ISSN 0030- 6096

O S A K A
C I T YVol.

66

M E D I C A L

2020

J O U R N A L
V o l . 6 62 0 2 0

PUBLISHED BYOSAKA CITY MEDICAL ASSOCIATIONOSAKA JAPANISSN 0030- 6096

O S A K A
C I T YVol.

66

M E D I C A L

2020

J O U R N A L
V o l . 6 62 0 2 0

PUBLISHED BYOSAKA CITY MEDICAL ASSOCIATIONOSAKA JAPANOsaka City Medical Journal
Vo l . 6 6 ,December 2020

CONTENTS
page
Disruptive Mood Dysregulation Disorder in Children with Autism
Spectrum Disorder
YUSUKE MIKI, DAI MIYAWAKI, AYAKO GOTO, KAORU HIRAI,
YUJI HARIMA, SHOKO SAKAMOTO, and KOKI INOUE･･････････････････････････････････････････････

1

Can a General-purpose Interactive Robot Detect Poor Cognitive Function?
A Pilot Study
JUMPEI MARUTA, YASUNORI MATSUDA, KENTARO UCHIDA,TADASHI OHTOMO, HIDEO KUROZUMI, SATOSHI NOGI,SATOSHI AKADA, AKI NAKANISHI, MIKI SHINODA,
MASATSUGU SHIBA, and KOKI INOUE ･･････････････････････････････････････････････････････････････ 13
Efficacy of Practical Training Using a Simulator for Auscultation of Lung Sounds
YOSHIHIRO TOCHINO, KANAKO SATO, KENJI SAWA,
SACHIKO OKU, KAZUTO HIRATA, and TAICHI SHUTO･････････････････････････････････････････････ 23
Analysis of Gait in Stroke Patients with Hemiplegia Using a Wearable
Accelerometer
TAMOTSU NAKATSUCHI, MITSUHIKO IKEBUCHI, TOMOYA NISHIKAWA,TETSUYA SUGAHARA, SHIGEYOSHI NAKAJIMA, MASANOBU MORIMOTO,
and HIROAKI NAKAMURA･････････････････････････････････････････････････････････････････････････････････ 31
Finite Time Span of High-intensity Signal on T1-weighted Magnetic ResonanceImaging Produced by a Human Blood Clot Using a Circulating
Vessel Phantom System
SHOICHI EHARA, KENJI MATSUMOTO, DAISUKE KIMURA,DAICHI TAKEMORI, EIJI YAMADA, TAKAO ICHIDA,
and MINORU YOSHIYAMA ････････････････････････････････････････････････････････････････････････････････ 39
Identification of Factors Predicting the Onset of Gallbladder Cancer
Complicated with Pancreaticobiliary Maljunction
MASAKI HORIIKE, YOSHIKI MOROTOMI, SHIGEKAZU TAKEMURA,SHOGO TANAKA, HIROJI SHINKAWA, TOSHIHIKO SHIBATA,
and SHOJI KUBO ･･･････････････････････････････････････････････････････････････････････････････････････････ 49― Case Report ―“Crack and Pave” and Intentional Protrusion of an Endoconduit into theTerminal Aorta for Endovascular Abdominal Aneurysm Repair
ATSUTAKA ARATAME, TAKASHI MURAKAMI, GOKI INNO,KENTA NISHIYA, YASUYUKI BITO, MASANORI SAKAGUCHI,
and TAKANOBU AOYAMA･･････････････････････････････････････････････････････････････････････････････････ 59

Osaka City Med. J. Vol. 66, 1-11, 2020

Disruptive Mood Dysregulation Disorder in Children with
Autism Spectrum Disorder
YUSUKE MIKI, DAI MIYAWAKI, AYAKO GOTO, KAORU HIRAI,
YUJI HARIMA, SHOKO SAKAMOTO, and KOKI INOUE
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine

Abstract
Background
Irritability is one of the most important reasons for which children get referred to child mental
health services. Disruptive mood dysregulation disorder (DMDD) is a diagnostic category
characterized by severe and chronic irritability in children, and is associated with long-term adverse
outcomes. However, little is known about DMDD in autism spectrum disorder (ASD). The aim of thisstudy was to assess the prevalence of DMDD and the association between DMDD and comorbid
psychiatric disorders in children with ASD.
Methods
Study participants consisted of 87 children with ASD aged 6-18 years, who were referred to a childpsychiatry outpatient clinic at Osaka City University Hospital. A diagnosis of DMDD and associatedsymptoms were assessed through a semi-structured interview and the Child Behavior Checklist(CBCL).
Results
Of all study participants, approximately 17% (n＝15) had a diagnosis of DMDD, although 60% (n＝52) showed symptoms of DMDD. The total, internalizing and externalizing CBCL scores, as well as 6of the 8 subscales (Anxious/Depressed, Social Problems, Thought Problems, Attention Problems,Delinquent Behavior, Aggressive Behavior), were significantly higher in children with DMDD than inchildren without DMDD.
Conclusions
Not assessing the frequency or duration of the symptomatic irritability is likely to increase therisk of over-diagnosing DMDD. Children with ASD and DMDD had more severe psychopathologicalsymptoms than children with ASD without DMDD. Identifying DMDD in children with ASD may be
helpful to the assessment of comorbid internalized/externalized symptoms as well as to the selectionof appropriate therapeutic interventions, including pharmacotherapy.

