Yonago Acta medica 2013;56:7–12

Original Article

Radiation-Induced Microbleeds after Cranial Irradiation: Evaluation by Phase-Sensitive
Magnetic Resonance Imaging with 3.0 Tesla
Tomohiko Tanino,* Yoshiko Kanasaki,* Takatoshi Tahara,* Koichi Michimoto,* Kazuhiko Kodani,* Suguru Kakite,*Toshio Kaminou,* Takashi Watanabe† and Toshihide Ogawa**Division of Radiology, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Facultyof Medicine, Yonago 683-8504, Japan and †Division of Neurosurgery, Department of Brain and Neurosciences, School of Medicine,
Tottori University Faculty of Medicine, Yonago 683-8504, Japan

ABSTRACT

Conclusion Radiation-induced microbleeds occurred
more frequently in the present study than has been previously reported. PSI can be used to detect these vascular changes earlier than other conventional MR imaging
techniques.

Background

Although there are many reports regarding radiation-induced microbleeds, its frequency,
relation to dose and latency after radiation are not fully
elucidated. The purpose of this study was to evaluate thefrequency, latency, patient factors and dose relation ofradiation-induced microbleeds after cranial irradiation
using phase-sensitive magnetic resonance imaging (PSI)
at 3.0 T.
Methods Retrospective evaluation of 34 patients (agerange, 13–78 years; mean, 49 years; follow-up period,
3–169 months; mean 29 months) who had undergone
cranial irradiation using magnetic resonance (MR)imaging including PSI was performed. Twenty-threepatients received high-dose irradiation (44–60 Gy), and11 patients received 24–30 Gy whole brain irradiation.
When microbleeds were detected on MR imaging inthese high-dose irradiation patients, dose distribution
maps were reproduced by reviewing the clinical records.
Then the irradiated areas were divided into 6 radiationdose classes: regions > 55 Gy, 45–55 Gy, 35–45 Gy,
25–35 Gy, 15–25 Gy and 5–15 Gy. The frequency of
microbleeds in each radiation-dose class was analyzed.
Results Microbleeds were detected in 7 (21%) of 34
patients on T2-weighted imaging, whereas they weredetected in 16 (47%) of the 34 patients on PSIs. The
frequency of microbleeds was higher than previously reported. The latency of radiation-induced microbleeds after radiation was 3 months to 9 years (mean, 33 months).
In high-dose irradiation patients, the frequency of microbleeds significantly was associated with radiation
dose. There were no foci that were observed in regionsthat had received < 25 Gy.

Key words
cranial irradiation; magnetic resonanceimaging; radiation injury

Radiation therapy is an efficacious treatment for brain
neoplasms. However, cranial irradiation can cause complications as well as benefits. Complications of cranial
irradiation include necrosis, diffuse white matter injury,
central nervous system atrophy, mineralization, microangiopathy, telangiectasia, optic neuropathy, and large
vessel vasculopathy.1 Although clinically importantcomplications are infrequent with modern radiation
therapy techniques, asymptomatic complications following radiation therapy, such as diffuse white matterinjury, central nervous system atrophy, and vascular injury, can be present by follow-up computed tomography(CT) and magnetic resonance (MR) imaging. Radiationinduced vascular injury can be classified into 2 types:
large arterial injury and telangiectasia, or cryptic vascular malformation. Radiation-induced telangiectasia
in the brain results in varying amounts of hemorrhage
and may have an appearance similar to that of cryptic
vascular malformation.2 These lesions are usually small
and can be mixed with cavernous malformation. As thedifferentiation of these small lesions is often difficult on
MR imaging, we refer to these conditions as radiationinduced microbleeds. Although there have been many
reports concerning radiation-induced microbleeds in thepast, the frequency, dose relation, and latency of radiation-induced microbleeds are not fully elucidated.
MR imaging is useful for diagnosis and evaluation of these cerebral complications following radiation
therapy.3 MR imaging is currently considered to be thebest imaging technique for evaluation of brain injury
following radiation therapy.4 Susceptibility-weighted imaging (SWI) is a 3-dimensional gradient echo MR imaging technique using the blood oxygen level-dependent

