Progressive Cerebral Ischemia and Intracerebral Hemorrhage
after Indirect Revascularization for a Patient with Cerebral
Proliferative Angiopathy
Tomomi Kimiwada, MD, PhD,* Toshiaki Hayashi, MD, PhD,†
Misaki Takahashi, MD, PhD,* Reizo Shirane, MD, PhD,* and
Teiji Tominaga, MD, PhD‡
We previously reported a patient with cerebral proliferative angiopathy (CPA) who
showed cerebral ischemia in resting and acetazolamide-stressed N-isopropyl-p-[123I]
iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT).
At onset, the patient was treated conservatively. However, during the 2 years following
initial onset, his hemiparesis and aphasia had gradually aggravated and his IQ scores
were markedly decreased. MRI revealed progressive vascular proliferation and brain
atrophy. 123I-IMP-SPECT showed more severely impaired cerebral blood flow (CBF)
and cerebrovascular reactivity over the affected hemisphere. We performed an indirect
revascularization to augment CBF; however, his neurological deficits were not
improved and new arteriovenous shunts via extracranial-intracranial bypass were
developed, followed by an asymptomatic small intracerebral hemorrhage.
There are no reports on CPA patients who have shown cerebral hemorrhage after
indirect revascularization. Treatments for CPA are still challenging and controversial. Cases with severe stenosis of the proximal arteries may benefit from indirect
revascularization. But indirect bypass should not be indicated for such patients
without main arterial stenosis, even if they have persistent ischemia.
Key Words: Cerebral proliferative angiopathy—progressive cerebral ischemia—
indirect revascularization—intracerebral hemorrhage
© 2018 Published by Elsevier Inc. on behalf of National Stroke Association.

Introduction
We previously reported a case of cerebral proliferative
angiopathy (CPA) that showed cerebral hypoperfusion in
resting and acetazolamide-stressed N-isopropyl-p-[123I]
iodoamphetamine single-photon emission computed
tomography (123I-IMP-SPECT).1 CPA is a rare hypervascular lesion with intermingled normal brain parenchyma,
and an effective treatment strategy has not yet been established. Because the main mechanism of this disease is ischemia, therapies that increase cortical blood supply, such as
indirect revascularization procedures, can be indicated.2-7

Our previously reported patient was treated conservatively
at the time of diagnosis,1 but he showed progressive right
hemiparesis and motor aphasia. Follow-up MRI revealed
aggravation of the vascular malformation and brain atrophy,
and resting and acetazolamide-stressed 123I-IMP-SPECT demonstrated progressive cerebral hypoperfusion over the
affected hemisphere. We performed indirect revascularization
surgery to augment flow to the compromised hemisphere.
However, neither his neurological deterioration nor cerebral
hypoperfusion in 123I-IMP-SPECT was improved. Furthermore, arteriovenous (A-V) shunts developed through the

From the *Department of Neurosurgery, Miyagi Children’s Hospital, Sendai, Japan; †Department of Neurosurgery, Sendai City Hospital, Sendai,
Japan; and ‡Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Received April 9, 2018; revision received November 1, 2018; accepted November 16, 2018.
Financial Disclosure: None.
Address correspondence to Tomomi Kimiwada, MD, PhD, Department of Neurosurgery, Miyagi Children’s Hospital, 4-3-17 Ochiai, Aoba-ku,
Sendai 989-3126, Japan. E-mail: kimiwada@miyagi-children.or.jp.
1052-3057/$ - see front matter
© 2018 Published by Elsevier Inc. on behalf of National Stroke Association.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.11.021

Journal of Stroke and Cerebrovascular Diseases, Vol. 28, No. 4 (April), 2019: pp 853 858

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indirect extracranial-intracranial (EC-IC) bypass after surgery,
followed by a small asymptomatic intracerebral hemorrhage.
It is indicated that, in the case of CPA, selected patients
may benefit from a procedure to enhance blood supply to
the hypoperfused cortex. However, the surgical indication
for indirect revascularization still remains to be solved.
There are no reports on CPA that show cerebral hemorrhage after indirect revascularization. Here, we review literature regarding indirect revascularization for patients
with CPA, and discuss the surgical indication for this vascular malformation-related hypoperfusion.