Received August 27, 2019; accepted October 8, 2019.
Correspondence to: Yusuke Miki, MD.
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: d16mb043@ka.osaka-cu.ac.jp-1-Miki et al

Key Words: ‌Disruptive mood dysregulation disorder; Autism spectrum disorder;
Depression; Anxiety disorder; Irritability

Introduction
Irritability is a common symptom in children and is one of the most common reasons for whichchildren are referred to child and adolescent mental health services1). In a community sample,
approximately 28%-51% of children aged 9-16 years experienced irritability-related symptoms2).
Chronic and severe irritability is the cardinal symptom of Disruptive mood dysregulation disorder(DMDD), having newly appeared in the Diagnostic and Statistical Manual of Mental Disorders, 5thedition (DSM-5)3). DMDD is associated with long-term poor and adverse outcomes1).
DMDD is characterized by (a) severe recurrent temper outbursts that are grossly out of proportion
in intensity or duration to the situation (on average three or more times a week), (b) persistentirritable/angry mood between temper outbursts throughout most of the day, nearly every day. In
order to meet diagnostic criteria, these symptoms must be seen in at least two of three settings (athome, at school, with peers), and be present for at least 12 months. Additionally, DMDD cannot be
first diagnosed prior to the age of 6-years-old or after the age of 18-years old, and should have an
onset prior to the age of 10-years-old. Finally, DMDD cannot be diagnosed if the child has alreadybeen diagnosed with bipolar disorder (or any manic or hypomanic episode)3).
In the 1990s, children with severe non-episodic, chronic irritability were considered to have
pediatric bipolar disorder without significant manic episodes. However, some researchers wereconcerned about over-diagnosing children and using excessive medication to treat bipolar disorder.
Longitudinal studies have suggested that such children showed a higher risk of having depression
and anxiety in the future, rather than having bipolar disorder4,5). With respect to the prevalence of
DMDD symptoms, which consist of temper outbursts and irritable mood, Dougherty et al report that
8% of 6-year-old children from a community sample have DMDD symptoms6), while 26% of 6-12-yearold children from a clinical sample showed both symptoms for 6 months in at least 2 settings7). It
must be noted that these reports used other assessment scales for psychiatric disorders for
oppositional-defiant disorder (ODD), prior to the establishment of a DMDD diagnosis in the DSM-5
which could then frame the assessment of DMDD symptoms. Therefore, researchers have pointed
out that these studies are limited in that they used arbitrarily chosen thresholds, without strictly
applying the duration and frequency criteria of the symptoms as per the criteria set forth by theDSM-5 for the diagnosis of DMDD.
Irritability is also common in children with autism spectrum disorder (ASD), which ischaracterized by persistent deficits in social communication/interaction and restricted, repetitive
patterns of behavior, interests, or activities, as described in the DSM-53). Irritability presents assevere temper tantrums or over reactivity8). Maladaptive emotional responses in youth with ASD
have a variety of phenotypes, including but not limited to irritability, poor anger control, tempertantrums, self-injurious behavior, and aggression9,10). These maladaptive emotional responses are
directly associated with core features of ASD 11). According to the DSM-5, children with ASD
frequently present with temper outbursts only when, for example, their routines are disturbed. Insuch an example, the temper outbursts would be considered secondary to the ASD, and the childshould not receive a diagnosis of DMDD3). However, with regards to whether children with ASD havecomorbid DMDD or not, there are no studies strictly assessing or excluding the diagnosis of DMDD

-2-

DMDD in Children with ASD

which take into account the severity of the temper outbursts and irritable mood. The prevalence of
DMDD in youth with ASD, and the association between a DMDD diagnosis and symptoms and otherpsychiatric comorbidities in youth with ASD, remain unknown. Therefore, the aims of this study are1) to examine the prevalence of DMDD diagnoses and symptoms in children with ASD in a clinicalsample, applying rigorous criteria based on the DSM-5, and 2) to examine the association between
the diagnosis of DMDD and other psychiatric disorders (i.e. depression, anxiety) in children with ASD
in a clinical sample.

Methods
Participants consisted of 94 children with ASD aged 6 to 18-years-old who had been referred to thechild psychiatry outpatient unit in Osaka City University Hospital between April 2018 and December
2018. We excluded children with intellectual disability (n＝5) who had difficulties in evaluating
symptoms, as well as children with bipolar disorder (n＝2), as assessed according to the DSM-5
diagnostic criteria. As a result, a total of 87 cases were retained for the study. We explained toparticipants and their parents the purpose of the study, as well as its procedures, potential risks, andalternatives to participation, and we obtained written informed consent from all children and theirparents. The Human Subject Review Committee of Osaka City University reviewed and approved of
the study protocol.
The diagnosis of ASD was based on the following sources: 1) a comprehensive developmental
history from the parents, 2) an interview of both the child and their parents conducted by theclinician, 3) direct observations of the subject by the two child psychiatrists. Finally, a diagnosis of
ASD was delivered according to the criteria of the DSM-5. To diagnose comorbid psychiatricdisorders, we used the Japanese version of the Kiddie Schedule for Affective Disorder andSchizophrenia Present and Lifetime version (K-SADS-PL-J)12). This consists of a semi-structured
interview designed to assess any current and past episodes of psychiatric disorders in children andadolescents according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, textrevision (DSM-Ⅳ-TR) criteria and is administrated through interviews with the child and theirparents. This diagnostic interview has good inter-rater reliability and concurrent validity13). Afterthe diagnostic interview was completed, a multidisciplinary team meeting was held to decide on themost appropriate diagnosis for all participants.
Although ODD cannot co-exist with DMDD according to the DSM-53), because comorbidity of
DMDD was of interest in this study, this exclusion was not applied here. Additionally, we collected
information, from interviews, on 1) whether a child only had one parent (absence of father or mother),2) family income, and 3) years of education of the parents. With regards to family income, wecategorized households with public assistance or with an annual income of less than three million yen
as low-income .
Assessment of DMDD diagnosis and DMDD symptoms
As previously mentioned, there are no diagnostic interview tools specifically designed for the
diagnosis of DMDD that take into account the exact duration and frequency criteria in the DSM-5.
Therefore, in this study, we created a new semi-structured interview, based on the DSM-5, to conduct
with children s parents. The content of the interview was based on the criteria of the DSM-5, andeach item asked the following: 1) Does your child often have temper outbursts? How many times aweek on average does your child have temper outbursts? When did the symptoms start? How long-3-

