Surgery Today (2022) 52:763–773
https://doi.org/10.1007/s00595-021-02388-1

ORIGINAL ARTICLE

National survey on deceased donor organ transplantation
during the COVID‑19 pandemic in Japan
Taihei Ito1 · Takashi Kenmochi1 · Atsuhiko Ota2 · Kaori Kuramitsu3 · Akihiko Soyama4 · Osamu Kinoshita5 ·Susumu Eguchi4 · Kenji Yuzawa6 · Hiroto Egawa7
Received: 9 June 2021 / Accepted: 11 August 2021 / Published online: 23 October 2021
© The Author(s) 2021

Abstract
Purpose We investigated the status of deceased organ donation and transplantation through a questionnaire distributed totransplant centers in Japan during the COVID-19 pandemic.
Methods The questionnaire was distributed electronically to 206 transplant centers for heart (n = 11), lung (n = 10), liver(n = 25), kidney (n = 130), pancreas (n = 18), and small intestine (n = 12) transplantation. Organ donations and organ transplantation data were extracted from the Japan Organ Transplant Network website.
Results We received questionnaire responses from 177 centers (response rate, 86%). In 2020, the number of brain-deaddonors (BDDs) decreased to 68 (69% of the year-on-year average) and the number of donors after cardiac death (DCDs)
decreased to 9 (32% of the year-on-year average). Eighty-five (48%) transplant centers (heart, n = 0; lung, n = 0; liver, n = 4;
kidney, n = 78; pancreas, n = 22; and small intestine, n = 0) suspended transplant surgeries in response to the COVID-19
pandemic. Consequently, the number of organ transplantations from deceased donors was significantly lower in 2020 thanin 2019.
Conclusion Although the COVID-19 pandemic has had less impact in Japan than in other countries, it has affected transplantation activity significantly, suspending transplantation surgeries in 48% of the transplantation centers, including 78%of the kidney transplantation centers, and reducing the number of organ donations to 61% of the year-on-year average.
Keywords COVID-19 · Brain-dead donors · Donors after cardiac death · Solid organ transplantation* Taihei Ito
i-taihei@fujita-hu.ac.jp
1

Department of Transplantation and Regenerative
Medicine, Fujita Health University, School of Medicine,
Dengakugakubo 1‑98, Kutsukakecho, Toyoake,
Aichi 470‑1192, Japan2

Department of Public Health, Fujita Health University
School of Medicine, Toyoake, Aichi, Japan

3

Division of Hepato‑Biliary‑Pancreatic Surgery, Kobe
University Graduate School of Medicine, Kobe, Hyogo,
Japan

4

Department of Surgery, Nagasaki University Graduate
School of Biomedical Sciences, Nagasaki, Nagasaki, Japan

5

Department of Cardiac Surgery, Graduate Schoolof Medicine, The University of Tokyo, Bunkyo, Tokyo,
Japan

6

Department of Transplantation Surgery, National Hospital
Organization Mito Medical Center, Mito, Ibaraki, Japan

7

Department of Surgery, Institute of Gastroenterology, Tokyo
Women’s Medical University, Shinjuku, Tokyo, Japan

Introduction
In the first 10 years after the establishment of the Brain
Death Organ Transplant Act in 1997, the annual number ofbrain-dead donors (BDDs) in Japan was less than 10. This
low number at the time was attributed to the fact that brain
death referred only to human death in cases of donation fororgan transplantation, and brain-dead donors (BDDs) wererequired to have made their intention clear before brain
death. The law was revised in 2009 to state that even if thedonor's intention to donate organs was unknown, organ
donation from BDDs was able to be approved with the consent of the family. The law was enforced in 2010, resulting
in increased numbers of organ donations from BDDs [1].
This had a positive impact on patients awaiting solid organtransplantation (SOT) for organ failure [2–6].
The COVID-19 pandemic has ravaged the globe since
early 2020 [7–11]. While the numbers of patients with
COVID-19 and related deaths in Japan have been relatively

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low in comparison with other countries [12, 13], the treatment of COVID-19 patients in emergency medical care andthe intensive-care unit (ICU) has been difficult, raising concern about the decline of general medical practices [14–16].
In transplant medical care, essential immunosuppressive
therapy after transplantation has a negative impact on mortality from this new viral infection. The COVID-19-related
mortality rate in SOT recipients has been reported to range
from 18 to 34% [17–19]. Moreover, COVID-19 is a serious
life-threatening infectious disease for individuals with organ
failure who are awaiting transplantation, and the decline
in transplant activity also impacts the prognosis of thesepatients. For example, the COVID-19-related mortality ratein patients awaiting kidney transplantation who required
dialysis was reported to range from 20 to 32% [18, 20–32].
In response to the impact of the COVID-19 pandemicon transplant activity, on March 6, 2020, the Japan Society
for Transplantation published the first edition of the basic
guidelines for transplantation medicine for new coronavirus
infection (COVID-19). The guidelines have been updated
according to the outbreak situation in Japan, with the latest
edition, version 4.1 released on February 4, 2021 [33]. In
the first edition, the recommendation for the implementation of SOT was as follows: “If possible, waiting for organtransplantation until the situation of the COVID-19 pandemic improves is recommended in order to avoid the riskof infection from donors or community-acquired infection
under immunosuppression after transplantation”. However,
the recommendation in the latest version (version 4.1) is asfollows: “In the implementation of solid organ transplantation, the risk of the COVID-19 infection from the donor andthe risk of the aggravation of COVID-19 infection under
immunosuppression after transplantation must be properly
explained to obtain sufficient informed consent about…”.
Thus, although the COVID-19 pandemic may influenceorgan donation and transplant activity in Japan remarkably,
no report has clarified the real situation.
We investigated the status of deceased organ donation andorgan transplantation in Japan during the COVID-19 pandemic, using a questionnaire that was distributed to transplant centers, to clarify the current status of transplantation
activity in Japan during the COVID-19 pandemic.

Methods
A questionnaire survey was conducted as part of a welfare
and labor science special research project entitled, “Survey
research for organ transplantation from BDDs and donors
after cardiac death (DCDs) during the pandemic of COVID19”. The questionnaire, including 23 questions on the medical system, the SOT policy, and the implementation status ineach center during the COVID-19 pandemic, was distributed

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Surgery Today (2022) 52:763–773

electronically to 206 transplant centers in Japan (heart centers, n = 11; lung centers, n = 10; liver centers, n = 25; kidney centers, n = 130; pancreas centers, n = 18; and smallintestine centers, n = 12) from December, 2020 to January,
2021 during the third wave of the COVID-19 pandemic,
with the development of a website entrusted to Tokai Kyodo
Printing. The representatives of each center registered theiranswers. The numbers of deceased organ donations and
SOTs were counted by searching the Japan Organ Transplant
Network website (https://​www.​jotnw.​or.​jp/). The number of
COVID-19-positive patients in Japan was estimated basedon announcements made by the Ministry of Health, Laborand Welfare (https://​www.​mhlw.​go.​jp/​stf/​covid-​19/​kokun​
ainoh​assei​jouky​ou.​html).
The Microsoft Excel software program (Microsoft, USA)was used to summarize the data. Categorical data are shownas frequencies and percentages.

Results
Changes in the number of COVID‑19‑positive
patients and organ donations in Japan
Figure 1 shows the changes in the number of BDDs and
DCDs in Japan. In 1997, the law on organ transplantation
was enacted, with organ donations from BDDs (black solidbars) implemented. Despite this legislation, there was nomarked increase in organ donations from BDDs. The law
was revised in 2009 and enforced in 2010, after which thenumber of brain-dead organ donations began to steadily
increase, reaching a record high of 98 in 2019. In contrast,
the number of DCDs (white solid bars) has decreased since
the revision of the law, to about 30 in recent years. In early
2020, the first cases of COVID-19 were detected in Japan,
and in 2020, the number of BDDs and DCDs decreased to
68 and 9, respectively.
Figure 2 shows the changes in the number of COVID19-positive patients (gray solid bar) and the monthly numberof organ donations (BDDs, black solid bars; DCDs, whitesolid bars) from January, 2020. The first case of COVID-19
in Japan was confirmed in February, 2020, with the number
peaking in April, 2020 in the first wave of the COVID-19
pandemic. This was followed by a second wave in August,
2020, and a third wave in February, 2021. By the timeof writing, at the end of March 2021, the third wave had
begun to converge. By March 20, 2021, the total number of
COVID-19 positive patients in Japan had reached 451,830,
with 8788 COVID-19-related deaths.
In contrast, the number of BDDs at the beginning of2020 did not decrease significantly from that in 2019. However, since the autumn of 2020, when the third wave of the
COVID-19 pandemic started, the number of organ donations

Surgery Today (2022) 52:763–773

765

n
㻝㻞㻜
㻝㻜㻜

The enactment of the law ofBrain Death Organ Transplant

The revision of the law

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The COVID-19 epidemic

㻰㻯㻰

㻤㻜
㻢㻜

㻠㻜
㻞㻜
㻜

Fig. 1  Annual numbers of deceased organ donations in Japan.
Organ donations from brain-dead donors (BDDs) (black solid bars)
began in 1997, when the law on organ transplantation was enacted.
When the law was revised in 2009, the number of brain-dead organ
donations increased steadily, reaching a record high of 98 cases in

2019. In contrast, the number of donors after cardiac death (DCDs)(white solid bars) has decreased since the revision of the law, falling
to approximately 30 in recent years. In 2020, after detection of thefirst COVID-19-positive patients in Japan, the number of BDDs and
DCDs decreased to 68 and 9, respectively

has decreased, with no organ donations in December, 2020.
It is noteworthy that the number of DCDs, which requirea long waiting period for transplant doctors, has dropped
significantly since early 2020, to only nine cases in 2020.
This represents the first single-digit figure in the records, andhighlights the significant impact of the COVID-19 pandemic
on organ donation in Japan (Fig. 2).
As a result, the annual number of SOTs from deceased
donors decreased significantly in 2020 compared with
the number in 2019, with the exception of small-intestinetransplants (Fig. 3). There were 84 cases of heart transplantation in 2019 vs. 54 in 2020 (64% of the year-on-year average) and 79 cases of lung transplantation in 2019 vs. 58 in2020 (73% of the year-on-year average). Regarding abdominal organ transplantation, there were 88 cases of liver transplantation in 2019 vs. 63 in 2020 (72% of the year-on-year
average) and 176 cases of kidney transplantation, including
46 cases of simultaneous pancreas transplantation (SPK)and 6 cases of simultaneous liver transplantation (SLK), in2019 vs. 124 in 2020 (SPK, n = 24; SLK, n = 5; 71% of theFig. 2  Numbers of COVID-19-positive patients and deceased donors
in 2020. The change in the number of COVID-19-positive patientsis displayed as solid gray bars, and the monthly numbers of organ
donations from BDDs and DCDs since January 2020 are shown as
solid black bars and solid white bars, respectively. Since the autumn

of 2020, when the third wave of the COVID-19 pandemic started,
the number of organ donations has decreased. In December 2020,
there were no organ donations. It is noteworthy that the number of
DCDs, which require a long waiting period for transplant doctors, has
dropped significantly since early 2020

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Surgery Today (2022) 52:763–773
n
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㻰㻯㻰

㻞㻜㻜
㻝㻡㻜
㻝㻜㻜
㻡㻜

㻜

㻞㻜㻝㻥

㻞㻜㻞㻜

㻴㼑㼍㼞㼠

㻞㻜㻝㻥

㻞㻜㻞㻜

㻸㼡㼚㼓

㻞㻜㻝㻥

㻞㻜㻞㻜

㻸㼕㼢㼑㼞

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㻷㼕㼐㼚㼑㼥㻞㻜㻝㻥㻞㻜㻞㻜㻼㼍㼚㼏㼞㼑㼍㼟

㻞㻜㻝㻥

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㻿㼙㼍㼘㼘㻌㼕㼚㼠㼑㼟㼠㼕㼚㼑

Fig. 3  Annual numbers of transplantations from deceased donors in2019 and 2020 in Japan. There were 84 cases of heart transplantation in 2019 vs. 54 in 2020 (64% of the year-on-year average) and 79
cases of lung transplantation in 2019 vs. 58 in 2020 (73% of the yearon-year average). For abdominal organ transplantation, there were 88
cases of liver transplantation in 2019 vs. 63 in 2020 (72% of the yearon-year average) and 176 cases of kidney transplantation, including

46 of simultaneous pancreas transplantation (SPK) and 6 of simultaneous liver transplantation (SLK), in 2019 vs. 124 (SPK, n = 24;
SLK, n = 5; 71% of the year-on-year average) in 2020. Pancreas transplants also decreased from 49 cases in 2019 to 28 in 2020 (57% of theyear-on-year average). Small-intestine transplants increased slightly
from two cases in 2019 to three in 2020

year-on-year average). Pancreas transplants also decreased
from 49 cases in 2019 to 28 in 2020 (57% of the year-onyear average), whereas small-intestine transplants increasedslightly from 2 cases in 2019 to 3 in 2020.

held at 151 centers (85%) (Q10), 85 centers (48%) suspended
transplant medical care because of the COVID-19 pandemic(Q12). While no center discontinued its transplant surgery
for heart and lung transplants, one center (4%) suspended
liver transplants, 80 (78%) suspended kidney transplants,
and 4 (22%) suspended pancreas transplants (Fig. 4a). In 41
centers (23%), this discussion involved a single department,
in 57 (32%) it involved multiple departments concerned with
SOT, and in 44 (25%) it involved the whole hospital (Q11).
The reasons for suspending transplant surgeries (Q13)were as follows: there were COVID-19-positive patients in
the hospital (n = 12; 7%), there were COVID-19-positive
patients in the prefecture (n = 26; 15%), the in-hospital medical care system or examination system was inadequate forassessing COVID-19 (n = 34; 19%), all surgical treatment(including transplantation) was restricted (n = 33; 19%), andtransplant surgery was suspended in accordance with theguidelines of the Japan Society for Transplantation (n = 57;32%) (Fig. 4b). Fifty-six centers (31%) suspended all transplants, including both deceased and living donor transplantation, 25 (14%) suspended only living donor transplantation,and 1 (1%) suspended only deceased donor transplantation(Fig. 4c) (Q14).
During the period of the questionnaire (December,
2020–January, 2021), transplant surgery was still suspended
at seven centers (4%), all of which were kidney transplant
programs. The reasons for resuming transplant surgeries(Q15) were as follows: reduction in the number of COVID19 infections at the hospital (n = 9; 5%), lack of spread of
COVID-19 infection confirmed in the hospital (n = 11; 6%),
reduction in the number of COVID-19 infections in the local
area (n = 29; 16%), establishment of an in-hospital medical

Current status of transplant medical care
at transplant centers in Japan
We received questionnaire responses from 177 of the 206
centers, representing a response rate of 86% (heart centers,
100%; lung centers, 90%; liver centers, 100%; kidney centers, 79%; pancreas centers, 100%; small-intestine centers,
92%).
Table 1 summarizes the medical care for COVID-19(other than transplants) that was provided in transplant centers. Among the responding centers, 98 (55%) were designated hospitals for infection (Q1), and 155 (88%), including
those other than designated hospitals for infection, had wards
dedicated to the treatment of COVID-19-positive patients(Q3). ICUs were set up in-hospital at 172 centers (97%)(Q4), and patients with severe COVID-19 sequelae weretreated in the ICU at 144 centers (81%) (Q5). Regarding inhospital tests for COVID-19, PCR testing was performed at
169 centers (95%) (Q6), antigen tests were performed at 151
centers (85%) (Q7), and antibody tests were performed at 90
centers (51%) (Q8). A total of 161 centers (90%) had established rules on surgical treatment (including surgery otherthan transplantation) during the COVID-19 pandemic (Q9).
Table 2 summarizes the results of the questionnaire on thestatus of transplant programs at transplant centers in Japan
during the COVID-19 pandemic. Regarding the continuationof providing transplant medical care, following discussions

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767

Table 1  Medical care for COVID-19 in transplant centers
Answer Overall (%)
n = 177
Q1 Is your center an infectious disease designated Yes
hospital?
No
Yes
Q2 Do you have a special outpatient clinic thatprovides care for patients with fever in your No
hospital?
Yes
Q3 Do you have a ward dedicated to treating COVID-19 infected patients in yourNo
hospital?
Q4 Do you have an ICU in your hospital?
Yes
No
Yes
Q5 Does the ICU accept treatment for patients
infected with COVID-19?
No
Q6 Is it possible to perform PCR tests in-hospital Yes
for COVID-19 in your center?
No
Q7 Is it possible to perform antigen tests inYes
hospital for COVID-19 in your center?
No
Q8 Is it possible to perform antibody tests inYes
hospital for COVID-19 in your center?
No
Yes
Q9 Do you have any rules related to COVID-19
concerning the performance of surgicalNo
treatment (including surgery other thantransplantation) in your center?

Heart
n = 11

Lung
n=9

Liver
n = 25Kidneyn = 103

Pancreasn = 18Small intestinen = 1198 (55)79 (45)127 (72)49 (28)2 (18)
9 (82)
5 (45)
6 (55)

6 (67)
3 (33)
6 (67)
3 (33)

18 (72)7 (28)
18 (72)7 (28)

52 (50)51 (50)79 (77)23 (22)12 (67)6 (33)
12 (67)6 (33)

8 (73)
3 (27)
7 (64)
4 (36)

155 (88)
22 (12)

11 (100) 9 (100) 20 (80)
0 (0)
0 (0)
5 (20)

90 (87)13 (13)17 (94)1 (6)8 (73)
3 (27)

172 (97)5 (3)144 (81)32 (19)169 (95)7 (4)151 (85)
21 (12)90 (51)78 (44)161 (90)
12 (7)

11 (100)
0 (0)11 (100)
0 (0)11 (100)0 (0)9 (82)0 (0)8 (73)
2 (18)
9 (82)0 (0)98 (95)5 (5)76 (74)26 (25)95 (92)7 (7)90 (87)13 (13)46 (45)54 (52)94 (91)8 (8)18 (100)0 (0)15 (83)3 (17)
18 (100)0 (0)16 (89)2 (11)
10 (56)
7 (39)
17 (94)1 (6)

11 (100)0 (0)10 (91)1 (9)11 (100)0 (0)8 (73)
2 (18)
6 (55)
3 (27)
9 (82)
2 (18)

care system and testing for COVID-19 (n = 51; 29%), restrictions on surgeries other than transplantation (n = 28; 16%),and surgeries re-established in accordance with the guidelines of the Japan Society for Transplantation (n = 34; 19%).
Of the centers with ongoing transplant surgery at the timeof the questionnaire, 112 (63%) were providing transplant
medical care without special restrictions, while 34 (19%)
were limiting transplant surgery to cases considered difficult
to postpone (Fig. 4d) (Q16). Depending on the future spreadof the COVID-19 pandemic, only 30 centers (17%) answeredthat they would continue to provide transplant medical carewithout any restrictions, while 92 (52%) answered thatthey would consider suspending their transplant surgeries depending on the presence of COVID-19 in the ICU
or hospital. Thirty-four centers answered that they would
discontinue transplant surgeries in the event of nosocomial
COVID-19 infection (Q17).
During the COVID-19 pandemic, 21 centers (12%)
answered that they had been restricted from dispatching toorgan recovery (Q18), and 14 centers (8%) answered thatthey had abandoned organ recovery efforts because of the
COVID-19 pandemic (Q19). Even when organ recovery was
possible, 12 centers (7%) reported that they had abandonedtransplant surgery because of the COVID-19 pandemic(Q20).
Before any transplant surgery, 161 institutions (90%)
performed a preoperative COVID-19 screening test of SOT

9 (100)0 (0)9 (100)0 (0)9 (100)0 (0)8 (89)
1 (11)
6 (67)
3 (33)
9 (100)0 (0)25 (100)0 (0)23 (92)2 (8)25 (100)0 (0)20 (80)3 (12)
14 (56)9 (36)
23 (92)
1 (4)recipients (Q21). A total of 112 centers (63%) answeredthat the post-transplant follow-up systems had changed inaccordance with the COVID-19 pandemic (Q22), and most(123 centers, 69%) answered that follow-up outpatient visits
after transplantation were set at longer intervals (Q23).

Discussion
The findings of this study confirmed that the COVID-19
pandemic reduced the number of organ donations, especiallyfrom DCDs. In Japan, organ donation from DCDs was performed without the withdrawal of life-support including respiration, which sometimes forces the organ recovery teamto wait a long time in the donor's hospital. This was considered why DCDs were so markedly reduced by the COVID19 pandemic. Our questionnaire survey revealed the organ
donation situation in Japan. In addition to a reduction in thenumber of organ donations, half of the transplant centerssuspended transplant surgery, particularly abdominal organtransplant surgeries, because of the COVID-19 pandemic.
While transplant surgeries were resuming in most institutions when the questionnaire was distributed, approximately
20% of the transplant centers limited SOT surgery to thosepatients whose prognosis would have been severely affectedby postponing surgery, and about 10% of centers indicatedthat it was necessary to abandon organ recovery or SOT in

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13
151 (85)
26 (15)Yes
No

Single department
41 (23)
Multiple department
57 (32)All over hospital
44 (25)
Others7 (4)Q12 Have the organ transplant surgeries in your hospital Yes
85 (48)been stopped due to the COVID-19 pandemic?
No
92 (52)Presence of COVID-19-positive patients after
0 (0)Q13 What was the reason for the decision to suspendtransplantation in the hospitalthe organ transplant surgeries? (Multiple answers
allowed)Presence of COVID-19-positive patients in the
12 (7)
hospitalPresence of COVID-19-positive patients in the area 26 (15)(prefecture)
In-hospital medical care system or examination sys- 34 (19)
tem inadequate for assessing COVID-19
All surgical treatments restricted, including trans33 (19)plantation
Following the guidelines of the Japan Society for
57 (32)
Transplantation
Others16 (9)
Q14 What kind of organ transplants were suspended?
Both deceased donor transplants and living donor
56 (31)transplantation
Only living donor transplantation
25 (14)
Only high-risk transplantation including ABO
0 (0)incompatible cases
Deceased donor transplantation
1 (1)Others3 (2)Q10 Have you ever discussed the continuation of thetransplant surgeries in the hospital during the
COVID-19 pandemic?
Q11 To what extent did that discussion take place?

Overall (%)
n = 177

AnswerTable 2  Results of the questionnaire on the status of transplant programs

1 (17)0 (0)5 (83)0 (0)0 (0)9 (100)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

6 (67)
3 (33)

Lung
n=9

0 (0)
5 (63)
3 (38)0 (0)0 (0)11 (100)
N/A

8 (73)
3 (27)

Heartn = 1130 (32)31 (33)25 (27)6 (6)80 (78)23 (22)0 (0)26 (33)54 (68)

0 (0)
0 (0)

0 (0)
0 (0)

1 (1)
3 (4)

25 (31)
0 (0)

0 (0)
15 (19)1 (100) 51 (64)0 (0)1 (100) 30 (38)

1 (100) 33 (41)0 (0)1 (100) 11 (14)

5 (25)
9 (45)
5 (25)1 (5)1 (4)
24 (96)
0 (0)

0 (0)
0 (0)

0 (0)
0 (0)

1 (25)
4 (100)3 (75)

2 (50)

0 (0)

0 (0)

0 (0)

3 (20)
8 (53)
4 (27)0 (0)4 (22)
14 (78)0 (0)15 (83)3 (17)

Kidney Pancreasn = 103 n = 18

20 (80) 94 (91)
5 (20) 9 (9)Livern = 25

N/A
N/A

N/A
N/A

N/A
N/A

N/A

N/A

N/A

N/A

N/A

2 (25)
4 (50)
2 (25)0 (0)0 (0)11 (100)
N/A

8 (73)
3 (27)

Small intestinen = 11

768
Surgery Today (2022) 52:763–773

N/A
N/A

29 (16)51 (29)28 (16)34 (19)Reduction in numbers of COVID-19 infections in
the local area
Establishment of an in-hospital medical care system and examination system for COVID-19
Restrictions on surgeries other than transplantation
liftedFollowing the guidelines of the Japan Society forTransplantation

0 (0)5 (45)
5 (45)1 (9)1 (9)2 (18)0 (0)0 (0)11 (100)
3 (27)
8 (73)

18 (10)30 (17)60 (34)32 (18)34 (19)24 (13)23 (13)21 (12)148
14 (8)
156 (88)

8 (11)

27 (36)32 (43)2 (8)
3 (12)1 (4)
22 (88)2 (8)6 (24)

15 (16)16 (17)18 (17)79 (77)30 (31)19 (20)2 (8)10 (10)4 (16) 13 (14)15 (60) 20 (21)0 (0)8 (11)
14 (56) 66 (69)
9 (36) 15 (16)0 (0)1 (100) 25 (33)

1 (100) 48 (64)0 (0)3 (17)
15 (83)4 (22)
4 (22)1 (6)
17 (94)0 (0)3 (17)

4 (22)
4 (22)
6 (33)0 (0)9 (50)
5 (28)

2 (50)

2 (50)

2 (50)

2 (50)

2 (50)

1 (25)

Kidney Pancreasn = 103 n = 18

1 (100) 8 (11)

0 (0)

Liver
n = 25

0 (0)
0 (0)
8 (8)
9 (100) 23 (92) 90 (87)

1 (11)0 (0)0 (0)9 (100)

0 (0)

0 (0)

1 (11)
1 (11)
7 (78)

N/A
N/A
11 (100) 6 (67)0 (0)1 (11)

N/A

N/A

N/A

N/A

N/A

N/A

Lung
n=9

8 (4)
112 (63)
34 (19)

N/A

N/A

N/A

11 (6)

A lack of spread of COVID-19 infection confirmedin the hospital

N/A

Heart
n = 119 (5)Overall (%)
n = 177

Reduction in numbers of COVID-19 infections in
the hospital

AnswerOthersQ16 What kind of organ transplants are being performed Without any particular restrictions
if the program is ongoing?
Limited to cases considering being difficult topostpone
OthersWithout any particular restrictions
Q17 If the COVID-19 epidemic expands more in thenear future, how do you think that organ transConsidering discontinuing their transplant surgeries
plants be carried out in your hospital?
depending on the presence of COVID-19 patientsin the ICU
Considering discontinuing their transplant surgeries
depending on the presence of COVID-19 patientsin the hospital
Discontinue the transplant surgeries should nosocomial COVID-19 infection be observed
Not decided, yet
OthersYes
Q18 Have you placed any restrictions on the dispatchof organ recovery from your center during theNo
COVID-19 pandemic?
Yes
Q19 Have you experienced any cases in which organ
recovery was abandoned due to a COVID-19
No
infection?

Q15 What was the reason for resuming the organ transplant surgeries? (Multiple answers allowed)

Table 2  (continued)

0 (0)11 (100)

0 (0)
0 (0)
1 (9)
10 (91)1 (9)

3 (27)

1 (9)
3 (27)
7 (64)

N/A
6 (55)
4 (36)

N/A

N/A

N/A

N/A

N/A

N/A

Small intestinen = 11

Surgery Today (2022) 52:763–773
769

13

13

Q23 If you answered "yes" to Q22, please explain
how the post-transplant follow-up systems havechanged. (Multiple answers allowed)

Q22 Have there been any changes in the post-transplantfollow-up systems during the COVID-19 pandemic in your hospital?

Q20 Have you experienced any cases in which organtransplantation was abandoned due to a COVID19 infection even though organ recovery was
possible?
Q21 How do you handle patients who are candidates
for organ transplantation during the COVID-19
pandemic? (Multiple answers allowed)

Table 2  (continued)

8 (73)1 (9)9 (82)1 (9)1 (9)6 (55)
5 (45)0 (0)0 (0)6 (100)4 (67)0 (0)2 (33)
3 (50)
2 (33)

158 (89)
125 (70)
16 (9)
161 (90)
6 (3)
6 (3)
65 (37)80 (45)29 (16)3 (2)123 (69)
66 (37)14 (8)
51 (29)36 (20)21 (12)No
Be sure to perform chest CT
Perform chest CT if the patient has some symptoms
Be sure to screen for COVID-19 (PCR test, antigen
test, etc.)
Screen for COVID-19 (PCR test, antigen test, etc.),
if there are chest CT findings or the patient has
some symptoms
OthersNo change
The system has changed a little
The system has changed considerably
The system has all changed
Outpatient visits for patients after transplantation
were set to be performed at longer intervals
Try to give more medicine than usual
Examination are limited as much as possible
Try to patients stay in the out-patients clinic asshort as possible
Try to make each other patients avoid contact
Others10 (91)1 (9)

12 (7)YesHeartn = 11

Overall (%)
n = 177

Answer9 (9)2 (40)
3 (60)

3 (60)
1 (20)
3 (60)0 (0)3 (33)
6 (67)0 (0)0 (0)4 (80)0 (0)5 (24)
5 (24)

9 (43)
2 (10)
5 (24)0 (0)9 (36)
11 (44)5 (20)0 (0)
16 (76)2 (8)21 (26)8 (10)

44 (54)9 (11)
35 (43)5 (5)37 (36)45 (44)18 (17)3 (3)77 (94)2 (2)2 (15)
1 (8)

4 (31)
2 (15)
4 (31)0 (0)6 (33)
9 (50)
3 (17)0 (0)12 (92)0 (0)13 (72)3 (17)
18 (100)

17 (94)1 (6)Kidney Pancreasn = 103 n = 18

23 (92) 89 (86)

0 (0)

Liver
n = 256 (67) 11 (44) 85 (83)0 (0)5 (20) 3 (3)9 (100) 22 (88) 93 (90)

8 (89)

1 (11)Lung
n=9

3 (33)
2 (22)

2 (22)0 (0)2 (22)0 (0)4 (36)
4 (36)
3 (27)0 (0)8 (89)

1 (9)

2 (18)
4 (36)
10 (91)

11 (100)

0 (0)Small intestinen = 11

770Surgery Today (2022) 52:763–773

Surgery Today (2022) 52:763–773

771

Fig. 4  Answers to questions about porting program continuation.
Q12: Have organ transplant surgeries in your hospital been stopped
due to the COVID-19 pandemic? (a), Q13: What was the reason forthe decision to suspend organ transplant surgeries? (Multiple answers
allowed) (b), Q14: What kind of organ transplants were suspended?
(c), Q16: What kind of organ transplants are being performed if transplant surgery is ongoing? (d). Response summaries: Q12: While nocenter discontinued its transplant surgeries for heart and lung transplants, one center (4%) suspended its transplant surgeries for livertransplants, 80 (78%) suspended their transplant surgeries for kidneytransplants, and 4 (22%) suspended their transplant surgeries for pancreas transplants (a). Q13: The reasons for discontinuing transplantation were as follows: COVID-19-positive patients in the hospital(n = 12; 7%), COVID-19-positive patients in the prefecture (n = 26;15%), in-hospital medical care system or examination system inadequate for assessing COVID-19 (n = 34; 19%), all surgical treatment(including transplantation) restricted (n = 33; 19%), and suspended inaccordance with guidelines of the Japan Society for Transplantation(n = 57; 32%) (b). Q14: Fifty-six centers (31%) discontinued all transplants, including both deceased and living donor transplantation, 25(14%) discontinued only living donor transplantation, and 1 (1%) discontinued only deceased donor transplantation (c). Q16: Of the centers with an ongoing transplant surgeries at the time of the questionnaire, 112 (63%) were providing transplant medical care without any
specific restrictions, while 34 (19%) were limiting transplant surgery
to cases when it was considered difficult to postpone (d)some cases because of the COVID-19 pandemic. The present study confirmed that the COVID-19 pandemic has hada significantly negative impact on both organ donation andthe performance of SOT.
In the United States, the number of patients registered as
waiting for SOT and transplant surgery in April, 2020, wasreported to have decreased in all United Network for Organ
Sharing regions, and the mortality rate of these waiting
patients had increased in more than half of the regions [34].
It was also reported that in March and April, 2020, when
the COVID-19 pandemic began, the number of new waitlist patient enrollments, deceased-donor kidney transplants,
and living-donor kidney transplants, fell below expectations

by 18%, 24%, and 87%, respectively [35]. In Europe, the
COVID-19 pandemic was reported to have had a similarly
severe impact on transplant medical care, with the numberof referrals of potential donors decreasing by 39% in the
United Kingdom [36] and the number of potential deceasedorgan donors decreasing by 16% in comparison with previous years in France [37]. Conversely, in South Korea,(as in Japan), where the COVID-19 pandemic manifested
relatively early with a less impact than in the United Statesand Europe, there was no significant change reported in thenumber of liver transplantations or kidney transplantations
as of March and April, 2020 [38, 39], respectively, from theprevious year, for both living donor transplants and BDD

13

772

transplants. These findings showed that the ability to perform organ transplantation is dependent on the severity ofthe spread of COVID-19 in a given country; however, as
these reports relate to the situation in spring 2020, subsequent reports on the overall situation of organ transplantation in 2020 are awaited.
Unfortunately, during the severe COVID-19 pandemic at
the present time, in many countries, including Japan, available medical resources are likely to be assigned to countermeasures against the COVID-19 pandemic, necessitating a
reduction in transplantation activity. In several countries,
newly developed vaccines are improving the impact of the
COVID-19 pandemic [40–45], and facilitating the rebuildingof a normal lifestyle. It is thought that the acquisition of herd
immunity through vaccination will improve the survival ofpatients with organ failure who are awaiting transplantationand promote transplant medical care.
The present study had several limitations. The overall
response rate to the questionnaire was 86%, which may beconsidered relatively high; however, the response rate of thekidney transplant centers was approximately 80%, whichis slightly low. The questionnaire survey in this study was
conducted from December, 2020 to January, 2021, when
the background of the COVID-19 pandemic in Japan was
in a state of flux. In particular, the number of COVID19-positive patients in the third wave increased rapidly, andfrom January 2021, a state of emergency was declared insome cities, including Tokyo. The movement of people wasgreatly restricted and the situation was changing, which
may have affected organ recovery; thus, the answers to ourquestionnaire survey might have varied greatly dependingon the time of the response. Furthermore, the number ofliving donor organ transplantations was not mentioned inthis paper, as the effects of the COVID-19 pandemic on thestate of living transplantation in Japan is being investigatedin another study.

Conclusion
At the end of March, 2021, the number of patients infectedwith COVID-19 in the third wave of the pandemic began to
decline. Although the COVID-19 pandemic in Japan is lesssevere than in other countries, it has had a large impact on
the overall transplantation activity, suspending transplantation surgeries in 48% of the transplantation centers, including 78% of the kidney transplantation centers, and reducing
the number of organ donations to 61% of the year-on-year
average. This situation should be monitored closely.
Acknowledgements We like to thank the 177 transplant centers that
responded to the questionnaire during the national COVID-19 pandemic crisis.

13

Surgery Today (2022) 52:763–773
Funding This research was funded by Health, Labour and Welfare
Policy Research Grants.

Declarations
Conflict of interest We have no conflicts of interest to declare in association with this study.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article areincluded in the article's Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view acopy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

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Publisher's Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.

13Surgery Today (2022) 52:763–773
https://doi.org/10.1007/s00595-021-02388-1

ORIGINAL ARTICLE

National survey on deceased donor organ transplantation
during the COVID‑19 pandemic in Japan
Taihei Ito1 · Takashi Kenmochi1 · Atsuhiko Ota2 · Kaori Kuramitsu3 · Akihiko Soyama4 · Osamu Kinoshita5 ·Susumu Eguchi4 · Kenji Yuzawa6 · Hiroto Egawa7
Received: 9 June 2021 / Accepted: 11 August 2021 / Published online: 23 October 2021
© The Author(s) 2021

Abstract
Purpose We investigated the status of deceased organ donation and transplantation through a questionnaire distributed totransplant centers in Japan during the COVID-19 pandemic.
Methods The questionnaire was distributed electronically to 206 transplant centers for heart (n = 11), lung (n = 10), liver(n = 25), kidney (n = 130), pancreas (n = 18), and small intestine (n = 12) transplantation. Organ donations and organ transplantation data were extracted from the Japan Organ Transplant Network website.
Results We received questionnaire responses from 177 centers (response rate, 86%). In 2020, the number of brain-deaddonors (BDDs) decreased to 68 (69% of the year-on-year average) and the number of donors after cardiac death (DCDs)
decreased to 9 (32% of the year-on-year average). Eighty-five (48%) transplant centers (heart, n = 0; lung, n = 0; liver, n = 4;
kidney, n = 78; pancreas, n = 22; and small intestine, n = 0) suspended transplant surgeries in response to the COVID-19
pandemic. Consequently, the number of organ transplantations from deceased donors was significantly lower in 2020 thanin 2019.
Conclusion Although the COVID-19 pandemic has had less impact in Japan than in other countries, it has affected transplantation activity significantly, suspending transplantation surgeries in 48% of the transplantation centers, including 78%of the kidney transplantation centers, and reducing the number of organ donations to 61% of the year-on-year average.
Keywords COVID-19 · Brain-dead donors · Donors after cardiac death · Solid organ transplantation* Taihei Ito
i-taihei@fujita-hu.ac.jp
1

Department of Transplantation and Regenerative
Medicine, Fujita Health University, School of Medicine,
Dengakugakubo 1‑98, Kutsukakecho, Toyoake,
Aichi 470‑1192, Japan2

Department of Public Health, Fujita Health University
School of Medicine, Toyoake, Aichi, Japan

3

Division of Hepato‑Biliary‑Pancreatic Surgery, Kobe
University Graduate School of Medicine, Kobe, Hyogo,
Japan

4

Department of Surgery, Nagasaki University Graduate
School of Biomedical Sciences, Nagasaki, Nagasaki, Japan

5

Department of Cardiac Surgery, Graduate Schoolof Medicine, The University of Tokyo, Bunkyo, Tokyo,
Japan

6

Department of Transplantation Surgery, National Hospital
Organization Mito Medical Center, Mito, Ibaraki, Japan

7

Department of Surgery, Institute of Gastroenterology, Tokyo
Women’s Medical University, Shinjuku, Tokyo, Japan

Introduction
In the first 10 years after the establishment of the Brain
Death Organ Transplant Act in 1997, the annual number ofbrain-dead donors (BDDs) in Japan was less than 10. This
low number at the time was attributed to the fact that brain
death referred only to human death in cases of donation fororgan transplantation, and brain-dead donors (BDDs) wererequired to have made their intention clear before brain
death. The law was revised in 2009 to state that even if thedonor's intention to donate organs was unknown, organ
donation from BDDs was able to be approved with the consent of the family. The law was enforced in 2010, resulting
in increased numbers of organ donations from BDDs [1].
This had a positive impact on patients awaiting solid organtransplantation (SOT) for organ failure [2–6].
The COVID-19 pandemic has ravaged the globe since
early 2020 [7–11]. While the numbers of patients with
COVID-19 and related deaths in Japan have been relatively

13Vol.:(0123456789)

764

low in comparison with other countries [12, 13], the treatment of COVID-19 patients in emergency medical care andthe intensive-care unit (ICU) has been difficult, raising concern about the decline of general medical practices [14–16].
In transplant medical care, essential immunosuppressive
therapy after transplantation has a negative impact on mortality from this new viral infection. The COVID-19-related
mortality rate in SOT recipients has been reported to range
from 18 to 34% [17–19]. Moreover, COVID-19 is a serious
life-threatening infectious disease for individuals with organ
failure who are awaiting transplantation, and the decline
in transplant activity also impacts the prognosis of thesepatients. For example, the COVID-19-related mortality ratein patients awaiting kidney transplantation who required
dialysis was reported to range from 20 to 32% [18, 20–32].
In response to the impact of the COVID-19 pandemicon transplant activity, on March 6, 2020, the Japan Society
for Transplantation published the first edition of the basic
guidelines for transplantation medicine for new coronavirus
infection (COVID-19). The guidelines have been updated
according to the outbreak situation in Japan, with the latest
edition, version 4.1 released on February 4, 2021 [33]. In
the first edition, the recommendation for the implementation of SOT was as follows: “If possible, waiting for organtransplantation until the situation of the COVID-19 pandemic improves is recommended in order to avoid the riskof infection from donors or community-acquired infection
under immunosuppression after transplantation”. However,
the recommendation in the latest version (version 4.1) is asfollows: “In the implementation of solid organ transplantation, the risk of the COVID-19 infection from the donor andthe risk of the aggravation of COVID-19 infection under
immunosuppression after transplantation must be properly
explained to obtain sufficient informed consent about…”.
Thus, although the COVID-19 pandemic may influenceorgan donation and transplant activity in Japan remarkably,
no report has clarified the real situation.
We investigated the status of deceased organ donation andorgan transplantation in Japan during the COVID-19 pandemic, using a questionnaire that was distributed to transplant centers, to clarify the current status of transplantation
activity in Japan during the COVID-19 pandemic.