Corresponding author: Tomohiko Taninot.tanino@med.tottori-u.ac.jp
Received 2012 December 4
Accepted 2012 December 13
Abbreviations: CT, computed tomography; FA, flip angle; FLAIR,
fluid attenuated inversion recovery; FOV, field of view; FSE, fast
spin echo; FSPGR, fast spoiled gradient recalled acquisition insteady state; MR, magnetic resonance; PSI, phase-sensitive magnetic resonance imaging; SWI, susceptibility-weighted imaging;TE, echo time; TI, inversion time; TR, repetition time7

T. Tanino et al.

effect.5 SWI is highly sensitive to differences of themagnetic susceptibility properties between tissues, suchas blood products (including deoxyhemoglobin, methemoglobin and hemosiderin). T2*-weighted imaging is
also considered to be a highly sensitive MR techniquefor visualization of cerebral hemorrhage. However, SWI
is currently considered to be more sensitive than otherconventional MR imaging techniques, including T2*weighted imaging, for detection of hemorrhage.6 Phasesensitive MR imaging (PSI), based on principles similar
to those of SWI, is obtained by multiplication of thephase and magnitude images using Windows-based software.
The purpose of this study was to evaluate the frequency, latency, patient factors, and dose relation of radiation-induced microbleeds after cranial irradiation using
PSI, and to evaluate the usefulness of PSI for detectionof radiation-induced microbleeds.

Table l. Patient characteristics
34
Number of patients		
GenderMale
18
Female
16
Range
13–78
Age (yr)
Mean
49
Median51
60 and over
12
Less than 60
22
3–169
Follow-up period (mo) Range
Average29
Localized irradiation
22
Irradiation
Opposing portal irradiation
1
Whole brain irradiation
11
Localized irradiation
44–60
Total dose (Gy)
Opposing portal irradiation
60
Whole brain irradiation
24–30
Number of fractions
Localized irradiation
22–30
Opposing portal irradiation
30
Whole brain irradiation
10–12
Diagnosis
High-grade gliomas
17
Central neurocytomas
2
Germinoma
2
Medulloblastoma
1
Meningioma
1
Metastasis from occult primary cancer 1
Brain metastases
8
Prophylactic cranial irradiation
for lung small cell carcinoma
2
Done
30
Chemotherapy
Not done
4
Patient with hypertension
4
Hypertension
Patient without hypertension
30
Available
21
Serial imaging
Not available
13

MATERIALS AND METHODSPatients

MR imaging and clinical records of 34 patients (18 men
and 16 women; age range, 13–78 years; mean age, 49
years) who had undergone brain irradiation and undergone MR imaging including PSI with a follow-up periodof at least 3 months were retrospectively reviewed. The
average follow-up period was 29 months (3–169 months).
Eleven patients received 24–30 Gy of whole brain irradiation. Eight of these patients had been diagnosed withbrain metastases, 1 had been diagnosed with germinoma
by biopsy, and 2 had received prophylactic cranial irradiation for lung small cell carcinoma. Twenty-two patients
received 44–60 Gy of localized brain irradiation, and1 patient received 60 Gy of opposing portal irradiation.
These patients had undergone surgical resection or biopsy and diagnoses proved by their pathological diagnosis.
The diagnoses included 17 high-grade gliomas, 2 central
neurocytomas, 1 medulloblastoma, 1 meningioma, 1germinoma and 1 metastasis from occult primary cancer. When microbleeds were detected on MR imaging inpatients who had received high-dose irradiation (44–60
Gy), dose distribution maps were reproduced by reviewing clinical records. Then, the area that had received
irradiation was divided into 6 radiation-dose classes:
regions with > 55 Gy, 45–55 Gy, 35–45 Gy, 25–35 Gy,
15–25 Gy and 5–15 Gy. One patient who received 60
Gy of opposing portal irradiation was regarded to havereceived > 55 Gy. Microbleeds were then evaluated ineach radiation-dose class region.
All 34 patients were divided into 2 groups by factors such as gender (male versus female), age (over 60

years versus less than 60 years), hypertension (with versus without), and chemotherapy (done versus not done).
Patient characteristics are summarized in Table 1. Ageis defined as the patient’s age at the beginning of the irradiation. Patients who had received medication for hypertension were classified as having hypertension.
Brain radiation therapy