Miki et al

does your child had the symptoms? 2) Does your child usually get irritable or angry? Does theirritable mood persist throughout most of the day? When did the symptoms start? How long has yourchild had the symptoms? 3) In how many situations are the symptoms present? Are the symptoms
present at home, at school, with peers? On obtaining answers to these questions from the interviews
with parents, we delivered a diagnosis of DMDD when 1) temper outbursts occurred 3 or more times
per week and, at the same time, irritable mood lasted most of the day, 2) these symptoms had
persisted for more than 12 months, 3) these symptoms were present in at least two of three settings(at home, at school, with peers), and 4) age at onset met the criteria set forth by the DSM-5. By
assessing these symptoms, we investigated whether symptoms (temper outbursts and irritable mood)were of diagnostic severity or subthreshold (below the level warranted for a diagnosis of DMDD). For
example, if the child had temper outbursts at least 3 times a week, we categorized these as temper
outbursts as symptoms of DMDD , and, if not, we categorized them as subthreshold temper
outbursts . Additionally, we examined the test-retest reliability and inter-rater reliability of thisinterview, re-obtaining participant answers again at a later date. The test-retest reliability was
kappa ＝0.832 (n＝23), with a 46-day interval on average, and the inter-rater reliability was 0.806 (n＝13), with a 63-day interval on average. Both of the reliability rates were considered to confirm thevalidity of the interview.
Child Behavior Checklist (CBCL)
For the evaluation of holistic psychopathologies, we used the standardized Japanese version ofChild Behavior Checklist (CBCL)14). CBCL is a parent-report rating scale of child psychopathology
consisting of 113 questions developed by Achenbach and Dumenci15). Each question has the following
response scale: 0＝not true (as far as you know), 1＝somewhat or sometimes true, 2＝very often or
often true. The scales consist of three domains (total score, internalizing score, externalizing score)and eight subscales (Withdrawal, Somatic Complaints, Anxious/Depressed, Social Problems, Thought
Problems, Attention Problems, Delinquent Behavior, Aggressive Behavior).
Statistical Analysis
All statistical analysis was performed using SPSS version 25.0 statistical software (SPSS Japan,
Inc., Tokyo, Japan). Descriptive data were presented as means, standard deviations (SD), medians,
and ranges. A chi-square test or Fisher s exact test was used to compare categorical variables, as
appropriate. A Mann-Whitney s U-test or Student s t-test was used to compare continuous valuables,
whether the data was normally distributed or not. P-values＜0.05 (using a two-sided probability)
were considered to reﬂect statistical significance.

Results
Of all the participants (n＝87), the mean age of the sample was 12.5-years-old (ranging from 6 to
17-years-old, SD 2.8), and 55.2% (n＝48) of the sample was male. 21.8% (n＝19) of the sample wasfrom a low-income household, 25.3% (n ＝22) only had one parent (absence of father or mother).
Parents education had a mean duration of 13.9 years (ranging from 9-16 years, SD 1.6). The
prevalence of comorbidities was 44.8% (n＝39) for generalized anxiety disorder, 43.7% (n＝38) for
ODD, 39.1% (n＝34) for attention-deficit hyperactivity disorder (ADHD), 32.2% (n＝28) for social
anxiety disorder, 19.5% (n＝17) for major depressive disorder, 13.8% (n＝12) for obsessive-compulsive
disorder, 12.6% (n＝11) for chronic tic disorder, 9.2% (n＝8) for conduct disorder (CD), 8.0% (n＝7) for
adjustment disorder, 6.9% (n＝6) for dysthymia, 6.9% (n＝6) for Tourette disorder, 5.7% (n＝5) for-4-

DMDD in Children with ASD
Table 1. Prevalence of DMDD symptoms and diagnoses in children with ASD
N＝87

Symptoms present in
at least 2 settings

60 (69.0)

35 (40.2)

Symptoms [(n (%)]
temper outbursts
temper outbursts less than 3 times a week

25 (28.7)

temper outbursts 3 or more times a week (DMDD symptoms)

35 (40.2)

irritable mood64 (73.6)

irritable mood present but less than most of the day

36 (41.4)

irritable mood present most of the day (DMDD symptoms)

28 (32.2)

33 (37.9)

temper outbursts and irritable mood

52 (59.8)

32 (36.8)

temper outbursts 3 or more times a week and irritable mood present
throughout most of the day

23 (26.4)

16 (18.4)

DMDD diagnosis

15 (17.2)

DMDD, Disruptive Mood Dysregulation Disorder; and ASD, Autism Spectrum Disorder.

