Case Report

Detection of Transient Increase of Cerebral Blood Flow and Reversible Neuronal
Dysfunction by Iodine-123-Iomazenil Single Photon Emission Computed Tomography
After Cerebral Hyperperfusion Syndrome After Revascularization Surgery for Moyamoya
Disease
Mami Yamasaki, Hideyuki Yoshioka, Kazuya Kanemaru, Takashi Yagi, Koji Hashimoto, Nobuo Senbokuya,
Hiroyuki Kinouchi

Key words
- Cerebral hyperperfusion
- IMZ SPECT
- Moyamoya disease
- Neuronal damage

Abbreviations and Acronyms
CBF: Cerebral blood flow
CBZ: Central benzodiazepine
CMRO2: Cerebral metabolic oxygen rates
123
I-IMP: 123I-N-isopropyl-p-iodoamphetamine
123
I-IMZ: 123I-iomazenil
MCA: Middle cerebral artery
MR: Magnetic resonance
PET: Positron emission tomography
SPECT: Single photon emission computed
tomography
STA: Superficial temporal artery
Department of Neurosurgery, Interdisciplinary Graduate
School of Medicine and Engineering, University of
Yamanashi, Yamanashi, Japan
To whom correspondence should be addressed:
Hiroyuki Kinouchi, M.D., Ph.D.
[E-mail: hkinouchi@yamanashi.ac.jp]
Citation: World Neurosurg. (2020) 141:335-338.
https://doi.org/10.1016/j.wneu.2020.06.014

- BACKGROUND: Early and late images of single photon emission computed
123
123

tomography (SPECT) using I-iomazenil ( I-IMZ) can demonstrate cerebral
blood flow and cortical neuronal viability. Hyperperfusion syndrome is one of the
serious complications after revascularization surgery for moyamoya disease;
therefore, the real-time observation of the hemodynamics and neuronal viability
is important for the treatment after the revascularization. Here we report, a case
of moyamoya disease where 123I-IMZ SPECT had a significant efficacy to
delineate the hemodynamics and transient neuronal dysfunction in hyperperfusion state after revascularization.

- CASE DESCRIPTION: A 47-year-old woman presented with motor aphasia 3

days after superficial temporal arteryemiddle cerebral artery anastomosis with
indirect revascularization. Magnetic resonance imaging (MRI) on the same day
showed no new ischemic changes but high intensities along the left frontal sulci
observed on fluid-attenuated inversion recovery images, and 123I-IMZ SPECT
demonstrated the increased uptake on the early images and the decreased
uptake on the late images around the anastomosis site. The patient was
completely recovered 1 month after surgery, and abnormal changes on MRI and
123
I-IMZ SPECT returned to normal along with the symptom withdrawal.
findings indicate that 123I-IMZ SPECT could be the
index for the treatment of revascularization for obstructive vascular diseases
such as moyamoya disease.

- CONCLUSIONS: These

Journal homepage: www.journals.elsevier.com/worldneurosurgery
Available online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2020 Elsevier Inc. All
rights reserved.

INTRODUCTION
123

I-iomazenil (123I-IMZ) is a specific radioligand for central benzodiazepine (CBZ) receptors expressing sufficiently in the
membrane of neurons, and single photon
emission computed tomography (SPECT)
using this ligand has been used to reveal
pathologic lesions such as epilepsy, stroke,
and traumatic brain injury.1-4 123I-IMZ
SPECT study is conducted in 2 phases: 1)
images obtained within 30 minutes after
administration of 123I-IMZ (early images)
correlate with the distribution of cerebral
blood flow (CBF),5 and 2) those at 180

minutes after the tracer administration
(late images) are in proportion to the
density of the CBZ receptors representing
brain neural density.2,6,7 Furthermore, it
has been indicated that late images could
demonstrate a reversible neuronal damage
or dysfunction.8,9 Therefore, early and late
images of 123I-IMZ SPECT have different
roles to measure hemodynamics, and
cortical neuronal function and viability,
respectively.
Cerebral hyperperfusion is the hemodynamic state of a significant increase in
CBF with the disruption of autoregulation,
and has been reported to occur in 15%e
38% of patients with adult moyamoya
disease after superficial temporal artery
(STA) emiddle cerebral artery (MCA)