Eleven patients who received whole brain irradiation
were treated with total doses between 24–30 Gy, at 2.0–
3.0 Gy dose per fraction. The treatment duration was
2–2.4 weeks. The other 23 patients were treated withtotal doses between 44–60 Gy, at a dose of 1.8–2.0 Gy
per fraction. The treatment duration was 4.4–6 weeks.
A 6 MV-Xray was used (Clinic iX 4217, Varian Medical
Systems, Palo Alto, CA; or Linac EXL-15SP Mitsubishi
Electric, Tokyo, Japan) in all patients.
MR imaging

Before and at least 3 months after completion of radiation therapy, all patients underwent MR imaging. All
8

Radiation-induced microbleeds PSI study

A

D

B

C

5500.0 cGy4500.0 cGy
3500.0 cGy
2500.0 cGy
1500.0 cGy
500.0 cGy

E

Fig. 1. A 31-year-old man with surgical resection of a high-grade glioma in the left parietal lobe, which was followed by localized irradiation at a dose of 60 Gy.
A: PSI obtained 17 months after completion of radiation therapy.
B: PSI obtained 33 months after completion of radiation therapy. A hypointense focus that cannot be detected in A appears in the leftparietal white matter in B (arrow). This focus can be interpreted as microbleed.
C: T2-weighted image obtained 33 months after completion of radiation therapy. The microbleed detected in B cannot be detected.
D: Fused PSI image. The microbleed is contoured.
E: Reproduced dose distribution map. The microbleed is recognized in regions with > 55 Gy.
PSI, phase-sensitive magnetic resonance imaging.

images were obtained using similar sequences.
PSI, on the basis of principles similar to those of
SWI,7 was acquired after the radiation therapy using
a 3-dimensional-spoiled gradient recalled acquisition
steady state sequence with flow compensation using thefollowing imaging parameters: TR/TE of 45/30 ms, FAof 20˚, FOV of 21 cm, 512 × 192 matrix, section thickness of 1.5 mm and an acquisition time of 7 min 40–50
s. All images were obtained in the axial plane. PSI were
post-processed using a high-pass filter and then the images were converted into negative phase masks that were
multiplied 4 times into the corresponding magnitude images using research software (PSIRecon: GE Yokogawa
Medical Systems, Tokyo). A minimum intensity projection was performed to display the processed data using
contiguous 10-mm-thick sections with 7-mm overlap in
the axial plane. The follow-up interval for the MR imaging was dependent on the clinical course, and serial MR
images including PSI were obtained in 21 patients afterradiation therapy.

MR brain images were obtained at 3.0 T (Signa EXCITE HD, General Electric, Milwaukee, WI) using an
8-channel phased-array coil (USA Instruments, Aurora,
OH), except for 1 patient. That patient was examined at
1.5 T (Symphony, Siemens, Germany) prior to radiation
therapy and was examined with the 3.0 T MR system
mentioned above after radiation therapy. At 3.0 T, we obtained axial T1-weighted images with and without intravenous gadopentetate dimeglumine (Magnevist; Bayer,
Osaka, Japan) using a fast spoiled gradient recalled acquisition in steady state (FSPGR) sequence, T2-weighted
fast spin echo (FSE) images, and fluid attenuated inversion recovery (FLAIR) images. The imaging parameters
were as follows: FSPGR, repetition time (TR)/echo time(TE) of 9/2 ms, flip angle (FA) of 13˚, 512 × 256 matrix,
1 excitation, 21 cm field of view (FOV), bandwidth of
122 Hz/pixel and a slice thickness of 1.4 mm without
intersection gap; T2-weighted FSE, TR/TE of 4000/95
ms, 512 × 320 matrix, 21 cm FOV, section thickness/intersection gap of 5/1.5 mm; and FLAIR, TR/TE/inversion time (TI) of 10,000/116/2500 ms, 384 × 192 matrix,
21 cm FOV and a section thickness/intersection gap of
5/1.5 mm. At 1.5 T, T1-weighted images with and without contrast medium, T2-weighted images, and FLAIR