panic disorder, and 4.6% (n＝4) for separate anxiety. Psychotropic agents had already been taken in
18.4% (n＝16) of all children. Of these, 10 children had taken antipsychotics, 5 had taken stimulants,
1 had taken benzodiazepines. None of the children had taken antidepressants or a mood stabilizer.
Prevalence rate of DMDD diagnosis and DMDD symptoms
Table 1 shows the prevalence rates of DMDD-related symptoms by severity or by number ofsituations in which symptoms are present (≧2 or not), as well as the prevalence of DMDD diagnoses
in the sample. Of the subjects, 69.0% (n＝60) of children with ASD had temper outbursts, while
40.2% (n＝35) of the sample showed temper outbursts as a DMDD symptoms (i.e. 3 or more times perweek). Of all participants, 73.6% (n＝64) of the children with ASD had irritable mood, but 32.2% (n＝28) had irritable mood as a DMDD symptoms (i.e. for most of the day). With regards to both temper
outbursts and irritable mood, 59.8% (n＝52) had both symptoms at the same time, but 26.4% (n＝23)
had both DMDD symptoms (i.e. temper outbursts three or more times a week and irritable moodthroughout for most of the day). Moreover, when considering the number of settings in which
symptoms occur, the original 59.8% (n＝52) of the children with both symptoms dropped to 36.8% (n＝32) of the children with both symptoms present in at least 2 settings. Of the subjects, 26.4% (n＝23)
with both DMDD symptoms dropped to 18.4% (n＝16) with both symptoms present in at least 2
settings. Consequently, 17.2% (n＝15) of the subjects strictly met DMDD diagnostic criteria according
to the DSM-5, incorporating frequency, duration, and the number of settings in which symptoms
occur.
Sociodemographic factors and comorbidities
Table 2 shows the association between sociodemographic data, comorbidities, and DMDD. There
were no significant differences between the DMDD and non-DMDD groups in terms of age, sex,family income (low income), or duration in years of parents education. The rate of absence of achild s father or mother was significantly higher in the DMDD group than in the non-DMDD group[Odds ratio (OR) ＝6.81, 95% Confidence interval (CI) ＝2.06-22.49]. On investigating the association
between comorbidities and a DMDD diagnosis, there were no significant differences in comorbid
depressive or anxiety disorders between the DMDD and non-DMDD groups, while the DMDD group
had a significantly higher comorbidity with ADHD (OR ＝4.00, 95% CI＝1.23-13.02), and ODD/CD (OR-5-Miki et al
Table 2. DMDD and associated sociodemographic factors and comorbidities in children with ASD
DMDD
N＝15

Non-DMDD
N＝72

U/t/χ2page [year: mean (SD)]11.8 (2.6)

12.6 (2.8)

450.0c0.312

male [n (%)]

8 (53.3)

32 (44.4)

0.025

0.876

1.09 (0.36-3.34)

Absence of parent [n (%)]

9 (60.0)

13 (18.1)

11.43b0.001＊

6.81 (2.06-22.49)

low-income [n (%)]

6 (40.0)

13 (18.1)

3.462b

0.063

3.03 (0.92-9.99)

parents education [year: mean (SD)]

14.0 (2.0)

13.8 (1.6)

357.0c0.484

IQ [score: mean (SD)]102.6 (13.5)

93.6 (13.4)

1.882a0.067

Mood Disorders

7 (46.7)

20 (27.8)

2.046b

0.153

2.28 (0.73-7.10)

Anxiety Disorders

9 (60.0)47 (68.1)

0.361b0.558

0.70 (0.22-2.22)

ADHD

10 (66.7)

24 (33.3)

5.727b

0.021＊

4.00 (1.23-13.02)

ODD/CD

14 (93.3)

24 (33.3)

17.96b0.000＊

28.0 (3.47-226)

OR (95% CI)

Sociodemographic factorsbComorbidities

Student t-test; Fisher s exact-test; Mann-Whitney U-test; and p＜0.05.
Mood Disorders includes major depressive disorder, dysthymia, adjustment disorder. Anxiety disorders includes panic
disorder, social anxiety disorder, separation anxiety, general anxiety disorder, obsessive compulsive disorder, tic disorder,
Tourette s disorder. OR, Odds ratio; CI, Confidence interval. DMDD, Disruptive Mood Dysregulation Disorder; ADHD,
Attention Deficit/Hyperactivity Disorder; ODD, Opposite Defiant Disorder; and CD, Conduct Disorder.
a

b

＊

c

＝28.00, 95% CI＝3.47-226) than the non-DMDD group.

CBCL scores and DMDD diagnosis/symptoms
Table 3 shows CBCL scores (total, internalizing, externalizing, and the scores of the eightsubscales) of the DMDD and non-DMDD groups. On comparing the two groups, the total scores,
internalizing scores, and externalizing scores were significantly higher in the DMDD group than in
the non-DMDD group. With regards to the CBCL subscales, 6 of the 8 subscale scores (Anxious/
Depressed, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, Aggressive
Behavior) were significantly higher in the DMDD group than in the non-DMDD group.