WORLD NEUROSURGERY 141: 335-338, SEPTEMBER 2020

anastomosis.10,11 Symptoms are reversible
in most patients, but rarely severe and
life-threatening. Therefore, accurate and
prompt demonstration of the hemodynamic state and the neuronal dysfunction
is critical to adequate management.
CBF cannot be examined in the ordinary
clinical practice without using special diagnostic equipment such as computed
tomography and magnetic resonance (MR)
perfusion imaging, SPECT using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) and
99m
Tc-ethyl cysteinate dimer, and positron
emission tomography (PET) scan using 15O
with a steady-state method.12,13 Similarly,
neuronal activity can be only measured as
cerebral metabolic rate of oxygen using
15
O-PET.14 Therefore, demonstration of the

www.journals.elsevier.com/world-neurosurgery

335

CASE REPORT
MAMI YAMASAKI ET AL.

causal brain lesion for a temporary
neurologic
symptom
because
of
hyperperfusion without abnormal findings
on ordinary neuroradiologic imaging is
difficult.
Here, we report the efficacy of 123IIMZ SPECT to reveal the hyperperfusion
state after revascularization by demonstrating hemodynamic state on the early
image and temporary neuronal dysfunction on the late image in moyamoya
disease.
CLINICAL PRESENTATION
A 47-year-old woman was referred to our
hospital with speech disturbance for 2
weeks. On admission, her spontaneous
speech was fluent, but word-finding difficulties were noticed. MR imaging demonstrated subacute hemorrhage in the left
subcortical temporal lobe (Figure 1A and B).
Digital subtraction angiography revealed
stenotic changes around the terminal
portions of the bilateral internal carotid
arteries with abnormal proliferation of
moyamoya vessels, and she was diagnosed
with moyamoya disease (Figure 1C and D).
Preoperative MR imaging revealed no
abnormal lesion other than a scar resulting
from intracerebral hemorrhage (Figure 2A),
and MR angiography showed severe
stenoses of the bilateral internal carotid
arteries at the terminal portions
(Figure 2B). 123I-IMP SPECT showed
decrease of CBF in the bilateral cerebral
hemispheres (Figure 2C). On the early and
late images of 123I-IMZ SPECT before
treatment, there were no evident lateralities
(Figure 2D and E).
For the prevention of a future
rebleeding, she underwent STA-MCA
double anastomoses with indirect revascularization surgery in the left hemisphere at 3 months after the onset of
intracranial hemorrhage. The recipient
arteries at the M4 segment of the left
frontal and temporal lobes were anastomosed to the parietal and frontal
branches of the left STA, respectively,
then, encephalo-duro-myo-synangiosis
was also performed in the left frontotemporal area. We controlled systolic
blood pressure from 100 to 140 mm Hg
after the operation.
She presented with motor aphasia on day
3. MR imaging showed no new ischemic
changes, but high intensities along the left

336

www.SCIENCEDIRECT.com

IMZ SPECT OF HYPERPERFUSION IN MOYAMOYA

frontal sulci were observed on fluidattenuated inversion recovery images
(Figure 2F). The patency of STA-MCA
anastomosis was confirmed by MR angiography (Figure 2G). The images of 123I-IMP
SPECT revealed marked increase of the CBF
around the anastomosis site of the frontal
lobe (Figure 2H). The uptake in the
responsible lesion for motor aphasia was
increased on the early images of 123I-IMZ
SPECT corresponding to those of 123I-IMP
SPECT (Figure 2I), whereas the uptake on
the late images was remarkably decreased
(Figure 2J). We diagnosed this as
hyperperfusion syndrome, and the
patient's systolic blood pressure was more
strictly controlled from 100 to 120 mm Hg
with continuous administration of a
calcium channel blocker. The symptom
gradually resolved by blood pressure
control, and the patient was completely
recovered 1 month after surgery. High
intensities on fluid-attenuated inversion
recovery images along the left frontal sulci
disappeared (Figure 2K). MR angiography
showed the patency of the bypass
(Figure 2L). 123I-IMP SPECT demonstrated
normalization
of
hyperperfusion
(Figure 2M). Abnormal findings on both
early and late images of 123I-IMZ SPECT
were also normalized along with symptom
withdrawal (Figure 2N and O).
Consent
The second author of this paper has obtained patient consent for anonymized
publication of the case.
DISCUSSION
This case report demonstrated the effectiveness of 123I-IMZ SPECT in detecting
transient increase of CBF and reversible
vulnerability of neurons in cerebral
hyperperfusion syndrome after revascularization surgery for moyamoya disease.
123
I-IMP SPECT with autoradiographic
method and 15O-PET remain the criterion
standard for the accurate diagnosis of
postoperative hyperperfusion. Early images of 123I-IMZ SPECT were reported to
correlate with CBF images on 15O-PET,5
and the early images of the present case
showed increased uptake, corresponding
to the findings of 123I-IMP SPECT.
Therefore, 123I-IMZ SPECT early images
can be an alternative modality for the
diagnosis of cerebral hyperperfusion.

