doi: 10.2169/internalmedicine.7701-21
Intern Med 61: 1603-1608, 2022
http://internmed.jp

【 CASE REPORT 】

Moyamoya Disease-like Cerebrovascular Stenotic Lesions
Are an Important Phenotype of POEMS
Syndrome-associated Vasculopathy
Yusuke Takahashi 1, Yusuke Mochizuki 1, Katsuya Nakamura 2, Nagaaki Katoh 1 and
Yoshiki Sekijima 1

Abstract:
A 41-year-old woman was diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, and
skin changes (POEMS) syndrome based on polyneuropathy, hepatosplenomegaly, sclerotic bone lesions, IgAλ M-protein, and an elevated level of serum vascular endothelial growth factor. One month after the initiation
of lenalidomide-dexamethasone with prophylactic aspirin, she developed facial paralysis, dysarthria, and left
hemiplegia. Multiple cerebral infarctions and internal carotid artery stenosis were detected. Five months after
switching to pomalidomide-dexamethasone, she again developed cerebral infarction. Progressed stenotic lesions in the bilateral internal carotid artery terminal portions were detected, showing a moyamoya diseaselike appearance. Quasi-moyamoya disease can be an important phenotype of systemic vasculopathies of
POEMS syndrome.
Key words: cerebral infarction, IMiDs, POEMS syndrome, quasi-moyamoya disease, vasculopathy
(Intern Med 61: 1603-1608, 2022)
(DOI: 10.2169/internalmedicine.7701-21)

Introduction
Polyneuropathy, organomegaly, endocrinopathy, Mprotein, and skin changes (POEMS) syndrome is characterized by these chief symptoms, which are considered to be
associated with an underlying plasma cell disorder and elevated levels of vascular endothelial growth factor
(VEGF) (1). In addition to these five main symptoms,
disease-related vasculopathy, including thrombosis (2, 3),
vascular stenosis (2-6), occlusion/infarction (2-5), and hemorrhage (4, 5) have been reported in the limbs (2, 3), visceral organs (2, 3), and central nervous system (2-6). Although not well-recognized features, these POEMS
syndrome-associated vasculopathies (PAV) are important
complications. We herein report a case with recurrent cerebral infarctions due to moyamoya disease-like cerebrovascular stenotic lesions (quasi-moyamoya disease) as one of the
main features of POEMS syndrome. Quasi-moyamoya dis-

ease is a very rare manifestation of POEMS syndrome with
only two previous cases reported in the literature to
date (4, 5). However, this condition could be one of the phenotypes of PAV, and clinicians should pay attention to the
possibility of this disease entity in patients with POEMS
syndrome.

Case Report
A 41-year-old woman with no family history of neurological disorders, such as neuropathy or cerebrovascular disease, was referred to our hospital for further examination
and treatment of polyneuropathy. Six months prior to presentation at our hospital, she developed muscle weakness in
the legs when walking, and began to feel numbness and
pain in her feet and lower legs at 4 months prior to presentation. At 3 months prior to presentation, she developed leg
edema and visited a local hospital. Although her edema improved after the administration of diuretics, her neuropathic

１

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan and ２ Center for Medical Genetics,
Shinshu University Hospital, Japan
Received: April 2, 2021; Accepted: September 23, 2021; Advance Publication by J-STAGE: November 6, 2021
Correspondence to Dr. Nagaaki Katoh, nagaaki@shinshu-u.ac.jp

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Figure 1. Histopathological picture of a sural nerve biopsy
(toluidine blue staining). The histological findings were highly
suggestive of POEMS syndrome, such as myelin spheres, indicated distal axonal degeneration due to proximal demyelination, and subperineurial edema (§). Axonal loss was unclear.
There was no evident thinning of the myelin sheath or onion
bulb formation. Scale bar =100 μm.