Discussion
Our results suggest two points: First, not assessing the frequency, duration and number ofsettings in which symptoms are present is likely to increase the risk of over-diagnosing children with
ASD and DMDD. Applying strict criteria incorporating these considerations demonstrated that
17.2% of children with ASD in a clinical sample had a concurrent DMDD diagnosis according to DSM5 criteria. Second, children with ASD and DMDD had a more severe and broader psychopathology
than children with ASD without DMDD.
First, our findings suggest that DMDD is likely to become over-diagnosed in children with ASD.
In our study, approximately 60% of the children with ASD had temper outbursts and irritable mood.
However, the prevalence dropped to less than 50% when taking into consideration frequency criteria(temper outbursts 3 or more times a week and irritable mood throughout for most of the day) set forth
by the DSM-5. Moreover, when taking into consideration the duration of the symptoms (symptoms-6-

DMDD in Children with ASD
Table 3. ‌The association of the CBCL scores and DMDD
DMDD
N＝15

Non-DMDD
N＝72

U/t

p

Total score75.3 (11.2)

64.7 (8.66)

187.0b

0.002＊

Internalizing score75.3 (14.0)

65.4 (9.00)

2.45a

0.028＊

Externalizing score69.9 (9.83)

60.4 (11.4)

2.77

0.007＊

Withdrawal

72.6 (11.4)

64.1 (8.39)

224.5b0.09

Somatic Complaints

67.5 (11.7)

62.9 (10.4)

319.0

0.183

Anxious/Depressed

74.3 (14.6)

62.8 (8.83)

b

216.5

0.007＊

Social Problems

69.0 (12.4)

61.5 (8.40)

262.5b

0.036＊

Thought Problems

69.0 (14.0)

60.1 (11.3)

265.0b

0.034＊

Attention Problems

71.5 (11.5)

61.8 (8.11)

3.63a

0.001＊

Delinquent Behavior

67.3 (7.32)

59.0 (8.75)

214.0b

0.005＊

Aggressive Behavior

68.9 (9.71)

60.6 (9.40)

220.0b0.007＊

CBCL, mean (SD)a

CBCL subscalesbStudent t-test; b Mann-Whitney U-test; and ＊ p＜0.05.
CBCL, the Children Behavior Checklist; and DMDD, Disruptive Mood Dysregulation Disorder.

apresent at least 12 months) and number of settings symptoms are present (at least 2 of 3 settings),
the prevalence of rigorously defined DMDD dropped to 17.2% according to the criteria set forth by theDSM-5.
Previous reports have suggested that the prevalence of DMDD is wide-ranging. In a community
sample, the 3-month prevalence of DMDD was 0.8%-3.3%16), 5.3%17), 8.2%6), and 9.0%18). However, in aclinical sample, the prevalence of DMDD was higher than in the community sample. The 6-monthprevalence of DMDD symptoms among 6 to 12-year-old children who had been referred to a childpsychiatric outpatient clinic was 26%-31%7,19). However, these previous studies failed to use dedicatedassessment measure of a DMDD diagnosis, and their diagnoses were performed by evaluating
arbitrarily chosen criteria on the frequency or duration of symptoms, rather than the criteria set
forth by the DSM-5. For example, most studies used alternative questionnaires or assessment tools
for other psychiatric disorders for diagnosing DMDD prior to the development of the DSM-5. For thisreason, previous reports often assessed the frequency or duration of DMDD symptoms as often orvery often , and investigated the 3-month or 6-month prevalence. Thus, these previous studies had
investigated the prevalence of a form of proxy-DMDD , rather than true DMDD as defined by theDSM-5. Some researchers have expressed their concern about the validity of a DMDD diagnosis
because of the high comorbidity of other psychiatric disorders in addition to its own high prevalence
rate 20-22). However, considering the likelihood of over-diagnosing DMDD in children with ASD as
pointed out by our results, the prevalence of DMDD in previous studies may have been artificiallyinﬂated as a result of not strictly using criteria set forth by the DSM- 5.
Second, children with ASD and DMDD had significantly more severe psychopathologicalsymptoms linked to depression and anxiety than those without DMDD. Several studies have noted
the association between DMDD and other psychiatric disorders. In the 1990s to the mid-2000s,
children with severe and chronic irritability had been diagnosed with pediatric bipolar disorder and-7-

Miki et al

received treatment for bipolar disorder, for which there were growing concerns of overdiagnosis andovermedication. These concerns led to the establishment of newly defined criteria in the DSM-5 forthe diagnosis of DMDD3,23) alongside a number of epidemiological and prognostic studies on children
with DMDD. As further evidence, a DMDD diagnosis in children means they are predisposed tohigher future rates of depression and anxiety or a higher rate of comorbidity of depression and ODD,
but not bipolar disorder6,16). Few reports had investigated DMDD in children with ASD. Axelson et alreported the prevalence of DMDD in a clinical sample consisting of OCD, CD, ADHD, depression,anxiety disorders, and autism, but the number of children with autism was too small to draw any
conclusions about this subgroup7). Our study complements a previous study in which children with
ASD comorbid with DMDD had more severe psychopathological symptoms characterized bydepression and anxiety than children without DMDD.
In addition to symptoms of depression/anxiety, children with ASD and DMDD had a broader rangeof psychopathological symptoms. The significant prevalence of severe psychopathology linked toDelinquent Behaviors and Aggressive Behaviors from the CBCL subscales in the DMDD group may
be explained by the evidence, as noted in previous studies, that DMDD itself often co-exists withODD/CD characterized by behavioral problems 6,18,21,24). The significant severe psychopathology linked
to attention problems from the CBCL subscales in the DMDD group may also be explained by aprevious suggestion that children with ADHD often have comorbid DMDD25-27). A previous study had
demonstrated that ADHD, ODD, and CD were significantly more common comorbidities in the DMDD
group than in the non-DMDD group in a general clinical sample. Our study has further
demonstrated that ADHD, ODD, and CD are significantly more common comorbidities in patientswith DMDD, even in an ASD clinical sample.
Irritability is a transdiagnostic factor which can be seen in various psychiatric diseases. Despite
the difficulty in defining its characteristics, irritability tends to be a focus for treatment bypsychotherapy and/or medication. Recent research has pointed to a link between irritability andemotional symptoms in late childhood/early adolescence 28). Although Malhi et al suggested apreliminary model in which irritability was a symptom leading to the development of internalizing
symptoms such as anxiety and depression29), mechanisms of irritability remain unclear. As suggested
in our study, DMDD co-exists with many other psychiatric disorders, specifically with ODD, and
DMDD has been incorporated into a new subclassification of ODD in the International Classificationof Diseases 11th Revision (ICD-11) as ODD with chronic irritability/anger 30). As such, there remains
a nosological debate to this day surrounding the conceptualization of irritability, and whether it is a
developmental indicator of internalizing symptoms such as depression and/or anxiety, or asubordinate phenotype of externalizing symptoms such as ODD/CD. Our study clarifies that children
with ASD and DMDD have higher scores on internalizing symptoms, such as depression/anxiety, andhigher scores on externalizing symptoms, such as Delinquent Behaviors or Aggressive Behaviors,
than children with ASD without DMDD. In this study, our results suggest that irritability itself may
be an intermediate phenotype between internalizing and externalizing symptoms.
Clinical implications
There is no established management of therapeutic interventions for irritability in children,
despite the need thereof in clinical settings. In children with disruptive behavior, research on
psychosocial interventions has been limited, especially on parental management training andcognitive behavioral therapy, which have been suggested to be effective 31-33). With regards to DMDD,-8-DMDD in Children with ASD