Image evaluation

Microbleeds were determined to be present if a small
focus of very low signal-intensity was recognized on PSI
9

T. Tanino et al.
Table 2. Results of comparison between groups divided by several factors

and/or T2-weighted imaging. The presence or absence of
microbleeds was evaluated by 2 experienced neuroradiologists. Areas of surgical intervention and calcifications
were excluded by reviewing surgical records and subsequent CT performed within 1 month from MR imaging.
Regions of metastasis or residual tumor were excludedby the combined inspection of T1-weighted images andcontrast enhanced T1-weighted images. In cases withmicrobleeds found on MR imaging performed only once
after radiation therapy, previously existing microbleeds(prior to irradiation) were excluded through comparisonof previous MR images with MR images including PSI
after radiation therapy. The final decision regarding thepresence of microbleeds on MR imaging was made bymeans of mutual consent between 2 neuroradiologists.
In patients who had received high-dose irradiation andwho had detected microbleeds, PSI was fused to thedose distribution map. Then, the microbleed was evaluated in each radiation-dose class region.

Number of patients		
With
Without
Total
microbleeds microbleeds

Gender				 0.74†
Male
18
9
9
Female1679Age*				 0.29†
60 and over
1248Less than 60 22
12
10
0.60†
Chemotherapy				
Done
30
15
15
Not done
4
1
3
1†
Hypertension				
With
4
2
2
Without
30
15
15
*yr.
†No significant difference between 2 groups with Fisher’s exact test.

irradiation group, while they were found in 4 patients inthe whole brain irradiation group. Five patients had 1 focus, and the other 11 patients had 2 or more foci. There
were 45 foci in 15 patients, except 1 patient who had too
many foci to count. Of the 16 patients with microbleeds,
the appearance of microbleed was detected on the 2nd
and/or 3rd follow-up PSI after radiation therapy in 11
patients. In the remaining 5 patients, the appearance of
microbleed was detected on the 1st PSI after radiation
therapy. The 2 neuroradiologists concluded that thesemicrobleeds developed after the radiation therapy on
the basis of detailed comparison of T2-weighted images
before and after radiation therapy and PSI after radiation
therapy. No microbleeds disappeared during 3 to 169
months after the end of radiation therapy.
In the present study the latency period for radiationinduced microbleeds was 3 months to 9 years. The mean
and median latency periods in which microbleeds werefirst observed were 33 months and 19 months, respectively. In 27 patients that were examined by PSI within 2
years after radiation therapy, microbleeds were detected
in 10 patients (37%).
There was no statistically significant difference inthe frequency of microbleeds between the groups, whichwere divided by gender (P = 0.74), age (P = 0.29), hypertension (P = 1.0) and chemotherapy (P = 0.60). Resultsof comparison of each group are summarized in Table 2.
In 23 patients who received high-dose irradiation of
44–60 Gy, 12 patients developed microbleeds. In these12 patients, frequency of microbleeds was significantly
associated with radiation dose (P < 0.001, CochranArmitage trend test). The frequency of microbleeds according to the dose class is summarized in Table 3. No

Statistical analyses

To compare the detection rate of PSI and T2-weighted
imaging, the Fisher exact test was used. The Fisher exact test was used for comparisons between the groups,
which were divided by several factors (including gender,
age, hypertension and chemotherapy). In patients withmicrobleed in the high-dose irradiation group, CochranArmitage trend test was used to identify appearance of
microbleed associated with radiation dose. A P value <0.05 was considered to indicate statistical significance.
RESULTS
Microbleeds were detected in 7 (21%) of 34 patients on
T2-weighted imaging, whereas they were detected in
16 (47%) of the 34 patients on PSIs. A typical case of
microbleed is shown in Fig. 1. There was a significant
difference in detection of microbleeds in PSIs and T2weighted images (P = 0.039, Fisher exact test). Microbleeds were found in 12 patients in the high-dose
Table 3. Results from 12 patients with high-dose irradiation with microbleeds according to radiation-doseclassesRadiationdose class(Gy)