However, CBF images of 123I-IMZ SPECT
are not quantitative, which is a
disadvantage compared with 123I-IMP
SPECT, the current criterion standard for
CBF measurement. Although the dose is
not high, 123I-IMZ SPECT has a
disadvantage that patients are exposed to
approximately 5 mSv of radiation,15
which is almost equivalent to cranial CT
scan (3 mSv).
On the other hand, in recent years, MR
perfusion has been used to detect postoperative hyperperfusion state. Cerebral
blood volume can be measured by perfusion
MR imaging with gadolinium-based
contrast agents, and it has been applied to
detect hyperperfusion state not only
after carotid revascularization,16 but
also after STA-MCA anastomosis in moyamoya disease.17 In addition, intracranial
hemodynamics have been recently
examined by arterial spin labeling
perfusion without contrast agents, and its
usefulness in detecting hyperperfusion
state in moyamoya disease has been
reported.18,19 Accuracy of diagnosis may be
inferior to SPECT, but MR perfusion has
an advantage of avoiding radiation
exposure, and this imaging technique
should be developed further in the near
future.
Late 123I-IMZ SPECT images demonstrated postoperative cortical neuronal loss
in hyperperfusion after carotid endarterectomy, and postoperative cognitive impairment was significantly associated with the
decrease of uptake.20 Recently, effectiveness
was also demonstrated in hyperperfusion
after revascularization for carotid stenosis
and moyamoya disease,21,22 which is
consistent with this report.
Although reduced uptake on the late
123
I-IMZ SPECT images is considered as
irreversible, recent reports have shown
that the late images of this radioligand
could also demonstrate a reversible
neuronal damage or dysfunction. The
reduced uptake after head trauma recovered as the neurologic function improved,8
and the reduction of uptake around the
tumor recovered after the surgical
removal along with the improvement of
cognitive function.9 Consisting with
these reports, the reduction of the uptake
on late images of the present case
recovered along with the disappearance
of the symptom. It is suggested that 123IIMZ SPECT late images have the

WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2020.06.014

CASE REPORT
MAMI YAMASAKI ET AL.

IMZ SPECT OF HYPERPERFUSION IN MOYAMOYA

Figure 1. (A) T1- and (B) T2-weighted magnetic resonance
images demonstrating subacute intracranial hemorrhage in the
left temporal lobe. Anteroposterior views of carotid angiograms

potential to detect reversible viability of
neurons.
Although the detailed mechanism for
the reduction of CBZ receptors binding
affinity during the acute phase of brain
injury remains obscure, one of the speculated mechanisms is the reduction of

(C: right, D: left) showing severe stenosis of bilateral internal
carotid arteries at the terminal portions and progression of
moyamoya collateral vessels.

cerebral metabolic oxygen rates (CMRO2).
The relationship between the binding affinity of CBZ receptors and cerebral
metabolism was investigated in patients
with traumatic brain injury using flumazenil PET, and all the areas of decreased
flumazenil uptake showed low CMRO2.23

Figure 2. (AeE) Preoperative images. Fluid-attenuated inversion recovery
(FLAIR) (A). Magnetic resonance (MR) angiography (B).
123
I-N-isopropyl-p-iodoamphetamine (123I-IMP) single photon emission
computed tomography (SPECT) revealing decrease of cerebral blood flow
(CBF) in the bilateral cerebral hemispheres (C). 123I-iomazenil (123I-IMZ)
SPECT (D: early, E: delay) showing no lateralities. (FeJ) Images during the
period of hyperperfusion syndrome. FLAIR images showing high intensities
along the left frontal sulci (F). MR angiography revealing the patency of
superficial temporal arteryemiddle cerebral artery anastomosis (G).