Methods
A questionnaire survey was conducted as part of a welfare
and labor science special research project entitled, “Survey
research for organ transplantation from BDDs and donors
after cardiac death (DCDs) during the pandemic of COVID19”. The questionnaire, including 23 questions on the medical system, the SOT policy, and the implementation status ineach center during the COVID-19 pandemic, was distributed

13

Surgery Today (2022) 52:763–773

electronically to 206 transplant centers in Japan (heart centers, n = 11; lung centers, n = 10; liver centers, n = 25; kidney centers, n = 130; pancreas centers, n = 18; and smallintestine centers, n = 12) from December, 2020 to January,
2021 during the third wave of the COVID-19 pandemic,
with the development of a website entrusted to Tokai Kyodo
Printing. The representatives of each center registered theiranswers. The numbers of deceased organ donations and
SOTs were counted by searching the Japan Organ Transplant
Network website (https://​www.​jotnw.​or.​jp/). The number of
COVID-19-positive patients in Japan was estimated basedon announcements made by the Ministry of Health, Laborand Welfare (https://​www.​mhlw.​go.​jp/​stf/​covid-​19/​kokun​
ainoh​assei​jouky​ou.​html).
The Microsoft Excel software program (Microsoft, USA)was used to summarize the data. Categorical data are shownas frequencies and percentages.

Results
Changes in the number of COVID‑19‑positive
patients and organ donations in Japan
Figure 1 shows the changes in the number of BDDs and
DCDs in Japan. In 1997, the law on organ transplantation
was enacted, with organ donations from BDDs (black solidbars) implemented. Despite this legislation, there was nomarked increase in organ donations from BDDs. The law
was revised in 2009 and enforced in 2010, after which thenumber of brain-dead organ donations began to steadily
increase, reaching a record high of 98 in 2019. In contrast,
the number of DCDs (white solid bars) has decreased since
the revision of the law, to about 30 in recent years. In early
2020, the first cases of COVID-19 were detected in Japan,
and in 2020, the number of BDDs and DCDs decreased to
68 and 9, respectively.
Figure 2 shows the changes in the number of COVID19-positive patients (gray solid bar) and the monthly numberof organ donations (BDDs, black solid bars; DCDs, whitesolid bars) from January, 2020. The first case of COVID-19
in Japan was confirmed in February, 2020, with the number
peaking in April, 2020 in the first wave of the COVID-19
pandemic. This was followed by a second wave in August,
2020, and a third wave in February, 2021. By the timeof writing, at the end of March 2021, the third wave had
begun to converge. By March 20, 2021, the total number of
COVID-19 positive patients in Japan had reached 451,830,
with 8788 COVID-19-related deaths.
In contrast, the number of BDDs at the beginning of2020 did not decrease significantly from that in 2019. However, since the autumn of 2020, when the third wave of the
COVID-19 pandemic started, the number of organ donations

Surgery Today (2022) 52:763–773

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㻞㻜
㻜

Fig. 1  Annual numbers of deceased organ donations in Japan.
Organ donations from brain-dead donors (BDDs) (black solid bars)
began in 1997, when the law on organ transplantation was enacted.
When the law was revised in 2009, the number of brain-dead organ
donations increased steadily, reaching a record high of 98 cases in

2019. In contrast, the number of donors after cardiac death (DCDs)(white solid bars) has decreased since the revision of the law, falling
to approximately 30 in recent years. In 2020, after detection of thefirst COVID-19-positive patients in Japan, the number of BDDs and
DCDs decreased to 68 and 9, respectively

has decreased, with no organ donations in December, 2020.
It is noteworthy that the number of DCDs, which requirea long waiting period for transplant doctors, has dropped
significantly since early 2020, to only nine cases in 2020.
This represents the first single-digit figure in the records, andhighlights the significant impact of the COVID-19 pandemic
on organ donation in Japan (Fig. 2).
As a result, the annual number of SOTs from deceased
donors decreased significantly in 2020 compared with
the number in 2019, with the exception of small-intestinetransplants (Fig. 3). There were 84 cases of heart transplantation in 2019 vs. 54 in 2020 (64% of the year-on-year average) and 79 cases of lung transplantation in 2019 vs. 58 in2020 (73% of the year-on-year average). Regarding abdominal organ transplantation, there were 88 cases of liver transplantation in 2019 vs. 63 in 2020 (72% of the year-on-year
average) and 176 cases of kidney transplantation, including
46 cases of simultaneous pancreas transplantation (SPK)and 6 cases of simultaneous liver transplantation (SLK), in2019 vs. 124 in 2020 (SPK, n = 24; SLK, n = 5; 71% of theFig. 2  Numbers of COVID-19-positive patients and deceased donors
in 2020. The change in the number of COVID-19-positive patientsis displayed as solid gray bars, and the monthly numbers of organ
donations from BDDs and DCDs since January 2020 are shown as
solid black bars and solid white bars, respectively. Since the autumn

of 2020, when the third wave of the COVID-19 pandemic started,
the number of organ donations has decreased. In December 2020,
there were no organ donations. It is noteworthy that the number of
DCDs, which require a long waiting period for transplant doctors, has
dropped significantly since early 2020

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766

Surgery Today (2022) 52:763–773
n
㻞㻡㻜

㻮㻰㻰

㻰㻯㻰

㻞㻜㻜
㻝㻡㻜
㻝㻜㻜
㻡㻜

㻜

㻞㻜㻝㻥

㻞㻜㻞㻜

㻴㼑㼍㼞㼠

㻞㻜㻝㻥

㻞㻜㻞㻜

㻸㼡㼚㼓

㻞㻜㻝㻥

㻞㻜㻞㻜

㻸㼕㼢㼑㼞

㻞㻜㻝㻥

㻞㻜㻞㻜

㻷㼕㼐㼚㼑㼥㻞㻜㻝㻥㻞㻜㻞㻜㻼㼍㼚㼏㼞㼑㼍㼟

㻞㻜㻝㻥

㻞㻜㻞㻜

㻿㼙㼍㼘㼘㻌㼕㼚㼠㼑㼟㼠㼕㼚㼑

Fig. 3  Annual numbers of transplantations from deceased donors in2019 and 2020 in Japan. There were 84 cases of heart transplantation in 2019 vs. 54 in 2020 (64% of the year-on-year average) and 79
cases of lung transplantation in 2019 vs. 58 in 2020 (73% of the yearon-year average). For abdominal organ transplantation, there were 88
cases of liver transplantation in 2019 vs. 63 in 2020 (72% of the yearon-year average) and 176 cases of kidney transplantation, including

46 of simultaneous pancreas transplantation (SPK) and 6 of simultaneous liver transplantation (SLK), in 2019 vs. 124 (SPK, n = 24;
SLK, n = 5; 71% of the year-on-year average) in 2020. Pancreas transplants also decreased from 49 cases in 2019 to 28 in 2020 (57% of theyear-on-year average). Small-intestine transplants increased slightly
from two cases in 2019 to three in 2020

year-on-year average). Pancreas transplants also decreased
from 49 cases in 2019 to 28 in 2020 (57% of the year-onyear average), whereas small-intestine transplants increasedslightly from 2 cases in 2019 to 3 in 2020.

held at 151 centers (85%) (Q10), 85 centers (48%) suspended
transplant medical care because of the COVID-19 pandemic(Q12). While no center discontinued its transplant surgery
for heart and lung transplants, one center (4%) suspended
liver transplants, 80 (78%) suspended kidney transplants,
and 4 (22%) suspended pancreas transplants (Fig. 4a). In 41
centers (23%), this discussion involved a single department,
in 57 (32%) it involved multiple departments concerned with
SOT, and in 44 (25%) it involved the whole hospital (Q11).
The reasons for suspending transplant surgeries (Q13)were as follows: there were COVID-19-positive patients in
the hospital (n = 12; 7%), there were COVID-19-positive
patients in the prefecture (n = 26; 15%), the in-hospital medical care system or examination system was inadequate forassessing COVID-19 (n = 34; 19%), all surgical treatment(including transplantation) was restricted (n = 33; 19%), andtransplant surgery was suspended in accordance with theguidelines of the Japan Society for Transplantation (n = 57;32%) (Fig. 4b). Fifty-six centers (31%) suspended all transplants, including both deceased and living donor transplantation, 25 (14%) suspended only living donor transplantation,and 1 (1%) suspended only deceased donor transplantation(Fig. 4c) (Q14).
During the period of the questionnaire (December,
2020–January, 2021), transplant surgery was still suspended
at seven centers (4%), all of which were kidney transplant
programs. The reasons for resuming transplant surgeries(Q15) were as follows: reduction in the number of COVID19 infections at the hospital (n = 9; 5%), lack of spread of
COVID-19 infection confirmed in the hospital (n = 11; 6%),
reduction in the number of COVID-19 infections in the local
area (n = 29; 16%), establishment of an in-hospital medical

Current status of transplant medical care
at transplant centers in Japan
We received questionnaire responses from 177 of the 206
centers, representing a response rate of 86% (heart centers,
100%; lung centers, 90%; liver centers, 100%; kidney centers, 79%; pancreas centers, 100%; small-intestine centers,
92%).
Table 1 summarizes the medical care for COVID-19(other than transplants) that was provided in transplant centers. Among the responding centers, 98 (55%) were designated hospitals for infection (Q1), and 155 (88%), including
those other than designated hospitals for infection, had wards
dedicated to the treatment of COVID-19-positive patients(Q3). ICUs were set up in-hospital at 172 centers (97%)(Q4), and patients with severe COVID-19 sequelae weretreated in the ICU at 144 centers (81%) (Q5). Regarding inhospital tests for COVID-19, PCR testing was performed at
169 centers (95%) (Q6), antigen tests were performed at 151
centers (85%) (Q7), and antibody tests were performed at 90
centers (51%) (Q8). A total of 161 centers (90%) had established rules on surgical treatment (including surgery otherthan transplantation) during the COVID-19 pandemic (Q9).
Table 2 summarizes the results of the questionnaire on thestatus of transplant programs at transplant centers in Japan
during the COVID-19 pandemic. Regarding the continuationof providing transplant medical care, following discussions

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Surgery Today (2022) 52:763–773

767

Table 1  Medical care for COVID-19 in transplant centers
Answer Overall (%)
n = 177
Q1 Is your center an infectious disease designated Yes
hospital?
No
Yes
Q2 Do you have a special outpatient clinic thatprovides care for patients with fever in your No
hospital?
Yes
Q3 Do you have a ward dedicated to treating COVID-19 infected patients in yourNo
hospital?
Q4 Do you have an ICU in your hospital?
Yes
No
Yes
Q5 Does the ICU accept treatment for patients
infected with COVID-19?
No
Q6 Is it possible to perform PCR tests in-hospital Yes
for COVID-19 in your center?
No
Q7 Is it possible to perform antigen tests inYes
hospital for COVID-19 in your center?
No
Q8 Is it possible to perform antibody tests inYes
hospital for COVID-19 in your center?
No
Yes
Q9 Do you have any rules related to COVID-19
concerning the performance of surgicalNo
treatment (including surgery other thantransplantation) in your center?

Heart
n = 11

Lung
n=9

Liver
n = 25Kidneyn = 103

Pancreasn = 18Small intestinen = 1198 (55)79 (45)127 (72)49 (28)2 (18)
9 (82)
5 (45)
6 (55)

6 (67)
3 (33)
6 (67)
3 (33)

18 (72)7 (28)
18 (72)7 (28)

52 (50)51 (50)79 (77)23 (22)12 (67)6 (33)
12 (67)6 (33)

8 (73)
3 (27)
7 (64)
4 (36)

155 (88)
22 (12)

11 (100) 9 (100) 20 (80)
0 (0)
0 (0)
5 (20)

90 (87)13 (13)17 (94)1 (6)8 (73)
3 (27)

172 (97)5 (3)144 (81)32 (19)169 (95)7 (4)151 (85)
21 (12)90 (51)78 (44)161 (90)
12 (7)

11 (100)
0 (0)11 (100)
0 (0)11 (100)0 (0)9 (82)0 (0)8 (73)
2 (18)
9 (82)0 (0)98 (95)5 (5)76 (74)26 (25)95 (92)7 (7)90 (87)13 (13)46 (45)54 (52)94 (91)8 (8)18 (100)0 (0)15 (83)3 (17)
18 (100)0 (0)16 (89)2 (11)
10 (56)
7 (39)
17 (94)1 (6)

11 (100)0 (0)10 (91)1 (9)11 (100)0 (0)8 (73)
2 (18)
6 (55)
3 (27)
9 (82)
2 (18)

care system and testing for COVID-19 (n = 51; 29%), restrictions on surgeries other than transplantation (n = 28; 16%),and surgeries re-established in accordance with the guidelines of the Japan Society for Transplantation (n = 34; 19%).
Of the centers with ongoing transplant surgery at the timeof the questionnaire, 112 (63%) were providing transplant
medical care without special restrictions, while 34 (19%)
were limiting transplant surgery to cases considered difficult
to postpone (Fig. 4d) (Q16). Depending on the future spreadof the COVID-19 pandemic, only 30 centers (17%) answeredthat they would continue to provide transplant medical carewithout any restrictions, while 92 (52%) answered thatthey would consider suspending their transplant surgeries depending on the presence of COVID-19 in the ICU
or hospital. Thirty-four centers answered that they would
discontinue transplant surgeries in the event of nosocomial
COVID-19 infection (Q17).
During the COVID-19 pandemic, 21 centers (12%)
answered that they had been restricted from dispatching toorgan recovery (Q18), and 14 centers (8%) answered thatthey had abandoned organ recovery efforts because of the
COVID-19 pandemic (Q19). Even when organ recovery was
possible, 12 centers (7%) reported that they had abandonedtransplant surgery because of the COVID-19 pandemic(Q20).
Before any transplant surgery, 161 institutions (90%)
performed a preoperative COVID-19 screening test of SOT

9 (100)0 (0)9 (100)0 (0)9 (100)0 (0)8 (89)
1 (11)
6 (67)
3 (33)
9 (100)0 (0)25 (100)0 (0)23 (92)2 (8)25 (100)0 (0)20 (80)3 (12)
14 (56)9 (36)
23 (92)
1 (4)recipients (Q21). A total of 112 centers (63%) answeredthat the post-transplant follow-up systems had changed inaccordance with the COVID-19 pandemic (Q22), and most(123 centers, 69%) answered that follow-up outpatient visits
after transplantation were set at longer intervals (Q23).

Discussion
The findings of this study confirmed that the COVID-19
pandemic reduced the number of organ donations, especiallyfrom DCDs. In Japan, organ donation from DCDs was performed without the withdrawal of life-support including respiration, which sometimes forces the organ recovery teamto wait a long time in the donor's hospital. This was considered why DCDs were so markedly reduced by the COVID19 pandemic. Our questionnaire survey revealed the organ
donation situation in Japan. In addition to a reduction in thenumber of organ donations, half of the transplant centerssuspended transplant surgery, particularly abdominal organtransplant surgeries, because of the COVID-19 pandemic.
While transplant surgeries were resuming in most institutions when the questionnaire was distributed, approximately
20% of the transplant centers limited SOT surgery to thosepatients whose prognosis would have been severely affectedby postponing surgery, and about 10% of centers indicatedthat it was necessary to abandon organ recovery or SOT in

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13
151 (85)
26 (15)Yes
No

Single department
41 (23)
Multiple department
57 (32)All over hospital
44 (25)
Others7 (4)Q12 Have the organ transplant surgeries in your hospital Yes
85 (48)been stopped due to the COVID-19 pandemic?
No
92 (52)Presence of COVID-19-positive patients after
0 (0)Q13 What was the reason for the decision to suspendtransplantation in the hospitalthe organ transplant surgeries? (Multiple answers
allowed)Presence of COVID-19-positive patients in the
12 (7)
hospitalPresence of COVID-19-positive patients in the area 26 (15)(prefecture)
In-hospital medical care system or examination sys- 34 (19)
tem inadequate for assessing COVID-19
All surgical treatments restricted, including trans33 (19)plantation
Following the guidelines of the Japan Society for
57 (32)
Transplantation
Others16 (9)
Q14 What kind of organ transplants were suspended?
Both deceased donor transplants and living donor
56 (31)transplantation
Only living donor transplantation
25 (14)
Only high-risk transplantation including ABO
0 (0)incompatible cases
Deceased donor transplantation
1 (1)Others3 (2)Q10 Have you ever discussed the continuation of thetransplant surgeries in the hospital during the
COVID-19 pandemic?
Q11 To what extent did that discussion take place?

Overall (%)
n = 177

AnswerTable 2  Results of the questionnaire on the status of transplant programs

1 (17)0 (0)5 (83)0 (0)0 (0)9 (100)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A

6 (67)
3 (33)

Lung
n=9

0 (0)
5 (63)
3 (38)0 (0)0 (0)11 (100)
N/A

8 (73)
3 (27)

Heartn = 1130 (32)31 (33)25 (27)6 (6)80 (78)23 (22)0 (0)26 (33)54 (68)

0 (0)
0 (0)

0 (0)
0 (0)

1 (1)
3 (4)

25 (31)
0 (0)

0 (0)
15 (19)1 (100) 51 (64)0 (0)1 (100) 30 (38)

1 (100) 33 (41)0 (0)1 (100) 11 (14)

5 (25)
9 (45)
5 (25)1 (5)1 (4)
24 (96)
0 (0)

0 (0)
0 (0)

0 (0)
0 (0)

1 (25)
4 (100)3 (75)

2 (50)

0 (0)

0 (0)

0 (0)

3 (20)
8 (53)
4 (27)0 (0)4 (22)
14 (78)0 (0)15 (83)3 (17)

Kidney Pancreasn = 103 n = 18

20 (80) 94 (91)
5 (20) 9 (9)Livern = 25

N/A
N/A

N/A
N/A

N/A
N/A

N/A

N/A

N/A

N/A

N/A

2 (25)
4 (50)
2 (25)0 (0)0 (0)11 (100)
N/A

8 (73)
3 (27)

Small intestinen = 11

768
Surgery Today (2022) 52:763–773

N/A
N/A

29 (16)51 (29)28 (16)34 (19)Reduction in numbers of COVID-19 infections in
the local area
Establishment of an in-hospital medical care system and examination system for COVID-19
Restrictions on surgeries other than transplantation
liftedFollowing the guidelines of the Japan Society forTransplantation

0 (0)5 (45)
5 (45)1 (9)1 (9)2 (18)0 (0)0 (0)11 (100)
3 (27)
8 (73)

18 (10)30 (17)60 (34)32 (18)34 (19)24 (13)23 (13)21 (12)148
14 (8)
156 (88)

8 (11)

27 (36)32 (43)2 (8)
3 (12)1 (4)
22 (88)2 (8)6 (24)

15 (16)16 (17)18 (17)79 (77)30 (31)19 (20)2 (8)10 (10)4 (16) 13 (14)15 (60) 20 (21)0 (0)8 (11)
14 (56) 66 (69)
9 (36) 15 (16)0 (0)1 (100) 25 (33)

1 (100) 48 (64)0 (0)3 (17)
15 (83)4 (22)
4 (22)1 (6)
17 (94)0 (0)3 (17)

4 (22)
4 (22)
6 (33)0 (0)9 (50)
5 (28)

2 (50)

2 (50)

2 (50)

2 (50)

2 (50)

1 (25)

Kidney Pancreasn = 103 n = 18

1 (100) 8 (11)

0 (0)

Liver
n = 25

0 (0)
0 (0)
8 (8)
9 (100) 23 (92) 90 (87)

1 (11)0 (0)0 (0)9 (100)

0 (0)

0 (0)

1 (11)
1 (11)
7 (78)

N/A
N/A
11 (100) 6 (67)0 (0)1 (11)

N/A

N/A

N/A

N/A

N/A

N/A

Lung
n=9

8 (4)
112 (63)
34 (19)

N/A

N/A

N/A

11 (6)

A lack of spread of COVID-19 infection confirmedin the hospital

N/A

Heart
n = 119 (5)Overall (%)
n = 177

Reduction in numbers of COVID-19 infections in
the hospital

AnswerOthersQ16 What kind of organ transplants are being performed Without any particular restrictions
if the program is ongoing?
Limited to cases considering being difficult topostpone
OthersWithout any particular restrictions
Q17 If the COVID-19 epidemic expands more in thenear future, how do you think that organ transConsidering discontinuing their transplant surgeries
plants be carried out in your hospital?
depending on the presence of COVID-19 patientsin the ICU
Considering discontinuing their transplant surgeries
depending on the presence of COVID-19 patientsin the hospital
Discontinue the transplant surgeries should nosocomial COVID-19 infection be observed
Not decided, yet
OthersYes
Q18 Have you placed any restrictions on the dispatchof organ recovery from your center during theNo
COVID-19 pandemic?
Yes
Q19 Have you experienced any cases in which organ
recovery was abandoned due to a COVID-19
No
infection?

Q15 What was the reason for resuming the organ transplant surgeries? (Multiple answers allowed)

Table 2  (continued)

0 (0)11 (100)

0 (0)
0 (0)
1 (9)
10 (91)1 (9)

3 (27)

1 (9)
3 (27)
7 (64)

N/A
6 (55)
4 (36)

N/A

N/A

N/A

N/A

N/A

N/A

Small intestinen = 11

Surgery Today (2022) 52:763–773
769

13

13

Q23 If you answered "yes" to Q22, please explain
how the post-transplant follow-up systems havechanged. (Multiple answers allowed)

Q22 Have there been any changes in the post-transplantfollow-up systems during the COVID-19 pandemic in your hospital?

Q20 Have you experienced any cases in which organtransplantation was abandoned due to a COVID19 infection even though organ recovery was
possible?
Q21 How do you handle patients who are candidates
for organ transplantation during the COVID-19
pandemic? (Multiple answers allowed)

Table 2  (continued)

8 (73)1 (9)9 (82)1 (9)1 (9)6 (55)
5 (45)0 (0)0 (0)6 (100)4 (67)0 (0)2 (33)
3 (50)
2 (33)

158 (89)
125 (70)
16 (9)
161 (90)
6 (3)
6 (3)
65 (37)80 (45)29 (16)3 (2)123 (69)
66 (37)14 (8)
51 (29)36 (20)21 (12)No
Be sure to perform chest CT
Perform chest CT if the patient has some symptoms
Be sure to screen for COVID-19 (PCR test, antigen
test, etc.)
Screen for COVID-19 (PCR test, antigen test, etc.),
if there are chest CT findings or the patient has
some symptoms
OthersNo change
The system has changed a little
The system has changed considerably
The system has all changed
Outpatient visits for patients after transplantation
were set to be performed at longer intervals
Try to give more medicine than usual
Examination are limited as much as possible
Try to patients stay in the out-patients clinic asshort as possible
Try to make each other patients avoid contact
Others10 (91)1 (9)

12 (7)YesHeartn = 11

Overall (%)
n = 177

Answer9 (9)2 (40)
3 (60)

3 (60)
1 (20)
3 (60)0 (0)3 (33)
6 (67)0 (0)0 (0)4 (80)0 (0)5 (24)
5 (24)

9 (43)
2 (10)
5 (24)0 (0)9 (36)
11 (44)5 (20)0 (0)
16 (76)2 (8)21 (26)8 (10)

44 (54)9 (11)
35 (43)5 (5)37 (36)45 (44)18 (17)3 (3)77 (94)2 (2)2 (15)
1 (8)

4 (31)
2 (15)
4 (31)0 (0)6 (33)
9 (50)
3 (17)0 (0)12 (92)0 (0)13 (72)3 (17)
18 (100)

17 (94)1 (6)Kidney Pancreasn = 103 n = 18

23 (92) 89 (86)

0 (0)

Liver
n = 256 (67) 11 (44) 85 (83)0 (0)5 (20) 3 (3)9 (100) 22 (88) 93 (90)

8 (89)

1 (11)Lung
n=9

3 (33)
2 (22)

2 (22)0 (0)2 (22)0 (0)4 (36)
4 (36)
3 (27)0 (0)8 (89)

1 (9)

2 (18)
4 (36)
10 (91)

11 (100)

0 (0)Small intestinen = 11

770Surgery Today (2022) 52:763–773

Surgery Today (2022) 52:763–773

771

Fig. 4  Answers to questions about porting program continuation.
Q12: Have organ transplant surgeries in your hospital been stopped
due to the COVID-19 pandemic? (a), Q13: What was the reason forthe decision to suspend organ transplant surgeries? (Multiple answers
allowed) (b), Q14: What kind of organ transplants were suspended?
(c), Q16: What kind of organ transplants are being performed if transplant surgery is ongoing? (d). Response summaries: Q12: While nocenter discontinued its transplant surgeries for heart and lung transplants, one center (4%) suspended its transplant surgeries for livertransplants, 80 (78%) suspended their transplant surgeries for kidneytransplants, and 4 (22%) suspended their transplant surgeries for pancreas transplants (a). Q13: The reasons for discontinuing transplantation were as follows: COVID-19-positive patients in the hospital(n = 12; 7%), COVID-19-positive patients in the prefecture (n = 26;15%), in-hospital medical care system or examination system inadequate for assessing COVID-19 (n = 34; 19%), all surgical treatment(including transplantation) restricted (n = 33; 19%), and suspended inaccordance with guidelines of the Japan Society for Transplantation(n = 57; 32%) (b). Q14: Fifty-six centers (31%) discontinued all transplants, including both deceased and living donor transplantation, 25(14%) discontinued only living donor transplantation, and 1 (1%) discontinued only deceased donor transplantation (c). Q16: Of the centers with an ongoing transplant surgeries at the time of the questionnaire, 112 (63%) were providing transplant medical care without any
specific restrictions, while 34 (19%) were limiting transplant surgery
to cases when it was considered difficult to postpone (d)some cases because of the COVID-19 pandemic. The present study confirmed that the COVID-19 pandemic has hada significantly negative impact on both organ donation andthe performance of SOT.
In the United States, the number of patients registered as
waiting for SOT and transplant surgery in April, 2020, wasreported to have decreased in all United Network for Organ
Sharing regions, and the mortality rate of these waiting
patients had increased in more than half of the regions [34].
It was also reported that in March and April, 2020, when
the COVID-19 pandemic began, the number of new waitlist patient enrollments, deceased-donor kidney transplants,
and living-donor kidney transplants, fell below expectations

by 18%, 24%, and 87%, respectively [35]. In Europe, the
COVID-19 pandemic was reported to have had a similarly
severe impact on transplant medical care, with the numberof referrals of potential donors decreasing by 39% in the
United Kingdom [36] and the number of potential deceasedorgan donors decreasing by 16% in comparison with previous years in France [37]. Conversely, in South Korea,(as in Japan), where the COVID-19 pandemic manifested
relatively early with a less impact than in the United Statesand Europe, there was no significant change reported in thenumber of liver transplantations or kidney transplantations
as of March and April, 2020 [38, 39], respectively, from theprevious year, for both living donor transplants and BDD

13

772

transplants. These findings showed that the ability to perform organ transplantation is dependent on the severity ofthe spread of COVID-19 in a given country; however, as
these reports relate to the situation in spring 2020, subsequent reports on the overall situation of organ transplantation in 2020 are awaited.
Unfortunately, during the severe COVID-19 pandemic at
the present time, in many countries, including Japan, available medical resources are likely to be assigned to countermeasures against the COVID-19 pandemic, necessitating a
reduction in transplantation activity. In several countries,
newly developed vaccines are improving the impact of the
COVID-19 pandemic [40–45], and facilitating the rebuildingof a normal lifestyle. It is thought that the acquisition of herd
immunity through vaccination will improve the survival ofpatients with organ failure who are awaiting transplantationand promote transplant medical care.
The present study had several limitations. The overall
response rate to the questionnaire was 86%, which may beconsidered relatively high; however, the response rate of thekidney transplant centers was approximately 80%, whichis slightly low. The questionnaire survey in this study was
conducted from December, 2020 to January, 2021, when
the background of the COVID-19 pandemic in Japan was
in a state of flux. In particular, the number of COVID19-positive patients in the third wave increased rapidly, andfrom January 2021, a state of emergency was declared insome cities, including Tokyo. The movement of people wasgreatly restricted and the situation was changing, which
may have affected organ recovery; thus, the answers to ourquestionnaire survey might have varied greatly dependingon the time of the response. Furthermore, the number ofliving donor organ transplantations was not mentioned inthis paper, as the effects of the COVID-19 pandemic on thestate of living transplantation in Japan is being investigatedin another study.

Conclusion
At the end of March, 2021, the number of patients infectedwith COVID-19 in the third wave of the pandemic began to
decline. Although the COVID-19 pandemic in Japan is lesssevere than in other countries, it has had a large impact on
the overall transplantation activity, suspending transplantation surgeries in 48% of the transplantation centers, including 78% of the kidney transplantation centers, and reducing
the number of organ donations to 61% of the year-on-year
average. This situation should be monitored closely.
Acknowledgements We like to thank the 177 transplant centers that
responded to the questionnaire during the national COVID-19 pandemic crisis.

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Surgery Today (2022) 52:763–773
Funding This research was funded by Health, Labour and Welfare
Policy Research Grants.

Declarations
Conflict of interest We have no conflicts of interest to declare in association with this study.
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13

Journal of Rural Medicine
Original article

A multicentric study on the newly developed
reconstruction locking plate formidshaft clavicular fracture
Takeshi Ogawa1, 2, Masafumi Uesugi3, Yuki Hara2, Yuichi Yoshii4, and Masashi Yamazaki2
1

Department of Orthopaedic Surgery, National Hospital Organization, Mito Medical Center, Japan
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Japan3
Department of Orthopaedic Surgery, Ibaraki Seinan Medical Centre Hospital, Japan
4
Department of Orthopaedic Surgery, Tokyo Medical University Ibaraki Medical Center, Japan
2

Abstract
Objectives: To examine the efficacy and clinical and radiological outcomes of the use of a streamlined clavicle plate® (MEIRA,
Aichi, Japan) for midshaft clavicular fractures.
Methods: This was a retrospective cohort study of 155 patients with displaced midshaft clavicular fractures treated using a streamlined clavicle plate between 2015 and 2019 in 18 hospitals across Japan. A questionnaire regarding bone union and postoperativecomplications was used, and 136 cases were followed up for one year or until bone union. Plate fitting was evaluated retrospectively
using surgical records, radiographic findings, and surgeon’s opinion.
Results: During surgery, plate bending was needed in 19 cases (12.3%), poor fitting was observed in 8 cases (5.2%), and bone union
was achieved in 133 cases (97.8%). Total implantation failure, including plate breakage and screw loosening, occurred in 10 cases(6.5%) from the intraoperative to postoperative period. Subjective complications were observed in 26 cases (16.8%): incongruity
around the surgical scar or in the anterior chest in 23, and contracture of the shoulder in three. Plate removal was performed in 66
cases (48.5%) per patient’s request.
Conclusion: The use of a streamlined clavicle plate is effective for midshaft fractures of the clavicle, and the success rates of bone
union and implantation using this approach are comparable to those of other existing plates.
Key words: clavicle midshaft fracture, multicentric study, superior plate of the clavicle(J Rural Med 2021; 16(3): 148–153)

Introduction
Clavicle fractures are common injuries in adults, accounting for 5% of all fractures. Eighty percent of clavicular
fractures in adults occur in the middle one-third of the bone1,
2). There are various methods for treating midshaft clavicle
fractures, such as the use of intramedullary Kirschner wires,
Received: March 10, 2021
Accepted: March 15, 2021
Correspondence: Takeshi Ogawa, Department of Orthopaedic Surgery, National Hospital Organization, Mito Medical Center, 280
Sakuranosato, Ibarakimachi, Ibaraki 311-3193, Japan
E-mail: ogawat@md.tsukuba.ac.jp
This is an open-access article distributed under the terms of theCreative Commons Attribution Non-Commercial No Derivatives(by-nc-nd) License <http://creativecommons.org/
licenses/by-nc-nd/4.0/>.

©2021 The Japanese Association of Rural Medicine

Steinmann pin fixation, and plate fixation3–7). Currently,
open reduction and internal fixation of severely displaced
fractures of the middle third of the clavicle are recommended for adult patients8). In particular, plate fixation can help
in obtaining a stable anatomical reduction in severely displaced or comminuted fractures. Plates such as reconstruction and reconstruction locking compression plates (LCPs),
which can be bent to accommodate the S-shaped curvatureof the clavicle, are preferred9–11). Plate fixation can be technically difficult because of the complex anatomy of the clavicle, with its S-shaped curvature and cephalad-to-caudadbow2). To address this problem, pre-contoured anatomic
plates have been developed. Some anatomical clavicle plates
include the LCP Superior Anterior Clavicle plate® (Depuy
Synthes, Massachusetts, USA), VariAx Clavicle Locking
Plate System® (Stryker Corporation, Michigan, USA), andLocking Clavicle Plating System® (Acumed, Oregon, USA),each with features that are low-profile and designed to fit

doi: 10.2185/jrm.2021-011 | 148

Journal of Rural Medicine
the superior surface of the clavicle with minimal soft-tissue
irritation. A streamlined clavicle plate® (MEIRA, Aichi,
Japan; SC plate) was developed based on the computed tomography (CT) data of Japanese patients; its thickness was
2.9 mm—the thinnest among the locking plates—with astrength of no less than the existing plates. There are several
reports and single-center studies on patients treated throughplate fixation; however, there are few studies that involve
multiple centers and a large sample size1). In this multicenter
study, we aimed to assess the safety, adaptability, efficacy,
and clinical and radiological outcomes of using the SC
plate®, a reconstruction locking plate, for midshaft clavicular fractures.

Materials and Methods
This was a retrospective cohort study of patients withdisplaced midshaft clavicular fractures treated using an SC
plate between 2015 and 2019 in 18 hospitals across Japan.
The ethics committee of the University of Tsukuba Hospital
approved the study (reference number: R01-044), and informed consent was obtained from all participants. The inclusion criteria included surgical cases with midshaft fractures that were evaluated to require surgery by orthopedic
surgeons in each hospital. The exclusion criterion was the
distal or proximal end of the clavicle fracture. We collected
relevant information on 155 cases using a questionnaire ateach facility. In addition to the patient’s basic information(age, sex, mechanism of injury, radiographic findings, waiting period from the injury, and so on), the questionnaire
asked about the size of the plate used for fixation (eight, nine,ten holes), whether plate bending was needed, the quality offit between the plate and the clavicle, the time of surgery,and occurrence of any complications during the surgery.
The SC plate length ranged between 85 mm (eight holes)
and 105 mm (ten holes), and the width between 24.8 mm(eight holes) and 31.1 mm (nine and ten holes), all of which
passed the mechanical load tests under the approval number 22800BZX00003000. The injury patterns were classified according to the guidelines of the Orthopaedic Trauma
Association/Arbeitsgemeinschaft fur Osteosynthesefragen(OTA/AO) and Robinson’s classification12). The quality ofthe plate fitting was retrospectively evaluated from the surgical records, radiographs, and surgeon’s opinion. We also
investigated the achievement of bone union, the occurrenceof implantation failure, and the need for reoperation due toimplantation failure. In 136 cases, follow-up was performed
for more than one year or until bone union to observe any
postoperative complications. Unfortunately, we could not
follow-up 19 cases because the patients dropped out or weretransferred to another hospital. The indication and the technique of the surgery, as well as the rehabilitation plans, were
decided by each hospital.

One orthopedic surgeon in each facility retrospectively
evaluated bone healing using radiographs. The level of bonehealing was judged by three or more cortical bone continuity in two directions of the radiographic images. In case ofany difficulty in assessing the bone union using the radiographic images, a consensus was reached between the surgeon and the first author.
Furthermore, we investigated the quality of the fitting
in 22 patients who had undergone CT postoperatively at thefirst author’s facility. The quality of the fitting was definedas good (no overhang), fair (mild anterior or posterior overhang of the plate over the clavicle), or poor (both anterior
and posterior plate overhang or screw-hole overhang). The
decision regarding the quality was made via a three-dimensional CT (3DCT) using the modified Huang’s evaluation 2).

Results
A total of 155 patients (123 men and 32 women; meanage, 41.7 ± 19.7 years) underwent SC plate fixation for midshaft clavicular fractures between April 2015 and December
2019 at the institutes included in this study. Eighty-sevenpatients had fractures on the right side, whereas 68 had
fractures on the left side. Thirty-two patients were smokers, and 94 patients were non-smokers. Smoking status remained unknown in 28 patients. Regarding the mechanismof injury, high-energy incidents, including traffic accidents,
falls from great heights or during sports, occurred in 79
patients; low-energy incidents, such as falling down, occurred in 72 patients, and the mechanism was unknown infour patients. According to the OTA/AO classification, 27,76, and 52 patients were categorized as 15.2A, B, and C,
respectively. According to Robinson’s classification, four,
five, 98, and 48 patients were categorized as Types 2A1, A2,
B1, and B2, respectively (Table 1). Eight-hole, nine-hole,and ten-hole plates were used for 67, 62, and 26 patients, re-Table 1 Patient characteristics and the number of each patient
Patient characteristics

Number of patients

GenderMale 123, Female 32
Age, average (range)
41.2 (13–87) years
Smoking, current
Yes 32, No 94, Unknown 28
Mechanism of injury
High 79, Low 72, Unknown 4
Fracture type (AO classification)
A
27
B
76
C
52
Fracture type (Robinson classification)
A1
4
A2
5
B1
98
B2
48

2021; 16(3): 148–153 | doi: 10.2185/jrm.2021-011 | 149

Journal of Rural Medicine
spectively. During the surgery, plate bending was needed in
19 patients (12.3%), and poor fitting was confirmed in eightpatients (5.2%). The average time of surgery was 91 minutes (range: 51–156 minutes). Intrasurgical complications
occurred in three cases (breakage of the plate during plate
bending occurred in one case and difficulty in insertion of
the most proximal screw occurred in two cases). Bone union
was achieved in 133 (97.8%) of the 136 patients who could
be followed up for over one year or until bone union had
been achieved. The average time to bone union was 153.1
days (range: 44–482 days). Postoperative complications, including screw loosening, were observed in seven patients(5.1%), and plate breakage did not occur. Total implantation
failure occurred in ten patients (6.5%) from the intraoperative to postoperative period. Subjective complications wereseen in 26 patients (16.8%): a sense of incongruity aroundthe surgical scar or anterior chest in 23 patients and contracture of the shoulder in three patients. Plate removal was
implemented per patient’s request in 66 (48.5%) of the 136
patients who will be followed up for over one year or untilbone union (Table 2).
Upon evaluation of the quality of the plate fitting in 22
cases using 3DCT, the fitting was found to be good in ten
patients, fair in four patients, and poor in eight patients. The
summary of the representative cases is as follows:In case 1, a 35-year-old man sustained a Robinson 2B1
clavicular fracture. The fracture was fixed with a ten-hole
SC plate, and bone union was achieved after three months.

The fitting of the plate was good in the 3DCT scan using themodified Huang’s evaluation 2) (Figure 1). He exhibited excellent function but retained a sense of incongruity aroundthe surgical scar; thus, the plate was removed one year after
the surgery.
In case 2, a 17-year-old boy sustained a Robinson 2A2

Table 2 Outcomes. The total number of patients is155; however, bone union was evaluated inonly 136 patients
Outcomes

The number of patients

Plate size
8 hole9 hole10 holeTotal 155
67
62
26

Plate bending
Yes
No

19
136

Plate fittingGood
Not good147
8Implant failure

10Bone union
Yes
No

Total 136
133
3

Figure 1 a: Robinson 2B1 clavicular fracture (39-year-old man). b: Fracture fixated using a ten-hole SC plate. c: Bone unionachieved after three months. d: 3DCT shows a good quality plate fitting.