symptoms remained. One month prior to presentation, she
was referred to the neurology department of the local hospital. She was suspected to have polyneuropathy based on
muscle weakness in the legs, reduced tendon reflexes in the
extremities, and decreased nerve conduction velocities, and
was then admitted to our hospital.
On admission, the physical examination findings were not
remarkable except for leg edema. There was no detectable
hypertension, skin lesion, or palpable hepatosplenomegaly.
Neurological examinations revealed distal dominant muscle
weakness in her legs, absent tendon reflexes in the upper
and lower extremities, decreased touch, pain, and vibration
sensations in the distal legs, numbness and pain in the legs,
and disturbed walking with a cane. Laboratory tests revealed
an elevated platelet count (450,000/μL, normal 158,000348,000/μL), IgA-λ M-protein, and elevated serum vascular
endothelial growth factor (VEGF, 7,350.0 pg/mL). There
was no hyperlipidemia or diabetes mellitus. The cardiac
functions and dimensions were normal on echocardiography
but mild pericardial effusion was detected. An enhanced
computed tomography (CT) scan of the neck, chest, abdomen, pelvis, and femur detected hepatosplenomegaly and
sclerotic bone lesions in the lower thoracic spine. No stenotic or occlusive arteriovenous vascular lesions were detected.
A nerve conduction test detected lower extremity-dominant
amplitude reduction in both motor and sensory nerves with
decreased velocities, suggesting sensorimotor polyneuropathy with axonal degeneration. A sural nerve biopsy was performed and the histological findings of axonal degeneration
with subperineurial edema were thus identified (Fig. 1).
Taken together, a diagnosis of POEMS syndrome was made.
Lenalidomide-dexamethasone (Rd) therapy with prophylactic
aspirin was started. The affected free light chain (FLC) λ
decreased from 34.4 mg/L to 17.7 mg/L after one cycle. Rd
therapy was therefore considered to be effective and a sec-

ond cycle was started as scheduled. On day 6 of the second
cycle, she began to feel slight weakness in her left arm. On
day 8, she noticed dysarthria and muscle weakness progression in her left arm and leg. These symptoms remained and
she visited our hospital on day 9. A neurological examination revealed left unilateral facial paralysis, dysarthria, and
mild left hemiplegia. Magnetic resonance imaging (MRI)
was performed and multiple cerebral infarctions were detected in the right middle cerebral artery area (Fig. 2A, B).
Dual antiplatelet therapy with aspirin and clopidogrel was
started. In addition, stenotic lesions at the terminal portion
of the bilateral internal carotid artery (ICA) were detected
by magnetic resonance angiography (MRA) (Fig. 2C). Although almost all the results of carotid duplex ultrasonography were unremarkable, 1.6 mm intima media thickness was
detected in the bifurcation portion of left common carotid
artery. POEMS syndrome-associated vasculopathy (PAV)
and possible side effects of Rd therapy were suspected, and
chemotherapy
was
switched
to
pomalidomidedexamethasone (Pd). After the Pd initiation, hematologic
and clinical disease activities were maintained to be plateau
state. Five months later, during the sixth cycle of Pd treatment, she developed speaking difficulty and apathy, and new
cerebral infarctions were detected in both frontal lobes by
MRI (Fig. 2D, E). A progression of stenotic lesions in both
sides of ICA terminal portions was demonstrated by MRA,
showing a moyamoya disease-like appearance (Fig. 2F).
“Moyamoya vessels” (typical collateral vessels observed in
moyamoya disease) were not evident in MRA (Fig. 2G). 123IIMP cerebral blood flow scintigraphy revealed severely decreased tracer uptake in both lobes, especially in the frontotemporal lobe area (Fig. 3). As a result of screening tests for
systemic arteriovenous vascular lesions, subclinical bilateral
renal infarctions were detected by whole-body enhanced CT
scan. Quasi-moyamoya disease, which developed in association with disease progression of PAV, was diagnosed. A direct sequence analysis of the RNF213 gene for the variant
(NM_001256071.2:c.14429G>A:p.Arg4810Lys) was performed and the patient was found to be heterozygous for
this variant. The patient was referred to the neurosurgery department for further examination with cerebral angiography
to discuss the indications for surgical revascularization. She
underwent bilateral superficial temporal artery to MCA
(STA-MCA) bypass operations successfully (Fig. 4). After
the surgical intervention, she has been in a good clinical
state without any new cerebral ischemia attacks or a progression of neuropathy under the additional chemotherapy
including daratumumab, lenalidomide, and dexamethasone
for 2 years and 5 months.