WORLD NEUROSURGERY 141: 335-338, SEPTEMBER 2020

Shimada et al.22 recently reported that
crossed cerebellar hypoperfusion was
observed on 123I-IMP SPECT, indicating
the reduction of metabolism in the
contralateral cerebral hemisphere, in
company with the decreased uptake on
123
I-IMZ SPECT late images during

123
I-IMP SPECT revealing increased rest CBF around the anastomosis site
of the left frontal lobe (H) in accordance with the increased uptake on the
early images of 123I-IMZ SPECT (I). Late images of 123I-IMZ SPECT showing
the remarkable decrease of the uptake in the lesion (J). (KeO) Images 1
month after the surgery. Fluid-attenuated inversion recovery images
showing no additional abnormal changes (K). MR angiography revealing the
patency of bypass (L). 123I-IMP SPECT demonstrating disappearance of
hyperperfusion at the left frontal lobe (M). Both early (N) and late (O) images
of 123I-IMZ SPECT showing improvement of abnormal findings.

www.journals.elsevier.com/world-neurosurgery

337

CASE REPORT
MAMI YAMASAKI ET AL.

hyperperfusion after revascularization
surgery of moyamoya disease. Then, they
suggested that the reduction of cerebral
metabolism would downregulate cortical
neurotransmitter receptors including
CBZ. However, the reduction of CBZ
receptors binding affinity in the present
case cannot be explained by this
mechanism because crossed cerebellar
diaschisis was not observed in the
present case (data not shown). Moreover,
a previous study reported that CMRO2 in
patients with hyperperfusion after
revascularization of moyamoya disease
was not reduced.24 Therefore, further
investigation of the CBZ receptors
binding affinity and cerebral metabolism
is necessary to clarify the mechanism
and the discrepancy of these findings.
Finally, 123I-IMZ SPECT can indicate
information not only about CBF, but also
neuronal viability. Therefore, this imaging
modality would be useful for the understanding of complex pathologic conditions in patients with moyamoya disease
after revascularization, which would
enable us to manage patients appropriately and promptly. In addition, there is a
possibility that 123I-IMZ SPECT would
predict the prognosis of patients after
hyperperfusion syndrome because it can
disclose the reversibility of neurologic
dysfunction. Further studies should be
conducted to prove these issues.
CONCLUSIONS
I-IMZ SPECT findings of the present
case suggest its effectiveness in detecting
transient increase of CBF and reversible
vulnerability of neurons simultaneously.

123

REFERENCES
1. Abiko K, Ikoma K, Shiga T, et al. I-123 iomazenil
single photon emission computed tomography for
detecting loss of neuronal integrity in patients with
traumatic brain injury. EJNMMI Res. 2017;7:28.
2. Hatazawa J, Satoh T, Shimosegawa E, et al.
Evaluation of cerebral infarction with iodine 123e
iomazenil SPECT. J Nucl Med. 1995;36:2154-2161.
3. Umeoka S, Matsuda K, Baba K, et al. Usefulness
123
I-iomazenil
single-photon
emission
of
computed tomography in discriminating between
mesial and lateral temporal lobe epilepsy in patients in whom magnetic resonance imaging
demonstrates normal findings. J Neurosurg. 2007;
107:352-363.