treatment options for children with DMDD are currently limited. A few studies have pointed to theefficacy of psychotherapy in children with DMDD 34,35), and in the case of children with DMDD
comorbid with ADHD, a few reports have pointed to the efficacy of pharmacotherapy for thetreatment of ADHD symptoms 36-39). When treating irritability in child psychiatry, clinicians often facedifficult decision on whether to treat the irritability directly, the comorbid condition, or both1). With
regards to children with ASD, some antipsychotics have been approved to treat their irritability.
However, due to the broad phenotype of irritability symptoms in ASD, there is no establishedtreatment tailored to the severity and/or characteristics of the irritability. Therefore, treating
irritability in children with ASD is often challenging for clinicians because of concerns surrounding
the overassessment of symptoms and the overmedication with psychotropics. Although there is noevidence-based therapeutic intervention for DMDD children with ASD at this point, by extrapolation
based on the treatment options in previous DMDD studies, our results may support the use of
medication to treat severe irritability in children with ASD and DMDD.
Our study suggested that broad psychopathology, including symptoms of depression and anxiety,were more common in ASD children with DMDD than without DMDD. As mentioned above, althoughirritability is hard to recognize, recognizing DMDD in children with ASD may be helpful for
identifying their internalizing and externalizing problems.
Strengths and limitations
A strength of our study was that it investigated the prevalence of DMDD in a clinical sample ofchildren with ASD by performing a semi-structured interview tailored to DMDD. Additionally,
though it was already known that DMDD was associated with depression and anxiety, our study
enabled us to clarify that ASD children with DMDD had significantly more psychiatric problems,
including symptoms of depression and anxiety, than children without ASD.
There were some limitations to our study. Firstly, in diagnosing DMDD, we used a parentreportassessment of DMDD symptoms. When assessing symptoms in children with ASD, a previous study
had suggested that children with high functioning ASD (HFASD), who do not have intellectual
disability, underreport their irritability symptoms40). In contrast, another study had suggested thatboth self-report and parent-report of irritability symptoms were reliable in male children with
HFASD41), revealing inconsistent findings. As such, in future studies, it may be useful to examine
both self-reports and parent-reports. Secondly, irritability symptoms may have been dampened or
hidden entirely since 10 children were already taking antipsychotics. However, 1 of 10 children
taking antipsychotics also met diagnostic DMDD criteria as set forth in the DSM-5, and the other 9children did not meet diagnostic DMDD criteria from before the initiation of their antipsychotics
treatment to the time of symptom evaluation. Therefore, any effects on the results were consideredsmall. Finally, this study was based on a clinical sample of children with ASD from a single
institution, thereby warranting careful interpretation in the generalization of our results to all
children with ASD.
Conclusion
In conclusion, the prevalence of children with ASD and DMDD was as high as approximately 17%,and they may have been likely to be over-estimated. ASD children with DMDD are more likely tohave broad psychiatric problems, including depression and anxiety at a symptomatic level.
Identifying DMDD in children with ASD may be helpful for the risk management of exacerbating
symptoms of depression or anxiety, both at the time of assessment and in the future, and for the-9-Miki et aldevelopment of appropriate therapeutic interventions. Since this is a cross-sectional study, further
longitudinal studies are needed to both investigate in further depth the clinical course of children
with ASD and to contribute to their appropriate treatment and intervention.
Acknowledgements
All authors have no COI to declare regarding the present study.
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Osaka City Med. J. Vol. 66, 13-21, 2020

Can a General-purpose Interactive Robot Detect Poor
Cognitive Function? A Pilot Study
JUMPEI MARUTA1,2), YASUNORI MATSUDA3), KENTARO UCHIDA1), TADASHI OHTOMO4),
HIDEO KUROZUMI1), SATOSHI NOGI1), SATOSHI AKADA1), AKI NAKANISHI2), MIKI SHINODA5),MASATSUGU SHIBA6), and KOKI INOUE1,6)
Departments of Neuropsychiatry1) and Center for Brain Science6),
Osaka City University Graduate School of Medicine;
Medical Center for Dementia2), Osaka City Kosaiin Hospital;
Tsuruhashi Mental Clinic3); Shigisan Hospital4); andDepartment of General Welfare and Clinical Psychology5), Osaka City University Graduate
School of Human Life Science