2021; 16(3): 148–153 | doi: 10.2185/jrm.2021-011 | 150

Journal of Rural Medicine

Figure 2 a: Robinson 2A2 clavicular fracture (17-year-old boy). b: Fracture fixated using an eight-hole SC plate. c: The plate removed
one year after surgery. d: 3DCT performed three months after surgery indicates poor fitting; the plate was anteriorly set. e:
Bone union achieved three months after surgery.

Figure 3 a: Robinson 2B1 clavicular fracture (69-year-old man). b: Fracture fixated using a nine-hole SC plate. c: 3DCT
performed one month after surgery indicates poor fitting. d: Loosening of the two proximal screws; however, bone
union was achieved three months after surgery.

clavicular fracture, which was fixed with an eight-hole SC
plate. From the 3DCT results performed three months after surgery, we realized that the distal part of the plate wasplaced anterior to the bone. The plate fitting quality wasevaluated as poor; however, bone union was achieved threemonths after surgery. Plate removal was performed one year
after the surgery (Figure 2).
In case 3, a 69-year-old man sustained a Robinson
2B1 clavicular fracture, which was fixed with a nine-hole

SC plate. One month after surgery, 3DCT showed that thequality of the plate fitting was poor. At three months after surgery, loosening of the two proximal screws was observed; nevertheless, bone union was achieved by limiting
the shoulder’s range of motion for two months after surgery(Figure 3).

2021; 16(3): 148–153 | doi: 10.2185/jrm.2021-011 | 151

Journal of Rural Medicine
Discussion
This was a multicenter study that included a larger number of cases of midshaft fracture treated with plate fixation
for the clavicle than in previous studies1, 9, 13). The bone union
rate was 97.8%, while the implantation failure rate was 6.5%
(10/155 cases). Woltz et al. described the rate of implantation failure to be 12.6% in their retrospective cohort study1).
Gilde et al. reported significantly more implant-related
complications when using a reconstruction plate than whenusing a dynamic compression plate (8.5% vs. 1.2%, p=0.03).
Although their plate was an anteroinferior type plate, unlike our superior reconstruction locking plate, it is expected
to be a more durable and effective implant9). Robinson etal. described a reoperation rate of 2.3% in 86 cases due toimplantation failure of the locking clavicle plating system®
(Acumed, Oregon, USA)13). Their plate system had two direction types (anterior and superior), and all surgeries were
performed by shoulder specialists (Table 3).
In our study, orthopedic specialists or residents performed several surgeries. Plate breakage or deviations may
thus have been caused by both the lack of strength of theplate, as well as by technical problems by the surgeons.
However, in superior types of clavicle plates, insertion ofproximal screws is difficult because it is obstructed by thepatient’s head. Hence, in several cases, a cortical screw wasselected for the proximal hole to lean in the direction of theinsertion. A locking screw was not used because of the poor
angle of insertion in some cases. These problems may leadto loosening of the screw; however, the strength and durability of our plates are not inferior to those of other existing
plates. The SC plates in our study feature slight elasticity, allowing them to pull up the bone in the proper reduction position. The three locking holes on both sides create slightly
smaller hole distances, unlike in other existing plates, helping to reduce the mechanical load on both sides. There arealso some notches on the plate to be used for wiring in thecase of comminuted fractures; therefore, the bending of theplate is easier in the SC plate compared to that in the otherexisting plates.
This SC plate was designed to set the upper part of theclavicle, and the quality of the fitting was good in 132 cases(94.8%). Although plate bending was needed in 19 cases(12.3%), all these cases had good quality plate fitting according to the surgeon’s opinion. In contrast, another study
reported poor fitting in eight of 22 cases, suggested by
3DCT findings with the modified Huang’s method 2). Although bone union was achieved in all these cases, technicalerrors, including poor reduction or poor setting position of
the plate, were revealed. Ordinarily, CT is not used to investigate the achievement of bone union, except when patients
exhibit any complications; however, it is true that plate setting is difficult if the fracture site is too distal or too proximal. In such cases, fair fitting may not be inevitable using
this SC plate, as it only has three size options and a superior
type of setting. Further development of this plate is neededto address several types of midshaft clavicle fractures. Kim
et al. described a real-size 3D-printed model as a preoperative and intraoperative tool for minimally invasive platingof comminuted midshaft clavicle fractures14). Such trials areuseful for providing more precise treatment, as well as fordeveloping new types of plates.
There are some limitations to this multicenter study.
First, we conducted a retrospective study using questionnaires; thus, the evaluations were sourced from several investigators. In order to assess the quality of plate fitting, we
depended on the surgical records and the surgeon’s opinion.
We evaluated only 22 cases using 3DCT; however, due tothe harmful effects of radiation, it is inappropriate to use CTfor patients who follow a favorable recovery process. Second, it could not be directly compared with other plates ortreatment methods, such as conservative or intramedullary
nails. Further research is warranted to address these limitations.

Conclusion
In conclusion, this multicenter study demonstrated theeffectiveness of our SC plate for treating midshaft clavicle
fractures. The rates of bone union and implant failure were
97.8% and 6.5%, respectively, indicating that this plate may
have sufficient strength for bone union and would not leadto serious complications. Therefore, this SC plate is not considered inferior to the existing plates.

Table 3 Summary of literature: nonunion, implant failure, and plate removal rates
Study
Shin et al., 2012 11)
Robinson et al., 2013 12)
Waltz et al., 2016 1)
Gilde et al., 2014 9)
Ours

Number ofpatients
125
86
111
85
71
155

Nonunion(%)

Plate type
Recon.
Precontoured locking
3.5 mm Recon.
2.7 mm DCP
2.7 mm Recon.
2.8 mm Recon. Locking

Superior
Superior/Anterior
all directions
Anteroinferior
AnteroinferiorSuperior

1.7
2.7
1.2
7
2.2

Implant
Plate
failure (%) removal (%)
12
2.3
8.1
1.2
8.5
6.5

11.6
37.8
11.8
7
48.5

2021; 16(3): 148–153 | doi: 10.2185/jrm.2021-011 | 152

Journal of Rural Medicine
Funding: No beneﬁts in any form have been received orwill be received by the authors related directly or indirectly
to the subject of this article.
Conflicts of interest: None.

Acknowledgments
The authors would like to thank all the investigating
members, who are specialists in orthopedics at the University of Tsukuba and related facilities, for their contributions
to this study. We present their names and the hospitals towhich they are affiliated in the list below.
Dr. Akira Ikumi, M.D., Ph.D.
– Takahagi Kyodo Hospital and Mito Kyodo General
Hospital
Dr. Arata Watanabe, M.D., Ph.D.
– Ichihara Hospital
Dr. Hisanori Gamada, M.D.
– Ibaraki Western Medical Center
Dr. Katsuya Aoto, M.D., Ph.D.
– National Hospital Organization Kasumigaura Medical
CenterDr. Kazuhiro Ikeda, M.D.
– Kikkoman General Hospital
Dr. Kensei Katsura, M.D.
– Total Moriya Daiichi Clinics

Dr. Masato Murakami, M.D.
– Ryugasaki Saiseikai Hospital
Dr. Ryuhei Michinobu, M.D.
– University of Tsukuba Hospital
Dr. Satoshi Nakamura, M.D.
– Tsukuba Central HospitalDrs. Satoki Ii, M.D., Kazuo Ohyama, M.D., Jun Nishine,
M.D., and Takamasa Kudo, M.D.
– Tokyo Medical University Ibaraki Medical Center
Dr. Shigeo Izawa, M.D.
– Tsukuba Gakuen Hospital
Dr. Shota Nakagawa, M.D.
– Matsudo City General Hospital
Dr. Takumi Hirabayasi, M.D.
– General Hospital in Hitachinaka
Dr. Tomohiro Yoshizawa, M.D., Ph.D.
– Tsukuba Medical Center Hospital
Dr. Yohei Tomaru, M.D., Ph.D.
– Namegata District General Hospital
Dr. Yosuke Ogata, M.D.
– Japanese Red Cross Mito Hospital
The authors also thank Mr. Yoshitaka Okayama and Mr.
Ryo Namiki, who are sales representatives of MEIRA Corporation Inc., for serving as liaisons between the authors
and the above investigators.

References
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2. Huang JI, Toogood P, Chen MR, et al. Clavicular anatomy and the applicability of precontoured plates. J Bone Joint Surg Am 2007; 89: 2260–2265.
[Medline] [CrossRef]
3. Hulsmans MH, van Heijl M, Houwert RM, et al. Surgical fixation of midshaft clavicle fractures: a systematic review of biomechanical studies. Injury 2018;
49: 753–765. [Medline] [CrossRef]
4. Huttunen TT, Launonen AP, Berg HE, et al. Trends in the incidence of clavicle fractures and surgical repair in Sweden: 2001–2012. J Bone Joint Surg Am
2016; 98: 1837–1842. [Medline] [CrossRef]
5. Honeycutt MW, Fisher M, Riehl JT. Orthopaedic Tips: A comprehensive review of midshaft clavicle fractures. J Orthop Physician Assistants 2019; 7:e0053. [CrossRef]
6. van der Meijden OA, Gaskill TR, Millett PJ. Treatment of clavicle fractures: current concepts review. J Shoulder Elbow Surg 2012; 21: 423–429. [Medline][CrossRef]
7. Zlowodzki M, Zelle BA, Cole PA, et al. Evidence-Based Orthopaedic Trauma Working Group Treatment of acute midshaft clavicle fractures: systematic
review of 2144 fractures: on behalf of the Evidence-Based Orthopaedic Trauma Working Group. J Orthop Trauma 2005; 19: 504–507. [Medline] [CrossRef]
8. Hill JM, McGuire MH, Crosby LA. Closed treatment of displaced middle-third fractures of the clavicle gives poor results. J Bone Joint Surg Br 1997; 79:
537–539. [Medline] [CrossRef]
9. Gilde AK, Jones CB, Sietsema DL, et al. Does plate type influence the clinical outcomes and implant removal in midclavicular fractures fixed with 2.7-mm
anteroinferior plates? A retrospective cohort study. J Orthop Surg Res 2014; 9: 55. [Medline] [CrossRef]
10. Hsiao YC, Lin TY, Wang YC, et al. Prognostic factors and outcomes of secondary surgery after plate fixation for midshaft clavicle fracture: Comparison of
traditional DCP and pre-contoured locking plate. Injury 2020; 51: 2241–2244. [Medline] [CrossRef]
11. Shin SJ, Do NH, Jang KY. Risk factors for postoperative complications of displaced clavicular midshaft fractures. J Trauma Acute Care Surg 2012; 72:
1046–1050. [Medline] [CrossRef]
12. Robinson CM. Fractures of the clavicle in the adult. Epidemiology and classification. J Bone Joint Surg Br 1998; 80: 476–484. [Medline] [CrossRef]
13. Robinson CM, Goudie EB, Murray IR, et al. Open reduction and plate fixation versus nonoperative treatment for displaced midshaft clavicular fractures:a multicenter, randomized, controlled trial. J Bone Joint Surg Am 2013; 95: 1576–1584. [Medline] [CrossRef]
14. Kim HN, Liu XN, Noh KC. Use of a real-size 3D-printed model as a preoperative and intraoperative tool for minimally invasive plating of comminuted
midshaft clavicle fractures. J Orthop Surg Res 2015; 10: 91. [Medline] [CrossRef]

2021; 16(3): 148–153 | doi: 10.2185/jrm.2021-011 | 153

Journal of Orthopaedic Science xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Orthopaedic Sciencejournal homepage: http://www.elsevier.com/locate/jos

Original Article

High-deﬁnition magnetic resonance images on medial elbow injuries
in preadolescent Little Leaguers
Tomomi Kajiwara a, Takeshi Ogawa b, *, Naotaka Mamizuka c, Ryuhei Michinobu d,
Toshiyuki Irie e, Atsushi Hirano daDepartment of Internal Medicine, Mito Clinical Education and Training Center, University of Tsukuba Hospital, Mito Kyodo General Hospital, 3-2-7 MiyaMachi, Mito, Ibaraki, 310-0015, Japanb
Department of Orthopedic Surgery, National Hospital Organization Mito Medical Center, 280 Sakuranosato, Ibarakimachi, Ibaraki, 311-3193, JapancBaseball and Sports Clinic, 2-228-1 Kosugi, Park city Musashikosugi the Garden Towers West 1st Floor W4, Nakahara-ward, Kawasaki-city, Kanagawa,
211-0063, Japand
Department of Orthopaedic Surgery and Sports Medicine, Mito Clinical Education and Training Center, University of Tsukuba Hospital, Mito Kyodo General
Hospital, 3-2-7 Miya-Machi, Mito, Ibaraki, 310-0015, Japane
Department of Radiology, Mito Clinical Education and Training Center, University of Tsukuba Hospital, Mito Kyodo General Hospital. 3-2-7 Miya-Machi,
Mito, Ibaraki, 310-0015, Japana r t i c l e i n f o

a b s t r a c t

Article history:
Received 15 July 2021
Received in revised form
9 December 2021
Accepted 14 December 2021
Available online xxx

Background: The incidence of throwing-related elbow injuries is still rising. The study aimed to enhance
the pathology of acute medial elbow injuries among young Little Leaguers by examining the medial
elbows of symptomatic 9e10 years old Little Leaguers using High-Deﬁnition Magnetic Resonance Images(HDMRI), which uses a small-diameter surface coil on the target area, leading to greater image
resolution.
Method: We identiﬁed Little Leaguers aged 9e10 years old. To minimize the detection of the chronic
adaptative changes, players who experienced the medial elbow pain previously and whose HDMRI had
not been taken within 4 weeks from the onset of medial elbow pain were excluded. This study
considered 21 players, and the mean age was 9.4 ± 0.5 years.
Result: The fragmentation of the medial epicondyle apophysis via HDMRI was found in 15 elbows(71.4%), while the avulsion was seen in three cases. The signal hyperintensity at the medial epicondyleapophysis was observed in 2 cases. Our data showed abnormal changes to the medial epicondyleapophysis and surrounding structures, such as the ulnar collateral ligament (UCL), ﬂexor-pronator tendons or the coronoid process of the ulna. We detected 11 abnormalities on X-ray imaging, while 20
subjects showed some abnormal ﬁndings via HDMRI.
Discussion: The current study showed that initial medial elbow injury in Little Leaguers without a historyof previous elbow injury could be attributed to multi-structure injury. Over 90% of subjects were injuredin the perichondrium, while 71.4% demonstrated a fragmentation of the secondary ossiﬁcation center,and 14.3% experienced an avulsion of the medial epicondyle apophysis. Because the injuries were notlimited to bony structures, HDMRI may be beneﬁcial for the appropriate evaluation of medial elbow pain.
The pathology of initial medial elbow injuries in young baseball players may be due to acute trauma
instead of repetitive microtrauma.
© 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

1. Introduction* Corresponding author. Fax: þ81 29 240 7788
E-mail address: ogawat@tsukuba-seikei.jp (T. Ogawa).

In 1960, Brogdon and Crow ﬁrst deﬁned “Little Leaguer's elbow”
as the symptomatic separation and fragmentation of the medial
epicondyle apophysis among Little League pitchers. Subsequent
researchers have shown various possible risk factors of elbow injuries such as amount of pitching, poor pitching biomechanics,

https://doi.org/10.1016/j.jos.2021.12.011
0949-2658/© 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Please cite this article as: T. Kajiwara, T. Ogawa, N. Mamizuka et al., High-deﬁnition magnetic resonance images on medial elbow injuries in
preadolescent Little Leaguers, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2021.12.011

T. Kajiwara, T. Ogawa, N. Mamizuka et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

recognized HDMRIs of 50 Little Leaguers and excluded sevenplayers who had histories of previous elbow injuries and 20 whose
HDMRI had been taken later than 4 weeks of the onset. Two players
injured by direct trauma to the medial elbow were also excluded.
Thus, 21 players were considered in this study (Fig. 1). A 1.5 or 3-T
magnetic resonance apparatus (Magnetom Symphony, Siemens,
Munich, Germany) with a small-diameter surface coil (Loop Flex
Coil, Siemens) was used to evaluate all subjects. Images were
evaluated in the coronal plane with a series of fat-suppressed T2
weight fast spine-echo images (T2FS), proton density-weight images (PDW), and GRE T2*-weighted images (T2*). The morphological abnormality of UCL (rupture or sagging of the UCL) and the
perichondrium (rupture or translocation of the perichondrium)
were evaluated with PDW and T2*, respectively. The signal abnormality of UCL and its surrounding structures, and the secondary
ossiﬁcation center and the coronoid process of the ulna were
evaluated in T2FS. We also examined the radiographs of the elbowof the anteroposterior view with full extension and at 45 of ﬂexion
to compare the ﬁndings against HDMRI. The X-ray was taken on the
day of the ﬁrst visit. Two orthopedic surgeons and one radiologist
evaluated the images independently and retrospectively. A
consensus was reached when different MRI readings wereobserved among the three.

fatigue, pitch velocity, pitch count, year-round participation,
greater pressure, or earlier single sports specialization [1e7]. Major
League Baseball and USA Baseball released guidelines to reduce
throwing-related injuries based on these scientiﬁc data. However,
20%e30% of 8e12-year-old Little Leaguers have experienced elbow
pain [8]. Some studies have shown that the number of emergency
visits resulting from baseball-related elbow injuries has increased
from 2006 to 2016, compared with injuries to other body parts suchas shoulders, knees, ankles, or wrists. Ulnar collateral ligament(UCL) reconstruction in youth pitchers increased between 1994 and2010 [1] and increased by 343% between 2003 and 2014 [9].
While the little leaguer's elbow is known as the result of chronic
repetitive trauma to the most vulnerable component of the elbow
among young players, it is true that there are some patients present
after an acute injury [10]. However, little is known about the acutepathology of the medial elbow injury among young overheadthrowing athletes. The increase in the number of elbow injuries
must be explained by a bad adherence or a mal-understanding of
the guideline at least partially, but there may be other factors
behind it since the guideline mainly focuses on preventing overuse.
The purpose of this study was to enhance the pathology of acutemedial elbow injuries among young Little Leaguers by examining
the medial elbows of symptomatic 9e10 years old Little Leaguers
by using High-deﬁnition MRI (HDMRI), which uses a smalldiameter surface coil on the target area, leads to greater image
resolution by having a better signal-to-noise ratio and a smaller
voxel size.

3. Results
One person out of 21 players was left-handed. The mean age was
9.4 ± 0.5 years (range, 9e10-years). Twenty patients played rubberball baseball, and only one patient played hard-ball baseball. Theiractual years of baseball-playing experience are unknown. The
average days from the onset of pain to the imaging date was
18.1 ± 6.2 days. The fragmentation of the secondary ossiﬁcation
center via HDMRI (Fig. 2) was found in 15 elbows (71.4%), while theavulsion of the medial epicondyle apophysis (Fig. 3) was seen inthree (14.3%). The signal hyperintensity at the secondary ossiﬁcation center of the medial epicondyle apophysis without fragmentation was observed in two cases (9.5%). Translocation or rupture of

2. Methods
In this descriptive case series, we identiﬁed Little Leaguers aged
9e10 years old who visited our hospital with medial elbow painfrom 2014 to 2018 and included those boys that had HDMRI results
for the evaluation. To minimize the detection of the chronic
adaptative changes, players who experienced the medial elbow
pain previously and whose HDMRI had not been taken within 4
weeks from the onset of medial elbow pain were excluded. We

Fig. 1. Inclusion and exclusion criteria.
2

T. Kajiwara, T. Ogawa, N. Mamizuka et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

Fig. 2. A: Normal secondary ossiﬁcation center at medial elbow (T2*) (arrow head). B: Fragmented secondary ossiﬁcation center (T2*) (arrow).

UCL. The signal hyperintensity around the UCL, including ﬂexorpronator tendons, was observed in 13 players (61.9%). Signal
hyperintensity at the subchondral bone just below the coronoid
process of the ulna was found in 9 players (42.9%). All players
demonstrated signal changes via HDMRI in more than two structures. The separations of the secondary ossiﬁcation center of medial
epicondyle were seen in 11 players via X-ray imaging, while 9
players had no signs of injury on X-ray imaging. One player missed
an X-ray of the elbow that was taken at the ﬁrst visit. The results are
summarized in Table 1. Fourteen players (66.7%) reported that they
could remember a speciﬁc single throwing motion that caused their
medial elbow pain.
3.1. Representative caseA 9-year-old boy who played ﬁrst base and short stop felt asudden pain at the medial elbow when he threw a rubber baseball.
The pain worsened when he released a ball. He visited our hospitalon day Xþ12. The X-ray of the A-P view with full extension showedno abnormality of the medial epicondyle (Fig. 6A). On the other
hand, the X-ray of the A-P view with 45 of ﬂexion might seem likethe fragmentation at the tip of the ossiﬁcation center of the medial
epicondyle, although it is unclear (Fig. 6B, arrow). However, the
HDMRI, which was taken on day Xþ23, clearly showed a rupture of
the perichondrium and an avulsion of the medial epicondyleapophysis (Fig. 7A and B).
4. Discussion
We limited our subjects to 9e10 years old baseball players since
it has been reported that the UCL could be thickened or there would
be the sclerotic bony changes among asymptomatic baseballpitchers aged 15e19 years old with ten years' experience in pitching, possibly due to the positive adaptation or the initiation ofdegenerative change [11]. The younger the pitchers are, the fewer
the chances of having pre-existing irregular MRI changes because
the duration of playing baseball is shorter, and the cumulative
number of throwing is considered to be smaller. Players can

Fig. 3. High-signal intensity at the proximal part of the medial epicondyle apophysis(arrow) indicating avulsed apophysis (T2FS).

the perichondrium (Fig. 4) was observed in 19 players (90.5%).
Morphological abnormalities, such as the sagging of the anterior
oblique bundle of UCL (Fig. 5), were found in 16 players (76.2%). Of
these 16 cases, 4 (19%) demonstrated signal hyperintensity of the3

T. Kajiwara, T. Ogawa, N. Mamizuka et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

Fig. 4. A: Normal perichondrium shown as a low signal intensity line, just medial to the apophysis (T2*). B: The ruptured perichondrium shown as the low signal intensity line wasdiscontinued (T2*).

Fig. 5. A: Normal UCL shown as straight low signal intensity line (PDW). B: UCL was sagged, and the signal hyperintensity was seen (PDW).

participate in Little Leaguer's “major division” as young as 9 years
old; it is important to evaluate 9e10 years old players to minimize
the possibility of adaptive changes as shown in the images. We
included players whose HDMRI were taken 4 weeks from the onsetof pain. As Frank et al. stated, the healing of ligaments is variable
and unpredictable [12]; thus, it is difﬁcult to decide when chronicchanges after a traumatic event are shown in HDMRI images.

Animal models have not shown remaining gross external changes
at week 4 for a mild sprain and slight local thickening of the ligament at week 7 in the case of a severe sprain [13]. Hence, we
decided that 4 weeks was a reasonable timeframe in which tocapture acute changes and eliminate chronic changes.
Our data showed abnormal changes not only to the medial
epicondyle apophysis but also to the surrounding structures, such4

T. Kajiwara, T. Ogawa, N. Mamizuka et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

The morphological change of the UCL was observed in 76.2%
players, while the signal change within the UCL was seen in only
19.0% of the subjects. Zell et al. stated that the origin of UCL always
remained medial to the cartilaginous interface of the apophysis andwas centered approximately 3 mm medial to the lateral edge of theapophysis [15], which may indicate that the UCL originates from theperichondrium. We hypothesized that the UCL was not always
damaged but sagged because it originated from the ruptured ortranslocated perichondrium. Thus, the possibility exists that the
instability against the valgus stress could happen without avulsion
or fragmentation of the medial epicondyle apophysis or the secondary ossiﬁcation center. In addition, our data showed that 66.7%of players complained of pain after one speciﬁc throwing motion.
This may indicate that the acute pathology of the initial medial
elbow pain among preadolescent Little Leaguers is more often than
we have recognized, and the principal pathology may be on the
perichondrium.
We detected 11 abnormalities on X-ray imaging, while all subjects demonstrated some abnormal ﬁndings via HDMRI. One subject missed X-ray imaging; however, we decided to include it to thestudy because the ﬁndings of the HDMRI were valuable. Given that
HDMRI had 100% sensitivity, nine out of 20 (45%) structural abnormalities on the medial elbow might have been missed via x-ray
imaging. The example case is shown in Figs. 6 and 7. Wei et al.
stated that the underlying etiology of Little Leaguer's elbow might
be related not only to skeletal changes but also to the ﬂexorpronator muscles or the common tendon; thus, the X-ray imaging
may understate the injury [16]. Yoshioka et al. showed that HDMRI
with a small-diameter surface coil helped characterize the normal
anatomy and depict injuries of the elbow [17]. MRI is an efﬁcient
tool to evaluate soft tissues, but Wei also stated that the MRI did notchange the clinical management of Little Leaguer's elbow; thus, he
did not recommend routine evaluation using MRI. Since little is
known about the treatment of the ruptured or translocated perichondrium, the meaning of evaluating the medial elbow via MRI or
HDMRI needs to be discussed further.
This study had several limitations. First, we only examined thesymptomatic side of the elbow without considering an analysis of
the unaffected part of the elbow. Second, we selected subjects withno previous history of elbow injury as far as they or their parents

Table 1The list of abnormal ﬁndings by structures on imaging.
MRI
1. Medial epicondyle apophysis
TOTALi) Fragmentationii) Avulsioniii) Signal hyperintensity at secondary
ossiﬁcation center only
2. Perichondrium
TOTALi) Ruptureii) Translocation
3. UCLTOTALi) Morphological changeii) Signal hyperintensity (overlapped)
4. Signal hyperintensity around UCL(includes ﬂexor-pronator tendons)
5. Signal hyperintensity at coronoid process of ulna

Percentage

Number

95.2
71.4
14.3
9.5

20
15
3
2

90.4
42.9
47.6

19
9
10

76.2
76.2
19.0
61.9

16
16
4
13

42.9

9

55.0
e

11
1

X-ray
Abnormal ﬁndings of the medial elbow
no X-ray imaging at the ﬁrst visit

as the UCL, ﬂexor-pronator tendons, or the coronoid process ofulna. Furthermore, we found a thin, linear area of low signal intensity wrapping around the medial epicondyle of the humerus tothe medial side of the trochlea of the ulna; this is known as the
perichondrium (Fig. 4A). Laor et al. described the perichondrium as
the thin layer that envelops the physis and continues longitudinallyaround the most adjacent newly formed trabecula of the metaphysis [14]. It shows low signal intensity on all sequences of MRI. It
was stated that a tear of the perichondrium might be helpful todetect minimally displaced fractures of the knee in children [14].
There are no known studies evaluating the perichondrium ofadolescent baseball players with medial elbow pain. The current
study showed that the translocation or the rupture of the perichondrium existed in 90.5% of the initial medial elbow pain
among young baseball players. This may enlighten the possibility
that the perichondrium involves the acute pathology of the medial
elbow pain.

Fig. 6. Right elbow of a 9-year-old boy on the X-ray. A: anteroposterior (AeP) view with full extension. B: AP view with 45 of ﬂexion. The avulsion at the tip of the ossiﬁcation
center of the medial epicondyle might be shown on B (arrow), but it was unclear on A.
5

T. Kajiwara, T. Ogawa, N. Mamizuka et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

Fig. 7. 9-year-old boy (same patient as Fig. 4). A: HDMRI revealed the rupture of the perichondrium (T2*). B: HDMRI (T2FS) revealed the high signal intensity (arrow head). It shows
an avulsion of the medial epicondyle apophysis.

References

could remember; there might be a bias. Actually, fragmentation at
the secondary ossiﬁcation center was observed in 15 cases; however, of these, three did not demonstrate signal hyperintensity at
the region, which may indicate the presence of chronic changes.
Third, we considered only 4-week-old HDMRI imaging and were
unsure if the players had been symptomatic or not at the time ofimaging; some players were symptomatic only when they performed overhead throwing. We did not encourage throwing as wewere not aware of their symptoms. This means that they may havebeen asymptomatic on the day of HDMRI; therefore, our ﬁndings
might have captured some normal variation. Fourth, the sample
size was small and selected from outpatients of a single facility.
Lastly, the perichondrium needs to be veriﬁed histologically.

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[12] Frank C, Shrive N, Phil D, Bray R. Ligament healing: a review of some current
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[14] Laor T, Jaramillo D. It's time to recognize the perichondrium. Pediatr Radiol
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5. Conclusion
The current study showed that the initial medial elbow injury in
Little Leaguers without a history of previous elbow injury could be
attributed to multi-structure injury, including perichondrium or UCL.
Because the injuries were not limited to bony structures, HDMRI may
be beneﬁcial for the appropriate evaluation of medial elbow pain.
Furthermore, medial elbow injuries in preadolescent baseballplayers could occur via acute trauma, which requires further study.
Declaration of competing interest
This work was supported by JSPS KAKENHI Grant Number
JP19K11435.
Acknowledgments
The authors thank Katsutoshi Kobayashi and Takuya Hirochi,
radiological technicians at the Mito Kyodo General Hospital, fortheir contributions to MRI analysis. In addition, we also thankAtsuko Taya, medical clerks at the Mito Kyodo General Hospital, forher contributions to data collection. Moreover, we would like tothank Editage for English language editing services.

6

Journal of Tissue Viability 30 (2021) 621–625

Contents lists available at ScienceDirect

Journal of Tissue Viability
journal homepage: www.elsevier.com/locate/jtv

Case report

Squamous cell carcinoma arising from an ischial pressure ulcer initiallysuspected to be necrotizing soft tissue infection: A case report
Takehiro Kasai a, *, Tetsuya Isayama a, Mitsuru Sekido bab

Department of Plastic and Reconstructive Surgery, National Hospital Organization Mito Medical Center, Ibaraki, 311-3193, Japan
Department of Plastic and Reconstructive Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8576, JapanA R T I C L E I N F O

A B S T R A C T

Keywords:
Squamous cell carcinoma
Marjolin’s ulcer
Pressure ulcer
Chronic wound
Tissue biopsy
Necrotizing soft tissue infection

Background: Pressure ulcers are the most common complications in bedridden patients or those with spinal cord
injuries. Marjolin’s ulcer refers to a malignant transformation arising from burn scars or chronic nonhealing
wounds—such as pressure ulcers—over many years. Squamous cell carcinoma is the major histopathologic typeof Marjolin’s ulcer, and the gold standard for diagnosis is tissue biopsy. Medical professionals may have difficulty
distinguishing pressure ulcers from Marjolin’s ulcer, especially when the latter presents with invasive infections.
Thus, malignant transformations arising from pressure ulcers are frequently overlooked. Herein, we describe acase of squamous cell carcinoma arising from pressure ulcers on the left ischium, which was initially identified asa necrotizing soft tissue infection.
Case report: A 59-year-old paraplegic patient presented with stage 3 left ischial pressure ulcer, which involves
full-thickness skin loss and extends into deep subcutaneous tissue, and arrived at our hospital with suspected
sepsis. Upon physical examination, the patient presented with fever and shivering. Initial examination and im­aging findings revealed the presence of necrotizing soft tissue infections. Three weeks later, rapid increase in
granulation in the deep part of the ulcer was observed. Samples from multiples ulcer sites were collected fortissue biopsy. Finally, histological examination revealed well-differentiated squamous cell carcinoma. The pa­
tient received radiation therapy and chemotherapy and died 11 months after the diagnosis.
Conclusion: Malignant transformations arising from pressure ulcers may closely resemble pressure ulcer in­
fections. In these cases, tissue biopsies should be performed during primary care for the infection to exclude
malignant transformations.

1. Introduction
Pressure ulcers are the most common complication in bedridden
patients or those with spinal cord injuries because of lower body pa­
ralysis. Marjolin’s ulcer refers to malignant transformations arising fromburn scars and chronic nonhealing wounds, such as pressure ulcers, overmany years [1,2]. Squamous cell carcinoma (SCC) is the major histo­
pathologic type of Marjolin’s ulcer [3]; the gold standard for its diag­nosis is tissue biopsy of the chronic nonhealing wound [4].
However, malignant transformations arising from pressure ulcers are
frequently overlooked. Physicians and medical professionals may havedifficulty distinguishing pressure ulcers from Marjolin’s ulcers uponphysical examination, especially when the pressure ulcers present withinvasive infections. This delay in diagnosis may result in a worse

prognosis.
Herein, we describe a case of SCC arising from longstanding pressure
ulcers on the left ischium initially identified as a necrotizing soft tissue
infection (NSTI).
2. Case report
A 59-year-old paraplegic male patient was admitted with infective
complications in a left ischial pressure ulcer. His paraplegia was caused
by a traffic accident at the age of 20. Prior to being admitted to our
hospital, he had undergone two operations for ischial pressure ulcers, atanother hospital. The first operation was performed over 20 years ago
and involved a right ischial pressure ulcer, while the second one was
performed 19 years ago and involved a left ischial pressure ulcer. Once

* Corresponding author.Department of Plastic and Reconstructive Surgery, National Hospital Organization Mito Medical Center, Sakuranosato 280, ibarakimachiHigashiibaraki-gun, Ibaraki-ken, 311-3193, Japan.
E-mail address: takehiro.kasai0725@gmail.com (T. Kasai).
https://doi.org/10.1016/j.jtv.2021.01.002
Received 26 November 2020; Accepted 3 January 2021
Available online 8 January 2021

T. Kasai et al.

Journal of Tissue Viability 30 (2021) 621–625

these pressure ulcers were completely cured, approximately one year
after the second surgery the recent left ischial pressure ulcer appeared
close to the last left ischial pressure ulcer. This time, he was transferredto our hospital with suspected sepsis. The patient presented with a 6-cm
slit-shaped left ischial pressure ulcer involving full-thickness skin loss
and a 4-cm subcutaneous pocket extending into the deeper subcutane­
ous tissue (Fig. 1); the ulcer was classified as stage 3 according to the
National Pressure Ulcer Advisory Panel [5].
Upon physical examination, the patient had a fever of 39.0 ◦ C,
tachycardia, and shivers. Laboratory examination revealed a whiteblood cell count of 12,800/μL, and C-reactive protein, hemoglobin, so­dium, creatinine, and glucose levels of 20.05 mg/dL, 9.7 g/dL, 134mmol/L, 0.46 mg/dL, and 101 mg/dL, respectively. The Laboratory Risk
Indicator for Necrotizing Fasciitis score was 8 at admission, indicating ahigh risk of necrotizing fasciitis. Microbiological culture in the wounddetected the presence of Staphylococcus aureus. His left gluteal region
was slightly reddish and painful (Fig. 1). Initial examination and im­aging findings showed the presence of NSTIs, from which the suspicionof sepsis originated. Upon computed tomography, abscess formation andthe presence of gas were observed in the left gluteus maximus muscle(Fig. 2); subsequently, emergency debridement was performed andempiric antibiotic therapy was administered to treat the NSTI. The
symptoms of infection rapidly improved thereafter (Fig. 3). After the
infection completely subsided, negative pressure wound therapy wasadministered to his ischial tissue wound.
Four weeks after the first debridement, with the patient still hospi­
talized, a rapid increase in granulation tissue originating from the deeppart of the wound was observed (Fig. 4). Samples from multiple wound
and ulcer sites were collected for tissue and left lymph node biopsies.
Finally, histological examination confirmed the diagnosis of welldifferentiated SCC (Fig. 5).
Computed tomography revealed enlarged lymph nodes in the left
groin and left common iliac areas. The tumor had likely spread to thepatient’s pelvic bones, left lung, or distant lymph nodes. The result of theleft groin lymph node biopsy confirmed the diagnosis of metastatic SCC.

After discussing with the patient and his family, the decision was madeto attempt radiation therapy (50 Gy in 20 fractions) and chemotherapy.
He received radiation therapy and chemotherapy (cisplatin 75 mg/m2
and doxorubicin 50 mg/m2). Eleven months after the SCC diagnosis, thepatient died due to cancer-related complications.
3. Discussion
Marjolin’s ulcer tends to be more aggressive and quicker to metas­
tasize than other skin cancers. Moreover, Marjolin’s ulcer has a higher
fatality rate when malignant transformation occurs in pressure ulcers
than in other chronic nonhealing wounds and burn scars [6]. Pressure
ulcers undergo malignant transformation in 0.5% of cases [7], with alatency period of 20–22 years [6,10]. In contrast, burn scars undergo
this transformation in 30–45 years [8–10]. Marjolin’s ulcers arising frompressure ulcers resemble common pressure ulcers, resulting in difficulty
in recognizing such transformation. This may cause delay in diagnosis
and worse prognosis. Particularly, patients with spinal cord injuries
have 2-year mortality rates of 67%–80% in cases of pressure
ulcer-related malignancies [6,7,11].
The case presented herein allowed us to identify two important
clinical issues. First, when the malignant transformation occurs under
the skin and is accompanied by infections, the possibility of mis­diagnosing it as pressure ulcer infections or NSTIs increases. In our case,the findings indicating infection, such as swelling and redness, weremore prominent than those indicating malignant transformation, suchas irregular granulation and malodor.
The characteristics of malignant transformation include everted
wound edges, exophytic growth, irregular base or margin, excess gran­ulation tissue extending beyond the wound margins, and translucent or
shiny granulation tissue affecting the ulcer margins. Moreover, the pa­
tient may experience an increase in pain, bleeding, exudate, malodor,
and ulcer size despite appropriate treatment [4,12]. A case report
described the development of a tumor under normal skin after pressure
ulcer operation [13]. Therefore, when characteristic features are notpresent and the malignant transformation occurs under the skin, phy­sicians encounter increased difficulty in recognizing the malignancy at
an early stage.
Despite the existence of few reports regarding pressure ulcer carci­
noma accompanied by infection, a case report described a case of SCC
arising from hidradenitis suppurativa that was initially misdiagnosed as
NSTI [14]. In our case, the pressure ulcer lacked malignant character­istics and imaging examination showed abscess formation and thepresence of gas in the left gluteus maximus muscle. Thus, in accordancewith NSTI treatment guidelines, wound debridement was promptly
performed. Pressure ulcer-related NSTIs have been reported to occur inregions such as the sacral region [15,16], with a recent Japanese study
reporting a mortality rate of 38% for these cases [17]. Moreover, pres­sure ulcers significantly increase the risk of developing Fournier’s
gangrene, an NSTI of the perineum, in patients with spinal cord injuries[18]. Patients with grade 3 and 4 pressure ulcers also have a signifi­
cantly increased risk of developing necrotizing fasciitis [15]. Thus, when
the ulcer appears infected, the appropriate treatments—such as
wide-open incision and drainage, lavage drainage, and debride­ment—should be quickly administered because of the infection rapid
progress. When the pressure ulcer infection is severe, treatment of theinfection requires priority.
The second important clinical issue involves excluding the possibilityof a malignant tumor while treating infections. When the malignant
transformation is accompanied by infections, the clinical picture may
become obfuscated [14]. Therefore, physicians should actively investi­
gate the presence of a malignant tumor in tandem with treating in­
fections. Particularly, conducting multiple tissue biopsies of pressure
ulcers in patients with spinal cord injuries undergoing long-term pres­sure ulcer treatment should be incorporated as a routine examinationand part of the infection treatment protocol.

Fig. 1. Photo and schema of ulcer presentation. Patient presented with a slitshaped pressure ulcer of approximately 6 cm. His left gluteal region wasslightly reddish and warm to the touch.
622

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Journal of Tissue Viability 30 (2021) 621–625

Fig. 2. Computed tomography scan of the patient’s left gluteal muscle showing fluid retention and the presence of gas (red arrow). (For interpretation of thereferences to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3. Left: Patient’s left ischial pressure ulcer after debridement. Right: Schema illustrating the debridement process; blue lines represent incisions; red arrows show
debridement areas; Arrow head indicates primal pressure ulcer location. (For interpretation of the references to colour in this figure legend, the reader is referred to
the Web version of this article.)