Discussion
In contrast to moyamoya disease that is defined by “idiopathic” steno-occlusion at the terminal portion of the internal carotid artery, quasi-moyamoya disease is characterized
by the presence of underlying primary disease manifesting

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A

B

C

D

E

F

G

Figure 2. Diffusion-weighted brain magnetic resonance imaging (MRI) (A, B, D, E) and magnetic
resonance angiography (MRA) (C, F, G). (A-C). Images taken at the first episode of stroke. Multiple
infarctions in the right middle cerebral artery area (A, B) and stenotic lesion of bilateral internal carotid artery (ICA) in the terminal portion (C) are shown. (D-G). Images taken at the second episode
of stroke 5 months after the first episode. These images revealed new cerebral infarctions in both
frontal lobes (D, E) and significantly progressed stenotic lesions in the bilateral ICA terminal portions, showing moyamoya disease-like appearance (F). Although coronal maximum intensity projection (MIP) picture focusing on ICA terminal portion was also examined (G), typical collateral vessels
(moyamoya vessels) were not evident.

the same cerebrovascular lesions (7). Various inherited or acquired disorders and conditions have been reported as associated pathologies of quasi-moyamoya disease. A nationwide
survey in Japan documented atherosclerosis (29%), Down
syndrome (15.1%), von Recklinghausen disease (14%), brain
tumor/irradiation (7.5%), autoimmune disease (7.5%), hyperthyroidism (7.5%), and other conditions as associated primary diseases (7).
On the other hand, PAV are regarded as specific types of
arteriovenous vascular events, including thrombosis (2, 3),
vascular stenosis (2-6), occlusion/infarction (2-5), and hemorrhage (4, 5) in the limbs (2, 3), visceral organs (2, 3), and

central nervous system (2-6). The underlying mechanism of
PAV has not yet been elucidated. Fu et al. suggested that
vasculitis is the dominant mechanism of vasculopathy based
on imaging studies showing contrast enhancement without
pathological analysis (3). In contrast, some reports indicated
that no vasculitis pathology on histological analysis (2, 5).
In an autopsy study, Sekiguchi et al. reported that the histological findings of PAV in quasi-moyamoya disease were
similar to those of moyamoya disease, showing fibrous intimal thickening and tortuosity of the internal elastic lamina
without vasculitis pathology (5).
VEGF is known to play an important role in the vascular

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Figure 3. Axial rainbow color scale images of 123I-IMP cerebral blood flow scintigraphy. The results
indicated a diffuse and severe decrease of the cerebral blood flow especially in the frontotemporal
lobe area.

A

B

C

D

Figure 4. Digital subtraction angiography (DSA) images of bilateral common carotid artery. DSA
images of right (A, C) and left (B, D) common carotid angiography. Images of pre- (C, D) and post- (A,
B) bilateral superficial temporal artery to MCA (STA-MCA) bypass operations are presented.

pathology of POEMS syndrome (1). Interestingly, some
studies have demonstrated that there a number of angiogenic
agents, including VEGF (8), basic fibroblast growth factor

(bFGF) (8), hepatocyte growth factor (HGF) (8, 9), transforming growth factor-β1 (TGF-β1) (8), and granulocytecolony stimulating factor (G-CSF) (8), are also overex-