Abstract
Background
Neuropsychological examinations have been routinely used to screen for dementia. However, theserequire human resources, and the subject might feel psychologically burdened by the humanexaminer. We investigated whether a robot could be used to screen for dementia.
Methods
We used a general-purpose humanoid interactive robot to conduct the Hasegawa Dementia Scale
Revised (HDS-R), modified for the robot (robot test). We recruited 12 patients with mild to moderate
Alzheimer s disease (AD) and 4 patients with mild cognitive impairment (MCI) from the outpatient
department of Osaka City Kosaiin Hospital. We recruited 10 healthy controls (HC) from patients
spouses. The subjects took the robot test, the Mini Mental State Examination (MMSE), and HDS-R
on the same day. The scores for the robot test (robot scores) were calculated by a human. To
demonstrate correlations between scores, we used the Spearman s rank-correlation method.
Between-group comparisons of scores were assessed using the nonparametric Kruskal-Wallis test,with multiple comparison corrections performed using the Steel-Dwass procedure.
Results
There were no dropouts in the robot test. The robot scores correlated significantly with the scoresof the MMSE (rho＝0.814, p＜0.001) and HDS-R (rho＝0.855, p＜0.001). Moreover, robot scores in the
AD group were significantly lower than in the MCI (H＝2.93, p＜0.001) and HC (H＝1.28, p＝0.009)
groups.

Received August 30, 2019; accepted November 26, 2019.
Correspondence to: Jumpei Maruta
Department of Neuropsychiatry, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3821; Fax: +81-6-6636-0439
E-mail: d16mb90s42@st.osaka-cu.ac.jp- 13 -

Maruta et al

Conclusions
Although the interviewer is a general-purpose interactive robot, it is able to talk and get thenecessary information to detect poor cognitive function in elderly participants.
Key Words: Interactive‌robot; Alzheimer s disease; Screening; Neuropsychologicalexamination

Introduction
Early detection of dementia is important because it increases the potential for an effective
intervention. For example, interventions such as drug therapy are most effective when they arestarted early 1). Brodaty et al reported that neuropsychological examinations such as General
Practitioner Assessment of Cognition, Mini-Cog, and Memory Impairment Screen were suitable fordementia screening in general practice2). However, since these need a human examiner and havelabor-associated costs, it is sometimes difficult to screen dementia due to lack of human resources.
Furthermore, the elderly people who undergo cognitive function examinations may feel
psychologically burdened by human examiners. Kobayashi et al showed that, due to psychologicalburden, elderly people may not perform to their full ability in examinations conducted by a human
compared to examinations performed using a personal computer3). Therefore, automatic andinexpensive tests that do not require a human examiner at the time of testing are needed to screen
for dementia.
Previous studies of automated dementia screening have mainly focused on developing screening
software for personal computers or tablet devices. However, as pointed out by Kobayashi, the use of amouse is often difficult for the elderly3), and examinations using a touch panel is currently preferred.
Tsuji et al reported a computer-based test that conducts a neuropsychological examination for elderly
subjects with dementia using a touch panel4). Onoda and Yamaguchi developed the revision of
Cognitive Assessment for Dementia, iPad version (CADi2) and used it for primary mass screening incommunity-based medical facilities5).
Recent advances in robot technology also have the potential to enable automated neuropsychologicalexaminations. Several studies have demonstrated the usefulness of robot therapy to treat the
behavioral and psychological symptoms of dementia. Gustafsson et al reported that their cat robot
increased well-being and quality of life for some individuals with dementia6). Treatment with PARO
(Daiwa House Industry, Osaka, Japan) a baby seal-like robotic pet was reported to be effective forstress reduction7) and resulted in reductions in the use of psychoactive medications in elderly people
with dementia8). In the MARIO Project, it has been reported that the companion robot MARIO may
be a useful tool in mitigating depression and loneliness for people with dementia9). It is currently
unknown whether touch panel devices or conversational robots are more effective for neuropsychologicalexaminations. However, considering robots have been used for elderly patients with dementia as
mentioned above, robots likely have the potential to greater reduce the psychological burden thantouch panel devices.
We hypothesized that a general-purpose interactive robot would be helpful to assess cognitive
function because of the possibility of reducing medical expenses and psychological burden in patients.
Hence, we have developed a neuropsychological examination auto-interviewing robot using a generalpurpose interactive robot.
In this study, we present our neuropsychological examination auto-interviewing robot and- 14 -

Can Robots Detect Poor Cognitive Function?

Figure 1. Image of SOTA with white coat.

investigate whether the robot can communicate with and get the necessary information to detect poorcognitive functioning from healthy and cognitive impaired elderly participants.