Generally, the prognosis of non-metastatic SCC is positive, with a 5year survival rate of 90% [9] In contrast, the prognosis of Marjolin’s
ulcer or pressure ulcer-derived malignancy is poor [19,20]. The ratio ofmetastasis in pressure ulcer carcinomas has been reported as high as
61% [7]. Additionally, 80% of patients with this type of carcinoma diedof recurrence within 18 months after operation [6]. This malignant
transformation easily invades deep structures such as bones, causing
hematogenous or lymphogenous metastases [21]. The sacral and gluteal
areas have a rich lymphatic drainage system to the pelvic region, which
explains the high lymphogenous metastatic rate [13]. This metastatic
tendency results in advanced-stage malignancies at the time of diagnosis[4,21].
In patients with long-term pressure ulcers and spinal cord injuries,
biopsies should be performed routinely to detect a possible malignancy
at an early stage. Additionally, a single tissue biopsy may not reveal thepresence of SCC [22]. Therefore, active tissue biopsies at multiple sites
are important for early diagnosis and treatment and to ensure that apossible SCC will not be overlooked.
This disease will exist as long as patients do not receive adequate
treatment for chronic nonhealing wounds. In addition, chronic wounds
such as pressure ulcers will not decrease in the future as the number of
bedridden patients increases as a result of an aging society. As illustrated
623

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Journal of Tissue Viability 30 (2021) 621–625

the presence of a malignant tumor while treating the infection. Partic­
ularly, patients with spinal cord injuries undergoing long-term pressure
ulcer treatment must undergo routine tissue biopsies at multiple ulcer
sites.
Declaration of competing interest
None.
Acknowledgements
The authors would like to thank Y. Fujisawa M.D. Ph.D. and the staffof the Department of Dermatology, Faculty of Medicine, University ofTsukuba, for technical assistance with the treatments.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jtv.2021.01.002.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Ethical considerations
This study has been approved by the research ethics committee of
National Hospital Organization Mito Medical Center (process number:
2020–80). Written informed consent was obtained from the patient for
publication of this case report and accompanying images.

Fig. 4. Clinical Photo after 4 weeks. Everted wound edges, exophytic growth,and excess granulation tissue (red arrow) were observed in the debridement
incisions. Tissue biopsies were performed using samples from multiple wound
and ulcer sites. (For interpretation of the references to colour in this figurelegend, the reader is referred to the Web version of this article.)

References[1] Barr LH, Menard JW. Marjolin’s ulcer. The LSU experience. Cancer 1983;52:173–5.
https://doi.org/10.1002/1097-0142(19830701)52:1<173:AIDCNCR2820520131>3.0.CO.2-6.
[2] Esther RJ, Lamps L, Schwartz HS. Marjolin ulcers: secondary carcinomas in chronic
wounds. J South Orthop Assoc 1999;8:181–7.
[3] Copcu E, Aktas A, Şişman N, Oztan Y. Thirty-one cases of Marjolin’s ulcer. Clin Exp
Dermatol 2003;28:138–41. https://doi.org/10.1046/j.1365-2230.2003.01210.x.
[4] Enoch S, Miller DR, Price PE, Harding KG. Early diagnosis is vital in the
management of squamous cell carcinomas associated with chronic non healing
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https://doi.org/10.1111/j.1742-4801.2004.00056.x.
[5] Edsberg LE, Black JM, Goldberg M, McNichol L, Moore L, Sieggreen M. Revised
national pressure ulcer advisory Panel pressure injury staging system: revisedpressure injury staging system. J Wound, Ostomy Cont Nurs 2016;43:585–97.
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[6] Grotting JC, Bunkis J, Vasconez LO. Pressure sore carcinoma. Ann Plast Surg 1987;
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[7] Mustoe T, Upton J, Marcellino V, Tun CJ, Rossier AB, Hachend HJ. Carcinoma inchronic pressure sores: a fulminant disease process. Plast Reconstr Surg 1986;77:
116–21. https://doi.org/10.1097/00006534-198601000-00017.
[8] Türegün M, Nişanci M, Güler M. Burn scar carcinoma with longer lag period arisingin previously grafted area. Burns 1997;23:496–7. https://doi.org/10.1016/S03054179(97)00041-7.
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[10] Huang CY, Feng CH, Hsiao YC, Chuang SS, Yang JY. Burn scar carcinoma.
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[11] Eltorai IM, Montroy RE, Kobayashi M, Jakowatz J, Guttierez P. Marjolin’s ulcer inpatients with spinal cord injury. J Spinal Cord Med 2002;25:191–6. https://doi.
org/10.1080/10790268.2002.11753621.
[12] Khan K, Giannone AL, Mehrabi E, Khan A, Giannone RE. Marjolin’s ulcer
complicating a pressure sore: the clock is ticking. Am J Case Rep 2016;17:111–4.
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[13] Knudsen MA, Biering-Sørensen F. Development of Marjolin’s ulcer following
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[14] Harview CL, Truong AK, Worswick SD, Sarantopoulos GP, Hsiao JL. Squamous cell
carcinoma of the perineum masquerading as necrotizing hidradenitis suppurativa.
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[15] Citak M, Backhaus M, Tilkorn DJ, O’Loughlin PF, Meindl R, Muhr G, et al.
Necrotizing fasciitis in patients with spinal cord injury: an analysis of 25 patients.

Fig. 5. Histopathology of the patient’s left ischial pressure ulcer revealing awell-differentiated squamous cell carcinoma with infiltrative pattern areas andthe presence of keratin pearls (red arrow) (magnification ×40; hematoxylin andeosin stain). (For interpretation of the references to colour in this figure legend,
the reader is referred to the Web version of this article.)by this case, overlooking malignant tumors originating from pressure
ulcers may be fatal. On the other hand, this case seems to contribute to
the improvement of pressure ulcer management in the future.
In conclusion, when pressure ulcer-derived malignant trans­
formation occurs under the skin with concurrent infection, this malig­
nancy may be overlooked and misdiagnosed as a pressure ulcer infection
or NSTIs. To avoid a misdiagnosis, physicians must actively investigate
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[17] Oonishi S, Koide T, Shiogama K, Tsutsumi Y. A case of decubitus-related gasproducing necrotizing fasciitis caused by group G β-hemolytic streptococcus.
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[18] Backhaus M, Citak M, Tilkorn DJ, Meindl R, Schildhauer TA, Fehmer T. Pressure
sores significantly increase the risk of developing a Fournier’s gangrene in patientswith spinal cord injury. Spinal Cord 2011;49:1143–6. https://doi.org/10.1038/
sc.2011.75.

[19] Bostwick 3rd J, Pendergrast Jr WJ, Vasconez LO. Marjolin’s ulcer: An
immunologically privileged tumor? Plast Reconstr Surg 1976;57:66–9.
[20] Copcu E. Marjolin’s ulcer: a preventable complication of burns? Plast Reconstr
Surg 2009;124. https://doi.org/10.1097/PRS.0b013e3181a8082e. 156e–64e.
[21] Homma K, Sugihara T, Yoshida T, Ishikawa T, Minakawa H, Matsumoto T, et al.
Pressure Sore Carcinoma -Report of five cases and review of the Japanese
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[22] Pavlovic S, Wiley E, Guzman G, Morris D, Braniecki M. Marjolin ulcer: anoverlooked entity. Int Wound J 2011;8:419–24. https://doi.org/10.1111/j.1742481X.2011.00811.x.

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Contents lists available at ScienceDirect

IDCasesjournal homepage: www.elsevier.com/locate/idcases

Case report

Emphysematous cystitis due to Streptococcus salivarius infection in apatient with a neurogenic bladder
Shuhei Okada, Yasushi Ichimura, Masahiro Iinuma]]]]]]]]]]⁎

Department of Urology, Mito Medical Center, 280 Sakuranosato, Ibaraki-machi, Higashi-Ibaraki-gun, Ibaraki-ken 311-3193, Japana r t i cl e i nfo

a bstr ac t

Article history:
Received 18 October 2021
Received in revised form 17 January 2022
Accepted 17 January 2022

Streptococcus salivarius (S. salivarius) is an oral commensal bacterium that rarely causes disease. Here, wereport a case of emphysematous cystitis due to S. salivarius infection in a patient with a neurogenic bladder.
A 56-year-old woman was hospitalized and managed for left putamen hemorrhage. Afterward, she devel­
oped poor oral intake. Although the patient was afebrile, laboratory test results suggested an inflammatory
response. Urinalysis revealed pyuria and hematuria. Abdominal computed tomography revealed a thick­ened urinary bladder wall and intraluminal gas. Additionally, she was diagnosed with a neurogenic bladderas she had approximately 200 mL of residual urine. The patient was diagnosed with emphysematous cy­
stitis, and S. salivarius was isolated from urine culture specimens. The patient’s condition improved im­
mediately after treatment, which included bladder drainage and administration of appropriate antibiotics.
We could not find any report on S. salivarius causing urinary tract infections, such as emphysematous cy­
stitis. Accordingly, we report this case along with a review of the literature.
© 2022 Published by Elsevier Ltd.
CC_BY_NC_ND_4.0

Keywords:
Emphysematous cystitis
Streptococcus salivarius
Neurogenic bladder
Urinary tract infections
Putamen hemorrhage

Introduction
Streptococcus salivarius (S. salivarius) is a viridans streptococcus,that is relatively commonly isolated from the tongue, palate, andsaliva. It has low pathogenicity and is occasionally isolated from theintestine or vagina. We could not find any report on S. salivarius
causing urinary tract infections. Herein, we report a case of em­
physematous cystitis due to S. salivarius infection, along with a re­view of the literature.
Case presentation
A 56-year-old female patient, who had been generally healthy,
was admitted to the Department of Neurosurgery at our hospital andmanaged for a left putamen hemorrhage on February 5, 2020. There
was no relevant family, medical, or medication history. She gradually
recovered through conservative treatment and was scheduled to betransferred to another hospital for further rehabilitation. However,she developed poor oral intake around February 19, 2020, but wasafebrile. The patient was referred to our department on February 22,
2020, following routine blood sampling and an abdominal computed
tomography (CT) scan. The blood sample revealed an elevated⁎Corresponding author.
E-mail address: iinuma.masahiro.nv@mail.hosp.go.jp (M. Iinuma).

https://doi.org/10.1016/j.idcr.2022.e01410
2214-2509/© 2022 Published by Elsevier Ltd.
CC_BY_NC_ND_4.0

inflammatory response, and the scan showed a thickened bladderwall and intraluminal gas.
Physical examination revealed a blood pressure of 135/82 mmHg,
pulse rate of 106/min, SpO2 of 96% (room air), and body temperatureof 97.3 ℉. Suprapubic tenderness was observed on abdominal pal­pation; however, bilateral costovertebral angle tenderness was notdetected.
Laboratory findings
Elevated inflammatory response and renal dysfunction wereobserved. A complete blood count revealed a white blood cell countof 28,600/μL; the C-reactive protein (CRP) level was 47.2 mg/dL,
while blood urea nitrogen and serum creatinine levels were 97.0 mg/
dL and 2.49 mg/dL, respectively. Urinalysis revealed hematuria andpyuria. These findings are shown in Table 1.
CultureOnly S. salivarius was detected in the urine culture (106 CFU/mL).
Four days were required for confirmation, and no drug resistancewas observed. Peptostreptococcus anaerobius was detected in the
blood cultures; however, it was thought to have resulted from con­tamination. This is because only one of the two sets of blood cultures
was positive, and confirmation of findings took seven days. Notably,
images of the culture media are unavailable.

S. Okada, Y. Ichimura and M. Iinuma

IDCases 27 (2022) e01410

An indwelling bladder catheter was inserted on February 5, 2020,
and removed on February 10, 2020. On the day of catheter removal,
the residual urine volume was 291 mL, which was measured only
once. Afterward, her medical record did not report lower abdominal
distension. However, nurses only checked whether or not the diaper
was wet with urine, and the residual urine volume was not mea­
sured. The residual urine volume was approximately 250 mL when
an indwelling bladder catheter was re-inserted on February 22,2020. Therefore, we speculated that the residual urine volume wasmore than 200 mL after removing the indwelling bladder catheter.
There was no history of diabetes mellitus or pelvic surgery.
Therefore, increased residual urine volume was supposedly caused
by a neurogenic bladder associated with the left putamen hemor­rhage.

Table 1
Laboratory findings on February 22, 2021.
TP
ALB
AST
ALT
ALP
LDH
T-BIL
BUN
CRE
CK
Na
K
Cl
CRP

7.3
3.7
16
37
485
388
1.3
97.0
2.49
38
143
5.5
104
47.2

g/dL
g/dL
U/L
U/L
U/L
U/L
mg/dL
mg/dL
mg/dL
U/L
mmol/L
mmol/L
mmol/L
mg/dL

WBC
RBC
Hb
Ht
MCV
MCH
MCHC
PLT
PT
PT(INR)
APTT
D-dimer

28,6004.88 × 106
17.1
50.6
103.7
35.0
33.8
306 × 103
18.2
1.43
49.8
4.7

/μL
/μL
g/dL
%
fL
pg
g/dL
/μL
sec
sec
μ./mL

TP: total protein; ALB: albumin; AST: aspartate aminotransferase; ALT: alanine ami­
notransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; T-BIL: total
bilirubin; BUN: blood urea nitrogen; CRE: creatinine; CK: creatine kinase; Na: sodium;
K: potassium; Cl: chloride; CRP: C-reactive protein; WBC: white blood cell; RBC: red
blood cell; Hb: hemoglobin; Ht: hematocrit; MCV: mean corpuscular volume; MCH:
mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration;
PLT: platelet; PT: prothrombin time; INR: international normalized ratio; APTT: ac­tivated partial thromboplastin time.

Diagnosis
Based on the above findings, we diagnosed the patient withemphysematous cystitis due to S. salivarius infection. Neurogenic
bladder associated with left putamen hemorrhage is supposedly oneof the causes of this disease.

Imaging

Clinical course

A plain CT was performed after inserting an indwelling bladdercatheter; therefore, the bladder was collapsed. The bladder wall was
thickened compared to the previous CT scan performed on admis­
sion. In addition, perivesical fat stranding was observed (Fig. 1);
however, perirenal fat stranding and hydronephrosis were not ob­
served bilaterally. No other abnormal findings were observed. The
bladder was considered the focus of inflammation, and air bubbles
were observed around the bladder wall. Although iatrogenic gas
contamination could not be ruled out, emphysematous cystitis wasmost suspected because of a severe inflammation localized to thebladder. Since other diseases could also cause gas contamination
into the bladder, colovesical fistula and vesicovaginal fistula wereruled out based on CT findings. Since an abscess continuous from theumbilicus to the dome of the bladder was not observed, a urachal
abscess was similarly ruled out.

Pyuria drainage was achieved by re-inserting an indwelling
bladder catheter. Meropenem (2 g/day) and clindamycin (1200 mg/day) were administered intravenously from February 22, 2020. The
dose of meropenem was reduced from 3 g/day to 2 g/day due to renal
dysfunction. The inflammatory response and renal function gradu­
ally improved and were almost normalized on March 1, 2020 (whiteblood cell count: 6800/μL, C-reactive protein: 0.94 mg/dL, blood urea
nitrogen: 9.1 mg/dL, and serum creatinine: 0.50 mg/dL). On March 2,
2020, we changed the antibiotic to levofloxacin (500 mg/day), basedon antibiotic susceptibility testing. On March 15, 2020, levofloxacin
was discontinued, and no relapse of the inflammatory reaction wasobserved (Fig. 2). The patient was transferred to another hospital forfurther rehabilitation on March 24, 2020. Since she could not per­form intermittent self-catheterization, we inserted an indwelling
bladder catheter. After hospital discharge, the patient was scheduled
to be examined for neurogenic bladder at our department.

Urination
Discussion
Communication with the patient was difficult; however, ac­cording to her family, she experienced no disturbance on urination
before admission. In addition, the CT scan on admission showed no
thickening or deformation of the bladder wall. In our hospital, acutecare physicians occasionally perform a whole-body CT scan regard­
less of chief complaints; however, it is not routine in many centers.

Emphysematous cystitis is caused by gas-forming bacteria. The
mean age of emphysematous cystitis occurrence is approximately 66
years, and it occurs twice as often in women than in men [1]. Dia­
betes mellitus and urinary stasis are well-recognized risk factors [2].

Fig. 1. Computed tomography after urethral catheterization. Arrows indicate thethickened bladder wall and air bubbles around the bladder wall (the axial slice).

Fig. 2. Clinical course post-admission. MEPM, meropenem hydrate; CLDM, clin­
damycin phosphate; LVFX, levofloxacin hydrate.
2

S. Okada, Y. Ichimura and M. Iinuma

IDCases 27 (2022) e01410

In emphysematous cystitis, Escherichia coli and Klebsiella pneumoniae
are often isolated from urine cultures [1]. As for the genus Strepto­
coccus, group D streptococcus has been reported to cause emphy­
sematous cystitis [1]. To the best of our knowledge, there are noreports of S. salivarius as the causative pathogen of urinary tract
infections, such as emphysematous cystitis [3]. S. salivarius is a vir­idans streptococcus, which has low pathogenicity. It is relatively
commonly isolated from the tongue, palate, and saliva, and is oc­
casionally isolated from the intestine or vagina [4–6]. Its presence inthe vagina is considered to inhibit the growth of Group B Strepto­
coccus [4]. According to previous reports, it causes bacteremia,
meningitis, endocarditis, sinusitis, and liver abscesses [5–10]. There
are two possible mechanisms by which S. salivarius causes bacter­emia: (1) iatrogenic contamination associated with an invasive
procedure, such as spinal anesthesia, and (2) invasion associatedwith disruption of the gastrointestinal mucosa [5,11,12]. In this case,these mechanisms were unlikely because the patient did not havebacteremia. The route of infection was supposedly retrograde, with
S. salivarius arising from feces or vaginal discharge. However, thiswas not verified since culture tests of feces and vaginal discharge
were not performed. In addition, iatrogenic contamination of S.
salivarius was possible through the saliva of medical staff during theinsertion of an indwelling bladder catheter on admission. However,this is considered unlikely because all emergency room staff at our
hospital wear personal protective equipment. As mentioned above,since plain CT was performed after inserting an indwelling bladdercatheter, we could not deny the possibility of gas contamination. The
collection of gas in the bladder wall, which is characteristic of em­
physematous cystitis, was difficult to recognize because the bladder
was collapsed. In addition, according to the medical record, the in­dwelling bladder catheter was inserted at 11:00 am, and the plain CT
scan was performed at 2:00 pm. Thus, approximately 3 h had passed,
during which the intramural and intraluminal gas may have de­creased. However, emphysematous cystitis was suspected because ofstrong inflammation localized to the bladder. Although emphyse­matous cystitis is characterized by cobblestone and beaded-necklace
appearance on abdominal X-ray [13], such findings may not be ob­served when an indwelling bladder catheter is inserted. Hence, CT isuseful for establishing diagnoses, as in this case. Besides emphyse­matous cystitis, pyocystis (bladder abscess) also presents withstrong inflammation localized to the bladder. However, pyocystis isunlikely in this case because it has been reported in oliguric patients,
such as patients with supravesical urinary diversion or hemodia­
lysis-dependent patients [14]. Although there is no report of em­
physematous cystitis due to S. salivarius infection [1,2,15,16], S.
salivarius can lead to gas formation. The urease system in S. salivarius
breaks down urea to ammonia and CO2 [17]. Since substances otherthan glucose are supposedly substrates for gas formation, it is fea­
sible that urea was a substrate for gas formation in this case. The
initial management of emphysematous cystitis consists of drainageof the bladder by catheter placement, appropriate antibiotics ad­
ministration, and treatment of predisposing conditions, such as
glycemic control [15]. If these treatments are ineffective, surgicaltreatment, including cystectomy, may be required [15]. The overall
death rate from emphysematous cystitis has been reported to beapproximately 7%; however, if emphysematous pyelonephritis oc­
curs, the mortality rate increases to 14–20% [1,15]. Therefore, early
detection of emphysematous cystitis is desirable. Additionally, we
considered what could have been done to diagnose this case earlier.
Emphysematous cystitis can vary from asymptomatic cases to sepsis.
The frequent chief complaints of patients with emphysematous cy­
stitis are suprapubic pain, gross hematuria, fever, and pneumaturia[15]. In this case, gross hematuria was not observed, and the patient
had been afebrile. Due to the acute left putamen hemorrhage, it wasdifficult for the patient to complain of suprapubic pain. If pneuma­
turia existed, it was difficult to recognize because she wasincontinent. In addition, even if she had residual urine retention, it
was difficult to complain because of the acute left putamen he­morrhage. Therefore, in the acute phase of cerebrovascular disease,residual urine measurement and urinalysis after removing an in­
dwelling bladder catheter should be performed periodically to pre­vent emphysematous cystitis.
Conclusion
We reported a case of emphysematous cystitis due to S. salivarius
infection in a patient with a neurogenic bladder. We could not findany reports of S. salivarius causing urinary tract infections, including
emphysematous cystitis. Infectious diseases can be detected byclinical signs and blood work in afebrile patients as well. In the acutestage of cerebrovascular disease, it may be difficult for a patient tocomplain of bladder irritability or suprapubic pain. Therefore, em­physematous cystitis should be understood not only by urologists
but also by neurologists.
Ethical approval
This study has been approved by the institutional review board of
Mito medical center.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Shuhei Okada: Conceptualization, Investigation, Writing – ori­ginal draft. Yasushi Ichimura: Conceptualization, Investigation.
Masahiro Iinuma: Writing – review & editing, Supervision, Project
administration.
Declaration of interest
None.
Acknowledgments
None.
Approval of research protocol
Not applicable.
Consent
Written informed consent was obtained from the patient for
publication of this case report and accompanying images. A copy of
the written consent is available for review by the Editor-in-Chief of
this journal on request.
Registry and registration number
Not applicable.
References[1] Schicho A, Stroszczynski C, Wiggermann P. Emphysematous cystitis: mortality,
risk factors, and pathogens of a rare disease. Clin Pract 2017;7:54–5. https://doi.
org/10.4081/cp.2017.930[2] Adeyemi
OA,
FlahertyJP.
Emphysematous
cystitis.
Cureus2020;12:e11723https://doi.org/10.7759/cureus.11723

3

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IDCases 27 (2022) e01410[10] Kamachi S, Otsuka T, Tsuji C, Nakashita S, Ide Y, Mizuta T. A case of multiple liverabscesses associated with Streptococcus salivarius in a patient with chronic peri­odontitis. Nihon Shokakibyo Gakkai Zasshi Jpn J Gastro-Enterol 2014;111:1602–8.
[11] Veringa E, van Belkum A, Schellekens H. Iatrogenic meningitis by Streptococcus
salivarius following lumbar puncture. J Hosp Infect 1995;29:316–8. https://doi.
org/10.1016/0195-6701(95)90283-x[12] Idigoras P, Valiente A, Iglesias L, Trieu-Cout P, Poyart C. Meningitis due toStreptococcus salivarius. J Clin Microbiol 2001;39:3017. https://doi.org/10.1128/
JCM.39.8.3017.2001[13] Middela S, Green E, Montague R. Emphysematous cystitis: radiological diagnosisof complicated urinary tract infection. BMJ Case Rep 2009;bcr05.2009:1832.
https://doi.org/10.1136/bcr.05.2009.1832[14] Elsayed M, Finn A, Dapaah-Afriyie K. Unusual organism causing pyocystis in an
immunosuppressed haemodialysis patient. BMJ Case Rep 2016;bcr2015214264.
https://doi.org/10.1136/bcr-2015-214264[15] Amano M, Shimizu T. Emphysematous cystitis: a review of the literature. Intern
Med 2014;53:79–82. https://doi.org/10.2169/internalmedicine.53.1121[16] Thomas AA, Lane BR, Thomas AZ, Remer EM, Campbell SC, Shoskes DA.
Emphysematous cystitis: a review of 135 cases. BJU Int 2007;100:17–20. https://doi.org/10.1111/j.1464-410X.2007.06930.x[17] Zlatkovic N, Aleksić G, Gašić K. Biology of oral streptococci. Microbiol Spectr
2018;6. https://doi.org/10.1128/microbiolspec.GPP3-0042-2018[3] Facklam R. What happened to the streptococci: overview of taxonomic andnomenclature changes. Clin Microbiol Rev 2002;15:613–30. https://doi.org/10.
1128/CMR.15.4.613-630.2002[4] Patras KA, Wescombe PA, Rösler B, Hale JD, Tagg JR, Doran KS. Streptococcus
salivarius K12 limits Group B Streptococcus vaginal colonization. Infect Immun
2015;83:3438–44. https://doi.org/10.1128/IAI.00409-15[5] Legier JF. Streptococcus salivarius meningitis and colonic carcinoma. South Med J
1991;84:1058–9. https://doi.org/10.1097/00007611-199108000-00031[6] Elsawy AM, Faidah HS, Redwan EM. Streptococcus salivarius meningitis in im­
munocompetent: a case report. Int Arch Med Microbiol 2018;1. https://doi.org/
10.23937/iamm-2017/1710004[7] Nilson B, Olaison L, Rasmussen M. Clinical presentation of infective endocarditis
caused by different groups of non-beta haemolytic streptococci. Eur J Clin
Microbiol Infect Dis 2016;352:215–8. https://doi.org/10.1007/s10096-0152532-5[8] Radosz-Komoniewska H, Kapp-Burzyńska Z, Kłaptocz B, Wilk I, Ekiel A. Tlenowa i
beztlenowa flora bakteryjna w przewlekłym zapaleniu zatok przynosowych u
dorosłych [Aerobic and anaerobic bacterial flora in chronic sinusitis in adults].
Med Dosw Mikrobiol 1997;49:89–94.
[9] Ruiz-Tovar J, Gamallo C. Streptococcus salivarius causing multiple liver abscesses
in a patient with situs inversus. Surg Infect 2012;132:130–1. https://doi.org/10.
1089/sur.2011.082

4

IJU Case Reports (2021)

doi: 10.1002/iju5.12373

Case Report

Extramedullary plasmacytoma of the ureter
Shuhei Okada,

Yasushi Ichimura and Masahiro Iinuma

Department of Urology, Mito Medical Center, Higashiibaraki-gun, Ibaraki-ken, Japan

Abbreviations & Acronyms
AMY = amylase
CT = computed tomography
EAU = European
Association of Urology
EMP = extramedullaryplasmacytoma
Ig = immunoglobulin
SBP = solitary bone
plasmacytoma
T-BIL = total bilirubin
UC = urothelial carcinoma
UTUC = upper tract
urothelial carcinoma
Correspondence: Masahiro
Iinuma, M.D., Department ofUrology, Mito Medical Center,
280 Sakuranosato, Ibarakimachi, Higashiibaraki-gun,Ibaraki-ken 311-3193, Japan.
Email: iinuma.masahiro.nv@
mail.hosp.go.jp
How to cite this article: Okada
S, Ichimura Y, Iinuma M.
Extramedullary plasmacytoma of
the ureter. IJU Case Rep. 2021;
https://doi.org/10.1002/
iju5.12373.
This is an open access article
under the terms of the Creative
Commons AttributionNonCommercial-NoDerivs
License, which permits use anddistribution in any medium,provided the original work is
properly cited, the use is noncommercial and no
modiﬁcations or adaptations are
made.
Received 26 July 2021;
accepted 30 August 2021.

Introduction: We report a rare case of an extramedullary plasmacytoma of the ureter.
Case presentation: A 77-year-old man was referred to our hospital because of lefthydronephrosis. Computed tomography showed a tumor in the left ureter, and tumor
invasion into the periureteric fat was suspected. Urine cytology showed Eatypical cells
whose nuclei were hyperchromatic (class IIIb). The left ureteral tumor was diagnosed asurothelial carcinoma (cT3N0M0) preoperatively. Subsequently, we performed laparoscopic
radical nephroureterectomy with bladder cuff excision. The tumor was pathologicallydiagnosed as a plasmacytoma. Postoperative positron emission tomography did not reveal
abnormal uptake, and bone marrow aspiration findings were normal. Consequently, the left
ureter tumor was diagnosed as an extramedullary plasmacytoma of the ureter.
Conclusion: Extramedullary plasmacytoma commonly occurs in the upper respiratory
tract or upper gastrointestinal tract. Extramedullary plasmacytoma of the ureter is rare.
This is only the fourth reported case of extramedullary plasmacytoma of the ureter.

Key words: extramedullary plasmacytoma, hydronephrosis, tumor, ureter, urothelial
carcinoma.

Keynote message
The ureter is a rare location for an EMP. Therefore, preoperative diagnosis is challenging. To
the best of our knowledge, this is only the fourth reported case of EMP of the ureter.

Introduction
Solitary plasmacytoma is deﬁned as a localized mass of neoplastic monoclonal plasma cells.
EMP arises from soft tissue throughout the body. An EMP often occurs in the upper respiratory or gastrointestinal tract, accounting for approximately 80% of cases.1 The ureter is a rare
location for an EMP. Here, we report a case of a primary EMP of the ureter.

Case presentation
A 77-year-old man who presented with abdominal pain was referred to our hospital because
an ultrasound sonogram revealed left hydronephrosis. The patient’s height was 165.5 cm andhis body weight was 55.45 kg. The patient’s medical history included constipation, hyperuricemia, benign prostatic hyperplasia, auditory disturbance, and lower back pain. The
patient’s regular medications included elobixibat hydrate, febuxostat, silodosin, loxoprofen
sodium hydrate, and senna. Regarding family history, the patient’s father died of lung cancer
and his mother died of unknown causes. The patient had smoked 20 cigarettes per day for
10 years. CT revealed a tumor in the left ureter with a diameter of approximately 2.5 cm(Fig. 1). Tumor invasion into the periureteric fat was suspected. Distant metastasis and regional node involvement were not found on CT. Urine cytology showed atypical cells whose
nuclei were hyperchromatic (class IIIb). UC was suspected. The left ureteral tumor was diagnosed as UC (cT3N0M0) preoperatively.
An increased level of creatinine was observed (1.96 mg/dL). Laboratory ﬁndings are shownin Table 1. This renal impairment was partly due to atrophy of the right kidney. Segmental
ureterectomy was considered to be challenging because the diameter of the left ureteral tumor
was approximately 2.5 cm and tumor invasion into the periureteric fat was suspected. Subsequently, we performed laparoscopic radical nephroureterectomy with bladder cuff excision.

© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association

1

S OKADA ET AL.

inﬁltration and atypical cells, which included numerous eosinophil granules (Fig. 2). No UC component was observed in
the tumor. Immunohistochemical staining revealed that atypical cells were positive for CD138 and CD79a, characteristic
markers of B cells or plasma cells. In addition, we detected
light chain restriction (Igj > Igc). Therefore, the left ureter
tumor was pathologically diagnosed as a plasmacytoma.
After the diagnosis of EMP, the patient was referred to ahematologist. A postoperative positron emission tomographyscan did not show abnormal uptake, and bone marrow aspiration ﬁndings were normal. No monoclonal protein was
detected in the patient’s blood and urine. Therefore, we diagnosed the left ureter tumor as a primary EMP of the ureter.
The patient survived without renal replacement therapy andshowed no evidence of multiple myeloma, local recurrence,or distant metastasis until 22 months after surgery.

Discussion(a)(b)
Fig. 1 Abdominal CT image showing a left ureteral mass (arrows) causinghydronephrosis. (a) Coronal view. (b) Axial view.

Table 1 Laboratory findings
TP
ALB
AST
ALT
ALP
LDH
T-BIL
BUN
CRE
UA
AMY
Na
K
Cl
Ca
CRP

7.4
4.1
14
8
281
179
0.5
26.1
1.96
6.4
48
140
4.8
108
9.0
0.49

g/dL
g/dL
U/L
U/L
U/L
U/L
mg/dL
mg/dL
mg/dL
mg/dL
IU/L
mmol/L
mmol/L
mmol/L
mg/dL
mg/dL

WBC
RBC
Hb
Ht
MCV
MCH
MCHC
PLT
PT
PT(INR)
APTT

5200
4.12 9 106
12.1
36.5
88.6
29.4
33.2
256 9 103
13.8
1.05
38.5

/lL
/lL
g/dL
%
fl
pg
g/dL
/lL
sec
sec

Although the serum creatinine level increased to 3.75 mg/
dL after surgery, hemodialysis was not required. He was discharged on postoperative day 13. Macroscopically, a solid
tumor (20 9 15 mm) was observed in the middle of the left
ureter. Histopathological ﬁndings revealed inﬂammatory cell
2

Solitary plasmacytoma is deﬁned as a localized mass of neoplastic monoclonal plasma cells. SBP is characterized by a solelesion of bone. EMP arises from soft tissue throughout the
body.1 The International Myeloma Working Group deﬁnes
EMP using the following criteria: (i) a tumor comprising of
monoclonal plasma cells in a single extramedullary site, (ii) no
lesion in the whole-body bone, (iii) no lesion in the bone marrow, (iv) no involvement of organs, and (v) no monoclonal Ig
in serum or urine.2 Since our patient met the above criteria, theleft ureter tumor was diagnosed as a primary EMP of the ureter.
An EMP usually occurs in the upper respiratory or gastrointestinal tract, accounting for approximately 80% of cases.3 The
ureter is a rare location for an EMP. To the best of our knowledge, this is only the fourth reported case of EMP of the ureter(Table 2). Compared with EMP, SBP has a signiﬁcantly higher
risk for progression to multiple myeloma than EMP. Therefore,
SBP has poor prognosis in comparison with EMP. Symptomsof EMP vary depending on the tumor occurrence site. Alexiou
et al.4 reported approximately 65% of EMP had no recurrence
and did not progress to multiple myeloma after treatment.
Younger age was reported as a good independent prognostic
factor.5 In contrast, anaplastic type plasmacytoma, a higher histologic grade, and a high level of angiogenesis were reported
as poor prognostic factors.6,7 Solitary plasmacytoma is highly
radiosensitive. It has been reported that a local control rate of
94% was achieved by doses over 40 Gy.8 Radiotherapy should
encompass the primary tumor with a margin of at least 2 cm.9
Adjuvant chemotherapy might be considered for the tumor larger than 5 cm and/or of a high histological grade.
Complete resection of EMP is considered equivalent toradiotherapy. Since EMP is a highly radiosensitive tumor, postoperative radiotherapy is recommended for patients with inadequate surgical margins or local recurrence. Our case wasdiagnosed as a UC before surgery. As the diameter of the left
ureteral tumor was approximately 2.5 cm and tumor invasion
into the periureteric fat was suspected, segmental ureteralresection was considered challenging; therefore, we performed
laparoscopic radical nephroureterectomy with bladder cuff
excision. Although Landsmann et al.10 reported segmental
ureter resection and ureterocystostomy for an EMP of the© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association

EMP of the ureter

(a)

(b)

(c)

(d)

(e)
Fig. 2 Hematoxylin and eosin staining showing (a) inflammatory cell infiltration and atypical cells, which include numerous eosinophil granules, and tumor cells
positive for (b) CD79a, (c) CD138, (d) Igk, and (e) Igj. Staining is more pronounced for Igj than for Igk (light chain restriction). Magnification, 9100.

Table 2 Clinical features of reported cases of EMP of the ureter
Case number
Authors
Year
Age
Sex
Chief complaint
Preoperative
ureteroscopy
Preoperative diagnosis
Treatment
Follow-up (months)
Postoperative dialysis
Outcome1
Landsmann S
2009
80
FemaleRenal colic
Not mentioned

2
Klein T
2010
82
FemaleHematuria
Not performed

3
Nagai T
2016
45
Male
Hematuria
Not performed

4
Okada S
2021
77
Male
Abdominal pain
Not performed

Not mentioned
Segmental
ureterectomy
Not mentioned
Not required
No evidence of disease

Not mentioned
Nephro-ureterectomy(open)
Not mentioned
Not required
No evidence of diseaseUC (cT2N0M0)
Nephro-ureterectomy(laparoscopic)
5
Not required
No evidence of diseaseUC (cT3N0M0)
Nephro-ureterectomy(laparoscopic)
22
Not required
No evidence of disease

ureter, Klein et al.11 and Nagai et al.3 reported that radical
nephroureterectomy with bladder cuff excision was performed
because UC was suspected before surgery.
The EAU guidelines on upper UTUC deﬁne high-risk
UTUC by the following criteria: (i) multifocal disease, (ii)tumor size ≥2 cm, (iii) high-grade cytology, (iv) high-grade
ureterorenoscopy biopsy, (v) local invasion on CT, (vi)hydronephrosis, (vii) previous radical cystectomy for highgrade bladder cancer, and (viii) variant histology. Our casemet three of these high-risk UTUC criteria: tumor size

≥2 cm, local invasion on CT, and hydronephrosis. Per the
EAU guidelines on UTUC, radical nephroureterectomy is thestandard treatment for high-risk UTUC in the middle or proximal ureter. Therefore, we performed laparoscopic radical
nephroureterectomy. Indeed, without a biopsy of the ureteraltumor, preoperative diagnosis of an EMP of the ureter isalmost impossible. The differential diagnoses for ureteraltumors include UC, EMP, neuroendocrine tumor, metastatic
tumor, paraganglioma, ﬁbroepithelial polyp, and inﬂammatory
myoﬁbroblastic tumor. Among these tumors, EMP is a highly© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association

3

S OKADA ET AL.

radiosensitive tumor.12–16 If we had preoperatively diagnosed
the ureteral tumor as EMP, we would have been able tochoose radiotherapy instead of nephroureterectomy. We did
not perform diagnostic ureteroscopy because we considered
the left ureteral tumor as a high-risk UTUC before surgery.
In addition, the use of diagnostic ureteroscopy has been associated with a higher risk of developing bladder recurrence
after radical nephroureterectomy.17,18 The possibility of cancer dissemination has also been reported.18–20 Segmental ureteral resection is considered as another treatment option.21 In
segmental ureteral resection for the tumor in the middle orproximal ureter, when end-to-end anastomosis of the ureter ischallenging, an ileal-ureteral substitution is required, which istechnically challenging and more invasive.
In our case, the tumor size was ≥2 cm and tumor invasion
into the periureteric fat was suspected on preoperative CT.
Segmental ureteral resection was considered challenging.
Therefore, we performed laparoscopic radical nephroureterectomy. However, if we had preoperatively diagnosed the ureteral tumor as EMP, we would have been able to chooseradiotherapy instead of nephroureterectomy.

Conclusion
We report a rare case of a primary EMP of the ureter. The
patient survived without recurrence after laparoscopic radical
nephroureterectomy.

Conflict of interest
The authors declare no conﬂict of interest.

Approval of the research protocol by
an Institutional Reviewer Board
Not applicable.

Informed consent
Informed consent for publication was obtained from thepatient.

Registry and the Registration No. ofthe study/trial
Not applicable.

