-sided weakness
and dysarthria after 10 years of TKI treatment for CML.3 This
patient was successfully treated using surgical revascularization
via superficial temporal artery to middle cerebral artery bypass.
Subsequently, Ozaki et al reported a case of successful intracranial stent placement for symptomatic right ICA stenosis that
developed in a 47-year-old man after 7 years of TKI treatment
for CML.2 Our report represents the fourth documented case in
the literature of this extremely rare yet significant adverse effect
of TKI treatment for CML.
Nilotinib has been increasingly implicated in the development of vascular events.1 6 While the exact etiology is unclear,
various mechanisms of the pathophysiology underlying Nilotinib induced vasculopathy have been proposed. Nilotinib causes
multiple metabolic derangements, increasing the risk of vascular
disease. These include increased fasting glucose, type 2 diabetes
mellitus, and increased total high density and low density lipoprotein cholesterol. Nilotinib also interferes with endothelial cell
migration, cell proliferation, and promotes a pro-atherogenic
Chen C-J, et al. BMJ Case Rep 2018. doi:10.1136/bcr-2018-013777

Ischemic stroke
phenotype by increasing the expression of cell surface adhesion molecules.7 A recent paper revealed multiple pathways
through which Nilotinib encourages a prothrombotic state.8
Nilotinib potentiates PAR1 mediated release of platelet alpha
granules and also increases platelet thrombus volume. Furthermore, Nilotinib was associated with a phenotype of activated
endothelium (increased plasma levels of soluble forms of E-selectin, P-selectin, and VCAM) and also promoted a proinflammatory state via increased serum tumor necrosis factor α and
Interleukin 6 levels.7
Recently, surgical revascularization has gained acceptance as a
primary treatment for moyamoya syndrome, given the documented
safety profile of surgery in long term follow-up and the poor
response to medical therapy.9 Given the unclear mechanism and
natural history of TKI treatment associated intracranial vascular
stenosis, optimal therapy is also unknown. Despite a previous
report of successful stent placement for TKI treatment associated
intracranial vascular stenosis, the rapid disease progression seen
in our patient and the non-atherosclerotic vasculopathy demonstrated on angiography may argue against endovascular therapy.2
The rapid development of stent adjacent stenosis may also indicate

Learning points
►► Intracranial multifocal vascular stenosis is an extremely rare

adverse effect of tyrosine kinase inhibitor (TKI) treatment for
chronic myeloid leukemia (CML).
►► The mechanism of vasculopathy is unknown; proposed
mechanisms include induced atherosclerosis, impaired
vascular repair, and metabolic drug effect.
►► Rapid progression of vasculopathy can occur despite
intracranial stent placement for TKI treatment associated
intracranial vascular stenosis.
►► Surgical revascularization may need to be considered in
intracranial vascular stenosis associated with TKI treatment
for CML.

a more widespread systemic vascular pathology for which targeted
stent placement may not alter its natural history.
Contributors C-JC: conception of the project, data collection, drafting of the
manuscript, critically revising the manuscript, and approval of the final manuscript.
BJS and AS: drafting of the manuscript, critically revising the manuscript, and
approval of the final manuscript. MSP, AMS, and BBW: critically revising the
manuscript and approval of the final manuscript. MYSK conception of the project,
critically revising the manuscript, and approval of the final manuscript.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)
2018. All rights reserved. No commercial use is permitted unless otherwise expressly
granted.

References

1	Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial
occlusive disease and other vascular events during nilotinib therapy in CML. Am J
Hematol 2011;86:533–9.
2	Ozaki T, Nakamura H, Izutsu N, et al. Intracranial stenting for nilotinib treatmentassociated cerebrovascular stenosis in chronic myeloid leukemia. Interv Neuroradiol
2017;23:527–30.
3	Alshiekh-Nasany R, Zidan A, Martinez C. Extensive intracranial arterial stenoses
in conjunction with the use of tyrosine kinase inhibitor Nilotinib. Clin Case Rep
2016;4:1184–6.
4 Coon EA, Zalewski NL, Hoffman EM, et al. Nilotinib treatment-associated
cerebrovascular disease and stroke. Am J Hematol 2013;88:534–5.
5 Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic
myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk
Lymphoma 2016;57:1300–10.
6 Dahlén T, Edgren G, Lambe M, et al. Cardiovascular events associated with use of
tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort
study. Ann Intern Med 2016;165:161–6.
7 Hadzijusufovic E, Albrecht-Schgoer K, Huber K, et al. Nilotinib-induced vasculopathy:
identification of vascular endothelial cells as a primary target site. Leukemia
2017;31:2388–97.
8	Alhawiti N, Burbury KL, Kwa FA, et al. The tyrosine kinase inhibitor, nilotinib potentiates
a prothrombotic state. Thromb Res 2016;145:54–64.
9	Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med
2009;360:1226–37.

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