Case Report
Initial History
A 13-year-old boy with disabling headaches and reversible
focal neurological deficits (mild right extremity weakness,
motor aphasia, finger agnosia, right-left disorientation, and
acalculia) was referred to our department. Neuropsychological testing revealed an average IQ score and electroencephalography was normal. MRI confirmed the presence of a
diffusely dilated extensive vascular lesion mainly located in
the sulci of the left frontal and parietal lobes without a clearly
identifiable margin (Fig 1, A). Evidence of acute ischemia and
hemorrhages was not found. Cerebral angiography (in 2011)
revealed a large hypervascular lesion with a diffuse arterial
supply involving the left anterior cerebral artery, left middle
cerebral artery, left posterior cerebral artery, and left middle
meningeal artery. Early venous filling, flow-related aneurysms, and main arterial stenosis were not found (Fig 2, A-D);
we diagnosed this vascular lesion as CPA. 123I-IMP-SPECT at
resting state showed preserved uptake within the vascular

lesion, yet lower uptake in the area adjacent to the lesion. In
addition, acetazolamide-stressed 123I-IMP-SPECT exhibited
severely impaired cerebrovascular reactivity (CVR) over the
affected left hemisphere, suggesting that his focal neurological
deficits were related to the cerebral ischemia (Fig 3, A). At
that time, we decided to treat him conservatively with antiepileptic medication.

Later Presentation
Two years after initial onset, the patient’s hemiplegia
and motor aphasia had gradually aggravated, and neuropsychological testing revealed a marked decrease in IQ
score from 102 to 76. MRI revealed progressive vascular
proliferation and brain atrophy (Fig 1, B). Resting and
acetazolamide-stressed 123I-IMP-SPECT demonstrated
more severely decreased cerebral blood flow (CBF) and
impaired CVR over the affected hemisphere (Fig 3, B).

Operation
On the suspicion that the left cerebral hemisphere was
hemodynamically compromised as a consequence of vascular steal from the large vascular lesion, we performed
an indirect revascularization procedure including encephaloduroarteriosynangiosis (EDAS) and encephalomyosynangiosis (EMS) in an effort to augment flow to the
compromised hemisphere. The left parietal branch of the
superficial temporal artery (STA) was dissected from surrounding tissues, and the skull was opened over the precentral region. The dura matter incision was as large as
possible because there was no transdural supply on the
right convexity region. A surgical view is shown in

Figure 1. Axial T2-weighted images at onset in 2011 (A); at preoperative state in 2013 (B); 2 years after indirect revascularization in 2015 (C); 5 years after
indirect revascularization in 2018 (D). Progressive vascular proliferation and brain atrophy were found.

CEREBRAL PROLIFERATIVE ANGIOPATHY AND INDIRECT REVASCULARIZATION

855

Figure 2. Angiography studies of the left ICA (A, B) and left ECA (C, D) obtained at onset in 2011. Six-vessel catheter angiography revealed a large hypervascular lesion with diffuse arterial supplies. The early venous fillings, flow-related aneurysms, and main arterial stenosis were not identified.
Angiography studies of the left ICA (E, F) and left ECA (G, H) obtained 7 days after indirect revascularization in 2013. Prominent vascular malformations
were found via left ICA angiography, but early venous fillings, flow-related aneurysms, and main arterial stenosis were not identified.
Angiography studies of the left ICA (I, J) and left ECA (K, L) obtained 2 years after indirect revascularization in 2015. Vascular malformation became more
prominent. A part of the vascular lesion in left parietal lobe followed by the early venous filling (arrow) were found via left ECA angiography. Abbreviations:
ICA; ECA, external carotid artery.

Figure 4. The dissected STA was placed on the pial surface
of the brain. The dura matter was closed with galea and
temporal fascia. There were no complications.

Postoperative Course
Cerebral angiography, performed 7 days after indirect
revascularization (in 2013), revealed more prominent vascular proliferation via left internal carotid artery (ICA)
angiography. However, early venous filling, flow-related
aneurysms, and main arterial stenosis were not found
(Fig 2, E-H). The patient did not present any neurological

aggravation during the first year of the follow-up period
after the operation. However, 2 years after surgery, his
right hemiparesis and motor aphasia had gradually
aggravated, and neuropsychological testing revealed a
further decrease in IQ score to 60. MRI showed more progressed proliferation of the vascular lesions and brain
atrophy (Fig 1, C,D). In addition, a small asymptomatic
intracerebral hemorrhage was observed in left frontal lobe
(Fig 5, arrow). Cerebral angiography, performed 2 years
after indirect revascularization (in 2015), revealed a more
intense hypervascular malformation with diffuse arterial
supplies. A part of the vascular lesion in left parietal lobe,

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T. KIMIWADA ET AL.

Figure 3. 123I-IMP-SPECT studies at onset in 2011 (A); at preoperative state in 2013 (B); and 1 year after indirect revascularization in 2014 (C). Resting studies are shown in the upper row, and acetazolamide-stress studies are shown in the lower row. Progressive severely impaired CBF and CVR were found 2 years
after onset, and were not improved after indirect revascularization. Abbreviations: 123I-IMP-SPECT, [123I] iodoamphetamine single-photon emission computed
tomography; CBF, cerebral blood flow; CVR, cerebrovascular reactivity.