4

References
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J. 2012; 2012: 895765.
2 International Myeloma Working Group. Criteria for the classiﬁcation of monoclonal gammopathies, multiple myeloma and related disorders: a report of theInternational Myeloma Working Group. Br. J. Haematol. 2003; 121: 749–57.
3 Nagai T, Okamura T, Taki Y et al. Extramedullary plasmacytoma of theureter in an HIV-positive patient. Int. Cancer Conf. J. 2017; 6: 171–4.
4 Alexiou C, Kau RJ, Dietzfelbinger H et al. Extramedullary plasmacytoma:
tumor occurrence and therapeutic concepts. Cancer 1999; 85: 2305–14.
5 Kilciksiz S, Celik OK, Pak Y et al. Clinical and prognostic features of plasmacytomas: a multicenter study of Turkish Oncology Group-Sarcoma Working Party. Am. J. Hematol. 2008; 83: 702–7.
6 Kumar S, Fonseca R, Dispenzieri A et al. Prognostic value of angiogenesis
in solitary bone plasmacytoma. Blood 2003; 101: 1715–7.
7 Susnerwala SS, Shanks JH, Banerjee SS, Scarffe JH, Farrington WT, Slevin
NJ. Extramedullary plasmacytoma of the head and neck region: clinicopathological correlation in 25 cases. Br. J. Cancer 1997; 75: 921–7.
8 Mendenhall CM, Thar TL, Million RR. Solitary plasmacytoma of bone andsoft tissue. Int. J. Radiat. Oncol. Biol. Phys. 1980; 6: 1497–501.
9 Soutar R, Lucraft H, Jackson G et al. Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. Clin. Oncol. 2004; 2004: 405–13.
10 Landsmann S, Todorov J, Streitberg U, Seitz G, Weing€artner K. Plasmocytoma of the ureter – a rare cause of hydronephrosis: case report and reviewof the literature. Aktuelle Urol. 2009; 40: 175–8.
11 Klein T, Holz A, Neid M, Hinkel A, Noldus J. The ﬁrst description of an
extramedullary plasmacytoma of the ureter. Urol. Int. 2010; 84: 122–4.
12 Li F, Guo H, Qiu H et al. Ureteral inﬂammatory myoﬁbroblastic tumor: acase report and literature review. Medicine 2018; 97: e13177.
13 Wang Z, Yang J et al. Primary retroperitoneal paraganglioma mimicking a ureteraltumor: a case report and literature review. Postgrad. Med. 2020; 132: 657–61.
14 Hu J, Deng J, Guo J, Fu B. Ureteral involvement by metastatic malignant
disease. Clin. Exp. Metastasis 2019; 36: 499–509.
15 Wang H, Ma C, Jie W et al. Clinicopathologic features of the ureteral neuroendocrine tumors. Pathol. Res. Pract. 2020; 216: 152788.
16 Gupta M, Roy S, Wann C et al. Giant ﬁbroepithelial polyp of the ureter.
BMJ Case Rep. 2017; 2017: bcr2016218999.
17 Marchioni M, Primiceri G, Cindolo L et al. Impact of diagnostic ureteroscopy
on intravesical recurrence in patients undergoing radical nephroureterectomy
for upper tract urothelial cancer: a systematic review and meta-analysis. BJUInt. 2017; 120: 313–9.
18 Guo RQ, Hong P, Xiong GY et al. Impact of ureteroscopy before radical
nephroureterectomy for upper tract urothelial carcinomas on oncological outcomes: a meta-analysis. BJU Int. 2018; 121: 184–93.
19 Hendin BN, Streem SB, Levin HS, Klein EA, Novick AC. Impact of diagnostic ureteroscopy on long-term survival in patients with upper tract transitional cell carcinoma. J. Urol. 1999; 161: 783–5.
20 Territo A, Gallioli A, Meneghetti I et al. Diagnostic ureteroscopy for upper
tract urothelial carcinoma: friend or foe? Arab. J. Urol. 2021; 19: 46–58.
21 Ou YC, Hu CY, Cheng HL, Yang WH. Long-term outcomes of total
ureterectomy with ileal-ureteral substitution treatment for ureteral cancer: asingle-center experience. BMC Urol. 2018; 18: 73.

© 2021 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association

Open Access Original
Article

DOI: 10.7759/cureus.22421

Effects of Magnetic Resonance Imaging With
Axial Traction of the Thumb Carpometacarpal
Joint on Articular Cartilage Visibility: A
Feasibility Study

Review began 01/28/2022
Review ended 02/13/2022
Published 02/21/2022© Copyright 2022
Ikumi et al. This is an open access article
distributed under the terms of the Creative

Akira Ikumi 1, 2 , Sho Kohyama 3 , Shun Okuwaki 2 , Masaki Tatsumura 1 , Yuki Hara 4 , Takeo Mammoto 1 ,Takeshi Ogawa 5 , Yuichi Yoshii 6 , Haruo Kawamura 2 , Masashi Yamazaki 4

Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,and reproduction in any medium, provided
the original author and source are credited.

1. Department of Orthopedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education andTraining Center, Ibaraki, JPN 2. Department of Orthopedic Surgery, Kenpoku Medical Center Takahagi Kyodo Hospital,
Ibaraki, JPN 3. Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, JPN 4. Department ofOrthopedic Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, JPN 5. Department of Orthopedic Surgery,
National Hospital Organization, Mito Medical Center, Ibaraki, JPN 6. Department of Orthopedic Surgery, Tokyo
Medical University Ibaraki Medical Center, Ibaraki, JPN
Corresponding author: Akira Ikumi, ikumi@tsukuba-seikei.jp

Abstract
Objectives
The objective of this study was to verify the usefulness of magnetic resonance imaging (MRI) with axial
traction of the thumb for observing articular cartilage.

Materials and methods
Eleven healthy adult volunteers (39.7 ± 7.4 years) without thumb carpometacarpal joint arthritis or trauma
were included in this study. A 3-tesla (3T) MRI (Magnetom Skyra, Siemens Healthineers AG, Munich,Germany) of the right thumb with axial traction applied by a finger trap with three traction weights (0, 2,
and 5 kg) was performed. A 3D T2* multiecho data imaging combination (MEDIC) was selected to visualize
the articular cartilage. After multiplanar reconstruction, sagittal and coronal images of the thumbcarpometacarpal joint were used to evaluate the articular cartilage visibility and joint space widths at fivelocations. Articular cartilage visibility was evaluated using our original classification method that used thepercentage of the cartilage detectable area. The Friedman test was used to compare the differences between
each traction weight and location.

Results
Articular cartilage visibility significantly improved with axial traction. The average joint space widths withthe 5-kg application were 1.9 ± 0.8, 3.9 ± 0.6, 2.0 ± 0.9, 3.9 ± 1.1, and 2.5 ± 1.4 mm at the center, volar edge,
dorsal edge, radial edge, and ulnar edge, respectively. The joint space widths significantly increased
proportionally with the traction weight at all locations. The joint space widths at the volar and radial edges
were significantly greater than those at other locations.

Conclusion
Applying axial traction to the thumb increased the joint space widths and improved the visibility of thearticular cartilage in the carpometacarpal joint on MRI.

Categories: Radiology, Orthopedics
Keywords: joint space width, articular cartilage visibility, thumb carpometacarpal joint, magnetic resonance imaging,axial traction

Introduction
The thumb carpometacarpal (CMC) joint is a saddle joint that connects the first metacarpal bone and thetrapezium and can be moved in multiple different directions during daily activities such as pinching or
grasping due to its anatomical characteristics [1,2]. The incidence of thumb CMC joint arthritis is high,occurring in >15% of adults aged >30 years and one-third of postmenopausal women, despite it being a nonweight-bearing joint [3-6]. Thumb CMC joint arthritis is usually diagnosed on the basis of the patient’s
history, physical examination, and radiographs. The Eaton and Littler classification system is widely used todetermine the staging and severity of such types of arthritis [7,8]. However, the degree of damage in the
thumb CMC joint cartilage is not accurately assessed because the Eaton and Littler classification is based
only on radiographs. A study reported that the intra- and inter-examiner reliabilities of this classification
are low [9]; other studies have reported a poor correlation with clinical symptoms and intraoperative

How to cite this article
Ikumi A, Kohyama S, Okuwaki S, et al. (February 21, 2022) Effects of Magnetic Resonance Imaging With Axial Traction of the Thumb
Carpometacarpal Joint on Articular Cartilage Visibility: A Feasibility Study. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

articular cartilage findings [10,11].
Magnetic resonance imaging (MRI) is widely used to evaluate the damage to articular cartilage. However,accurate evaluation of the thumb CMC joint cartilage is difficult due to its anatomical complexity andrelatively small size compared with large joints such as the hip and knee. Although some reports haveevaluated the articular cartilage of the thumb CMC joint using MRI [12-14], an accurate method of
evaluation has not yet been established because of the overlap of the articular cartilage between the firstmetacarpal bone and the trapezium as well as the underestimation of the degree of cartilage damage
compared with other pathological findings [15]. Therefore, to enhance the visibility of the articular cartilage,
we have attempted to perform MRI while applying axial traction to the joint. This method of applying axial
traction to improve visualization of articular cartilage has been previously used to observe other joints,
including for osteochondritis dissecans in the capitellum [16].
This study aimed to examine the effects of MRI with axial traction of the thumb CMC joint on the visibilityof articular cartilage among healthy volunteers.

Materials And Methods
Study population
This study was approved by the institutional review board (IRB) of the first author's hospital (no. R2-06) andwas performed following the ethical standards laid down in the 1964 Declaration of Helsinki and its later
amendments or comparable ethical standards. We enrolled 11 healthy volunteers without a history of a
thumb injury and symptoms. All volunteers were hospital staff members. The first author provided detailed
information about the study (after IRB approval) within the hospital premises and recruited the volunteers.
Informed consent was obtained from each volunteer after thoroughly explaining the objective, method, andany expected complications of the study.

Image acquisition
MRI was performed at the Kenpoku Medical Center Takahagi Kyodo Hospital between January 2021 andMarch 2021. We used a 3-tesla (3T) whole-body MRI system (Magnetom Skyra, Siemens Healthineers AG,
Munich, Germany) using a four-channel 3T special purpose coil (Siemens Healthineers AG, Munich,Germany). For the MRI sequence, a three-dimensional T2* multiecho data imaging combination (MEDIC)
scan was used with the following parameters: slice thickness, 0.2 mm; slice gap, 0.15 mm; field of vision, 130
mm × 130 mm × 78 mm; matrix, 384 × 292; time to repeat, 20 ms; echo time, 11.0 ms; and flip angle, 25°. The
required time according to the protocol was 5 min and 43 s for each imaging. The volunteers were asked tolay supine on the table with their arms outstretched and forearms in pronation at the side of the body. The
hand under observation was centered parallel to the long axis of the gantry.

Application of axial traction during MRI
MRI was initially performed without traction, followed by MRI with traction. After performing the initial
MRI without traction, the volunteer’s thumb was enclosed within a Chinese finger trap (Allen® Sterile Mesh
Finger Traps, AliMed, Inc., Massachusetts, USA) using a rope. The other end of the rope was hung over theedge of the MR table via a pulley system and attached to nonmagnetic traction weights (Figure 1).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

2 of 10FIGURE 1: Application of axial traction during thumb carpometacarpal
joint MRI
(A) The volunteer’s thumb was enclosed within a Chinese finger trap and pulled distally. (B) The Chinese finger
trap was connected to the traction weight using a nonelastic rope routed through the pulley system.

The ideal traction weight for the thumb has not been determined to date; therefore, traction weights of 2
and 5 kgs were used based on previous literature [17].

Image analysis
We evaluated the following items: the effects of traction on the joint space width, articular cartilage outline
visibility, and pain and discomfort during imaging with traction. In this study, joint space width was definedas the space between opposing articular cartilages within the target joint. All MR images were independently
evaluated by two orthopedic surgeons (with 13 and six years of clinical experience, respectively). All study
images were interpreted on a workstation (Materialise Mimics, version 20.0; Materialise, Belgium); thisworkstation was also used to obtain multiplanar reconstructed (MPR) images. Specifically, coronal andsagittal images were reconstructed such that they were parallel to the longitudinal axis of the firstmetacarpal bone. This procedure was performed by the first author for all images. The images were initiallyenlarged, and the gray-scale contrast was adjusted to optimize the visualization of the structure being
assessed. The images were then randomly numbered to minimize bias among examiners.

Measurement of the joint space width
The joint space width was measured on the sagittal and coronal images at the center of the proximal
articular surface of the first metacarpal bone. On the sagittal image, the AB line, the line through both thevolar (point A) and dorsal (point B) borders at the proximal articular surface of the first metacarpal, and the
CD line, the line through both volar (point C) and dorsal (point D) borders of the distal articular surface oftrapezium, were drawn at first. Then, a perpendicular line was then drawn at the center of the AB line, andthe intersection points of the articular surface of the first metacarpal were labeled as point E and theintersection points of the articular surface of the trapezium were labeled as point F. Furthermore, theintersection points of the perpendicular line drawn from point A and B to the CD line were labeled as points
G and H. On the sagittal image, the IJ line, the line through the radial (point I) and ulnar (point J) borders of
the proximal articular surface of the first metacarpal, and the KL line, the line through the radial (point K)
and ulnar (point L) borders at the distal articular surface of the trapezium, were drawn first. Subsequently,
the intersection points of the perpendicular line drawn from points K and L to the IJ line were defined as
points M and N. The distance between points E and F was defined as the center of the joint space width, thatof points A-G and B-H was defined as volar and dorsal of the joint space width, and that of points I-M and JN was defined as radial and ulnar of the joint space width (Figure 2).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

3 of 10FIGURE 2: Definition of measurement points(A) The coronal and sagittal axes were defined using the axial plane at the first metacarpal bone head. (B)
Sagittal image of first carpometacarpal joint. Distances E-F, A-G, and B-H were defined as the center, volar, anddorsal distances, respectively. (C) Coronal image at the first carpometacarpal joint. Distances K-M and L-N were
defined as radial and ulnar, respectively.

Assessment of the articular cartilage outline visibility
Articular cartilage outline visibility was graded using the following three-point scale on each sagittal andcoronal image in which the joint space width was measured: 2 (complete), when 100% of the articularcartilage outline was clearly visible in the entire range when facing the opposing articular cartilage; 1(intermediate), when ≥50% but <100% of the articular cartilage outline was clearly visible in the range whenfacing the opposing articular cartilage; and 0 (poor), when the articular cartilage outline was visible in <50%of the entire range when facing the opposing articular cartilage (Figure 3).

FIGURE 3: Articular cartilage outline visibility grade(A) Grade 0 (poor): The articular cartilage outline was visible in <50% of the entire range when facing the
opposing articular cartilage. (B) Grade 1 (intermediate): ≥50% but <100% of the articular cartilage outline wasclearly visible in the range when facing the opposing articular cartilage. (C) Grade 2 (complete): 100% of thearticular cartilage outline was clearly visible in the entire range when facing the opposing articular cartilage. The
contact area of each articular cartilage is indicated by the white arrows.

Assessment of pain and discomfort during MRI with axial traction
The visual analog scale (VAS) was in a questionnaire format to assess the pain and discomfort during MRI
with axial traction and was completed by each volunteer immediately after undergoing MRI with axial
traction (0, minimum; 100, maximum).

Statistical analyses
We used GraphPad Prism 8 (GraphPad Software, LLC., CA, USA) for all statistical analyses. All data were
tested for normal distribution using the Shapiro-Wilk test. Only the VAS score followed the normal
distribution. We used a one-way analysis of variance (ANOVA) to assess the differences in the VAS scores foreach traction weight. None of the data on articular cartilage outline visibility and joint space width followed
normal distribution due to the small sample size. Therefore, the Friedman test was used to assess thedifferences in the joint space widths and articular cartilage outline visibility between each traction weight. A
P-value < 0.05 was considered significant.

Results
In this study, six of the 11 volunteers were men and five were women, with a mean age of 39.4 ± 7.4 (range,
27-49) years. Demographic data of the volunteers are presented in Table 1.

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

4 of 10No.

Sex

Age (Years)

History of thumb CMC joint injury

Symptoms of thumb CMC joint arthritis

1

Male

37

None

None

2

Male

49

None

None

3

Female

45

None

None

4

Female

43

None

None

5

Male

29

None

None

6

Male

30

None

None

7

Male

40

None

None

8

Female

41

None

None

9

Male

27

None

None

10

Female

49

None

None

11

Female

43

None

None

TABLE 1: Demographic data of the volunteers
CMC: Carpometacarpal.

The joint space width significantly increased at all points with the 5-kg traction than with no traction. No
significant differences in the joint space widths were observed between the 2-kg traction and non-traction at
all points (Figure 4).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

5 of 10FIGURE 4: Joint space widths at each point (median ± standard
deviation)
Joint space widths gradually widened after axial traction. At all points, significant differences were observed
between the 0-kg and 5-kg tractions.
**P < 0.01 compared with 0-kg traction.
#P < 0.05 compared with 2-kg traction.

On comparing each point, the volar and radial points were found to have significantly wider joint space
width for all traction weights than the center, dorsal, and ulnar. The visibility of the articular cartilage
outlines significantly improved with the 5-kg traction (P < 0.01), with approximately 82% of volunteers
showing complete visibility of the articular cartilage with the 5-kg traction (Figure 5).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

6 of 10FIGURE 5: Visibility of the articular cartilage outlines**P < 0.01 compared with the 0-kg traction.

The mean VAS score for pain and discomfort during MRI with axial traction was 0 (0-0) in non-traction, 25(10-47) in 2-kg traction, and 52 (33-89) in 5-kg traction (Figure 6).

FIGURE 6: Visual analog scale scores of the pain and discomfort during
traction
VAS: Visual analog scale.
**P < 0.01 compared with the 0-kg traction.
##P < 0.01 compared with the 2-kg traction.

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The scores significantly increased with traction (P < 0.01); however, the pain and discomfort were resolved
within 15 min after completing the traction and removing the finger trap in all volunteers.

Discussion
Our results showed that the cartilage outline visibility of the thumb CMC joint on MRI was significantly
better when axial traction was applied to the thumb.

Traction of the thumb
Joint traction during diagnostic testing and treatment has already been applied in multiple
situations [18,19]. Guntern et al. recently demonstrated that a 3-kg distraction load on the wrist significantly
expands the radiocarpal and midcarpal joints, particularly the radioscaphoid and lunocapitate spaces [18].
Lee et al. reported that traction significantly improves the cartilage surface visibility for standard MRI of thewrist, although the effect was not as obvious as that seen with MR arthrography or MR arthrography withtraction [17]. Orthopedic surgeons have also used axial traction of the wrist for treatment and diagnosis. The
distraction of the wrist by axial traction helps realign the fragments after displacement fractures of the distal
radius. Axial traction has been used as a carpal stress test in the diagnosis of scapholunate ligament injuries
in radiology [20]. Furthermore, four previous studies have reported the advantages of applying axial traction
during MR arthrography: one at the shoulder [21], two at the hip [22,23], and one at the knee [24]. Although
the articular cartilage visibility significantly improved by increasing the traction weight, the pain anddiscomfort caused by traction were also significantly increased in this study. An increase in the traction
weight results in increased tightness of the finger being tested. We suspected that the pain during traction
was caused by vascular insufficiency due to the use of the Chinese finger trap. The maximal traction weightin this study (5 kg) is acceptable in a clinical setting because 4.5 kg (10 pounds) of traction is usually applied
for fingers when performing wrist or thumb arthroscopy [17,19,25]. However, the traction of the thumb inpatients with thumb CMC joint arthritis may exacerbate pain and other symptoms, although these
symptoms disappear within a short period in healthy volunteers. Further research is warranted to determine
the optimal traction weight for the thumb.

MRI sequences to observe the articular cartilage
MEDIC was used to evaluate the articular cartilage in this study. Its T2*-weighted gradient-echo sequence is
specifically designed for musculoskeletal and neuroradiological purposes and combines up to six echoes in asingle image, leading to a higher signal-to-noise ratio (SNR) and reduced susceptibility [26-28]. A 3D-MEDIC
is useful in the diagnosis of fibrocartilaginous and ligamentous pathologies due to its high intrinsic SNR andhigh resolution of the 3D data stack [26,27]. Compared to other 3D sequences of the wrist, 3D-MEDIC
exhibits a high contrast and SNR as well as the best visibility of fibrocartilaginous and ligamentous tissues[26]. In this study, articular cartilage is defined as a white line contacting the subchondral bone. Therefore,
our results suggest that the MEDIC sequence can describe articular cartilage in the same way that it can beused to describe fibrocartilaginous and ligamentous tissues. Therefore, the optimal sequence to describe thearticular cartilage in MRI should be examined in a study that compares several MRI sequences in the future.

Importance of articular cartilage evaluation for the thumb CMC joint
Various surgical techniques have been previously reported for thumb CMC joint arthritis [29]. For patientswith mild osteoarthritic changes (Eaton classification stage 1 or 2), ligamentoplasty, arthroscopic
synovectomy, and first metacarpal osteotomy are selected for thumb CMC joint preservation surgery,whereas, for patients with advanced osteoarthritic changes (Eaton classification stage 3 or 4), arthroplasty
such as ligament reconstruction and tendon interposition, arthrodesis, and artificial joint replacement isgenerally selected as the thumb CMC joint non-preservation surgery. Although the clinical outcome isgenerally good with each type of treatment [30], Ogawa et al. have reported symptomatic improvement withjoint preservation surgery even in patients with advanced osteoarthritic changes [25]. We believe that jointpreservation surgery is preferable for younger patients or those who are involved in heavy labor, although arisk of osteoarthritic change progression exists even after a long-term joint preservation surgery.
Badia et al. reported a treatment algorithm based on intraoperative thumb CMC joint arthroscopic findings
in 2006 [11]. Depending on the degree of articular cartilage damage or loss, joint preservation or nonpreservation surgery is selected in this algorithm. This algorithm is more innovative than the Eaton
classification as it assesses the articular cartilage damage and loss with higher accuracy before deciding thesurgical technique. However, several limitations, such as the inability to preoperatively evaluate the articularcartilage, invasiveness, and the need to decide the surgical technique intraoperatively, were encountered.
Our results demonstrated that the axial traction MRI of the thumb CMC joint could be used to preoperatively
evaluate the articular cartilage condition, which will allow the selection of the optimal surgical techniquethat reflects the articular cartilage condition rather than depending on the Eaton classification.
This study has several limitations. First, the number of study participants was small. Second, we did not
examine the use of MRI with axial traction for patients with thumb CMC joint arthritis. Third, the axial
traction system in this study could not control the rotation force for the thumb CMC joint. A slight twist
caused by axial traction may affect the measurement of joint space widths at each point. Therefore, adding2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

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a system to control the rotation force during axial traction is necessary in future studies. Finally, we did not
validate the concordance rate between MRI findings and intraoperative or pathological findings. To addressthese problems, the usefulness of this method should be verified in patients with thumb CMC joint arthritis,
and the concordance rate must be verified with intraoperative and pathological findings in the future.

Conclusions
Axial traction of the thumb increased the joint space widths and improved the visibility of articular cartilage
in the thumb CMC joint on MRI. Our results suggest that axial traction MRI can be used to evaluate thearticular cartilage in a noninvasive manner in patients with thumb CMC joint arthritis, and it can be used toobtain useful information that will help to select the optimal surgical procedure.

Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Kenpoku Medical Center
Takahagi Kyodo Hospital issued approval R2-06. Animal subjects: All authors have confirmed that thisstudy did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform
disclosure form, all authors declare the following: Payment/services info: All authors have declared that nofinancial support was received from any organization for the submitted work. Financial relationships: All
authors have declared that they have no financial relationships at present or within the previous three years
with any organizations that might have an interest in the submitted work. Other relationships: All authors
have declared that there are no other relationships or activities that could appear to have influenced thesubmitted work.

Acknowledgements
The authors would like to thank Kazuki Hiruma and staff of the radiology department for performing MRI as
the radiology technician and Enago (www.enago.jp) for the English language review.

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Open Access Original
Article

DOI: 10.7759/cureus.22421

Effects of Magnetic Resonance Imaging With
Axial Traction of the Thumb Carpometacarpal
Joint on Articular Cartilage Visibility: A
Feasibility Study

Review began 01/28/2022
Review ended 02/13/2022
Published 02/21/2022© Copyright 2022
Ikumi et al. This is an open access article
distributed under the terms of the Creative

Akira Ikumi 1, 2 , Sho Kohyama 3 , Shun Okuwaki 2 , Masaki Tatsumura 1 , Yuki Hara 4 , Takeo Mammoto 1 ,Takeshi Ogawa 5 , Yuichi Yoshii 6 , Haruo Kawamura 2 , Masashi Yamazaki 4

Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,and reproduction in any medium, provided
the original author and source are credited.

1. Department of Orthopedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education andTraining Center, Ibaraki, JPN 2. Department of Orthopedic Surgery, Kenpoku Medical Center Takahagi Kyodo Hospital,
Ibaraki, JPN 3. Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, JPN 4. Department ofOrthopedic Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, JPN 5. Department of Orthopedic Surgery,
National Hospital Organization, Mito Medical Center, Ibaraki, JPN 6. Department of Orthopedic Surgery, Tokyo
Medical University Ibaraki Medical Center, Ibaraki, JPN
Corresponding author: Akira Ikumi, ikumi@tsukuba-seikei.jp

Abstract
Objectives
The objective of this study was to verify the usefulness of magnetic resonance imaging (MRI) with axial
traction of the thumb for observing articular cartilage.

Materials and methods
Eleven healthy adult volunteers (39.7 ± 7.4 years) without thumb carpometacarpal joint arthritis or trauma
were included in this study. A 3-tesla (3T) MRI (Magnetom Skyra, Siemens Healthineers AG, Munich,Germany) of the right thumb with axial traction applied by a finger trap with three traction weights (0, 2,
and 5 kg) was performed. A 3D T2* multiecho data imaging combination (MEDIC) was selected to visualize
the articular cartilage. After multiplanar reconstruction, sagittal and coronal images of the thumbcarpometacarpal joint were used to evaluate the articular cartilage visibility and joint space widths at fivelocations. Articular cartilage visibility was evaluated using our original classification method that used thepercentage of the cartilage detectable area. The Friedman test was used to compare the differences between
each traction weight and location.

Results
Articular cartilage visibility significantly improved with axial traction. The average joint space widths withthe 5-kg application were 1.9 ± 0.8, 3.9 ± 0.6, 2.0 ± 0.9, 3.9 ± 1.1, and 2.5 ± 1.4 mm at the center, volar edge,
dorsal edge, radial edge, and ulnar edge, respectively. The joint space widths significantly increased
proportionally with the traction weight at all locations. The joint space widths at the volar and radial edges
were significantly greater than those at other locations.

Conclusion
Applying axial traction to the thumb increased the joint space widths and improved the visibility of thearticular cartilage in the carpometacarpal joint on MRI.

Categories: Radiology, Orthopedics
Keywords: joint space width, articular cartilage visibility, thumb carpometacarpal joint, magnetic resonance imaging,axial traction

Introduction
The thumb carpometacarpal (CMC) joint is a saddle joint that connects the first metacarpal bone and thetrapezium and can be moved in multiple different directions during daily activities such as pinching or
grasping due to its anatomical characteristics [1,2]. The incidence of thumb CMC joint arthritis is high,occurring in >15% of adults aged >30 years and one-third of postmenopausal women, despite it being a nonweight-bearing joint [3-6]. Thumb CMC joint arthritis is usually diagnosed on the basis of the patient’s
history, physical examination, and radiographs. The Eaton and Littler classification system is widely used todetermine the staging and severity of such types of arthritis [7,8]. However, the degree of damage in the
thumb CMC joint cartilage is not accurately assessed because the Eaton and Littler classification is based
only on radiographs. A study reported that the intra- and inter-examiner reliabilities of this classification
are low [9]; other studies have reported a poor correlation with clinical symptoms and intraoperative

How to cite this article
Ikumi A, Kohyama S, Okuwaki S, et al. (February 21, 2022) Effects of Magnetic Resonance Imaging With Axial Traction of the Thumb
Carpometacarpal Joint on Articular Cartilage Visibility: A Feasibility Study. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

articular cartilage findings [10,11].
Magnetic resonance imaging (MRI) is widely used to evaluate the damage to articular cartilage. However,accurate evaluation of the thumb CMC joint cartilage is difficult due to its anatomical complexity andrelatively small size compared with large joints such as the hip and knee. Although some reports haveevaluated the articular cartilage of the thumb CMC joint using MRI [12-14], an accurate method of
evaluation has not yet been established because of the overlap of the articular cartilage between the firstmetacarpal bone and the trapezium as well as the underestimation of the degree of cartilage damage
compared with other pathological findings [15]. Therefore, to enhance the visibility of the articular cartilage,
we have attempted to perform MRI while applying axial traction to the joint. This method of applying axial
traction to improve visualization of articular cartilage has been previously used to observe other joints,
including for osteochondritis dissecans in the capitellum [16].
This study aimed to examine the effects of MRI with axial traction of the thumb CMC joint on the visibilityof articular cartilage among healthy volunteers.

Materials And Methods
Study population
This study was approved by the institutional review board (IRB) of the first author's hospital (no. R2-06) andwas performed following the ethical standards laid down in the 1964 Declaration of Helsinki and its later
amendments or comparable ethical standards. We enrolled 11 healthy volunteers without a history of a
thumb injury and symptoms. All volunteers were hospital staff members. The first author provided detailed
information about the study (after IRB approval) within the hospital premises and recruited the volunteers.
Informed consent was obtained from each volunteer after thoroughly explaining the objective, method, andany expected complications of the study.

Image acquisition
MRI was performed at the Kenpoku Medical Center Takahagi Kyodo Hospital between January 2021 andMarch 2021. We used a 3-tesla (3T) whole-body MRI system (Magnetom Skyra, Siemens Healthineers AG,
Munich, Germany) using a four-channel 3T special purpose coil (Siemens Healthineers AG, Munich,Germany). For the MRI sequence, a three-dimensional T2* multiecho data imaging combination (MEDIC)
scan was used with the following parameters: slice thickness, 0.2 mm; slice gap, 0.15 mm; field of vision, 130
mm × 130 mm × 78 mm; matrix, 384 × 292; time to repeat, 20 ms; echo time, 11.0 ms; and flip angle, 25°. The
required time according to the protocol was 5 min and 43 s for each imaging. The volunteers were asked tolay supine on the table with their arms outstretched and forearms in pronation at the side of the body. The
hand under observation was centered parallel to the long axis of the gantry.

Application of axial traction during MRI
MRI was initially performed without traction, followed by MRI with traction. After performing the initial
MRI without traction, the volunteer’s thumb was enclosed within a Chinese finger trap (Allen® Sterile Mesh
Finger Traps, AliMed, Inc., Massachusetts, USA) using a rope. The other end of the rope was hung over theedge of the MR table via a pulley system and attached to nonmagnetic traction weights (Figure 1).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

2 of 10FIGURE 1: Application of axial traction during thumb carpometacarpal
joint MRI
(A) The volunteer’s thumb was enclosed within a Chinese finger trap and pulled distally. (B) The Chinese finger
trap was connected to the traction weight using a nonelastic rope routed through the pulley system.

The ideal traction weight for the thumb has not been determined to date; therefore, traction weights of 2
and 5 kgs were used based on previous literature [17].

Image analysis
We evaluated the following items: the effects of traction on the joint space width, articular cartilage outline
visibility, and pain and discomfort during imaging with traction. In this study, joint space width was definedas the space between opposing articular cartilages within the target joint. All MR images were independently
evaluated by two orthopedic surgeons (with 13 and six years of clinical experience, respectively). All study
images were interpreted on a workstation (Materialise Mimics, version 20.0; Materialise, Belgium); thisworkstation was also used to obtain multiplanar reconstructed (MPR) images. Specifically, coronal andsagittal images were reconstructed such that they were parallel to the longitudinal axis of the firstmetacarpal bone. This procedure was performed by the first author for all images. The images were initiallyenlarged, and the gray-scale contrast was adjusted to optimize the visualization of the structure being
assessed. The images were then randomly numbered to minimize bias among examiners.

Measurement of the joint space width
The joint space width was measured on the sagittal and coronal images at the center of the proximal
articular surface of the first metacarpal bone. On the sagittal image, the AB line, the line through both thevolar (point A) and dorsal (point B) borders at the proximal articular surface of the first metacarpal, and the
CD line, the line through both volar (point C) and dorsal (point D) borders of the distal articular surface oftrapezium, were drawn at first. Then, a perpendicular line was then drawn at the center of the AB line, andthe intersection points of the articular surface of the first metacarpal were labeled as point E and theintersection points of the articular surface of the trapezium were labeled as point F. Furthermore, theintersection points of the perpendicular line drawn from point A and B to the CD line were labeled as points
G and H. On the sagittal image, the IJ line, the line through the radial (point I) and ulnar (point J) borders of
the proximal articular surface of the first metacarpal, and the KL line, the line through the radial (point K)
and ulnar (point L) borders at the distal articular surface of the trapezium, were drawn first. Subsequently,
the intersection points of the perpendicular line drawn from points K and L to the IJ line were defined as
points M and N. The distance between points E and F was defined as the center of the joint space width, thatof points A-G and B-H was defined as volar and dorsal of the joint space width, and that of points I-M and JN was defined as radial and ulnar of the joint space width (Figure 2).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

3 of 10FIGURE 2: Definition of measurement points(A) The coronal and sagittal axes were defined using the axial plane at the first metacarpal bone head. (B)
Sagittal image of first carpometacarpal joint. Distances E-F, A-G, and B-H were defined as the center, volar, anddorsal distances, respectively. (C) Coronal image at the first carpometacarpal joint. Distances K-M and L-N were
defined as radial and ulnar, respectively.

Assessment of the articular cartilage outline visibility
Articular cartilage outline visibility was graded using the following three-point scale on each sagittal andcoronal image in which the joint space width was measured: 2 (complete), when 100% of the articularcartilage outline was clearly visible in the entire range when facing the opposing articular cartilage; 1(intermediate), when ≥50% but <100% of the articular cartilage outline was clearly visible in the range whenfacing the opposing articular cartilage; and 0 (poor), when the articular cartilage outline was visible in <50%of the entire range when facing the opposing articular cartilage (Figure 3).

FIGURE 3: Articular cartilage outline visibility grade(A) Grade 0 (poor): The articular cartilage outline was visible in <50% of the entire range when facing the
opposing articular cartilage. (B) Grade 1 (intermediate): ≥50% but <100% of the articular cartilage outline wasclearly visible in the range when facing the opposing articular cartilage. (C) Grade 2 (complete): 100% of thearticular cartilage outline was clearly visible in the entire range when facing the opposing articular cartilage. The
contact area of each articular cartilage is indicated by the white arrows.

Assessment of pain and discomfort during MRI with axial traction
The visual analog scale (VAS) was in a questionnaire format to assess the pain and discomfort during MRI
with axial traction and was completed by each volunteer immediately after undergoing MRI with axial
traction (0, minimum; 100, maximum).

Statistical analyses
We used GraphPad Prism 8 (GraphPad Software, LLC., CA, USA) for all statistical analyses. All data were
tested for normal distribution using the Shapiro-Wilk test. Only the VAS score followed the normal
distribution. We used a one-way analysis of variance (ANOVA) to assess the differences in the VAS scores foreach traction weight. None of the data on articular cartilage outline visibility and joint space width followed
normal distribution due to the small sample size. Therefore, the Friedman test was used to assess thedifferences in the joint space widths and articular cartilage outline visibility between each traction weight. A
P-value < 0.05 was considered significant.

Results
In this study, six of the 11 volunteers were men and five were women, with a mean age of 39.4 ± 7.4 (range,
27-49) years. Demographic data of the volunteers are presented in Table 1.

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

4 of 10No.

Sex

Age (Years)

History of thumb CMC joint injury

Symptoms of thumb CMC joint arthritis

1

Male

37

None

None

2

Male

49

None

None

3

Female

45

None

None

4

Female

43

None

None

5

Male

29

None

None

6

Male

30

None

None

7

Male

40

None

None

8

Female

41

None

None

9

Male

27

None

None

10

Female

49

None

None

11

Female

43

None

None

TABLE 1: Demographic data of the volunteers
CMC: Carpometacarpal.

The joint space width significantly increased at all points with the 5-kg traction than with no traction. No
significant differences in the joint space widths were observed between the 2-kg traction and non-traction at
all points (Figure 4).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

5 of 10FIGURE 4: Joint space widths at each point (median ± standard
deviation)
Joint space widths gradually widened after axial traction. At all points, significant differences were observed
between the 0-kg and 5-kg tractions.
**P < 0.01 compared with 0-kg traction.
#P < 0.05 compared with 2-kg traction.

On comparing each point, the volar and radial points were found to have significantly wider joint space
width for all traction weights than the center, dorsal, and ulnar. The visibility of the articular cartilage
outlines significantly improved with the 5-kg traction (P < 0.01), with approximately 82% of volunteers
showing complete visibility of the articular cartilage with the 5-kg traction (Figure 5).

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

6 of 10FIGURE 5: Visibility of the articular cartilage outlines**P < 0.01 compared with the 0-kg traction.

The mean VAS score for pain and discomfort during MRI with axial traction was 0 (0-0) in non-traction, 25(10-47) in 2-kg traction, and 52 (33-89) in 5-kg traction (Figure 6).

FIGURE 6: Visual analog scale scores of the pain and discomfort during
traction
VAS: Visual analog scale.
**P < 0.01 compared with the 0-kg traction.
##P < 0.01 compared with the 2-kg traction.

2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

7 of 10

The scores significantly increased with traction (P < 0.01); however, the pain and discomfort were resolved
within 15 min after completing the traction and removing the finger trap in all volunteers.

Discussion
Our results showed that the cartilage outline visibility of the thumb CMC joint on MRI was significantly
better when axial traction was applied to the thumb.

Traction of the thumb
Joint traction during diagnostic testing and treatment has already been applied in multiple
situations [18,19]. Guntern et al. recently demonstrated that a 3-kg distraction load on the wrist significantly
expands the radiocarpal and midcarpal joints, particularly the radioscaphoid and lunocapitate spaces [18].
Lee et al. reported that traction significantly improves the cartilage surface visibility for standard MRI of thewrist, although the effect was not as obvious as that seen with MR arthrography or MR arthrography withtraction [17]. Orthopedic surgeons have also used axial traction of the wrist for treatment and diagnosis. The
distraction of the wrist by axial traction helps realign the fragments after displacement fractures of the distal
radius. Axial traction has been used as a carpal stress test in the diagnosis of scapholunate ligament injuries
in radiology [20]. Furthermore, four previous studies have reported the advantages of applying axial traction
during MR arthrography: one at the shoulder [21], two at the hip [22,23], and one at the knee [24]. Although
the articular cartilage visibility significantly improved by increasing the traction weight, the pain anddiscomfort caused by traction were also significantly increased in this study. An increase in the traction
weight results in increased tightness of the finger being tested. We suspected that the pain during traction
was caused by vascular insufficiency due to the use of the Chinese finger trap. The maximal traction weightin this study (5 kg) is acceptable in a clinical setting because 4.5 kg (10 pounds) of traction is usually applied
for fingers when performing wrist or thumb arthroscopy [17,19,25]. However, the traction of the thumb inpatients with thumb CMC joint arthritis may exacerbate pain and other symptoms, although these
symptoms disappear within a short period in healthy volunteers. Further research is warranted to determine
the optimal traction weight for the thumb.

MRI sequences to observe the articular cartilage
MEDIC was used to evaluate the articular cartilage in this study. Its T2*-weighted gradient-echo sequence is
specifically designed for musculoskeletal and neuroradiological purposes and combines up to six echoes in asingle image, leading to a higher signal-to-noise ratio (SNR) and reduced susceptibility [26-28]. A 3D-MEDIC
is useful in the diagnosis of fibrocartilaginous and ligamentous pathologies due to its high intrinsic SNR andhigh resolution of the 3D data stack [26,27]. Compared to other 3D sequences of the wrist, 3D-MEDIC
exhibits a high contrast and SNR as well as the best visibility of fibrocartilaginous and ligamentous tissues[26]. In this study, articular cartilage is defined as a white line contacting the subchondral bone. Therefore,
our results suggest that the MEDIC sequence can describe articular cartilage in the same way that it can beused to describe fibrocartilaginous and ligamentous tissues. Therefore, the optimal sequence to describe thearticular cartilage in MRI should be examined in a study that compares several MRI sequences in the future.

Importance of articular cartilage evaluation for the thumb CMC joint
Various surgical techniques have been previously reported for thumb CMC joint arthritis [29]. For patientswith mild osteoarthritic changes (Eaton classification stage 1 or 2), ligamentoplasty, arthroscopic
synovectomy, and first metacarpal osteotomy are selected for thumb CMC joint preservation surgery,whereas, for patients with advanced osteoarthritic changes (Eaton classification stage 3 or 4), arthroplasty
such as ligament reconstruction and tendon interposition, arthrodesis, and artificial joint replacement isgenerally selected as the thumb CMC joint non-preservation surgery. Although the clinical outcome isgenerally good with each type of treatment [30], Ogawa et al. have reported symptomatic improvement withjoint preservation surgery even in patients with advanced osteoarthritic changes [25]. We believe that jointpreservation surgery is preferable for younger patients or those who are involved in heavy labor, although arisk of osteoarthritic change progression exists even after a long-term joint preservation surgery.
Badia et al. reported a treatment algorithm based on intraoperative thumb CMC joint arthroscopic findings
in 2006 [11]. Depending on the degree of articular cartilage damage or loss, joint preservation or nonpreservation surgery is selected in this algorithm. This algorithm is more innovative than the Eaton
classification as it assesses the articular cartilage damage and loss with higher accuracy before deciding thesurgical technique. However, several limitations, such as the inability to preoperatively evaluate the articularcartilage, invasiveness, and the need to decide the surgical technique intraoperatively, were encountered.
Our results demonstrated that the axial traction MRI of the thumb CMC joint could be used to preoperatively
evaluate the articular cartilage condition, which will allow the selection of the optimal surgical techniquethat reflects the articular cartilage condition rather than depending on the Eaton classification.
This study has several limitations. First, the number of study participants was small. Second, we did not
examine the use of MRI with axial traction for patients with thumb CMC joint arthritis. Third, the axial
traction system in this study could not control the rotation force for the thumb CMC joint. A slight twist
caused by axial traction may affect the measurement of joint space widths at each point. Therefore, adding2022 Ikumi et al. Cureus 14(2): e22421. DOI 10.7759/cureus.22421

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a system to control the rotation force during axial traction is necessary in future studies. Finally, we did not
validate the concordance rate between MRI findings and intraoperative or pathological findings. To addressthese problems, the usefulness of this method should be verified in patients with thumb CMC joint arthritis,
and the concordance rate must be verified with intraoperative and pathological findings in the future.