Numberofregions

Number ofregions withmicrobleeds

Frequency of
microbleeds(%)

Over 55
45–55
35–45
25–35
15–25
5–15

8
11
11
11
11
11

6
7
3
3
0
0

75
63.6
27.2
27.2
0
0

P value10

Radiation-induced microbleeds PSI study

foci were observed in the regions that had received < 25
Gy irradiation.

in T2-weighted images. Therefore, many microbleeds
might have been overlooked. In fact, the frequency of
microbleeds in the present study in T2-weighted images
was similar to the frequency of telangiectasia in previous
reports. Therefore, it could be concluded that radiationinduced microbleeds occur more frequently than has
been previously assumed.
The latency period of radiation-induced microbleeds
has been reported on numerous occasions to have a wide
range, between 5 months and 22 years.1 In the present
study, the latency period was 3 months to 9 years. The
latency period in the present study is similar to previous
reports, but in general in the present study microbleeds
appeared relatively early. Lupo et al recently reported
using SWI with 7 T that 2 patients developed microbleed
in the 5 patients within 2 years after radiation therapy.18
In the present study, 10 patients developed microbleedsin the 27 patients within 2 years after radiation therapy.
This early appearance may be related to the high sensitivity of PSI.
In general, complications of radiation therapy to thebrain are dependent on total dose, patient age, underlying disease and concomitant therapy.3 Patient factors
such as gender, age, hypertension and chemotherapy
seem to be unrelated to the appearance of telangiectasia.
However, it is known that the immature brain is moresensitive to radiation than the adult brain.19 Koike et al.
reported that radiation-induced telangiectasia occurs
more frequently in younger patients.17 In the present
study there were only 3 patients whose age was under 20
years. If more pediatric patients were included, a significant difference might have been seen. Investigation of alarger number of younger patients is therefore desired.
To our knowledge, there have been no reports thathave proven a dose predominance in radiation-induced
microbleeds. In order to investigate the relationship between microbleeds and radiation dose, the irradiation
areas were separated into 6 regions according to theradiation dose in 12 patients who received high-dose radiation with microbleeds. Frequency of microbleeds was
significantly associated with radiation dose in the present report. In previous reports, telangiectasias have developed in patients who received radiation doses ranging
from 18 to 78 Gy.2, 20 In the present study there were nofoci that were observed in regions that had received lessthan 25 Gy. The radiation dose threshold for development of microbleed is still not clear. To our knowledge,
there is no report of radiation-induced microbleed with adose lower than 18 Gy. With low radiation doses, microbleed may be less likely to develop. However, the present
report suggests that vascular injury may occur around25 Gy. PSI can be used to detect these vascular changes

DISCUSSION
The mechanism of radiation-induced brain injury is not
yet fully understood.8 There is a considerable literature
regarding the pathogenesis of such side effects. Various
hypotheses emphasize vascular changes, a direct effecton glial cells and/or an immunological mechanism.9
A mechanism for vascular injury is as follows. In
acute vascular injury, transient vasodilatation occurs
with variable changes in capillary permeability thatsometimes manifests as vasogenic edema.10.11 Changes
in capillary permeability in response to radiation therapy
to the central nervous system have been quantitated andfound to entail specific variability in molecular sizes.12.13
In chronic radiation-induced injury such as endothelial
damage, vascular ectasia and microbleeds can occur.
These changes result in increased capillary permeability
at the site of vascular injury with resultant cytotoxic andvasogenic edema. Progressive vascular changes include
vessel wall thickening with consequent thrombosis, infarction and necrosis.11 Results of these studies provide
support for the concept that vascular injury plays a pivotal role in the development of radiation-induced brain
injury.
As noted above, radiation-induced vascular injury
commonly affects small arteries and capillaries.14 In
addition, less commonly progressive radiation-induced
large vessel vasculopathy may occur. Intracerebral hemorrhage occasionally occurs as a late delayed reaction.15
In an animal study, vascular abnormalities were shownto occur before the development of parenchymal changes in the brain.16 Therefore, radiation-induced vascularalterations, as represented by microbleeds, should be
evaluated in order to know the severity of brain injury.
The frequency of radiation-induced telangiectasia has been reported to be 20%.17 The frequency ofradiation-induced microbleeds in the present study was
higher than the frequency of telangiectasia, despite theshort follow-up period. As PSI was acquired only oncein the 5 patients with microbleeds, there is a possibility
that the present study included patients with previously
existing microbleeds. However, even after taking thispossibility into account, the frequency is still higher thanthat of the previous reports. This may be because PSI isa highly sensitive technique for visualization of cerebral
hemorrhage. SWI and PSI are currently recognized tobe more sensitive than the other conventional MR imaging techniques for detection of hemorrhage.6 In many
previous reports, microbleeds were detected mainly
11T. Tanino et al.