Figure 4. A: A red line shows the skin incision. B: Intraoperative view. The dura was inserted in the brain surface (black lines). Abnormally dilated vessels were
found on the brain surface. (Color version of figure is available online.)

which had been supplied by left ICA in 2011 and 2013, was
supplied by left STA via left external carotid artery angiography, which was the result of EDAS. In addition, early
venous filling mainly supplied by left STA was newly
observed, suggesting that indirect revascularization
resulted in (A-V) shunts via EC-IC bypass (Fig 2, E-H).
Flow-related aneurysms and main arterial stenosis were
not found. Resting and acetazolamide-stressed 123I-IMPSPECT did not show improved CBF and CVR after surgery
(Fig 3, C). We treat the patient conservatively after indirect
revascularization.

Discussion
There are only a few reports that describe treatments for
patients with CPA. Because hemorrhagic presentations are

exceptional and a transient cerebral ischemia is a nature of
this disease, we selected conservative therapy at onset.
However, 2 years after onset, the patient’s hand-grip
strength and motor aphasia worsened, and neuropsychological testing revealed a marked decrease in IQ score from 102
to 76. In addition, resting and acetazolamide-stressed
123
I-IMP-SPECT demonstrated more severely decreased
CBF and impaired CVR over the affected hemisphere. Thus,
we decided to perform indirect revascularization to augment flow to the compromised hemisphere.
Lasjaunias et al described that one of the major pathomechanisms of CPA was ischemia (which in itself is probably
multifactorial owing to incompetent angiogenesis, steal phenomena, arterial stenosis, and capillary wall involvement),
and a therapy that enhanced cortical blood supply could be
indicated.4 To our knowledge, there are only 6 reports on

+
+

NA

+
¡
¡
TIA, HA
TIA, HA papilledema
Hemiparesis HA,
decreased IQ
36/M
8/M
15/M
1
1
1
Liu et al in 2016
Puerta et al in 2017
Our case

8/M
1
Sakata et al in 2016

Abbreviations: CPA, cerebral proliferative angiopathy; EDAS, encephaloduroarteriosynangiosis; EMS, encephalomyosynangiosis; HA, headache; IVH, intraventricular hemorrhage; NA, not
available; TIA, transient ischemic attack.

+
¡
¡

+

Targeted embolization
burr holes
EDAS
Pial synangiosis
EMS, EDAS

+

¡

2
1
1

NA
4/F
33/M

HA
Hemiparesis
Decreased hand-grip
strength
TIA, IVH

+

+
+
+
Burr holes
EMS, pial synangiosis
EDAS

+
+

NA

NA
NA

857

Lasjaunias et al in 2008
Ellis et al in 2011
Kono et al in 2014

Progression of CPA
Arterial stenosis
Symptoms
Sex/age at surgery
No. of cases

CPA that was treated to improve cerebral hypoperfusion.2-7
All 6 reports described indirect revascularization such as calvarial burr holes, pial synangiosis, EMS, dural inversion, and
EDAS for hypoperfused cortex. Five reports among 6 demonstrated favorable outcome. One case, an 8-year-old boy
with CPA, underwent pial synangiosis and EMS; nevertheless, he developed a permanent hemiparesis with progressive gait disturbance6 as a natural course of CPA. These
previous reports are summarized in Table 1. Our case also
showed neurological aggravation after indirect revascularization with newly developed A-V shunts via EC-IC bypass
and asymptomatic intracerebral hemorrhage. The patient’s
neurological aggravation is probably due to the progressive
natural course of CPA, but there are no reports on CPA
which showed cerebral hemorrhage after indirect revascularization. It is not clear why hemorrhagic presentation of this
patient occurred. One speculation is due to a natural course
of CPA, and the other is due to hemodynamic changes
occurred in the affected hemisphere via newly developed
EC-IC bypass, followed by intracerebral hemorrhage.
Several reports suggest that some selected patients may
benefit from a procedure to enhance blood supply to the
hypoperfused cortex and prevent further neurological aggravation. However, it is not clear which patients benefit from
indirect revascularization. We have the following 2 speculations which affect the benefit to patients: 1 is the cause for
cerebral ischemia. There are mainly 2 causes for the cerebral
ischemia on CPA: stenosis of the proximal arteries and arterial steal. Our patient did not show any stenosis of the proximal arteries, suggesting the reason for cerebral ischemia was
arterial steal due to the large vascular malformation. According to the previous reports shown in Table 1, cases without
stenosis of the proximal arteries may not benefit from indirect revascularization. The other cause is relationship of the
location of the vascular malformation and indirect revascularization. We performed indirect revascularization over the

Authors (year)

Figure 5. Axial T1-weighted images at 2 years after indirect revascularization in 2015. A small intracerebral hemorrhage was found in left frontal lobe
(arrow).