Conclusions
Axial traction of the thumb increased the joint space widths and improved the visibility of articular cartilage
in the thumb CMC joint on MRI. Our results suggest that axial traction MRI can be used to evaluate thearticular cartilage in a noninvasive manner in patients with thumb CMC joint arthritis, and it can be used toobtain useful information that will help to select the optimal surgical procedure.

Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Kenpoku Medical Center
Takahagi Kyodo Hospital issued approval R2-06. Animal subjects: All authors have confirmed that thisstudy did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform
disclosure form, all authors declare the following: Payment/services info: All authors have declared that nofinancial support was received from any organization for the submitted work. Financial relationships: All
authors have declared that they have no financial relationships at present or within the previous three years
with any organizations that might have an interest in the submitted work. Other relationships: All authors
have declared that there are no other relationships or activities that could appear to have influenced thesubmitted work.

Acknowledgements
The authors would like to thank Kazuki Hiruma and staff of the radiology department for performing MRI as
the radiology technician and Enago (www.enago.jp) for the English language review.

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RESEARCH ARTICLE

Diﬀerence in Rupture Risk Between Familial
and Sporadic Intracranial Aneurysms
An Individual Patient Data Meta-analysis
Charlotte C.M. Zuurbier, MD, Liselore A. Mensing, MD, Marieke J.H. Wermer, MD, PhD, Seppo Juvela, MD, PhD,
Antti E. Lindgren, MD, PhD, Timo Koivisto, MD, PhD, Juha E. Jääskeläinen, MD, PhD, Tomosato Yamazaki, MD, PhD,
Rob Molenberg, BsC, J. Marc C. van Dijk, MD, PhD, Maarten Uyttenboogaart, MD, PhD, Marlien Aalbers, MD,
Akio Morita, MD, PhD, Shinjiro Tominari, MD, PhD, Hajime Arai, MD, PhD, Kazuhiko Nozaki, MD, PhD,
Yuichi Murayama, MD, Toshihiro Ishibashi, MD, Hiroyuki Takao, MD, PhD, Gabriel J.E. Rinkel, prof MD, PhD,
Jacoba P. Greving, PhD, and Ynte M. Ruigrok, MD, PhD

Correspondence
Dr. Ruigrok
ij.m.ruigrok@umcutrecht.nl®

Neurology 2021;97:e2195-e2203. doi:10.1212/WNL.0000000000012885

Abstract
Background and Objectives
We combined individual patient data (IPD) from prospective cohorts of patients with unruptured
intracranial aneurysms (UIAs) to assess to what extent patients with familial UIA have a higher
rupture risk than those with sporadic UIA.
Methods
For this IPD meta-analysis, we performed an Embase and PubMed search for studies published up
to December 1, 2020. We included studies that (1) had a prospective study design; (2) included 50
or more patients with UIA; (3) studied the natural course of UIA and risk factors for aneurysm
rupture including family history for aneurysmal subarachnoid haemorrhage and UIA; and (4) had
aneurysm rupture as an outcome. Cohorts with available IPD were included. All studies included
patients with newly diagnosed UIA visiting one of the study centers. The primary outcome wasaneurysmal rupture. Patients with polycystic kidney disease and moyamoya disease were excluded.
We compared rupture rates of familial vs sporadic UIA using a Cox proportional hazard regression
model adjusted for PHASES score and smoking. We performed 2 analyses: (1) only studies
deﬁning ﬁrst-degree relatives as parents, children, and siblings and (2) all studies, including those inwhich ﬁrst-degree relatives are deﬁned as only parents and children, but not siblings.
Results
We pooled IPD from 8 cohorts with a low and moderate risk of bias. First-degree relatives weredeﬁned as parents, siblings, and children in 6 cohorts (29% Dutch, 55% Finnish, 15% Japanese),
totaling 2,297 patients (17% familial, 399 patients) with 3,089 UIAs and 7,301 person-years
follow-up. Rupture occurred in 10 familial cases (rupture rate: 0.89%/person-year; 95% conﬁdence interval [CI] 0.45–1.59) and 41 sporadic cases (0.66%/person-year; 95% CI 0.48–0.89);
adjusted hazard ratio (HR) for familial cases 2.56 (95% CI 1.18–5.56). After adding the 2 cohorts
excluding siblings as ﬁrst-degree relatives, resulting in 9,511 patients, the adjusted HR was 1.44
(95% CI 0.86–2.40).
Discussion
The risk of rupture of UIA is 2.5 times higher, with a range from a 1.2 to 5 times higher risk, infamilial than in sporadic UIA. When assessing the risk of rupture in UIA, family history should
be taken into account.

From the Department of Neurology and Neurosurgery, UMC Utrecht Brain Center (C.C.M.Z., L.A.M., G.J.E.R., Y.M.R.), and Julius Centre for Health Sciences and Primary Care (J.P.G.),
University Medical Center Utrecht; Department of Neurology (M.J.H.W.), Leiden University Medical Center, the Netherlands; Department of Clinical Neurosciences (S.J.), University of
Helsinki; Neurosurgery of NeuroCenter (A.E.L., T.K., J.E.J.), University of Eastern Finland, Kuopio, Finland; Department of Neurosurgery (T.Y.), National Hospital Organization, Mito
Medical Center, Japan; Departments of Neurosurgery (R.M., J.M.C.v.D., M.U., M.A.), University Medical Center Groningen, the Netherlands; University of Tokyo–Nippon Medical
School (A.M.); Department of Health Informatics, School of Public Health (S.T.), Kyoto University; Department of Neurosurgery (H.A.), Juntendo University Medical School, Tokyo;
Department of Neurosurgery (K.N.), Shiga University of Medical Science; and Department of Endovascular Neurosurgery (Y.M., T.I., H.T.), Tokyo Jikei University School of Medicine,Japan.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

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GlossaryaSAH = aneurysmal subarachnoid hemorrhage; CI = conﬁdence interval; HR = hazard ratio; QUIPS = Quality in Prognosis
Studies; UIA = unruptured intracranial aneurysm.

Persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH) or unruptured intracranial
aneurysms (UIAs) have a 10% risk of having a UIA.1 A higher
rupture risk of UIA has been suggested in these patientscompared to patients without such a history. The Familial
Intracranial Aneurysm study reported a 17 times higher
rupture rate for individuals with a family history of aSAH plus
hypertension or smoking, or both, compared to individuals
with sporadic UIA. However, these data lack precision as they
are based on 2 cases of aSAH in 113 patients with UIAs.2
Another prospective, single-center cohort with familial patients not selected for smoking or hypertension, and taking
risk factors for rupture into account, found a not statisticallysigniﬁcant 3 times higher risk.3
The deﬁnition of a positive family history may also play a rolein the level of risk of rupture of familial UIA.4 In mostcountries, ﬁrst-degree relatives are deﬁned as parents, siblings,
or children, while in some other countries, ﬁrst-degree relatives are deﬁned as only parents and children, but not siblings.
We recently showed that within families, siblings have a higher
risk of UIA and aSAH than parents and children.4 Thus, toassess the risk of rupture of familial aneurysms, it is important
to include siblings in the category of ﬁrst-degree relatives.
We aimed to assess to what extent patients with familial UIA
have a higher risk of rupture than those with sporadic UIA,
when deﬁning ﬁrst-degree relatives as parents, siblings, or
children. Secondly, we assessed this association in cohorts bothincluding and excluding siblings in the deﬁnition of ﬁrst-degree
relatives.

Methods
Search Strategy and Selection Criteria
We performed a systematic search in Embase and PubMed toretrieve all studies on rupture risk of UIA published up to
December 1, 2020. Our search strategy included the keywords“(intracranial aneurysm[s] or cerebral aneurysm[s]) and (riskof rupture or aneurysm rupture or risk factors or rupture or
unruptured or subarachnoid hemorrhage) and (follow-up or
natural history or natural course)” (eFigure 1, available from
Dryad: doi.org/10.5061/dryad.3bk3j9kjz). We searched thereference list of all relevant publications for additional studies.
We included studies that (1) had a prospective study design;(2) included 50 or more patients with UIA; (3) studied thenatural course of UIA and risk factors for aneurysm rupture
including family history for aSAH and UIA; and (4) had aneurysm rupture as an outcome. There was no language restriction other than the requirement of an abstract in English.
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One author (C.C.M.Z.) performed the literature search,
checked the titles and abstracts of search records, and assessed
eligible articles to decide which met the predeﬁned inclusion
criteria.
Study Design
For the eligible studies meeting the inclusion criteria, we
approached the research groups that performed these studies
asking if they could provide us with their individual patientdata. Only cohorts with available individual patient-level data
were included in our meta-analysis.
Data Collection
Data requested for each patient at baseline of the diﬀerent
included studies were the following: age, sex, history of aSAH,
smoking status, positive family history for aSAH or UIA, hypertension status, number of aneurysms, maximum diameter ofaneurysms, and aneurysm location. For each patient, we summarized the data on the diﬀerent risk factors for rupture bycalculating the PHASES score.5 Data requested for each patient
during follow-up were the following: occurrence of rupture,
date of rupture, data of a surgical or endovascular intervention,
date of death, date of last follow-up assessment, and whether apatient was lost to follow-up. Individuals with a positive family
history were deﬁned as individuals with at least 2 aﬀected ﬁrstdegree relatives with aSAH whether or not in combination ofﬁrst-degree relatives with UIA. A smoker was deﬁned as aformer or current smoker and a person with hypertension as ahistory of a systolic blood pressure >140 mm Hg or diastolicblood pressure >90 mm Hg or use of antihypertensive drugs.
The location of the aneurysm was classiﬁed into the categories
internal carotid artery, posterior communicating artery, anterior cerebral arteries (including the anterior cerebral artery,anterior communicating artery, and pericallosal artery), middle
cerebral artery, or posterior circulation (including the vertebral
artery, basilar artery, cerebellar arteries, and posterior cerebral
artery). Patients with polycystic kidney disease and moyamoya
disease were excluded as we are not sure whether the rupturerisk of patients with familial UIA and these diseases is similar to
the rupture risk of patients with sporadic UIA with these diseases or patients with familial UIA without these diseases. The
primary outcome was the rupture of an UIA. We followed
Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines throughout our review. We
assessed the quality of the observational studies using the
Quality in Prognosis Studies (QUIPS) tool.6
Statistical Approach
Information on the outcome measure and aneurysm characteristics was complete for all patients. In 4 studies, no data on
family history were available for a small subset of patients, andNeurology.org/N

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Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram

IPD = individual patient data.

these patients were excluded from the pooled analysis (146patients excluded).7-10 Information on patient characteristics
was also complete except for smoking, which was available in
9,276/9,511 (97.5%) patients, and for hypertension, which wasavailable in 9,424/9,511 (99.1%) patients. These missing data
were imputed using multiple imputation. In one study, smokers
were deﬁned as current smokers and no data on former smoking
were availaible.9 Forty-two patients were included in 2 Japanesecohorts10,11 and 11 patients were included in 2 Dutch cohorts3,8and these patients were excluded in one of these cohorts in thepooled analysis. For data analysis, we categorized according to
the presence of a family history of aSAH or UIA (familial UIAs)
or not (sporadic UIAs). Categorical variables of baseline characteristics were compared using the χ 2 test. Continuous variables of baseline characteristics were compared among groups
using the Mann-Whitney U test or the Student t test. A p value≤0.05 was considered statistically signiﬁcant. We analyzed
rupture rates per patient in all cohorts. In case of multiple
aneurysms, the largest aneurysm was used for analysis. In addition, we performed an aneurysm-based analysis, where all
UIAs were analyzed. Rupture rate was analyzed with a Cox
Neurology.org/N

proportional hazard regression model and adjusted for the
PHASES score5 and smoking. A 2-stage approach was used withrandom eﬀect for cohort, because beforehand we expected
heterogeneity as studies were performed in diﬀerent countries
that used diﬀerent treatment regimens, and a ﬁxed eﬀect for the
PHASES score and smoking. In the 2-stage IPD meta-analysis,
individual patient data from each study were analyzed separately
in order to obtain hazard ratios in each study, Next, these werecombined by a random eﬀect meta-analysis model. Proportional
hazard assumptions were checked using diagnostics based on
the scaled Schoenfeld residuals.12 Follow-up data for patients
started at time of UIA diagnosis and were censored at the timeof an aneurysm rupture, death, last follow-up assessment, or at
the time of surgical or endovascular aneurysm occlusion. Regarding the deﬁnition of ﬁrst-degree relatives, we performed ourprimary analysis on studies including parents, siblings, or children as aﬀected ﬁrst-degree relatives and our secondary analysis
on all studies including those in which ﬁrst-degree relatives aredeﬁned as only parents and children, but not siblings. A sensitivity analysis was performed with cohorts from European andJapanese populations.
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Role of the Funding Source
The funders of the study had no role in study design, datacollection, data analysis, data interpretation, writing of the report,
or the decision to submit for publication. All authors had fullaccess to all the data in the study; the corresponding author had
ﬁnal responsibility for the decision to submit for publication.
Data Availability
All study data are available on request.

Results
We found 8 studies that fulﬁlled the inclusion criteria,3,7-11,13,14
and 7 research groups provided us with their individual patientdata.3,7-11,13 All studies included patients with newly diagnosed
UIA visiting one of the study centers. We also found one additional cohort study on UIA, which did not report on family in
the PubMed search,15 but authors of this study provided unpublished data on family history for aSAH, and therefore we
could include this cohort as well. This prospective cohort study
consisted of data on patients with UIA collected between 1980
and 2017 from the IA database of Neurosurgery of Kuopio
University Hospital. This database included 1,181 patients with
1,653 UIA, of whom 248 had a positive family history. In total,
8 studies met our inclusion criteria (Figure 1). In these studies,
68 patients with polycystic kidney disease and 2 patients withmoyamoya disease were excluded. In 6 studies, ﬁrst-degree
relatives were deﬁned as parents, siblings, or children,3,7-10,15
while in 2 studies, only parents and children were referred to asﬁrst-degree relatives.11,13 The 8 cohorts are listed in Table 1
and the baseline characteristics of patients in all separate
cohorts in eTable 1 (available from Dryad: doi.org/10.5061/
dryad.3bk3j9kjz). Quality assessment of included cohort

studies by QUIPS tool is shown in eTable 2 (available from
Dryad: doi.org/10.5061/dryad.3bk3j9kjz). The 6 cohorts thatdeﬁned ﬁrst-degree relatives as parents, siblings, and children
totaled 2,297 patients with 3,089 UIA and 7,301 person-years
of follow-up. Baseline characteristics are shown in Table 2. The
mean age was 56 ± 12 years, 399 patients (17%) had a positive
family history for aSAH and UIA, and patients came from
Dutch (29%), Finnish (55%), and Japanese (15%) populations.
Patients with familial UIA were younger, less often had hypertension, and more often were smokers than patients withsporadic aneurysms. Familial cases more often had small UIA
and aneurysms were more often located at the middle cerebral
artery compared to sporadic cases. These described characteristics are all included in the PHASES score except smoking.6
Patients with familial UIA had a similar median PHASES scoreof 7.0 (range 0–19) as patients with sporadic UIA (7.0; range
0–21), but the mean PHASES score was lower in patients withfamilial UIA (7.1; SD 3.5) compared to sporadic UIA (7.7; SD
3.6). The mean follow-up time for patients with familial UIA
was 2.8 ± 4.5 years (median 1.0 [0–35] year) and for patientswith sporadic UIA 3.3 ± 6.2 years (median 1.1 [0–52] year).
Preventive neurosurgical or endovascular treatment duringfollow-up occurred in 47% of familial UIA (median 107 days)
and in 37% of sporadic UIA (median 121 days). Whenassessing the baseline aneurysm characteristics on aneurysm
level instead of patient level, results were similar (data notshown). Baseline characteristics of 9,511 patients with 11,647
UIA included in all cohorts including those in which ﬁrstdegree relatives are deﬁned as only parents and children, but
not siblings, are provided in eTable 3 (available from Dryad:
doi.org/10.5061/dryad.3bk3j9kjz).
In 53 patients, UIA rupture occurred. Of these 53 patients, 11
patients had multiple UIA, and in 51 of 53 patients (96%), theTable 1 Characteristics of Included Studies
Patients
withpositivefamilyhistory

Age, y,mean(range)Follow-up,
y, median(range)aSAHs
duringfollow-up,nCountry

Recruitment
periodPatients,
n

UIAs,
n

First-degree
relatives
includingsiblings

Finland

1956–1978

93

116

Yes

9

42 (15–61)

27.2 (1–52)

22

Lindgren et al.

Finland1977–2016

1,181

1,658

Yes

248

56 (16–85)

0.5 (0–23)

14

Mensing et al.3

The
Netherlands

1994–2016

474

633

Yes

62

56 (22–81)

0.8 (0–21)

10

Japan

2001–2004

5,702

6,675

No

327

63 (23–98)

1.0 (0–9)

111

Japan

2003–2012

1,561

1942

No

184

66 (25–100)

3.2 (0–11)

56

Wermer et al.

The
Netherlands

2002–2004

89

119

Yes

26

50 (20–69)

2.2 (1–15)

1

Molenberg et al.9

The
Netherlands

1998–2017

122

159

Yes

33

55 (33–77)

1 (0–2)0

Sonobe et al.10

Japan

2000–2004

349

419

Yes

31

62 (23–89)

3.2 (0–7)

6

Juvela et al.7aMorita et al.11
13

Murayama et al.
8

Abbreviations: aSAH = aneurysmal subarachnoid hemorrhage; UIA = unruptured intracranial aneurysm.
aUnpublished data.

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Table 2 Baseline Characteristics of Patients in Cohorts Defining First-Degree Relatives as Parents, Children, and Siblings
p Value

Pooled data

Familial

Sporadic

Total

Patients

399

1,898

2,297

Women

265 (66)

1,169 (62)1,434 (62)0.07

Age, y, mean (range)

51 (20–80)

57 (15–89)

56 (15–89)<0.01

Hypertensiona

139 (35)

818 (43)957 (42)<0.01

Ever smoker

212 (53)931 (49)

1,143 (50)0.138

34 (9)

242 (13)276 (12)0.018

Finnish257 (64)

1,018 (54)1,274 (55)

<0.01

Dutch

111 (28)563 (30)674 (29)

Japanese

31 (8)

318 (17)349 (15)122 (31)511 (27)633 (28)

0.227

<7.0

322 (81)

1,321 (70)1,643 (72)<0.01

7.0–9.943 (11)301 (16)344 (15)

10.0–19.9

30 (8)

220 (12)250 (11)

>20.0

4 (1)

56 (3)

60 (3)

Internal carotid artery

83 (21)413 (22)496 (22)

Middle cerebral artery

189 (47)783 (41)972 (42)

Anterior and posterior circulation

127 (32)702 (37)829 (36)

Aneurysm treatment during follow-upa

186 (47)702 (37)888 (38)<0.01

PHASES score, median (range); mean ± SD

7.0 (0–19); 7.1 ± 3.5

7.0 (0–21); 7.7 ± 3.6

7.0 (0–21); 7.6 ± 3.6

<0.01

a

Previous aSAH

aPopulationa

Multiple aneurysms
Aneurysm size, mma

Aneurysm location

a

0.065

Abbreviation: aSAH = aneurysmal subarachnoid hemorrhage.
Values are n (%) unless otherwise specified.
aStatistically significant difference.

largest aneurysm ruptured. Rupture of the largest aneurysm
occurred in 10 patients with familial UIA (rupture rate 0.89%/
person-year; 95% conﬁdence interval [CI] 0.45–1.59) and in
41 patients with sporadic UIA (0.66%/person-year; 95% CI
0.48–0.89). Characteristics of ruptured aneurysms are shownin Table 3. Characteristics of ruptured aneurysms in all cohorts including those in which ﬁrst-degree relatives are deﬁned as only parents and children but not siblings areprovided in eTable 4 (available from Dryad: doi.org/10.5061/
dryad.3bk3j9kjz).

European and Japanese populations provided similar results(eFigure 2, available from Dryad: doi.org/10.5061/dryad.
3bk3j9kjz). The unadjusted HR of patients with familial aneurysms compared to those with sporadic aneurysms in all cohorts
including those in which ﬁrst-degree relatives are deﬁned as only
parents and children, but not siblings, was 1.02 (95% CI
0.62–1.67) and 1.44 (95% CI 0.86–2.40, I2 = 0%; eFigures 3–5,
available from Dryad: doi.org/10.5061/dryad.3bk3j9kjz) after
adjustment for the PHASES score and smoking.

The unadjusted hazard rate (HR) of patients with familial
compared to those with sporadic aneurysms was 1.49 (95% CI
0.73–3.07) in cohorts deﬁning ﬁrst-degree relatives as parents,
children, and siblings. After adjustment for the PHASES scoreand smoking, the adjusted HR was 2.56 (95% CI 1.18–5.56, I2 =0%; Figure 2). In the aneurysm-based analysis, the results were
essentially the same (Figure 3). A sensitivity analysis with

Discussion

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In this individual patient data meta-analysis, we found a higher
risk of rupture for familial compared to sporadic UIA, with apoint estimate of a 2.5 times higher risk, and a range from a 1.2
to 5 times higher risk, when restricting our analysis to cohorts
referring to aﬀected ﬁrst-degree relatives as parents, siblings,
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Table 3 Characteristics of Ruptured Intracranial
Aneurysms in Cohorts Defining First-Degree
Relatives as Parents, Children, and Siblings per
Aneurysm
Familial

Sporadic

Total

10

43

53

10

41

41

0

2

2

Women

6 (60)

28 (65)34 (64)Age, y, mean (range)

58 (33–74)

52 (23–80)

53 (23–80)

Hypertension

1 (10)

23 (54)24 (45)Ever smoker

3 (30)

24 (56)27 (51)

Previous aSAH

3 (30)

20 (47)23 (43)Finnish7 (70)

29 (70)36 (70)Netherlands

3 (30)

8 (18)

11 (20)Japanese0

6 (13)

6 (10)0

11 (28)11 (21)<7.0

6 (60)

23 (54)29 (55)

7.0–9.9

1 (10)

10 (23)

11 (21)

10.0–19.9

3 (30)

9 (21)

12 (23)

>20.0

0

1 (2)

1 (2)

Internal carotid artery

1 (10)

11 (26)

12 (23)

Middle cerebral artery

5 (50)

15 (35)20 (38)Anterior circulation andposterior circulation

4 (40)

17 (40)21 (42)8.0 (2–16);
8.8 ± 4.7

9.0 (2–20);
9.5 ± 4.1

8.0 (2–20);
9.4 ± 4.2

Ruptured IA, n
Largest IA ruptureda

Not largest IA ruptured

Population

Multiple aneurysms
Aneurysm size at time ofdetection, mm

Aneurysm location

PHASES score, median(range); mean ± SD

Abbreviations: aSAH = aneurysmal subarachnoid hemorrhage; IA = intracranial aneurysm.
Values are n (%) unless otherwise specified.
a
In case of multiple aneurysms, the largest aneurysm was used for analysis.

and children in deﬁning a positive family history. We found aslightly but not statistically signiﬁcantly increased risk of aneurysm rupture for familial compared to sporadic UIA when
we analyzed all cohorts including those in which ﬁrst-degree
relatives are deﬁned as only parents and children, but not
siblings. When assessing the risk of rupture in UIA, the family
history that includes aﬀected siblings as ﬁrst-degree relatives
should be taken into account.
Our study showed a less strongly increased risk of rupture rate
in persons with a positive family history for aSAH/UIA thanreported in the previous Familial Intracranial Aneurysm study.2
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In this study, individuals diagnosed with an UIA were compared with historic controls14 and all patients had a positive
family history together with a positive history of smoking or
hypertension. The higher risk in this highly selective population
can be explained because this population already had a higher
risk of UIA rupture due to the presence of the additional risk
factors smoking and hypertension.2 Our ﬁndings are consistent
with a previous cohort study on the natural course of UIA inpatients with and without a positive family history.3 In ourstudy we found a statistically signiﬁcant higher risk of UIA
rupture for familial compared to sporadic patients, while in theprevious cohort study, a statistically nonsigniﬁcant eﬀect was
found, which can be explained by the smaller number of patients included. However, both our and the previous cohort
study3 found an increased risk for rupture in familial patients,
which is much lower than the 17 times higher risk found in the
Familial Intracranial Aneurysm study.2
Relatives of patients with familial aSAH have a higher incidence ofaSAH than relatives without such a family history.16 The higher
incidence of aSAH in relatives of patients with familial aSAH is inpart explained by a higher prevalence of UIA in these relatives.17
Our study shows that a higher rupture risk of familial UIA also
contributes to the higher incidence of aSAH in relatives with afamily history of aSAH. This higher incidence of familial aSAH islikely due to shared genes and/or common environmental risk
factors such as smoking and hypertension.1 A prospective cohort
study showed that smoking and hypertension were independent
additional risk factors for the presence of IAs in persons with apositive family history of aSAH.18 A population-based heritability
study assessed the contribution of genetic factors to aSAH cohorts and reported a 41% heritability,19 which is comparable withheritability estimates of other complex diseases.20 In a genomewide association study meta-analysis of intracranial aneurysms,
half of this heritability could already be explained.21
The patients with familial UIA analyzed in this study had alower PHASES score, thus indicating a lower risk of rupture
than patients with sporadic UIA. A lower PHASES score in
familial than in sporadic UIA was also found in a previous
study analyzing patients with familial and sporadic UIA.3
Numerous studies comparing the characteristics of familial
UIA with those of sporadic UIA have found that familial UIA
are more often located at the middle cerebral artery andrupture at a younger age.22 These ﬁndings may explain thelower PHASES score in these patients. Alternatively, selection
bias may have occurred, since the proportion of patients undergoing preventive treatment was higher in patients withfamilial than in patients with sporadic UIA. As a result, in thegroup of familial patients, the UIA with high PHASES scores
may have been preventively treated more often. Despite thelower PHASES score and the shorter period of follow-up,
both factors implying a lower risk of rupture, and the higher
proportion of familial aneurysms undergoing preventive
treatment, familial aneurysms still had a higher risk of rupture.
If proportions of patients undergoing preventive treatment
would have been similar for familial and sporadic UIA, theNeurology.org/N

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Figure 2 Hazard Ratio (HR) of the Rupture Rate in Patients With Familial Aneurysms Compared to Sporadic Aneurysms
Adjusted for the PHASES Score and Smoking in Cohorts Defining First-Degree Relatives as Parents, Children, andSiblings, Analyzing the Data per Patient

In the study by Wermer et al.,8 1 aneurysm ruptured in a patient with multiple aneurysms. The ruptured aneurysm was the smallest aneurysm andconsequently this rupture was not included in the analysis per patient. CI = confidence interval; UIA = unruptured intracranial aneurysm.

rupture risk of familial UIA might have even been higher than
we found.
A strength of our study is that we evaluated the association
between a positive family history and the rupture risk of UIA
using individual patient data from 8 prospective cohort studies,of which 6 cohorts deﬁned ﬁrst-degree relatives as parents,
children, and siblings, and by that were able to include a large
sample size with a large number of outcomes and person-years
of follow-up. This allowed us to estimate the risk with highprecision. In cohorts deﬁning ﬁrst-degree relatives as parents,
children, and siblings the subgroup of familial patients was 17%of the total group of patients with UIA and included 399 patients with familial UIA. All studies had a prospective design
and the quality was assessed with the QUIPS tool. A limitationof this study is that selection bias may have occurred due toinformative censoring (loss to follow-up) within each cohort
study. For example, in cohorts some patients were treated moreaggressively and many patients received treatment duringfollow-up. In treated patients, growth of the UIA may haveoccurred, which is associated with a higher risk of rupture,23
and consequently may have led to selection bias. Secondly, we

performed patient-level analysis and in patients with multiple
aneurysms we made the assumption that the largest aneurysms
ruptured. In previous studies, a greater likelihood of multiple
UIAs in patients with a positive family history is described.24 In
our study, familial cases did not have multiple IAs more often
than sporadic cases when rupture occurred. Performing an
additional analysis per aneurysm resulted in similar results, so
this assumption did not inﬂuence our analysis. Thirdly, data on
aspect ratio and irregular aneurysm shape were not available for
either of the cohort studies included. Aspect ratio and irregularaneurysm shape are also known factors for UIA rupture,25,26
and a higher prevalence of irregular aneurysms in familial cases
may contribute to the diﬀerence in rupture. However,according to a previous study, the prevalence of these risk
factors for aneurysm rupture was not higher in patients withaSAH compared to patients with sporadic aSAH.27 Fourth, in
our primary analysis, patients from Finnish populations wereoverrepresented (55%) compared to Dutch (29%) and Japanese (15%) populations. Across all populations a higher risk ofrupture for familial compared to sporadic UIA was found, withthe highest HR in the non-Finnish and non-Japanese cohort, so
our results are generalizable to all populations. Fifth, theFigure 3 Hazard Ratio of the Rupture Rate Adjusted for the PHASES Score and Smoking for Familial Aneurysms Comparedto Sporadic Aneurysms in Cohorts Defining First-Degree Relatives as Parents, Children, and Siblings, Analyzing theData per Aneurysm

CI = confidence interval; UIA = unruptured intracranial aneurysm.

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subgroup of familial patients was 17% of the total group ofpatients with UIA, ranging from 9% up to 29%. In previous
studies, the proportion of familial cases is around 10%.1 A
possible explanation for this higher proportion in studies included in our meta-analysis could be that many included patients were treated in tertiary referral centers and that patientswith a positive family history were referred to such centers
more often. Regardless of the proportion of familial patients for
all the diﬀerent cohorts, a higher rupture risk of familial aneurysms was found, suggesting that despite diﬀerences inproportion of familial cases, our results are generalizable. Sixth,
we had no data on conﬁrmed consanguinity for the diﬀerent
cohorts. Finally, the diﬀerence in deﬁnition for a positive family
history in all available studies resulted in systematic diﬀerencesin the rupture risk. In 6 studies, siblings were included in thedeﬁnition of ﬁrst-degree relatives,3,7-10 compared to 2 studies inwhich ﬁrst-degree were deﬁned as parents or children.11,13
Consequently, the increased rupture risk in familial cases may
have been diluted in these 2 studies because fewer patients are
categorized as patients with familial UIA and because siblings
with a positive family history are included in the group ofpatients with sporadic UIA. This eﬀect cannot be counteracted
by including both ﬁrst-degree relatives and second-degree relatives in this family group. In this way, siblings are included in
the familial group but also grandchildren and grandparents andthese family relatives are likely to dilute the rupture risk in thefamilial group as they are known to have a risk of aSAH
comparable to the general population.23 Alternatively, in ourdata we were also not able to re-analyze the 6 cohorts excluding
siblings in their deﬁnition as ﬁrst-degree relatives. Futurestudies should assess the extent to which siblings inﬂuence thehigher risk of rupture in familial cases.
We found a higher risk of rupture for familial compared tosporadic UIA, with a point estimate of a 2.5 times higher risk,
and a range from a 1.2 to 5 times higher risk when using adeﬁnition for a positive family history that includes aﬀectedparents, siblings, and children. On analyzing all cohorts including those in which ﬁrst-degree relatives are deﬁned as
only parents and children, but not siblings, a slightly but notstatistically signiﬁcantly increased risk of aneurysm rupture forfamilial compared to sporadic UIA was found. When assessing
the risk of rupture of UIAs in familial patients deﬁned as
individuals with at least 2 aﬀected ﬁrst-degree relatives including parents, children, and siblings, this higher risk should
be taken into account and a more aggressive treatment approach in these patients as compared to sporadic cases isjustiﬁed. To assess whether this increased rupture risk shouldinﬂuence the current screening strategy of families of patientswith familial UIA, an updated cost-eﬀectiveness analysis withthis increased rupture risk is needed.28-30 Further studies arealso needed on frequency of follow-up imaging in familial
UIA. Growth of UIA is associated with a higher risk of rupture.31 Thus, a higher frequency of follow-up imaging may
detect growth before rupture, and provide the opportunity fortargeted aggressive preventive treatment in familial UIA.
e2202

Neurology | Volume 97, Number 22 | November 30, 2021

Study Funding
Supported by the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON2015-08 ERASE. This project has received
funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 852173).
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
Publication History
Received by Neurology February 9, 2021. Accepted in ﬁnal form
September 20, 2021.

Appendix Authors
Name

LocationContribution

Charlotte C.M.
Zuurbier, MD

University Medical CenterUtrecht, the Netherlands

Literature search,statistical analysis,
writing of themanuscript

Liselore A.
Mensing, MD

University Medical CenterUtrecht, the Netherlands

Data collection, review
of manuscript

Marieke J.H.
Wermer, MD,
PhD

Leiden University Medical
Center, the Netherlands

Data collection, review
of manuscript

Seppo Juvela,
MD, PhD

University of Helsinki, Finland Data collection, review
of manuscript

Antti E. Lindgren, University of Eastern Finland, Data collection, review
MD, PhD
Kuopioof manuscript
Timo Koivisto,
MD, PhD

University of Eastern Finland, Data collection, review
Kuopioof manuscript

Juha E.
Jääskeläinen,
MD, PhD

University of Eastern Finland, Data collection, review
Kuopioof manuscript

Tomosato
Yamazaki, MD,
PhD

Department of
Neurosurgery, National
Hospital Organization, Mito
Medical Center, Japan

Data collection, review
of manuscript

Rob Molenberg,
BsC

Departments of
Neurosurgery, University
Medical Center Groningen,the Netherlands

Data collection, review
of manuscript

J. Marc C. van
Dijk, MD, PhD

Departments of
Neurosurgery, University
Medical Center Groningen,the Netherlands

Data collection, review
of manuscript

MaartenUyttenboogaart,
MD, PhD

Departments of Neurology
and Medical Imaging
Center, University Medical
Center Groningen, theNetherlands

Data collection, review
of manuscript

Marlien W.
Aalbers, MD

Departments of
Neurosurgery, University
Medical Center Groningen,the Netherlands

Data collection, review
of manuscript

Neurology.org/N

Copyright © 2021 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

8.

Appendix (continued)
Name

LocationContribution

9.
10.

Akio Morita, MD, University of Tokyo–Nippon
PhD
Medical School, Tokyo, Japan

Data collection, review
of manuscript

Shinjiro
Tominari, MD,
PhD

Department of Health
Informatics, School of Public
Health, Kyoto University,
Japan

Data collection, review
of manuscript

Hajime Arai, MD, Juntendo University Medical
PhD
School, Tokyo, Japan

Data collection, review
of manuscript

Kazuhiko
Nozaki, MD, PhD

Shiga University of Medical
Science, Japan

Data collection, review
of manuscript

Yuichi
Murayama, MD

Tokyo Jikei University Schoolof Medicine, Japan

Data collection, review
of manuscript

Toshihiro
Ishibashi, MD

Tokyo Jikei University Schoolof Medicine, Japan

Data collection, review
of manuscript

Hiroyuki Takao,
MD, PhD

Tokyo Jikei University Schoolof Medicine, Japan

Data collection, review
of manuscript

Gabriel J.E.
Rinkel, MD, PhD

University Medical CenterUtrecht, the Netherlands

Statistical analysis,
review of manuscript

Jacoba P.
Greving, PhD

University Medical CenterUtrecht, the Netherlands

Statistical analysis,
review of manuscript

21.

Ynte M. Ruigrok,
MD, PhD

University Medical CenterUtrecht, the Netherlands

Outline of study,
statistical analysis
review of manuscript

22.

11.
12.
13.
14.

15.

16.

17.

18.

19.
20.

23.

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Zuurbier C, Greving JP, Rinkel G, Ruigrok YM. Higher risk of intracranial aneurysms
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Molenberg R, Aalbers MW, Metzemaekers JDM, et al. Clinical relevance of short-term
follow-up of unruptured intracranial aneurysms. Neurosurg Focus. 2019;47(1):E7.
Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial
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UCAS Japan Investigators; Morita A, Kirino T, Hashi K, et al. The natural course of
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Grambsch TMT PM. Proportional hazards tests and diagnostics based on weighted
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Murayama Y, Takao H, Ishibashi T, et al. Risk analysis of unruptured intracranial
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Wiebers DO, Whisnant JP, Huston J III, et al. Unruptured intracranial aneurysms:
natural history, clinical outcome, and risks of surgical and endovascular treatment.
Lancet. 2003;362(9378):103-110.
Lindgren AE, Koivisto T, Bjorkman J, et al. Irregular shape of intracranial aneurysm
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Bor AS, Rinkel GJ, van Norden J, Wermer MJ. Long-term, serial screening for intracranial aneurysms in individuals with a family history of aneurysmal subarachnoid
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Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial
aneurysms, with emphasis on sex, age, comorbidity, country, and time period: asystematic review and meta-analysis. Lancet Neurol. 2011;10(7):626-636.
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Bakker MK, van der Spek RAA, van Rheenen W, et al. Genome-wide association studyof intracranial aneurysms identiﬁes 17 risk loci and genetic overlap with clinical risk
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Slot EMH, Rinkel GJE, Algra A, Ruigrok YM. Patient and aneurysm characteristics infamilial intracranial aneurysms: a systematic review and meta-analysis. PLoS One.
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degree relatives of patients with subarachnoid haemorrhage. BMJ. 1995;311(7000):
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Ruigrok YM, Rinkel GJ, Algra A, Raaymakers TW, Van Gijn J. Characteristics ofintracranial aneurysms in patients with familial subarachnoid hemorrhage. Neurology.
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Kleinloog R, de Mul N, Verweij BH, Post JA, Rinkel GJE, Ruigrok YM. Risk factors for
intracranial aneurysm rupture: a systematic review. Neurosurgery. 2018;82(4):431-440.
Tominari S, Morita A, Ishibashi T, et al. Prediction model for 3-year rupture risk ofunruptured cerebral aneurysms in Japanese patients. Ann Neurol. 2015;77(6):1050-1059.
Mensing LA, Rinkel GJ, Vlak MH, van der Schaaf IC, Ruigrok YM. Diﬀerence inaneurysm characteristics between patients with familial and sporadic aneurysmal
subarachnoid haemorrhage. PLoS One. 2016;11(6):e0154281.
Takao H, Nojo T, Ohtomo K. Screening for familial intracranial aneurysms: decisionand cost-eﬀectiveness analysis. Acad Radiol. 2008;15(4):462-471.
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intracranial aneurysms: a cost-eﬀectiveness analysis. Neurology. 2010;74(21):1671-1679.
Hopmans EM, Ruigrok YM, Bor AS, Rinkel GJ, Koﬃjberg H. A cost-eﬀectivenessanalysis of screening for intracranial aneurysms in persons with one ﬁrst-degree relative with subarachnoid haemorrhage. Eur Stroke J. 2016;1(4):320-329.
Brinjikji W, Zhu YQ, Lanzino G, et al. Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2016;37(4):615-620.