earlier than other conventional MR imaging techniques.
There are several limitations to the present study.
First, this study lacks histopathologic confirmation of
all cases. Second, PSI before irradiation was not available; however, exclusion of calcification and microbleeds
before irradiation was attempted in comparing previous
MR and subsequent CT images. Lastly, the short observation period and the irradiation volume effect were nottaken into consideration.

9 Sheline GE, Wara WM, Smith V. Therapeutic irradiation andbrain injury. Int J Radiat Oncol Biol Phys. 1980;6:1215-28.
PMID: 7007303.
10 Husain MM, Garcia JH. Cerebral “radiation necrosis”: vascular and glial features. Acta Neuropathol. 1976;36:381-5.
PMID: 1015244.
11 Burger PC, Boyko OB. The pathology of central nervous
system radiation injury. In: Gutin PH, Leibel SA, Sheline GE,
eds. Radiation injury to the nervous system. New York: Raven
Press; 1991. p. 191-208.
12 Levin VA, Edwards MS, Byrd A. Quantitative observationsof the acute effects of X-irradiation on brain capillary permeability: Part I. Int J Radiat Oncol Biol Phys. 1979;5:1627-31.
PMID: 94058.
13 Edwards MS, Levin VA, Byrd A. Quantitative observations of
the subacute effects of X irradiation on brain capillary permeability: Part II. Int J Radiat Oncol Biol Phys. 1979;5:1633-5.
PMID: 536271.
14 Roth NM, Sontag MR, Kiani MF. Early effects of ionizing
radiation on the microvascular networks in normal tissue. Radiat Res. 1999;151:270-7. PMID: 10073664.
15 Chung E, Bodensteiner J, Hogg JP. Spontaneous intracerebral
hemorrhage: a very late delayed effect of radiation therapy. J
Child Neurol. 1992;7:259-63. PMID: 1634747.
16 Fike JR, Sheline GE, Cann CE, Davis RL. Radiation necrosis.
Prog Exp Tumor Res. 1984;28:136-51. PMID: 6484197.
17 Koike S, Aida N, Hata M, Fujita K, Ozawa Y, Inoue T. Asymptomatic radiation induced telangiectasia in children after
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18 Lupo JM, Chuang CF, Chang SM, Barani IJ, Jimenez B, Hess
CP, et al. 7-Tesla susceptibility-weighted imaging to assess theeffects of radiotherapy on normal-appearing brain in patientswith glioma. Int J Radiat Oncol Biol Phys. 2012;82:493-500.
PMID: 22000750.
19 Oi S, Kokunai T, Ijichi A, Matsumoto S, Raimondi AJ. Radiation-induced brain damage in children--histological analysisof sequential tissue changes in 34 autopsy cases. Neurol Med
Chir (Tokyo). 1990;30:36-42. PMID: 1694271.
20 Poussaint TY, Siffert J, Barnes PD, Pomeroy SL, Goumnerova
LC, Anthony DC, et al. Hemorrhagic vasculopathy after treatment of central nervous system neoplasia in childhood: diagnosis and follow-up. AJNR Am J Neuroradiol. 1995;16:693-9.
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The authors declare no conflict of interest.
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