338

www.SCIENCEDIRECT.com

IMZ SPECT OF HYPERPERFUSION IN MOYAMOYA

4. van Huffelen AC, van Isselt JW, van Veelen CW,
et al. Identification of the side of the epileptic
focus with 123I-Iomazenil SPECT. A comparison
with 18FDG-PET and ictal EEG findings in patients
with medically intractable complex partial seizures. Acta Neurochir Suppl. 1990;50:95-99.
5. Suzuki T, Ogasawara K, Kuroda H, et al. Comparison of early and late images on 123I-iomazenil
SPECT with cerebral blood flow and oxygen
extraction fraction images on PET in the cerebral
cortex of patients with chronic unilateral major
cerebral artery occlusive disease. Nucl Med Commun. 2012;33:171-178.
6. Millet P, Graf C, Moulin M, Ibáñez V. SPECT
quantification of benzodiazepine receptor concentration using a dual-ligand approach. J Nucl
Med. 2006;47:783-792.
7. Nakagawara J, Sperling B, Lassen NA. Incomplete
brain infarction of reperfused cortex may be
quantitated with iomazenil. Stroke. 1997;28:
124-132.
8. Koizumi H, Fujisawa H, Kurokawa T, et al.
Recovered neuronal viability revealed by Iodine123-iomazenil SPECT following traumatic brain
injury. J Cereb Blood Flow Metab. 2010;30:1673-1681.
9. Koizumi H, Ideguchi M, Iwanaga H, et al.
Cognitive dysfunction might be improved in association with recovered neuronal viability after
intracranial meningioma resection. Brain Res.
2014;1574:50-59.
10. Fujimura M, Kaneta T, Mugikura S, Shimizu H,
Tominaga T. Temporary neurologic deterioration
due to cerebral hyperperfusion after superficial
temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya
disease. Surg Neurol. 2007;67:273-282.
11. Hayashi K, Horie N, Suyama K, Nagata I. Incidence and clinical features of symptomatic cerebral hyperperfusion syndrome after vascular
reconstruction. World Neurosurg. 2012;78:447-454.
12. Iida H, Itoh H, Nakazawa M, et al. Quantitative
mapping of regional cerebral blood flow using
iodine-123-IMP and SPECT. J Nucl Med. 1994;35:
2019-2030.
13. Tsuchida T, Nishizawa S, Yonekura Y, et al.
SPECT images of technetium-99m-ethyl cysteinate
dimer in cerebrovascular diseases: comparison
with other cerebral perfusion tracers and PET.
J Nucl Med. 1994;35:27-31.
14. Frackowiak RS, Lenzi GL, Jones T, Heather JD.
Quantitative measurement of regional cerebral
blood flow and oxygen metabolism in man using
15
O and positron emission tomography: theory,
procedure, and normal values. J Comput Assist
Tomogr. 1980;4:727-736.
15. Verhoeff NP, Busemann Sokole E, Hengst D,
Stubbs JB, van Royen EA. Dosimetry of iodine-123
iomazenil in humans. Eur J Nucl Med. 1993;20:
580-584.
16. Fukuda T, Ogasawara K, Kobayashi M, et al.
Prediction of cerebral hyperperfusion after carotid

endarterectomy using cerebral blood volume
measured by perfusion-weighted MR imaging
compared with single-photon emission CT. AJNR
Am J Neuroradiol. 2007;28:737-742.
17. Furuya K, Kawahara N, Morita A, et al. Focal
hyperperfusion after superficial temporal arterymiddle cerebral artery anastomosis in a patient
with moyamoya disease. Case report. J Neurosurg.
2004;100:128-132.
18. Sugino T, Mikami T, Miyata K, et al. Arterial spinlabeling magnetic resonance imaging after revascularization of moyamoya disease. J Stroke
Cerebrovasc Dis. 2013;22:811-816.
19. Uchino H, Ito M, Fujima N, et al. A novel application of four-dimensional magnetic resonance
angiography using an arterial spin labeling technique for noninvasive diagnosis of Moyamoya
disease. Clin Neurol Neurosurg. 2015;137:105-111.
20. Chida K, Ogasawara K, Suga Y, et al. Postoperative cortical neural loss associated with
cerebral hyperperfusion and cognitive impairment
after carotid endarterectomy: 123I-iomazenil
SPECT study. Stroke. 2009;40:448-453.
21. Ogasawara Y, Ogasawara K, Suzuki T, et al. Preoperative 123I-iomazenil SPECT imaging predicts
cerebral hyperperfusion following endarterectomy
for unilateral cervical internal carotid artery
stenosis. Am J Nucl Med Mol Imaging. 2012;2:77-87.
22. Shimada Y, Kojima D, Yoshida J, et al. Transient
symptomatic downregulation of cortical neurotransmitter receptor function due to cerebral
hyperperfusion after arterial bypass surgery for a
patient with ischemic moyamoya disease. Neurol
Med Chir (Tokyo). 2018;58:481-484.
23. Shiga T, Ikoma K, Katoh C, et al. Loss of neuronal
integrity: a cause of hypometabolism in patients
with traumatic brain injury without MRI abnormality in the chronic stage. Eur J Nucl Med Mol
Imaging. 2006;33:817-822.
24. Kaku Y, Iihara K, Nakajima N, et al. Cerebral
blood flow and metabolism of hyperperfusion
after cerebral revascularization in patients with
moyamoya disease. J Cereb Blood Flow Metab. 2012;
32:2066-2075.

Conflict of interest statement: The authors declare that the
article content was composed in the absence of any
commercial or financial relationships that could be construed
as a potential conflict of interest.
Received 19 February 2020; accepted 2 June 2020
Citation: World Neurosurg. (2020) 141:335-338.
https://doi.org/10.1016/j.wneu.2020.06.014
Journal homepage: www.journals.elsevier.com/worldneurosurgery
Available online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2020 Elsevier Inc. All
rights reserved.

WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2020.06.014