Neurology | Volume 97, Number 22 | November 30, 2021

Copyright © 2021 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

e2203

diagnostics
ArticlePreoperative Evaluation and Surgical Simulation for
Osteochondritis Dissecans of the Elbow Using
Three-Dimensional MRI-CT Image Fusion Images
Sho Kohyama 1, *, Yasumasa Nishiura 2 , Yuki Hara 3 , Takeshi Ogawa 4 , Akira Ikumi 5 , Eriko Okano 3 ,Yasukazu Totoki 3 , Yuichi Yoshii 6 and Masashi Yamazaki 3
1
2

3

4

5

6



Citation: Kohyama, S.; Nishiura, Y.;
Hara, Y.; Ogawa, T.; Ikumi, A.; Okano,E.; Totoki, Y.; Yoshii, Y.; Yamazaki, M.
Preoperative Evaluation and Surgical
Simulation for Osteochondritis
Dissecans of the Elbow Using
Three-Dimensional MRI-CT Image
Fusion Images. Diagnostics 2021, 11,2337. https://doi.org/10.3390/
diagnostics11122337
Academic Editor: Ayman El-Baz
Received: 1 November 2021
Accepted: 9 December 2021
Published: 11 December 2021

Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in*

Department of Orthopaedic Surgery, Kikkoman General Hospital, Noda 278-0005, Japan
Tsuchiura Clinical Education and Training Center, Department of Orthopaedic Surgery,Tsukuba University Hospital, Tsuchiura 300-8585, Japan; ynishi@md.tsukuba.ac.jp
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan;
yukihara@md.tsukuba.ac.jp (Y.H.); eokano@tsukuba-seikei.jp (E.O.); yasutotoki@tsukuba-seikei.jp (Y.T.);
masashiy@md.tsukuba.ac.jp (M.Y.)
Mito Medical Center, Department of Orthopaedic Surgery, National Hospital Organization,
Ibaraki 311-3193, Japan; ogawat@md.tsukuba.ac.jp
Mito Medical Education and Training Center, Department of Orthopaedic Surgery, Tsukuba University
Hospital, Mito 310-0015, Japan; bravelupus193@gmail.com
Department of Orthopaedic Surgery, Tokyo Medical University Ibaraki Medical Center,
Tokyo 300-0395, Japan; yyoshii@tokyo-med.ac.jp
Correspondence: sho_kohyama_1025@yahoo.co.jp

Abstract: We used our novel three-dimensional magnetic resonance imaging-computed tomography
fusion images (3D MRI-CT fusion images; MCFIs) for detailed preoperative lesion evaluation andsurgical simulation in osteochondritis dissecans (OCD) of the elbow. Herein, we introduce ourprocedure and report the findings of the assessment of its utility. We enrolled 16 men (mean age:
14.0 years) and performed preoperative MRI using 7 kg axial traction with a 3-Tesla imager and
CT. Three-dimensional-MRI models of the humerus and articular cartilage and a 3D-CT model ofthe humerus were constructed. We created MCFIs using both models. We validated the findings
obtained from the MCFIs and intraoperative findings using the following items: articular cartilage
fissures and defects, articular surface deformities, vertical and horizontal lesion diameters, theInternational Cartilage Repair Society (ICRS) classification, and surgical procedures. The MCFIs
accurately reproduced the lesions and correctly matched the ICRS classification in 93.5% of cases.
Surgery was performed as simulated in all cases. Preoperatively measured lesion diameters exhibitedno significant differences compared to the intraoperative measurements. MCFIs were useful inthe evaluation of OCD lesions and detailed preoperative surgical simulation through accurate
reproduction of 3D structural details of the lesions.
Keywords: osteochondritis dissecans; elbow; magnetic resonance imaging; tomography; X-ray
computed; imaging; three-dimensional; image interpretation; computer-assisted; simulation

published maps and institutional affiliations.

1. Introduction
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Osteochondritis dissecans of the elbow (OCD) is a rare intra-articular osteochondrallesion that is associated with overhead throwing sports [1–5]. The subchondral bone andarticular cartilage of the humeral capitellum are affected, and several possible causes,
including repetitive microtrauma and genetic factors, are implicated [3,4,6,7]. Although
the stability and size of the lesion are considered important factors impacting lesion
severity [6,8–10], no single imaging modality can adequately predict lesion severity [11–17],
thereby presenting a challenge to elbow surgeons. A recent study by Pu et al. concluded
that a combination of radiography, computed tomography (CT), and magnetic resonanceDiagnostics 2021, 11, 2337. https://doi.org/10.3390/diagnostics11122337

https://www.mdpi.com/journal/diagnostics

Diagnostics 2021, 11, 2337

2 of 16

imaging (MRI) can most accurately determine OCD lesion stability by compensating forthe respective flaws of the individual modalities [18]. However, at present, surgery is the
only means of conclusively confirming the severity of OCD lesions using the classification
proposed by the International Cartilage Repair Society (ICRS) [19–23].
Magnetic resonance arthrography (MRA) is another alternative modality for theevaluation of OCD lesions. As MRA involves the injection of contrast medium into the joint,
the joint capsule distends, and visualization and differentiation of intra-articular structures
can be enhanced [24,25]. Therefore, MRA could better depict articular cartilage. However,
MRA is an invasive imaging modality and may cause pain, anxiety, and complications
such as allergic reactions and infections [26,27]. As the majority of patients with OCD are
children, it is important to minimize the use of invasive procedures. In addition, MRA alone
cannot accurately evaluate the conditions of subchondral bone lesions such as sclerosis.
To address this difficulty, we developed and recently reported a method to create 3D
MRI-CT fusion images (MCFIs) of the OCD lesions [28]. This computer-aided technique
combines the advantages of CT and MRI and provides a minimally invasive, accurate preoperative evaluation of OCD lesions. In addition, detailed surgical simulation is possible,
which could aid surgeons in intraoperative decision making.
There are various surgical options to effectively manage OCD lesions. In severe caseswith unstable lesions, articular surface reconstruction must be considered. As the articularcartilage and subchondral lesion both require reconstruction, osteochondral autografttransplantation is a viable option. Generally, osteochondral autografts are harvested either
from the knee using the osteochondral autograft transplantation system (OATS) or fromthe rib [1,6,11,29]. When the lesion is small but unstable, or the lesion is stable but resistant
to conservative therapy, drilling of the lesion is an effective option. Drilling accelerates
the union of the lesion and surrounding bone tissue by promoting bleeding from the bonemarrow by puncturing the subchondral bone. If articular free bodies are present, theirremoval must be considered. Alternative surgical options include abrasion chondroplasty,
microfracture, and in situ fixation of the lesion [1]. In this article, we introduce the use of
MCFIs as a method of OCD lesion evaluation and surgical simulation for OCD lesions andreport the findings of the assessment of the clinical applicability of the computer-aided
technique. We aimed to assess the accuracy of MCFIs in evaluating OCD lesion severity
and in facilitating surgical simulation.
2. Materials and Methods
2.1. Patient Selection
The institutional review board of the University of Tsukuba Hospital approved thisstudy (Study Number: H29-58). Twenty-eight patients visited our facility and were diagnosed with OCD between July 2017 and March 2021. Among them, 16 patients whose
lesions were evaluated using MCFIs were enrolled in this study. These patients subsequently underwent surgery. We obtained written informed consent from each patient. It
was clearly stated that we would only use MCFIs for lesion evaluation and to decide thetreatment strategy. All patients were boys (mean age: 14.0 ± 1.0 years, range: 12–16 years),
and the right side was affected in fifteen patients, while the left side was affected in one
patient. The average body weight of the patients was 56.9 (48.0–65.0) kg.
2.2. Obtaining the MR and CT Images
A 3-Tesla imager (MAGNETOM© Verio, Siemens, Munich, Germany) was used for
MRI. We followed the procedures we published in a previous article on imaging sequenceand settings, position of patients, and application of axial traction (7 kg) [28]. Axial traction
widens the joint space and helps better visualize an outline of the articular cartilage of thehumeral capitellum [28,30] (Figure 1).

iagnostics 2021, 11, x FOR PEER REVIEW
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3 of 16

Figure 1. Acquisition of magnetic resonance images with axial traction. Axial traction (7 kg) was
Figure1. Acquisition of magnetic resonance images with axial traction. Axial tract
applied to the elbow to better visualize the articular cartilage of the humeral capitellum.
applied to the elbow to better visualize the articular cartilage of the humeral capitellu

We used a 320-row scanner (Aquilion ONETM , Toshiba, Tokyo, Japan) for CT, andimageswereobtainedwith a 0.5 scanner
mm slice thickness.
We didnot apply
axial traction
during Japan)
TM, Toshiba,
Weused
a 320-row(Aquilion
ONE
Tokyo,CT because CT data of the whole joint were not necessary for the procedure.

images were obtained with a 0.5 mm slice thickness. We did not apply axial
2.3.CT
Creationof 3D Models
ing
becauseCT data of the whole joint were not necessary for the proced

Using the obtained data, we created 3D MRI models of the humerus and articularcartilage and a 3D CT model of the humerus. The Materialise Mimics Innovation Suite
2.3.
Creation of 3D Models
version 20 (Materialise©, Leuven, Belgium) was used for this procedure. We referred to
the MRsignalthe
intensityof the articularcartilage
and humerus
in eachcase forofUsing
obtaineddata, wecreated
3D MRI
modelsofcreation
the humerus
3D MRI models. As the participants in this study were skeletally immature, the growth
cartilage
and a 3D CT model of the humerus. The Materialise Mimics Inno
cartilage was present in some cases. First, we set a threshold for the MR signal intensity for©, Leuven, Belgium) was used for this procedure. W
version20tissue.
(Materialiseeach target
According to
the set threshold, we selected the pixels that corresponded
to thetargettissue.
The thresholdwasarticularroughly setcartilage
automaticallyadjusted manuallytheMRsignalintensityof theandandhumerusin each case fo
while simultaneously referring to the monitor to ensure correct selection of the target tissue.
3D
MRI models. As the participants in this study were skeletally immatureThis procedure is called segmentation, which is crucial for creating better images. Whilecartilagewaspresentcartilage,
in some
we setcartilagea thresholdfor theasMR sig
segmenting
the articular
wecases.
definedFirst,
the articular
fissures (ACFs)
thelow-intensity
lines
withinthearticular
cartilage,
which
penetrateorareperpendicularfor each target tissue. According to the set threshold, we selected the pixe
to the articular surface [12,15,31–33]. Articular surface deformity (ASD) was defined as
spondedto the target tissue. The threshold was roughly set automaticallyirregularities in the outline of the articular cartilage [12,15] (Figure 2). The segmented
manuallywhile
simultaneously
referringto the monitor
to ensurese
structures, aswell asthe ACFs and ASDs
were reconstructed
and reproduced
intocorrect
3D
models.tissue.
Similarly,
we created
3D CT ismodelsof thehumerus. During
the procedure,
the for cr
targetThis
procedure
calledsegmentation,
which
is crucial
subchondral bone was considered segmented when the discontinuity of the subchondral
images. While segmenting the articular cartilage, we defined the articularbone to the floor was observed in all three planes: axial, sagittal, and coronal. We manuallysures
as3Dthelow-intensity
lines within
articular
cartilage,
created(ACFs)
a separate
modelof segmented subchondral
bonethe(SSB)
and displayed
it in red which
color
for
bettervisualization(Figure3).
are perpendicular to the articular surface [12,15,31–33]. Articular surface defo

was defined as irregularities in the outline of the articular cartilage [12,15] (Fsegmented structures, as well as the ACFs and ASDs were reconstructed andinto 3D models. Similarly, we created 3D CT models of the humerus. Durindure, the subchondral bone was considered segmented when the discontinuichondral bone to the floor was observed in all three planes: axial, sagittal,
We manually created a separate 3D model of segmented subchondral bone (played it in red color for better visualization (Figure 3).

Diagnostics 2021, 11, x FOR PEER REVIEW
Diagnostics
2021,2021,
11, 11,x FOR
Diagnostics
2337 PEER REVIEW

4 of 16

Figure 2. Creation of three-dimensional (3D) magnetic resonance imaging (MRI) m
correspond
toofthehumerus
andarticular
cartilage
which
wereimaging
independently
Figure2. Creation
three-dimensional(3D)themagnetic
resonance
imaging(MRI) models.
The pixels
Figure2. Creationof three-dimensional(3D)
magnetic
resonance(MRI) mscorrespondto thethe color
articular
cartilage
which
were
independently
selected
based
the set threshold.
Theandblue
represents
thehumerus,andtheyellowcolor repcorrespond
tohumerus
the humerus
and thearticular
cartilage
which
were
independentlysonularthe setthreshold.
The
blue
color
represents
thehumerus,andtheyellow
color
represents
thecartilage.
Green,
orangelines arereferencecorrespondthe setthreshold.
The redblueandcolor
represents
the thehumerus,andlines
the yellow
color toreps
articular cartilage. Green, red and orange lines are the reference lines correspond to sagittal, axial andcoronal,respectively.
(a) Coronalview.
(b) areAxial(c) Sagittal
view. Arrow:ularcartilage.
Green, redand orange
lines
theview.
referencelines correspondto sacoronal, respectively. (a) Coronal view. (b) Axial view. (c) Sagittal view. Arrow: articular cartilage
fissures.
Arrowheads:
articular
surfacedeformities.
(d)Reconstructed
3D
image
coronal,respectively.
Coronalview.(d)(b)
Axial view.
(c) Sagittal
view.andArrow:ofa
fissures.
Arrowheads:
articular(a)surfacedeformities.
Reconstructed
3D imageof the humerus
articular
cartilage.
fissures.
Arrowheads:
articular surface deformities. (d) Reconstructed 3D image ofarticular
cartilage.
articular cartilage.

Figure3. Creationof a three-dimensional(3D)
computed
tomography(CT) mode
Figure3. Creationof a three-dimensional(3D) computed
tomography(CT) modelof the humerus.
The
same
procedureas usedmagnetic
resonance
imaging
wasused. The
segmented
subchondralThe
same
procedure
as
used
with
magnetic
resonance
imaging
was
used.
The
segm
Figure3. Creation
ofwitha three-dimensional(3D)
computed
tomography
(CT)
model
bone
(SSB)
was
definedasthelesionwhose
continuity
to
the
floor
was
lost
in
all
three
planes.
The
dral
bone
(SSB)
was
definedasthelesionwhose
continuity
to
the
floor
was
lost
in
The same procedure as used with magnetic resonance imaging was used. The segm
separate SSB model was created manually and is displayed in red for better visualization. Green,
The boneseparateSSB
wasmanually
and is displayedin reddral(SSB)
wasmodeldefinedas createdthe lesion
whose continuity
to the floor
wasforlostbetinred and orange lines are the reference lines correspond to sagittal, axial and coronal, respectively.
Green,
red andorangelines
arecreatedthe referencelinesandcorrespondto sagittal,
andThe
separate
SSB
model
was
manually
is displayedin redaxial
for bett(a) Coronal view. (b) Axial view. (c) Sagittal view. (d) Reconstructed 3D image of the humerus.

tively. red(a) Coronalview.
(b)areAxial
view. (c) Sagittal
view. (d)toReconstructedGreen,and orange
lines
the referencelines correspondsagittal, axial 3D
andmerus.
tively. (a) Coronal view. (b) Axial view. (c) Sagittal view. (d) Reconstructed 3D i
merus.

2.4. Fusion of Created 3D Models
2.4. Fusionof Created
3D Models
We usedthe 3-matic
software version 12 (Materialise ©, Belgium) to fu©

Diagnostics 2021, 11, 2337

5 of 16

2.4. Fusion of Created 3D Models
We used the 3-matic software version 12 (Materialise©, Belgium) to fuse the 3Dmodels. First, we exported the created 3D models from the Materialise Mimics to the
3-matic. We then roughly fused both the 3D MRI and 3D CT models of the humerus using
a function called N-point registration. This function enables two separate 3D models tobe superimposed using an arbitrary number of corresponding points. In our procedure,
we registered four corresponding points that are easy to recognize and belong to different
planes, as reported in a previous study [28] (Figure 4a). Second, we used a function called
global registration to fine-tune the position of the superimposed 3D models (Figure 4b).
Using this function, the positions of the aligned 3D models can be automatically corrected
depending on their shapes. Throughout the procedures, the 3D MRI model of the articularcartilage was set to move together with the 3D MRI model of the humerus in order tomaintain the positional relationship between the structures. Finally, we completed thefusion of the 3D CT model of the humerus and the 3D MRI model of the articular cartilage
by hiding the 3D MRI model of the humerus (Figure 4c). We termed this fusion model
MCFI. The first author, an elbow surgeon with 14 years of clinical experience, created all
MCFIs. The average interval between the MCFI creation and surgery was 26 (5–70) days.

Figure 4. Procedures to create magnetic resonance imaging-computed tomography fusion images(MCFIs). The three-dimensional (3D) magnetic resonance imaging (MRI) model of the articular cartilage and 3D computed tomography (CT) model of the humerus were fused. (a) N-point registrationof the 3D MRI and 3D CT models of the humerus for rough superimposition. The marked points
Figure4. Procedures
createmagnetic resonanceimaging-computed
tomography
fusion images(MCFIs). The
inthis figure
are the totwoprotuberancesof the lateralepicondyle. (b)A superimposed
3D modelthree-dimensional(3D) (anteroposterior
magnetic resonanceimaging
theMRI
articular
cartilage
and 3D computed
after
global registrationview).
Here, (MRI)
the 3Dmodel
CT andof3D
modelsof the humerus
tomography (CT) model of the humerus were fused. (a) N-point registration of the 3D MRI and 3D CT models
andthe 3D MRI model of the articular cartilage are shown in gray, blue, and yellow, respectively.
of the humerus for rough superimposition. The marked points in this figure are the two protuberances of the(c) A complete MCFI (anteroposterior view). The 3D MRI model of the humerus was hidden. This
lateral epicondyle. (b) A superimposed 3D model after global registration (anteroposterior view). Here, the 3D
completed
CT and 3D the
MRIcreation
models ofof MCFIs.
the humerus and the 3D MRI model of the articular cartilage are shown in gray, blue
and yellow, respectively. (c) A complete MCFI (anteroposterior view). The 3D MRI model of the humerus was
2.5. Lesion Evaluation Using MCFIs
hidden. This completed the creation of MCFIs.

The first author evaluated the OCD lesion immediately after image creation basedon the MCFI. The evaluation was particularly focused on the findings of the articularcartilage and subchondral bone, such as the presence of ACFs, articular cartilage defect(ACD), or ASD (Figure 5a), and whether the subchondral bone was segmented or not. We
recorded the findings of each case. In order to differentiate ASDs from ACDs, deformities
were recorded as either protrusions or flattening of the articular surface. The positional
relationship between the ACF and the SSB was evaluated by adjusting the transparencyof the articular cartilage (Figure 5b). The articular surface of the humeral capitellum wasconsidered elliptical in the anteroposterior view of the MCFI and divided into four areas,
areas 1 to 4, clockwise from the anteromedial area (Figure 5c); we thereby recorded thelocation of each finding. Based on the findings reproduced in the MCFI, the vertical andhorizontal diameters of the lesion were also measured (Figure 5d).

Diagnostics 2021, 11, 2337
Diagnostics 2021, 11, x FOR PEER REVIEW

6 of 16
6 of 16

Figure5.5.Magnetic
Magneticresonanceresonanceimaging-computed
imaging-computedtomography
tomographyfusion
fusionimages
images(MCFIs).
(MCFIs).Here,
Here,thethe3D
3D
Figure
CT
model
of
the
humerus
and
the
3D
MRI
model
of
the
articular
cartilage
are
shown
in
gray
and
CT model of the humerus and the 3D MRI model of the articular cartilage are shown in gray andyellow, respectively. (a) Anteroposterior view of the lesion (enlarged). The articular cartilage fisyellow, respectively. (a) Anteroposterior view of the lesion (enlarged). The articular cartilage fissures
sures (ACFs) can be observed (arrows). The articular surface is protruded and not smooth, particu(ACFs) can be observed (arrows). The articular surface is protruded and not smooth, particularly inlarly in the area surrounded by the fissure. (b) Anteroposterior view of the lesion with a transparent
the area surrounded by the fissure. (b) Anteroposterior view of the lesion with a transparent articular
articular cartilage (enlarged). The segmented subchondral bone is shown in red and is located becartilage
The segmented
subchondralbone weis shown
in redand isaslocatedbeneathneath the(enlarged).
fissure (arrows).
Considering
all the findings,
predicted
the lesion
unstable.
(c) Onthefissure(arrows).
Consideringallthefindings,
wepredicted
thelesionasunstable.
(c)
On locathe
the anteroposterior view of the MCFI, we divided the surface into four areas and recorded theanteroposteriorview ofdividedin
thesurfaceTheintofour areas
and recorded
the location
tion of each finding.
(d)the
TheMCFI,
lesionwe
is marked
orange.
verticaland horizontal
diametersof themeasured.
determined
theinsizeof theThelesioncomprehensively
basedon the findings
oflesioneach were
finding.
(d) TheWe
lesionis marked
orange.
verticaland horizontal
diametersof theofthearticular
cartilage
andsubchondrallesion.
(e)Simulated
image
of
the
lesionWe
lesion were measured. We determined the size of the lesion comprehensively based on resection.
the findings
separatedthearea
selectedinFigure5d
from
theoriginal
three-dimensional
magnetic
resonanceof the articular cartilage and subchondral lesion. (e) Simulated image of the lesion resection. We
imaging articular cartilage model and hid it to simulate lesion selection.
separated the area selected in Figure 5d from the original three-dimensional magnetic resonanceimaging articular cartilage model and hid it to simulate lesion selection.

OCD lesions are defined as unstable when the lesion is displaced or dislocated, andsurface as
is deformed[12,14–16,32–34].
definedorunstable
OCD
lethereby
articular
OCDthelesions
are defined
unstable when
the lesion is We
displaceddislocated,andsions inthe
MCFIs
as thosewith isACFs
and/or [12,14–16,32–34].
ASDs, along with We
the SSB
underneath.
therebyarticular
surfacedeformed
definedunstable OCD
on theMCFI,
the and/or
ICRS classificationwas
independently
lesionsBasedin MCFIs
ascreated
those with
ACFs
ASDs, along[20]withthepredicted
SSB underneath.
andBasedcomprehensively
by MCFI,two elbow
surgeons(assessors
2 andwho had independently
13 and 12 years
on the createdthe ICRS
classification[20]
was3predicted
experience,by
respectively).
The surgeons
were requested
to predictthe ICRS
clasof clinicalandcomprehensively
two elbow surgeons(assessors
2 and 3 who
had 13 and12 yearsleast 3 daysrespectively).
preceding theThe
operation.
Theweresurgeons
were cognizant
theICRS
ICRS
ofsification
clinical atexperience,
surgeons
requested
to predictof
theclassificationleast
3 daysprecedingoperation.
Therecords.
surgeons
were
theclassificationatandwereblindedto the thepatients’
medicalThe
twocognizant
assessors ofparticICRS
classification
were blinded
tosurgeries
the patients’
medicalinrecords.
The two assessors
ipatedas assistant andsurgeons
in several
performed
this study.
participated as assistant surgeons in several surgeries performed in this study.
2.6. Surgical Simulation
2.6. Surgical Simulation
We used the 3-matic software version 12 (Materialise©, Leuven, Belgium) for the surWeused the The
3-matic
version 12
Leuven,gical simulation.
first software
author performedall(Materialise©,surgical simulationsin Belgium)
this study.for thesurgicalsimulation.
The
first
authorperformed
allsurgicalsimulations
instudy.
Articular surface reconstruction by costal osteochondral autograft thistransplantation
costalisosteochondral
autografttransplantation[19]
is our firstsurface
choicereconstruction
when the OCDby
lesionunstable and its
maximum
diameter exceeds[19] Articular
is10our
first
choicewhentheOCD
lesionisunstableanditsmaximum
diameterexceeds
mm; thus, we simulated the surgical procedure. First, we decided on the resection area
10mm; thus,towethe surgicalprocedure.
First, weon the resection
area
accordingthesimulated
reproduced
ACFs andASDs (Figure5d).decided
After selecting
the resection
accordingtothereproduced
ACFs
and
ASDs
(Figure5d).
Afterselectingtheresectionarea,
area, we separated the area from the original 3D model of the articular cartilage and crewe separated the area from the original 3D model of the articular cartilage and created anated an independent 3D model. This enabled us to freely
7 of 16
ing the lesion resection (Figure 5e). Second, we simulated
model of the average-sized costal osteochondral autograf
independent 3D model. This enabled us to freely hide the resection area, simulating the6). Wecreatedmodel
based
ontransplantation.
the size oftheactualDiagnostics 2021, 11, x FOR PEER REVIEW
7 of 1
lesionresection(Figure 5e).thisSecond,we simulated
autograft
A 3D
model
of the average-sized costal osteochondral autograft was created in advance (Figure 6). We
ously operated cases. This autograft model can be freely
created this model based on the size of the actual autograft harvested from previously
operatedcases. Thismodel can be freely placed
withinthe MCFI,
we
simulatedtheautograft
position,anddepthof andthetranspated
an independent
3D
model. This direction,
enabled us to freely
hide
the resection
area,
simulatDiagnostics 2021, 11, 2337

simulated the position, direction, and depth of the transplantation (Figure 7).

ing the lesion resection (Figure 5e). Second, we simulated autograft transplantation. A 3D
model of the average-sized costal osteochondral autograft was created in advance (Figur
6). We created this model based on the size of the actual autograft harvested from previ
ously operated cases. This autograft model can be freely placed within the MCFI, and w
simulated the position, direction, and depth of the transplantation (Figure 7).

Figure 6. A three-dimensional model of an average-sized costal osteochondral autograft. (a) Antero

Figure
6. A view.
three-dimensional
anDistal
average-sizedcostalosteochondral(a) Anteropos-view ofposterior(b) Lateralmodelview.of(c)view. (d)Proximalview.autograft.
(e) Anteroposterior
teriorview. (b)Lateralview. (c) Distalautograft.
view. (d) Proximalview.
(e) Anteroposteriorof osteochondrala harvested
harvestedcostalosteochondral(f) Lateralview
of a harvestedview
costalauto
costalgraft.osteochondral autograft. (f) Lateral view of a harvested costal osteochondral autograft.

Figure 6. A three-dimensional model of an average-sized costal
posterior view. (b) Lateral view. (c) Distal view. (d) Proximal
harvested costal osteochondral autograft. (f) Lateral view of a h
graft.

Figure7.7.Simulation
Simulation
costalosteochondral
autografttransplantation.
CT model oFigureof of
costalosteochondral
autografttransplantation.
Here, Here,the 3Dthe
CT3D
model
the
humerusareshown
showniningray
grayandandyellow,
yellow, respecofthehumerusand
andthethe3D
3DMRI
MRImodelmodel ofof thethe articular
articular cartilage
cartilage aretively. The three-dimensionalmodelof thecostalosteochondralon the mag
respectively.
The three-dimensionalmodelof thecostalosteochondralautograft
autograftwas
was placed
placed on
netic
resonance
imaging-computed
tomography
fusionimage
to tosimulatethemagnetic
resonance
imaging-computed
tomography
fusionimage
simulatethe
theposition,
position,direction
and depth
ofdepththe transplant.
(a) Anteroposteriorview.view.
(b) Lateralview.
(c)(c)
Oblique
direction,andof the transplant.
(a) Anteroposterior(b) Lateralview.
Obliqueview.
view.(d) Distoproximalview.
(e)Proximodistal
view.
(d) Distoproximal view. (e) Proximodistal view.

We simulated drilling when the OCD lesion was ICRS class IV and small, or whe
the lesion was stable, articular surface reconstruction was not necessary, and the lesio
did not respond to conservative therapy. Generally, subchondral OCD lesions withchronic history have a sclerotic component [1]. It is essential to penetrate the subchondraDiagnostics 2021, 11, 2337

R PEER REVIEW

8 of 16

We simulated drilling when the OCD lesion was ICRS class IV and small, or when
the lesion was stable, articular surface reconstruction was not necessary, and the lesion did
not respond to conservative therapy. Generally, subchondral OCD lesions with a chronic
history have a sclerotic component [1]. It is essential to penetrate the subchondral sclerosis
to promote bone healing. Therefore, as the first step of the simulation of drilling, we
manually selected the sclerotic region and highlighted it with a different color for better
visualization. Second, we simulated the entry point, direction, and depth of drilling. When
8 of 16
the lesion is stable and the articular surface is intact, it is important to avoid iatrogenic
articular cartilage damage. Therefore, we simulated posteroanterior drilling for those cases(Figure 8).

Figure 8. Surgical simulation of drilling. Here, the 3D CT model of the humerus and the 3D MRI model of the articular
Figure8. Surgical simulation of drilling. Here, the 3D CT model of the humerus and the 3D MRI
cartilage are shown in gray and yellow, respectively. (a) An anteroposterior view of the magnetic resonance imagingmodelof the articular cartilage are shown in gray and yellow, respectively. (a) An anteroposterior
computed tomography fusion image (MCFI) of case 1. The articular surface was smooth with only a small fissure inview
the magnetic
resonance
imaging-computed
tomography
image(MCFI)of case
1. Thearea 1of(arrow).
(b) MCFI witha transparent
articular cartilage. The
subchondralfusion
lesion withsclerosis
is shown
in red.
articular
surfacewas (enlarged
smooth anteroposterior
with only a small
fissuretheinarticulararea 1 cartilage).
(arrow).We(b)simulated
MCFI witha transparent(c) Simulationof drillingview without
to penetratethespots withcartilage.
sclerosis andThecystsubchondral
formation. The entry
point
is shown
as a redspot, andin
thered.
target(c)pointis shown inof
green.
articular
lesionwithsclerosis
is shown
Simulation
drilling(d) Posteroanteriorview. To avoidview
iatrogenic
articular
cartilage
damage,we simulated
drilling
in these thecases.spots(enlarged
anteroposterior
without
thearticular
cartilage).
Weposteroanterior
simulated topenetrate
The green circle with a red spot represents the entry point for drilling. (e) Lateral view. We simulated the direction andwithsclerosis and cyst formation. The entry point is shown as a red spot, and the target point is
depth of drilling.
shown in green. (d) Posteroanterior view. To avoid iatrogenic articular cartilage damage, we simulated posteroanterior drillingin theseEvaluation
cases. The
green
circle with a red spot represents the entry
2.7. Intraoperativeof ICRSClassification
point for drilling. (e) Lateral
We simulated
the direction
and depth
drilling.
Weview.
evaluated
all OCD lesions
intraoperatively
either ofunder
direct observation or

using arthroscopic examination to determine the ICRS classification [20]. According to thedefinition, class I and II lesions are stable, while class III and IV lesions are unstable.

2.7. Intraoperative Evaluation of ICRS Classification

2.8.OCD
Evaluationof MCFIs
We evaluated alllesions
intraoperatively either under direct observation or usWe
compared
the predicted
the actual intraoperative
findings fortheing arthroscopic examination to determine
thevalues
ICRSwithclassification[20]. According
to theACFs, ACDs, ASDs, vertical and horizontal lesion diameters, and ICRS classification. The
definition, class I and
II lesions rate
are between
stable,each
while
class
III andfrom
IV lesions
corresponding
findingdetermined
the MCFIareand unstable.
those determined
intraoperatively were evaluated. We calculated the corresponding rate as follows: (number of cases in which the findings determined by the MCFI corresponded to the actual
2.8. Evaluation of MCFIs
intraoperative findings)/(total number of cases) [17].
We compared the Each
predicted
valueswith the actual
intraoperative
findings fordeterthe
finding andthe corresponding
ICRS classification
were intraoperatively
mined
by
both
visualinspection
andpalpation.
In
class
III
lesionsthat
underwent
articular
ACFs, ACDs, ASDs, vertical and horizontal lesion diameters, and ICRS classification. The

corresponding rate between each finding determined from the MCFI and those determined intraoperatively were evaluated. We calculated the corresponding rate as follows:(number of cases in which the findings determined by the MCFI corresponded to the ac-

Diagnostics 2021, 11, 2337

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reconstruction, the diameter of the resected lesion was recorded. In class IV lesions, thediameters of the articular cartilage defect were recorded. In 9 of 16 cases, where the firstauthor conducted the surgery, another elbow surgeon with 23 years of clinical experienceevaluated the intraoperative findings. This surgeon did not evaluate the lesion using the
MCFI. The primary surgeon assessed the intraoperative findings in the remaining sevencases. Among the seven cases, six cases were assessed by an elbow surgeon with 23 yearsof clinical experience and one case by an elbow surgeon with 34 years of clinical experience.
We compared the predicted and intraoperatively measured vertical and horizontal lesion
diameters using the Mann–Whitney U test, which was selected because of the small sample
size. Statistical significance was set at p < 0.05.
3. Results
3.1. Lesion Evaluation Using MCFIs
Tables 1–3 show the findings predicted by the MCFIs and intraoperatively determinedfindings for the ACFs, ACDs, and ASDs, respectively. The reproducibility of each finding
was accurate in the MCFI, except for one case, in which the lesion was detached at the timeof surgery, resulting in a corresponding rate of 93.8%. Table 4 depicts the measurementsof the diameters of the lesions. The median values of the vertical diameter measured
preoperatively and intraoperatively were 14.8 and 14.0 mm, respectively; there was no
significant difference (p = 0.78). The median values of the horizontal diameter measured
preoperatively and intraoperatively were 13.1 and 12.0 mm, respectively; there was no significant difference (p = 0.14). Figure 9 shows the intraoperative findings and corresponding
MCFIs for representative cases.
3.2. ICRS Classifications
Table 5 presents the predicted and intraoperative ICRS classifications. The MCFI
resulted in a corresponding rate of 93.8% for both examiners. This is because there was one
case in which the lesion was detached at the time of surgery (case 15). We predicted thiscase as ICRS class III; however, the case was confirmed as class IV intraoperatively.
Table 1. Validation of the three-dimensional magnetic resonance imaging-computed tomography
fusion images (3D MRI-CT fusion images; MCFIs) against intraoperative findings: articular cartilage
fissures (ACFs). The reproducibility of the ACFs by the MCFIs was accurate in all cases.
Cases
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Localization of Articular Cartilage Fissures (If Present)
Findings from 3D MRI-CT Fusion Images

Intraoperative Findings

Area 1
Areas 1, 2, 3, and 4
None
Area 2
Areas 1, 2, and 3
None
Area 2
Areas 2 and 3
Areas 1, 3, and 4
Areas 1 and 4
Area 1
Areas 1, 2, 3, and 4
Areas 2 and 3
Areas 2 and 3
Areas 1, 2, 3, and 4
Areas 2 and 3

Area 1
Areas 1, 2, 3, and 4
None
Area 2
Areas 1, 2, and 3
None
Area 2
Areas 2 and 3
Areas 1, 3, and 4
Areas 1 and 4
Area 1
Areas 1, 2, 3, and 4
Areas 2 and 3
Areas 2 and 3
Areas 1, 2, 3, and 4
Areas 2 and 3

Diagnostics 2021, 11, 2337

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Table 2. Validation of the magnetic resonance imaging-computed tomography fusion image (MCFI)
against intraoperative findings: articular cartilage defects (ACDs). The reproducibility of the ACDs
by MCFIs was accurate except for case 15, whose capitellar osteochondritis lesion was detached fromthe floor at the time of surgery.
Cases

Localization of Articular Cartilage Defects (If Present)
Findings from 3D MRI-CT Fusion Images

Intraoperative Findings

1
2
3
4
5
6
7
8
9
10
11
12
13
14

None
None
Areas 2 and 3
Areas 2 and 3
None
Area 2
Areas 2 and 3
None
None
Area 1
Area 1
None
None
None

15

None

16

None

None
None
Areas 2 and 3
Areas 2 and 3
None
Area 2
Areas 2 and 3
None
None
Area 1
Area 1
None
None
None
Areas 1, 2, 3, and 4
Lesion detached
None

Table 3. Validation of the magnetic resonance imaging-computed tomography fusion images (MCFIs)
against intraoperative findings: articular surface deformities (ASDs). The MCFIs precisely reproduced
the ASDs in all cases except for case 15. The lesion appeared to be protruded on the MCFI but was
detached from the floor at the time of surgery.
Cases
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Localization of Articular Surface Deformities (If Present)
Findings from 3D MRI-CT Fusion Images

Intraoperative Findings

None
Areas 2 and 3 (protrusion)
None
None
Areas 2 and 3 (protrusion)
None
None
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 1, 2, 3, and 4 (flattening)
Areas 1, 2, 3, and 4 (flattening)
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 1, 2, 3, and 4 (protrusion)
Areas 2 and 3 (protrusion)

None
Areas 2 and 3 (protrusion)
None
None
Areas 2 and 3 (protrusion)
None
None
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 1, 2, 3, and 4 (flattening)
Areas 1, 2, 3, and 4 (flattening)
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 2 and 3 (protrusion)
Areas 1, 2, 3, and 4 (lesion detached)
Areas 2 and 3 (protrusion)

3.3. Surgical Simulation
We simulated drilling in four cases and osteochondral autograft transplantation in
eleven cases. One case was indicated to perform free-body removal alone. All surgeries
were conducted based on the simulations. We performed drilling for cases 1, 3, 11, and 15,
free-body removal for cases 6 and 15, and costal osteochondral autograft transplantation
for the remaining cases. Based on the MCFI, case 15 was indicated for articular surface
reconstruction, but the patient did not consent to the surgical procedure and opted for the
drilling procedure. We conducted all surgeries as simulated in all cases. Figure 10 shows
the intraoperative findings and corresponding surgical simulation for representative cases.

Diagnostics 2021, 11, 2337

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Table 4. Validation of the magnetic resonance imaging-computed tomography fusion images (MCFIs) against intraoperative
findings: vertical and horizontal lesion diameters. The reproducibility of the vertical and horizontal diameters of the lesions
was accurate in the MCFI. In case 1, there were no articular cartilage defects or articular surface deformity. Therefore, it was
impossible to measure the lesion size.
Cases

Vertical Diameters (mm)MCFI

Horizontal Diameters (mm)Intraoperative Findings

1
2
19.7
18
3
7.9
8
4
13.6
12
5
16.1
14
021, 11, x FOR PEER REVIEW
6
11.6
10
7
12.1
15
8
18.7
17
9
19.4
19
10
16.9
16
11
19.5
20
Median12
16
18
13value
11.6
11
14.8
14.0
14
14.8
14
(interqu15(12.1–16.9)13.5(11.5–17.5) 13
16artile
12.5
12
14.8
14.0
Median value
range)(12.1–16.9)(11.5–17.5)(interquartile
range)
p-valuep-value
0.78 0.78

MDFIs

12.3
11.5
14.5
15.6
8.8
14.3
12.5
14.1
14.7
16
12
7.8
13.1 11.8(11.8–14.3)14.2
13.1
13.1
(11.8–14.3)

Intraoperative Findings
12
11
14
15
811 of 16
13
12
14
12
15
12
8
12.0
10
(10–14) 1110
12.0(10–14)0.14 0.14

9. resonance
Magnetic imaging-computed
resonance imaging-computed
tomography
fusion andimages(MCFIs) andcorreFigure 9.Figure
Magnetic
tomography fusion
images (MCFIs)
corresponding
intraoperative
sponding
intraoperative
findings.
The
MCFIs
are
shown
in
the
left
panels,andthecorresponding
findings. The MCFIs are shown in the left panels, and the corresponding intraoperative findings are shown in the right
intraoperative
shown inand
thetheright
Here,the articular
3D CT modelof aretheshown
humerusandandpanels. Here,the 3D CT findings
model of are
the humerus
3D panels.
MRI modelof thecartilagein gray
the 3D MRI(a)modelof Thethe articularcartilage
are showngray andyellow,
respectively.
Caseyellow, respectively.
Case 12.
MCFI accurately
reproduced
theinarticular
cartilage
fissures(ACFs) in (a)areas
1, 2,12.
3, andThe
MCFI
reproduced
thearticular
cartilage fissures(ACFs)
in(SSB)areaswas
1, 2,
3, and4 (ar4 (arrows).
Thelesionaccurately
was predicted
as unstablebecausethe segmented
subchondralbone
present
underneathrows).
The
lesion surface
was predicted
as unstablebecausethe
thelesion
segmented
subchondral
boneintraoperatively.
(SSB) wasthe ACFs,
and thearticular
was protruded.
As predicted,
was classified
as unstable
present
underneath
the
ACFs,
and
the
articular
surfacewas
protruded.
As
predicted,
thelesionwaswas(b) Case 8. The MCFI correctly reproduced the protrusion of the articular surface in areas 2 and 3 (arrows). The lesion
classified
asunstable
intraoperatively.
(b)
Case
8.
The
MCFI
correctly
reproduced
theprotrusionofThepredicted as unstable owing to the presence of the articular surface deformity (ASD) and SSB underneath the ACF.
thearticular
surface inasareas
2 and(c)3Case(arrows).
lesionwasreproduced
predicted theas ACFunstableowing
to thelesion was
unstableon palpation,
predicted.
16. TheThe
MCFI
correctly
and ASDin areas
2 andpresenceof wasthe predicted
articular as
surfacedeformity(ASD)
and SSB
theclassified
ACF. The
waswas3 (arrows).
The lesion
unstablebased on thesefindings
andunderneath
intraoperatively
thatlesion
the lesion
palpation,
as predicted.
(c) Case
16. TheMCFI1,correctly
reproduced
the ACFASD asunstable.unstable(d) Case on
9. TheMCFI correctly
reproduced
the ACFsin areas
3, and 4 (arrows).
The lesion
wasandpredicted
in
areas
2
and
3
(arrows).
The
lesionwaspredicted
asunstable
based
on
these
findings
andinunstable based on the presence of the SSB underneath the ACF, as well as ASD. The lesion was unstable intraoperatively
traoperatively
classifiedthat
thelesionwasunstable.
(d)
Case
9.
The
MCFI
correctly
reproduced
theon palpation, as predicted. (e) Case 5. The MCFI correctly reproduced the ACF in areas 2 and 3 (arrows). The lesion was
in areas
1, 3,ofand(arrows).
Theandlesionwasunderneathpredictedandas unstableon thepresenceofpredictedACFs
as unstablebecausethe 4presenceof ACFthe SSB
ASD. The based
lesion wasclassified
as unstable
the SSB underneath the ACF, as well as ASD. The lesion was unstable intraoperatively on palpation,
on palpation.
as predicted. (e) Case 5. The MCFI correctly reproduced the ACF in areas 2 and 3 (arrows). The
lesion was predicted as unstable because of the presence of ACF and the SSB underneath and ASD.
The lesion was classified as unstable on palpation.