Table 1. Summary of literature cases of CPA with revascularization

Surgery

Surgical benefit

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vascular malformation because decreased CBF was prominent in this area. However, new A-V shunts via EC-IC
bypass developed. In cases with vascular malformation on
the brain surface, indirect revascularization for this hypervascularized brain surface may not be effective and can result in
new A-V shunts via EC-IC bypass. Marks et al reported a
markedly elevated level of vascular endothelial growth factor and basic fibroblast growth factor in the CSF with normal
plasma levels.8 These factors are thought to be implicated in
the angiogenesis occurring in brain A-V malformations.9-11
The authors tried bevacizumab, a monoclonal antibody that
binds to vascular endothelial growth factor, in the hope that
it would alter the vascular proliferation process, but without
favorable outcome. Because the angiogenesis tends to occur
in CPA as well, it is difficult to predict whether indirect
revascularization can be effective. From the point of view of
hemorrhage, Maekawa et al suggested that revascularization
surgery for CPA may attenuate the vascular proliferation in
the vicinity of the ventricle and prevent periventricular hemorrhage.12 They discussed that vulnerable collateral vessels
developed in response to cerebral ischemia were the supposed culprit of intraventricular bleeding like moyamoya
disease, and might prevent bleeding. However, more cases
are needed to establish management for CPA.
In conclusion, we have presented a patient with CPA
who showed progressive cerebral ischemia over a 2-year
period, with indirect revascularization followed by the
development of EC-IC A-V shunts and intracerebral hemorrhage. It is questionable whether an indirect revascularization for CPA-related cerebral hypoperfusion is
reasonable. But it seems to be possible that cases with
severe stenosis of the proximal arteries may benefit from
indirect revascularization. Further, restricted surgical
indication should be confirmed and long-term follow-up
is necessary to evaluate the effects of indirect revascularization for patients with CPA.

References
1. Kimiwada T, Hayashi T, Shirane R, et al. 123I-IMP-SPECT
in a patient with cerebral proliferative angiopathy: a case
report. J Stroke Cerebrovasc Dis 2013;22:1432-1435.
2. Ellis MJ, Armstrong D, Dirks PB. Large vascular malformation in a child presenting with vascular steal phenomenon managed with pial synangiosis. J Neurosurg
Pediatr 2011;7:15-21.
3. Kono K, Terada T. Encephaloduroarteriosynangiosis for
cerebral proliferative angiopathy with cerebral ischemia.
J Neurosurg 2014;121:1411-1415.
4. Lasjaunias PL, Landrieu P, Rodesch G, et al. Cerebral proliferative angiopathy: clinical and angiographic description of an
entity different from cerebral AVMs. Stroke 2008;39:878-885.
5. Liu P, Lv X, Lv M, et al. Cerebral proliferative angiopathy: clinical, angiographic features and literature review.
Interv Neuroradiol 2016;22:101-107.
6. Puerta P, Guillen A, Muchart J, et al. Cerebral proliferative angiopathy in a child. Pediatr Neurosurg
2017;52:214-216.
7. Sakata H, Fujimura M, Sato K, et al. Development of
abnormal hemispheric vascular networks mimicking
cerebral proliferative angiopathy in a child originally
diagnosed with deep-seated arteriovenous fistula. J
Stroke Cerebrovasc Dis 2016;25:e200-e204.
8. Marks MP, Steinberg GK. Cerebral proliferative angiopathy. J Neurointerv Surg 2012;4:e25.
9. Leblanc GG, Golanov E, Awad IA, et al. Biology of vascular malformations of the brain NWC: biology of vascular
malformations of the brain. Stroke 2009;40:e694-e702.
10. Lim M, Cheshier S, Steinberg GK. New vessel formation
in the central nervous system during tumor growth, vascular malformations, and Moyamoya. Curr Neurovasc
Res 2006;3:237-245.
11. Sonstein WJ, Kader A, Michelsen WJ, et al. Expression of
vascular endothelial growth factor in pediatric and adult
cerebral arteriovenous malformations: an immunocytochemical study. J Neurosurg 1996;85:838-845.
12. Maekawa H, Terada A, Ishiguro T, et al. Recurrent periventricular hemorrhage in cerebral proliferative angiopathy: case report. Interv Neuroradiol 2018;24:713-717.
https://doi.org/10.1177/1591019918787265.