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pressed in moyamoya disease. Therefore, some angiogenic
agents, such as VEGF, could be associated with both diseases, with similar pathological effects in the vessels. This
hypothesis would support the observations that the same
histopathological findings of involved vasculature were seen
in both diseases (5). On the other hand, different mechanisms were also suggested. As shown in the case presentation, rapid progression of ICA terminal stenosis had occurred in only a few months. It is possible to postulate that
additional pathological mechanisms in POEMS syndrome
have made vascular stenosis worsen more rapidly than in
idiopathic moyamoya disease and a few months was not
long enough for collateral circulation system to develop sufficiently.
Furthermore, this immature collateral circulation system
might have been affected by chemotherapy, resulting in the
patient’s pathology. Anti-plasma cell chemotherapy is considered to be effective for POEMS syndrome in principle (1). However, because VEGF is important in angiogenesis in POEMS syndrome (1), anti-plasma cell chemotherapy
might have caused collapse of immature collateral circulation system by decreasing the serum level of VEGF and
might have affected the ischemic mechanisms in the present
case. Therefore, it may be important to discuss how to use
optional anti-ischemic agents appropriately, such as antiplatelet, anticoagulant, and possible vasodilation agents,
when administering the chemotherapeutic drugs for POEMS
patient with stenotic vascular lesion(s).
POEMS syndrome-associated quasi-moyamoya disease is
extremely rare, and only two cases have been reported to
date (4, 5). Yamaguchi et al. reported a 49-year-old woman
with plasmacytoma-associated POEMS syndrome, who developed quasi-moyamoya disease-related intracranial hemorrhage during the disease remission period 5 years after radiation therapy for plasmacytoma (4). Sekiguchi et al. reported a 45-year-old man with plasmacytoma-associated POEMS syndrome, who developed quasi-moyamoya diseaserelated recurrent cerebral infarction while chemotherapy for
POEMS syndrome failed because of adverse effects (5).
These reports suggest that quasi-moyamoya disease can progress during the “treatment cessation period” (5) and can
also progress during the “remission period” of POEMS syndrome (4), resulting in cerebral stroke. Therefore, our case
is the first report of POEMS syndrome-associated quasimoyamoya disease that progressed and resulted in recurrent
cerebral infarction despite ongoing chemotherapy.
Our patient was treated with immunomodulatory drugs
(IMiDs), such as lenalidomide or pomalidomide. Thalidomide and its analogs, lenalidomide and pomalidomide, are
referred to as IMiDs and have been reported to have multiple actions with direct and/or indirect antitumor effects (10, 11). These actions include immunomodulatory, antiangiogenic, antiinflammatory, and antiproliferative effects (10, 11). These IMiDs are currently considered to be
fundamental antimyeloma agents with a high efficacy and
are now widely used (12). Furthermore, as most POEMS

syndrome patients have the same underlying plasma cell pathology as myeloma, IMiDs have also become promising
key drugs for its treatment (1, 13). Our patient, however,
showed a progression of quasi-moyamoya disease and developed recurrent cerebral ischemic attacks despite effective
treatment with IMiDs. As the 5-year risk of cerebral infarction in POEMS syndrome has been reported to be as high as
13.4% (14) and IMiDs therapy combined with dexamethasone is known to be associated with increased risk of venous thromboembolism (15), it is recommended to add antiplatelet therapy when treating patients with IMiDs (15).
However, antithrombotic therapy may be insufficient to
completely prevent cerebral infarction (6), because some reports have indicated that patient with POEMS syndrome
could develop cerebral infarction despite prophylactic antithrombotic therapy during the period of treatment with
IMiDs and/or dexamethasone (6, 16). As in these cases, our
patient also developed cerebral infarction even with prophylactic aspirin treatment. IMiDs therapy was therefore
thought to be associated with the underlying mechanism of
cerebral infarction in our patient to some degree. Hence, an
appropriate assessment of systemic vascular status, including
cerebral MRI/MRA before treatment initiation, is necessary
for the risk management of PAV. Careful monitoring of vascular status after initiating treatment is also recommended,
because treatment regimens with IMiDs are being used more
frequently (1, 13).
Another possible pathological mechanism of cerebrovasculopathy in this case might be associated with p.Arg4810
Lys variant in RNF213 gene. Because this variant was
known as susceptibility variant for Moyamoya disease (17)
and other intracranial artery stenosis (18), progressive cerebrovasculopathies in this patient might have been attributable to this gene variant to some extent.
In conclusion, moyamoya disease-like cerebrovascular
stenotic lesions (quasi-moyamoya disease) can be one phenotype of systemic vasculopathy of POEMS syndrome. A
patient with this condition can develop cerebral infarction
even during the period of ongoing effective chemotherapy
with prophylactic antiplatelet agents. Screening cerebral
MRI/MRA examinations at the diagnosis of POEMS syndrome and careful vascular monitoring after initiation of
treatment are recommended for all patients, especially when
treating patients with IMiDs.
The authors state that they have no Conflict of Interest (COI).

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Intern Med 61: 1603-1608, 2022

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