3.2. ICRS Classifications
Table 5 presents the predicted and intraoperative ICRS classifications. The MCFI resulted in a corresponding rate of 93.8% for both examiners. This is because there was one

5
6
7
Diagnostics 2021, 11, 2337
8
9
10
11
12
13
14
15
16

III
III
III
IV
IV
IV
IV
IV
IV
12 of 16
III
III
III
III
III
III
IV
IV
IV
Table 5. Comparison of the International Cartilage Repair Society (ICRS) classification predictedIVIV findings. The intraoperativeIVby examiners
and the actual intraoperative
ICRS classification accuIIIcorresponded to the magnetic resonanceIII
III fusion image-based
ratelyimaging-computed tomography
predictions
15. The match rate was 93.8%.
III in all cases except for caseIII
III
III
III
III
MCFI
Intraoperative Findings
Cases
III
IV
Assessor 2 III
Assessor 3
III 1
III
III II
II
II

2
III
III
III
3
IV
IV
IV
3.3. Surgical Simulation 4
IV
IV
IV
5
III
III
III
We simulated drillingin four casesand osteochondral
autograft transplantation
in
6
IV
IV
IV
eleven cases. One case wasremoval alone. All
7 indicated toIVperform free-bodyIVIV surgeries
8 the simulations.
III We performed
III drilling for cases 1,
III 3, 11, andwere conducted based on
9
III
III
III
15, free-body removal for10cases 6 and 15,
autograft transplantaIV and costal osteochondral
IV
IV
11 Based on the
IVMCFI, case 15 IVIVtion for the remaining cases.
was indicated for articularsurface
12
III
III
III
reconstruction, but the patient did not consent to the surgical procedure and opted for the
13
III
III
III
drilling procedure. We conducted
all surgeries
as simulated
in all cases. Figure
14
III
III
III 10 shows
15
III
III simulation for representativeIV
the intraoperative findings
and corresponding
surgical
16
III
III
III

cases.

Figure10. Surgicalsimulation
the resonancemagneticimaging-computed
resonance imaging-computed
tomography
fuFigure
10. Surgicalsimulation
using theusing
magnetic
tomography fusion
images and corresponding
intraoperative
findings. The surgicalsimulations areshown inthe surgicalleft panel,simulations
and corresponding
intraoperative
sion images
and corresponding
intraoperative
findings.
The
are shownin thefindings
are shown
the right panel. intraoperative
Costal osteochondral
autografttransplantation
was simulated
in all presented
left panel,andincorresponding
findings
are shownin the rightpanel. Costal
ostecases.
All surgeries
were conducted
as simulated.
the 3D CTof the humerus
3D MRI modelof theochondralautografttransplantation
wasHere,simulatedin modelall presented
cases.and
Allthesurgeries
were conarticularcartilage
are
shown
in
gray
and
yellow,
respectively.
(a)
Case
12.
Reconstructionofthearticular
surfaceandducted as simulated. Here, the 3D CT model of the humerus and the 3D MRI model of the articulateral
wall
of
the
capitellum
wasnecessary
for
this
case.
(b)
Case
8.
Reconstructionofthearticular
surfaceandlateralwall
lar cartilage are shown in gray and yellow, respectively. (a) Case 12. Reconstruction of the articularof the capitellum was necessary for this case. (c) Case 16. One costal osteochondral autograft transplantation proceduresurface and lateral wall of the capitellum was necessary for this case. (b) Case 8. Reconstruction of
was sufficient to cover the articular surface defect. (d) Case 9. The predicted lesion was large; therefore, we simulated
the articular surface and lateral wall of the capitellum was necessary for this case. (c) Case 16. One
reconstruction of the articular surface by two costal osteochondral autografts to cover as much surface as possible. (e) Case
costal osteochondral autograft transplantation procedure was sufficient to cover the articular sur5. Two costal osteochondral autografts were necessary to reconstruct the large, predicted lesion.
face defect. (d) Case 9. The predicted lesion was large; therefore, we simulated reconstruction of
the articular surface by two costal osteochondral autografts to cover as much surface as possible.
(e) Case 5. Two costal osteochondral autografts were necessary to reconstruct the large, predictedlesion.

4. Discussion

Diagnostics 2021, 11, 2337

13 of 16

4. Discussion
OCD lesion evaluation using MCFIs is a minimally invasive technique that enables
prediction of lesion severity with high accuracy [28]. In developing this technique, we
intended to maximize the advantages and compensate for the shortcomings of MRI and
CT. The application of axial traction widens the joint space of the radio-capitellar joint
and improves visualization of the articular cartilage outline of the humeral capitellum
with minimum pain and discomfort [30,31], making the creation of accurate 3D modelsof the articular cartilage possible, and enabling images with a slice thickness of 0.4 mm tobe obtained using a 3D sequence. We used a 7 kg traction weight according to previous
studies [30,31]. There are no studies clarifying the ideal traction weight for elbow MRI
in a skeletally immature population. Ideally, the traction weight must be decided on thebasis of the body weight, size, and muscle development of the patient. Therefore, in the
future, we will attempt to determine the ideal traction weight to lower discomfort during
application of traction during MRI as much as possible.
The assessor can evaluate the 3D structure of the lesion from arbitrary angles using the
MCFI. Additionally, it is possible to precisely obtain a positional relationship between thearticular cartilage and the subchondral bone by adjusting the transparency of the articularcartilage, which is not visible to surgeons even during surgery. We accurately predicted
the lesion severity in 15 out of 16 cases (93.8% accuracy). Although we predicted the case
15 lesion as ICRS class III, the lesion was diagnosed as class IV intraoperatively. This may be
due to the high instability of the lesion, which could have caused the lesion to be displaced
from the floor sometime between image acquisition and surgery. However, regarding
the detection of unstable lesions, our technique achieved 100% accuracy. Diagnosing thestability of the lesion is extremely important in determining treatment strategies for patientswith OCD [1,6,20]. Therefore, we believe that our technique is highly effective.
We simulated the surgical procedure in all cases and conducted surgery per thesimulations in each case, which is another advantage of the MCFI. Among the surgicalprocedures we performed, articular surface reconstruction using a costal osteochondral
autograft is the most complex surgery. Poor reconstruction of the articular surface leads
to osteoarthritis in the future. However, owing to the anatomical feature of the elbow
joint [35], articular surface reconstruction referring only to intraoperative findings can bechallenging in some cases. Detailed surgical planning using MCFIs has the potential tominimize the process of intraoperative decision making by surgeons.
We selected costal osteochondral autograft transplantation for articular surface reconstruction because we are accustomed to the procedure; however, some surgeons prefer toharvest the osteochondral autograft from the knee using the OATS technique. Our surgicalsimulation technique is also applicable to surgeries that incorporate the OATS technique.
When simulating the procedure, it is necessary to prepare a 3D model of a cylindrical
autograft resembling the autograft harvested using the OATS technique instead of the 3Dmodel of the costal osteochondral autograft. By preparing cylindrical autografts of various
diameters, surgeons can precisely simulate the location and direction of the transplant, as
well as the number of autografts necessary for the procedure (Figure 11).
A limitation of this technique is that the segmentation of the articular cartilage istime-consuming and technically demanding. Precise segmentation of the articular cartilage
is the most crucial part of the procedure, but it must be partly executed manually. No
available software can automatically and completely segment the articular cartilage, andit takes approximately 2 h per case to complete the procedure. Because we rely on thecreated MCFIs to determine the treatment strategies, it takes several weeks from theimage acquisition to the surgery. This delay may lead to the deterioration of the OCD
lesion in some cases, such as case 15, in which we misdiagnosed the ICRS classification.
Therefore, we need to simplify the procedure and minimize the waiting period to avoid
such consequences. In this study, evaluation of intraoperative findings was subjectively
performed by each surgeon. We hope to achieve objective superposition of the MCFI andthe surgical field in the future. Another limitation is that the number of cases was limited.

Diagnostics 2021, 11, 2337

14 of 16

The accumulation of cases takes time as OCD is a rare condition. We will continue to workon the current study to further evaluate the consistency between intraoperative findings
and MCFIs. Increasing the number of cases could lead to the development of softwarethat can automatically create the MCFI for OCD patients. We also aim to conduct more
cs 2021, 11, x FOR PEER REVIEW
quantitative evaluations of OCD lesions, including assessment of mild cases to predict the
progression of lesion severity, in the future. In addition, we hope to apply this techniqueto other joints, with the aim of assisting surgeons in various fields treating intra-articularosteochondral lesions.

Figure 11. Sample simulation of articular surface reconstru
transplantation system technique with three-dimensional (3case 16. We created two 3D models of cylindrical autografts
3D models were positioned to cover the lesion to simulate ttransplant. Here, the 3D CT model of the humerus, the 3D M
5. Conclusions
3DHerein,modelsof cylindrical
autografts
aresimulation
shownusing
in gray,
we introduced
OCD lesion evaluationand surgical
MCFIs yell
ofposterior
OCD, a novel view.
tool developedby us. This computer-aided
techniquethe accurate(b) Distoproximal
view.
(c) made
Lateralview. (d)evaluation of 3D structural details of the articular cartilage and subchondral bone possible,

Figure 11. Sample simulation of articular surface reconstruction using the osteochondral autografttransplantation system technique with three-dimensional (3D) models of cylindrical autografts forcase 16. We created two 3D models of cylindrical autografts with diameters of 5 mm and 7 mm. The
3D models were positioned to cover the lesion to simulate the location, direction, and depth of thetransplant. Here, the 3D CT model of the humerus, the 3D MRI model of the articular cartilage and 3Dmodels of cylindrical autografts are shown in gray, yellow and green, respectively. (a) Anteroposteriorview. (b) Distoproximal view. (c) Lateral view. (d) Proximodistal view.

as well as lesion stability, without surgical intervention. A detailed surgical simulation ispotentially useful for minimizing intraoperative decision making.

A limitation of this technique is that the segme
time-consumingandA patent for the 3D MRI-CT
fusiontechnicallyimage construction demanding.
technique described inPrecise
thisarticle was applied for in Japan; 3D model generation method, 3D model generation device,lage is the most crucial part of the procedure, but it mu
and 3D model-generation program. Application No. 2018-066054, pending approval.
available software can automatically and completely
it takes approximately 2 h per case to complete thecreated MCFIs to determine the treatment strategies, it
acquisition to the surgery. This delay may lead to the
6. Patents

Diagnostics 2021, 11, 2337

15 of 16

Author Contributions: Conceptualization, S.K.; Methodology, S.K., Y.N. and Y.H.; Validation, S.K.;
Formal Analysis, S.K.; Investigation, S.K., Y.N., Y.H., T.O., A.I., E.O. and Y.T.; Data Curation, S.K.,
A.I., E.O. and Y.T.; Writing—Original Draft Preparation, S.K.; Writing—Review and Editing, Y.N.,
Y.H., T.O., A.I., E.O., Y.T., Y.Y. and M.Y.; Visualization, S.K.; Supervision, Y.N. and M.Y.; Project
Administration, S.K., Y.N., Y.H. and M.Y. All authors have read and agreed to the published versionof the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Institutional Review Board of the University of Tsukuba
Hospital (Study Number: H29-58, approved 21 July 2017).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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Stroke
CLINICAL AND POPULATION SCIENCES

Sex Difference and Rupture Rate of Intracranial
Aneurysms: An Individual Patient Data
Meta-Analysis
Charlotte C.M. Zuurbier , MD, PhD; Rob Molenberg , BSc; Liselore A. Mensing, MD; Marieke J.H. Wermer , MD, PhD;
Seppo Juvela , MD, PhD; Antti E. Lindgren , MD, PhD; Juha E. Jääskeläinen, MD, PhD; Timo Koivisto, MD, PhD;
Tomosato Yamazaki, MD, PhD; Maarten Uyttenboogaart , MD, PhD; J. Marc C. van Dijk , MD, PhD;
Marlien W. Aalbers, MD; Akio Morita , MD, PhD; Shinjiro Tominari, MD, PhD; Hajime Arai, MD, PhD;
Kazuhiko Nozaki , MD, PhD; Yuichi Murayama , MD; Toshihiro Ishibashi , MD; Hiroyuki Takao , MD, PhD;
Renato Gondar , MD; Philippe Bijlenga, MD, PhD; Gabriel J.E. Rinkel, MD, PhD; Jacoba P. Greving , PhD;
Ynte M. Ruigrok , MD, PhD
BACKGROUND AND PURPOSE: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but
female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related
risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in
rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture.
METHODS: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual
patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional
hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier
Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal
subarachnoid hemorrhage.
RESULTS: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured
intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/personyears [95% CI, 0.89–1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58–0.94]). Women were older (61.9
versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24%versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio
was 1.43 (95% CI, 1.07–1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02–1.90).
CONCLUSIONS: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differencesin patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining
the higher risk of aneurysmal rupture in women.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.
Key Words: intracranial aneurysm ◼ prevalence ◼ risk factor ◼ sex ◼ subarachnoid hemorrhage

Correspondence to: Ynte M. Ruigrok, MD, PhD, UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, room G03-228, University Medical CenterUtrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Email ij.m.ruigrok@umcutrecht.nl
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.035187.
For Sources of Funding and Disclosures, see page 369.
© 2022 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under theterms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Stroke is available at www.ahajournals.org/journal/str

362   February 2022

Stroke. 2022;53:362–369. DOI: 10.1161/STROKEAHA.121.035187

Zuurbier et alaSAH
aneurysmal subarachnoid hemorrhage
ISUIA	International Study of Unruptured Intracranial Aneurysms Investigators
PHASES	Population, Hypertension, Age, Size of
Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site ofAneurysm
UIA
unruptured intracranial aneurysm

Approximately 3% of the general population has anunruptured intracranial aneurysm (UIA).1 Ruptureof an intracranial aneurysm results in aneurysmal
subarachnoid hemorrhage (aSAH), a subtype of stroke
which carries a high morbidity and case fatality.2 UIA andaSAH occur more often in women than in men with overall 65% of the patients being women.1,3
In the decision whether to treat UIA with neurosurgical orendovascular treatment to prevent future aSAH, the risk ofrupture and the risk of complications of preventive treatment
have to be balanced.4 The 5-year risk of rupture of UIA canbe assessed using the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), whichtakes into account several patient- and aneurysm-related
factors associated with rupture including geographic location, hypertension, age, history of aSAH, aneurysm size, andlocation.5 The PHASES score is based on a pooled analysis
of individual patient data from prospective cohort studies
on rupture rates of UIAs and risk factors for rupture. In thispooled analysis, women had a higher risk of rupture, but in
multivariable analysis, female sex was not an independentrisk factor. Another meta-analysis including both retrospective and prospective studies reported a statistically significantly higher rupture risk in women compared to men, butwhether female sex was an independent risk factor could
not be investigated because multivariable analysis was notpossible due to lack of individual patient data.6 The higher
risk of UIA rupture in women may therefore be explainedby a higher prevalence of patient- or aneurysm-related risk
factors for UIA rupture in women.
We performed a pooled analysis of individual patient
data from prospective cohort studies to assess if sex is arisk factor for intracranial aneurysm rupture independent
from other risk factors for rupture including the PHASES
score, smoking, and a positive family history for aSAH.

aneurysm(s) OR cerebral aneurysm(s) AND (risk of rupture
OR aneurysm rupture OR risk factors OR rupture OR unruptured OR subarachnoid hemorrhage) AND (follow up OR
natural history OR natural course)” (Figure S1). In addition,
we checked the reference list of all relevant publications forfurther eligible studies. We performed our systematic review
and meta-analysis according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses recommendations
and Meta-Analysis of Observational Studies in Epidemiology
guidelines.7,8 We included studies that (1) used a prospective
study design; (2) included at least 50 patients with UIA; and(3) studied the rupture rate of UIA and risk factors for aneurysm rupture. There was no language restriction other than therequirement of an abstract in English. When multiple publications reported on the same study population, the most recent
publication was used. One author (C.C.M.Z.) performed theliterature search, checked the titles and abstracts for studies
meeting the inclusion criteria. Next, full-text copies of eligible
studies were reviewed.
In total, 2613 articles were screened (Figure 1). For theeligible studies meeting the inclusion criteria, we approached
the research groups that performed these studies asking if
they could provide us with their individual patient data. Only
cohorts with available individual patient-level data were
included in our meta-analysis. We found twelve studies that
fulfilled the inclusion criteria,9–19 and 9 research groups provided us with their individual patient data.12–19 One of these
population-based cohort studies on UIA, did not report on
family history,20 but its authors could provide data including data on family history for aSAH for a selection of cases.
These were data on patients with UIA collected between
1980 and 2017 from the IA database of Neurosurgery of
Kuopio University Hospital and included 1181 patients with
1653 UIA, of whom 693 were women. The 9 cohorts arelisted in Table 1, and the baseline characteristics of patientsin all separate cohorts are listed in Table S1. Quality assessment of included cohort studies by QUIPS tool is shown in
Table S2.

Data Extraction

We performed a systematic search of the Pubmed and Embase
database to retrieve all studies on rupture risk published up
to December 1, 2020. We used the keywords “(intracranial

Data requested for each patient of the different included studies were the following: age, sex, history of aSAH, smoking
status, positive family history for aSAH, hypertension status,
number of aneurysms, maximum diameter of aneurysms, aneurysm location. These data were collected at baseline only andnot at later time points. These data were recorded individually
and also summarized in the PHASES score which includes dataon the risk factors geographic location, hypertension, age, history of aSAH, aneurysm size, and location.5 Data requested foreach patient during follow-up were the following: occurrenceof rupture, date of rupture, data of a surgical or endovascular intervention, date of death, date of last follow-up assessment, and whether a patient was lost to follow-up. A smoker
was defined as a former or current smoker, and person withhypertension as a systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg or use of antihypertensive
drugs. Individuals with a positive family history were defined as
individuals with at least 2 affected first-degree relatives withaSAH whether or not in combination of first-degree relatives
with UIA. The location of the aneurysm was classified as the

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February 2022   363

METHODS
Search Strategy and Selection Criteria

CLINICAL AND POPULATIONSCIENCES

Nonstandard Abbreviations and Acronyms

Sex Difference and Risk of Aneurysmal RuptureSex Difference and Risk of Aneurysmal Rupture

CLINICAL AND POPULATIONSCIENCES

Zuurbier et al

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

Missing data were imputed for smoking, hypertension, andfamily history of aSAH within each cohort using the linear

regression method (multivariable analyses). To assign values
for these missing data, we performed multiple imputation creating 10 imputation datasets using all relevant prognostic factors and outcome. A sensitivity analysis was done by excluding
participants for whom data were missing. In one study only
data on current smoking was available but no data on former
smoking, and therefore, in our analysis data on current smoking was considered as current or former smoking.17 Fifty-seven
Japanese patients were included both in the cohort of Morita
et al14 and of Murayama et al,15 whereas 11 patients were
included in both the cohort of Mensing et al13 and of Wermer
et al.16 In the pooled analysis, these patients were removed
from one of these cohorts. Categorical variables of baseline364   February 2022

Stroke. 2022;53:362–369. DOI: 10.1161/STROKEAHA.121.035187

internal carotid artery, posterior communicating artery, anterior
cerebral arteries (including the anterior cerebral artery, anterior
communicating artery, and pericallosal artery), middle cerebral
artery, or posterior circulation (including the vertebral artery,basilar artery, cerebellar arteries, and posterior cerebral artery).
Patients with polycystic kidney disease and moyamoya disease
were excluded. We predefined the primary end point as the rupture of UIA.

Statistical Approach

Zuurbier et al

Sex Difference and Risk of Aneurysmal Rupture

Study

Country

Recruitment
periodNo. ofpatients

No. ofUIA

Women (%)

Mean age inyears (range)

Median follow-up
in years (range)

No. of UIA rupture
during follow-up

Juvela et al12Finland

1956–1978

140

179

75 (54)42 (15–61)

21.0 (0–52)

33

Lindgren et al20

Finland1977–2016

1181

1658

693 (59)

56 (16–85)

0.5 (0–23)

14

Mensing at al13

the Netherlands

1994–2016

474

633

320 (68)

56 (22–81)

0.8 (0–21)

10Morita et alJapan

2001–2004

5702

6675

3779 (66)

63 (23–98)

1.0 (0–9)

111

Murayama et al15Japan

2003–2012

1561

1942

1039 (67)66 (25–100)

3.2 (0–11)

56

Wermer et al16

the Netherlands

2002–2004

93

125

70 (75)51 (20–69)

2.2 (1–15)

1

Molenberg et al

the Netherlands

1998–2017

198

257

145 (73)56 (28–79)

1 (0.3–2)

1

Sonobe et al18Japan

2000–2004

368

441

236 (64)

62 (23–89)

3.2 (0–7)

6

Gondar et al19

Switzerland

2006–2014

291

367

225 (86)

55 (20–91)

2.5 (0–13)

3

14

17

UIA indicates unruptured intracranial aneurysm.

We pooled individual patient data from 9940 patientswith 12 193 UIAs and 24 357 person-years follow-up
using data from nine prospective cohort studies.12–20
Studies were at low and moderate risk of bias. Baselinecharacteristics of patients are shown in Table 2. Dataon patient characteristics was almost complete except
for smoking which was available in 9705/9940 (98%),
for hypertension which was available in 9853/9940(99%), and for family history of aSAH which wasavailable in 9794/9940 (99%). Information on outcome
measure was complete for all patients. The mean age
was 61±12 years, 6555 patients (66%) were women,
and patients came from Dutch (8%), Finnish (12%),
Japanese (77%), and Swiss (4%) populations. Women
were older (61.9 versus 59.5 years), less often smokers(20% versus 44%), and more often had internal carotid
artery aneurysms (24% versus 17%) and larger aneurysms (≥7 mm, 24% versus 23%) than men. There weremore women than men in cohorts from Japan (67%versus 33%), the Netherlands (70% versus 30%), Switzerland (77% versus 23%), whereas this difference wasless pronounced in the cohort from Finland (58% versus 42%). The median PHASES score was the same inwomen (7.0 [range, 0–21]) and men (7.0 [range, 0–20]),and the mean PHASES score was 7.2±3.2 in womenand 7.4±3.0 in men. In our pooled analysis, the meanfollow-up time for women was 2.4±3.5 years (median:
1.5 (0-52) year) and 2.5±3.7 years (median: 1.5 (0-50)year) for men. Preventive neurosurgical or endovasculartreatment during follow-up occurred in 36% of women(median: 60 days) and in 37% of men (median: 61days). When assessing these characteristics per UIA,
similar differences in characteristics were found (datanot shown).
In 234 patients, rupture of the single, largest or
another than the largest UIA occurred. Of these 234
patients, 67 patients had multiple UIA, and in 226 of
234 patients (97%), the single aneurysm (n=167) or thelargest aneurysm in case of multiple aneurysms (n=59)
ruptured. In 8 of the 67 patients with multiple aneurysm,
another than the largest aneurysm ruptured. Of the 226
patients in whom the single or largest UIA ruptured, 163
were women (rupture rate 1.04%/person-years [95%CI, 0.89–1.21]), and 63 men (0.74%/person-years [95%CI, 0.58–0.94]). Characteristics of ruptured aneurysms
are shown in Table 3.
The unadjusted women-to-men hazard ratio was 1.43
(95% CI, 1.07–1.93). After adjustment for the PHASES
score, smoking, and positive family history for aSAH,
the women-to-men hazard ratio was slightly lower

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February 2022   365

characteristics were compared using the χ2 test. Continuous
variables of baseline characteristics were compared amonggroups using the Mann-Whitney U test or the Student t test. A
p≤0.05 was considered statistically significant. We pooled theindividual patient data of the included studies and estimatedsex-specific rupture rates for each cohort separately. In caseof multiple UIAs, the largest UIA was used to categorize thepatient regarding site and size of the aneurysm. In addition, we
performed an aneurysm-based analysis where all UIAs wereanalyzed. Rupture rate was analyzed with a per-patient analysis
and a per aneurysm analysis using a Cox proportional hazard
regression model, adjusted for the PHASES score,5 smoking,and positive family history for aSAH. A 2-stage approach wasused with random effect for cohort because we expected heterogeneity since studies were performed in different countries
which used different treatment regimes, and a fixed effectfor the PHASES score, smoking, and positive family history
for aSAH. As a sensitivity analysis, we also performed a onestage model. Proportional hazard assumptions were checked ineach individual cohort using diagnostics based on the scaled
Schoenfeld residuals.21 Follow-up data for patients started attime of UIA diagnosis and patients were followed up until aneurysmal rupture occurred. Patients were censored at the time ofdeath, last follow-up assessment, or at the time of surgical orendovascular aneurysm treatment without preceding rupture.
When patients underwent a surgical or endovascular aneurysm
treatment, data from the period up to the time of the intervention were included in the analysis, whereas data from the period
after the intervention were not included. The data that support
the findings of this study are available from the corresponding
author upon reasonable request.

RESULTS

CLINICAL AND POPULATIONSCIENCES

Table 1. Baseline Characteristics of Included Studies

CLINICAL AND POPULATIONSCIENCES

Zuurbier et al

Sex Difference and Risk of Aneurysmal Rupture

Table 2. Baseline Characteristics of Included Patients
Women-to-men difference*(95% CI)

Pooled data

Women, n (%)

Men, n (%)

Total, n (%)

No. of patients

6555

3385

9940

Mean age (range)

61.9 (15 to 100)

59.5 (16 to 94)

61.1 (15 to 100)

0.004 (0.003 to 0.005)

Hypertension†

2913 (44)1431 (42)4344 (44)0.019 (0.000 to 0.038)

Ever smoker†

1330 (20)1500 (44)2830 (29)−0.264 (−0.284 to −0.244)

Previous aSAH

405 (6)188 (6)593 (6)0.025 (−0.014 to 0.64)

Positive family history for aSAH†

676 (10)316 (9)992 (10)0.028 (−0.003 to 0.059)

Finnish768 (12)553 (16)1321 (13)Japanese5035 (77)2539 (75)7574 (76)Dutch

527 (8)227 (7)754 (8)Swiss

225 (4)66 (2)

291 (3)1466 (22)552 (16)2018 (20)Population

Multiple aneurysms

0.061 (0.045 to 0.078)

Aneurysm size

0.010 (−0.003 to 0.023)<7.0 mm4951 (76)2589 (77)7540 (76)

7.0–9.9 mm

887 (14)475 (14)1326 (14)10.0–919.9 mm

618 (9)266 (8)884 (9)>20.0 mm

99 (2)

55 (2)

154 (2)

Internal carotid artery

1551 (24)584 (17)2135 (22)Middle cerebral artery

2305 (35)1242 (37)3547 (36)Anterior circulation or posterior circulation

2699 (41)1559 (46)4258 (43)7.0 (0–921) 7.2±3.2

7.0 (0–920) 7.4±3.0

7.0 (0–921) 7.2±3.1

Aneurysm location

PHASES score (median, range, mean, SD)

0.083 (0.06 to 0.106)−0.043 (−0.055 to −0.031)−0.005 (−0.008 to −0.002)

aSAH indicates aneurysmal subarachnoid hemorrhage; and PHASES, Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From
Another Aneurysm, Site of Aneurysm.
*Unadjusted.
†Data are missing for hypertension in 87 persons (1%), for smoking in 235 persons (2%), and for family history of aSAH in 146 persons (1%).

(1.39 [95% CI, 1.02–1.90]; Figure 2). In the sensitivity
analysis on the subset of patients with no missing data
for smoking, hypertension, and family history of aSAH
(n=9566), we found similar but nonstatistically significant results (Figure S2). We also performed a one-stage
model which resulted in a hazard ratio of 1.36 (95%CI, 1.01–1.85). In the aneurysm-based analysis where
all UIAs were analyzed, the results were essentially thesame (Figure 3).

In our pooled analysis of individual patient data fromprospective cohort studies, we found that women havea higher risk of aneurysmal rupture, and this increased
rupture risk for women is not explained by differencesin patient- and aneurysm-related risk factors for aneurysmal rupture, being risk factors of the PHASES score,smoking, and a positive family history for aSAH.
Some of the risk factors for rupture were more often
present in women, but others in men. As the patient- andaneurysm-related risk factors for which we corrected in
our analysis, do not explain the increased rupture risk in
women, additional factors contributing to the increased

risk remain to be detected. We had no data on the shapeof the aneurysm in our data set. Because aspect ratio
and irregular aneurysm shape are also known factors for
UIA rupture,22,23 a higher prevalence of irregular aneurysms in women than in men may contribute to the sex
difference in rupture, but it is unlikely that such a difference would explain the sex difference in rupture completely. Because we could not find data in the literature
on sex differences regarding shape of the aneurysms, it
is currently unknown if or to what extent differences inshape of aneurysms between women and men play arole in the higher rupture risk in women.
Additional factors explaining the sex difference inrisk of UIA rupture may be female-specific hormonaland reproductive factors. A previous systematic literature review on female risk factors for aSAH found anincreased risk of aSAH for postmenopausal versus premenopausal women although the pathophysiology of thiseffect and its influence on the difference in incidenceof SAH between the sexes remains unclear.24 Alternatively, female-specific genetic factors, such as genetic
factors of the X-chromosome, sex-specific effects ofenvironmental risk factors, such as smoking25 or otheryet unknown clinical factors which occur more often or

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DISCUSSION

Zuurbier et al

Sex Difference and Risk of Aneurysmal Rupture

Characteristics of Ruptured Intracranial Aneurysms, per Aneurysm

Pooled data

Women, n (%)

Men, n (%)

Total, n (%)

No. of ruptured IA

169

65

234

Largest IA ruptured*

163

63

226

Not largest IA ruptured

6

2

8

Mean age (range)

64.2 (23-93)

61.2 (28-87)

63.4 (23-93)

Hypertension

89 (53)31 (48)120 (52)

0.50

Ever smoker

28 (17)33 (51)61 (26)<0.001

Previous aSAH

28 (17)12 (19)40 (17)0.73

Positive family history for aSAH

18 (11)8 (12)

26 (11)

0.72

Finnish30 (18)17 (26)47 (20)Japanese

129 (76)

43 (66)172 (74)

Dutch

9 (5)

3 (5)

12 (5)

Swiss

1 (1)

2 (3)

3 (1)

51 (30)16 (25)67 (29)<7.0 mm

79 (47)34 (52)113 (48)

7.0–9.9 mm

35 (21)7 (11)

42 (18)Population

Multiple aneurysms

0.19

0.20

Aneurysm size

0.40
0.33

10.0–19.9 mm

40 (24)16 (25)56 (24)>20.0 mm

15 (9)

8 (12)

23 (10)Aneurysm location

0.15

Internal carotid artery

26 (15)4 (6)30 (13)

Middle cerebral artery

45 (27)21 (32)66 (28)Anterior circulation or posterior circulation

98 (58)40 (62)138 (59)

9.0 (2–919) 10.1±4.0

9.0 (4–920) 10.4±3.9

9.0 (2–920) 10.3±4.0

PHASES score (median, range, mean, SD)

P value

0.60

aSAH indicates aneurysmal subarachnoid hemorrhage; IA, intracranial aneurysm; and PHASE, Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm.
*In case of multiple aneurysms, the largest aneurysm was used for analysis.

have stronger effect in women than in men may explain
the difference.
Our study has several strengths. It includes a large
data set with individual patient data from several cohorts
including risk factors for aneurysmal rupture. Also, almost
all study cohorts included in this meta-analysis showeda higher rupture rate in women compared to men. Thismeans that our data are consistent and generalizable forboth Asian and European countries.
A first limitation of this study is that selection bias
may have occurred due to informative censoring (loss tofollow-up) within each cohort study. If men were treatedmore aggressively during follow-up than women for
example upon growth of the UIA, which is associatedFigure 2. Hazard ratio of the rupture rate in women compared to men adjusted for the PHASES score (Population,
Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking
and positive family history of aneurysmal subarachnoid hemorrhage, analyzing the data per patient.
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February 2022   367

CLINICAL AND POPULATIONSCIENCES

Table 3.

Sex Difference and Risk of Aneurysmal Rupture

CLINICAL AND POPULATIONSCIENCES

Zuurbier et al

Figure 3. Hazard ratio of the rupture rate in women compared to men adjusted for the PHASES score (Population,
Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking
and positive family history of aneurysmal subarachnoid hemorrhage, analyzing the data per aneurysm.

with a higher risk of rupture,26 this may have led to selection bias. However, we found no difference in preventive
neurosurgical or endovascular treatment during followup between men and women as it was done in 36% of
women (median: 60 days) and in 37% of men (median:
61 days). Therefore, it is unlikely that differences inpreventive treatment have influenced our results considerably. Second, in most studies, we only had data on
smoking at the time of UIA detection but not for smoking
status during follow-up. As a previous study showed that
continuation of smoking is a significant risk factor for UIA
rupture, no conclusions can be drawn about the effectof a change in smoking status after aneurysm detection
during follow-up on our outcomes.27 Cessation of smoking might have occurred more often in men during follow-up compared to women. Similarly, in most studies, weonly had data on hypertension at time of UIA detection
and not during follow-up. Better control of blood pressure might have been achieved in men during followup compared with women. Third, although 9 researchgroups12–20 provided us with their individual patient data,
3 research groups9–11 were not able to do so, which
could possibly lead to a bias. However, the population
characteristics between the three cohorts not included(Matsumoto et al9: 63% female, Güresir et al10: 78%
female, and ISUIA [International Study of Unruptured
Intracranial Aneurysms Investigators]11: 75% female)and rupture risk (Matsumoto et al9: 6/111 patients, allfemale; Güresir et al10: 3/263 patients, all female; andISUIA11: 51/1692, sex unknown) differed not much fromthose of the nine cohorts analyzed (66% [range, 54–86]
female), and therefore, do not think that such a potential
bias influences our conclusions. Fourth, in our analysis,
patients from Japanese populations were overrepresented (77%) compared to Dutch (8%), Finnish (12%),and Swiss (4%) populations. Except for a small study
in the Swiss population, in all populations, a higher riskof rupture for women compared to men was found, so
we think our results are generalizable to all populations.

Fifth, in our study, we performed patient-level analysis,
and in patients with multiple UIAs, we analyzed data of
the largest UIA, which is not always the UIA that actuallyruptures.28 However, in our analysis for rupture rate on
aneurysm level, we found comparable results.

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Stroke. 2022;53:362–369. DOI: 10.1161/STROKEAHA.121.035187

CONCLUSIONS
Our results show that UIAs in women have a higher rupture risk than UIAs in men, which is not explained by differences in patient- and aneurysm-related risk factors foraneurysmal rupture, being risk factors of the PHASES
score, smoking, and a positive family history for aSAH.
When assessing the risk of rupture of UIAs in women,
this higher risk should be taken into account and a moreaggressive treatment approach in women as compared
to men is justified. Future studies should focus on theidentification of the factors explaining the higher rupturerisk of UIA in women, such as different approach during follow-up, female-specific hormonal and reproductive
factors, or female-specific genetic and environmental
risk factors.
ARTICLE INFORMATION
Received March 30, 2021; final revision received November 15, 2021; accepted
December 3, 2021.

Affiliations
UMC Utrecht Brain Center, Department of Neurology and Neurosurgery (C.C.M.Z,
L.A.M., G.J.E.R., Y.M.R.) and Julius Center for Health Sciences and Primary Care
(J.P.G.), University Medical Center Utrecht, the Netherlands. Departments of Neurosurgery (R.M., J.M.C.v.D., M.W.A.) and Neurology and Medical Imaging Center(M.U.), University Medical Center Groningen, the Netherlands. Department of
Neurology, Leiden University Medical Center, the Netherlands (M.J.H.W.). Department of Clinical Neurosciences, University of Helsinki, Finland (S.J.). Departmentof Clinical Radiology (A.E.L, J.E.J., T.K.) and Neurosurgery of NeuroCenter (A.E.L,
J.E.J., T.K.), Kuopio University Hospital, Finland. Institute of Clinical Medicine,
School of Medicine, Faculty of Health Sciences, University of Eastern Finland,
Kuopio (A.E.L, J.E.J., T.K.). Department of Neurosurgery, National Hospital Organization, Mito Medical Center, Japan (T.Y.). Medical Center UCAS Japan Coordinating Office- University of Tokyo- Nippon Medical School, Neurological Surgery(A.M.). Department of Health Informatics, School of Public Health, Kyoto Uni-

Zuurbier et al

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Stroke. 2022;53:362–369. DOI: 10.1161/STROKEAHA.121.035187

February 2022   369

Acknowledgments
Drs Mensing, Molenberg, van Dijk, Aalbers, Wermer, Juvela, Lindgren, Jääskeläinen, Koivisto, Yamazaki, Uyttenboogaart, Morita, Tominari, Arai, Nozaki, Murayama,
Ishibashi, Takao, Gondar, Bijlenga, Rinkel, Greving and Ruigrok contributed todata collection. Dr Zuurbier searched the literature. Dr Rinkel, Ruigrok, Greving,and Zuurbier communicated with coauthors for individual patient data. Dr Zuurbier performed the data analysis under the supervision of Dr Ruigrok, Greving, andRinkel. Dr Zuurbier generated the figures. Dr Zuurbier wrote the first draft of thearticle and all authors revised the article critically and approved the final version.

Sources of Funding
We acknowledge the support from the Netherlands Cardiovascular Research
Initiative: An initiative with support of the Dutch Heart Foundation, CVON201508 ERASE (Optimal Early Recognition of Persons at High Risk of Aneurysmal
Subarachnoid Hemorrhage). This project has received funding from the European
Research Council (ERC) under the European Union’s Horizon 2020 researchand innovation program (grant agreement No. 852173). The Swiss study was
performed within the framework of the AneuX project supported by SystemsX.ch,and evaluated by the Swiss National Science Foundation (2014/261).

Disclosures
None.

Supplemental Material
Figure S1Table S1–S2

REFERENCES

CLINICAL AND POPULATIONSCIENCES

versity, Japan (S.T.). Department of Neurosurgery, Juntendo University- Medical
School, Tokyo, Japan (H.A.). Department of Neurosurgery, Shiga University of
Medical Science, Japan (K.N.). Department of Endovascular Neurosurgery, Tokyo
Jikei University School of Medicine, Japan (Y.M., T.I., H.T.). Neurosurgery Division,
Department of Clinical Neurosciences, Faculty of Medicine, Geneva University
Medical Center, Switzerland (R.G., P.B.).

Sex Difference and Risk of Aneurysmal Rupture