Methods
Robot architecture
In this study, we used a general-purpose humanoid interactive robot, SOTA (Vstone Co. Ltd.,
Osaka, Japan), as shown in Figure 1. SOTA has been previously used in a study investigating theuse of robots for recreational activities in nursing homes10). SOTA measures 280 mm in height andweighs 800g. We used the NTT Data Cloud Robotics Platform to implement SOTA s communicationand testing program.
The main function of SOTA was to record the participant s voice and synthesize speech. SOTA
communicated with a participant via a loop incorporating the following steps: (a) participant speaks
to SOTA; (b) SOTA records the participant s voice with its microphone; (c) voice data is transferred to
the NTT Data Cloud Robotics Platform; (d) in the cloud platform, voice data is converted to text data;(e) a response to the text data is generated according to the scenario; (f) an audible response issynthesized; (g) the synthesized audible response is transferred to SOTA; and (h) SOTA respondswith a synthesized voice.
Particularly, in step (e), when SOTA received an unexpected response (or no response), SOTA wasdesigned to nod in response and continue to the next question. When the correct reply was received,
SOTA repeated the answer.
Robot test
The experiment was conducted in Osaka City Kosaiin Hospital after a baseline examination
including a cognitive function test. If for any reason it was not able to be conducted on the same day
as the baseline examination, the experiment was conducted as quickly as possible (i.e. within a- 15 -

Maruta et al
Table 1. ‌The robot’s brief script and instructions for administration of the test
Score

Q1

1

Script (originally in Japanese)

Instructions for administration

I m SOTA.

Introduction for test.

Tell me your birthday.

Q2

1

How old are you?

Within 1 year of the patient s correct age

Q3

3

Then asks the patient for all three after the robot has
said them. Give a point for each correct answer.

Q42

Remember three objects.
Cherry, Cat, Train.
Remember three or four numbers, andsay them in reverse order.

Q5

2

Serial sevens (starting from 90).

83, 76 (One point for each correct)

Q6

6

Recall the 3 objects repeated above.

Q7

5

Q8

3

Remember the following short story:
Yesterday I sent a ﬂower to the teacher
who had a reunion in Kyobashi, Osaka.
Look for similarity between;
an orange and apple ,a bicycle and bus ,a drum and whistle .

Give 2 points for each correct. If a patient could not
answer completely, give hints and ask one more time.
Give 1 point for each correct with a hint.
Give 1 point for each correct word (total five words inJapanese) and subtract 5. In case of a negative score, it
is assumed to be 0 points.
Give 1 point for each correct word.
Fruit
VehicleMusical instrument

Q93

What is the date/month/year?

One point for each correct

If the participant answered the three numbers correctly,
then proceed to four numbers.

Q10

1

Where are we?

Kosaiin or Hospital

Q11

5

Recall the previous short story.

Give 1 point for each correct word and subtract 5. Incase of a negative score, it is assumed to be 0 points.

Q12

1

Say my name.

SOTA

month), to avoid any changes to the participant s cognitive abilities between experiments.
Participants were guided to the room and introduced to SOTA. We asked the participant to follow
any instructions given by SOTA but did not give any advice such as how to use a robot during thetest.
We created a scenario in which a cognitive function test, with a duration of 10 minutes, wasconducted by SOTA (Table 1) in Japanese. The test scenario was developed with reference to the
Hasegawa Dementia Scale Revised (HDS-R), which is a validated screening test for dementia11), andis widely used in Japan. Because of restricted nature of robot conversation, we modified the HDS-R
to be suitable for a robot. In particular, recalling 5 objects and generating vegetables were removed.
Instead of them, Q7 (immediate recall of short story), Q8 (conceptualization), and Q11 (delayed recallof short story) were added. Furthermore, to get used to the dialogue with the robot, Q1 (birthday)
was added as the first question, which is relatively easy to answer even for participants withdementia. Q12 (recall robot s name) was added to verify whether cognitive function can be tested ina natural conversation. To minimize learning effects, we modified questions relating to delayed recall
and changed the starting number for the serial sevens so that it differed from the original HDS-R.
After the robot test, a human graded the recorded interview according to a manual (Table 1). The
score distribution was determined with reference to HDS-R.
Participants
A total of 26 participants enrolled in the study and completed a baseline examination, including
the Mini-Mental State Examination (MMSE) and the HDS-R conducted by a clinical psychologist.

- 16 -

Can Robots Detect Poor Cognitive Function?

Participants were either outpatients at Osaka City Kosaiin Hospital, Japan, from April 2017 to
December 2017, or patients spouses. Participants were assigned to one of three groups: mild tomoderate Alzheimer s disease (AD), mild cognitive impairment (MCI), or healthy controls (HC).
The AD group met the following inclusion criteria: (a) met the National Institute of Neurologic,
Communicative Disorders and Stroke, AD and Related Disorders Association, Alzheimer s criteria forprobable AD12); and (b) scored 11 or more points on the MMSE13). MCI patients were defined as having
complaints about cognitive impairment, and observable cognitive decline, but whose basic daily living
functions were normal. They met the revised MCI criteria 14). The HC group met the following
inclusion criteria: (a) had never been diagnosed with dementia at any hospital; (b) were able to live
independently; and (c) had no complaints of memory loss.
We obtained written informed consent from all participants. The study protocol was approved by
the Ethics Committee of Osaka City Kosaiin Hospital in accordance with the declaration of Helsinki.
Statistical analysis
Analyses of the demographic and clinical characteristics were performed with Easy R (EZR)(Saitama Medical Center, Jichi Medical University, Saitama, Japan)15). EZR is a graphical userinterface implemented in R 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria).
Between-group comparisons of MMSE, HDS-R and age were assessed by using the nonparametric
Kruskal-Wallis test, with multiple comparison corrections performed using the Steel-Dwass procedure.
Categorical variables such as sex were compared with Fisher s exact tests. To demonstrate correlations
between test scores produced by the robot and humans, we used the Spearman s rank-correlation
method. Alpha values less than 0.05 were considered significant.

Results
Acceptance of the robot
No participants dropped out of the robot tests. The participants did not get angry with or confusedby our robot enough to prevent the continuation of the robot test.
Demographic characteristics & baseline examinations
For the AD, MCI, and HC groups, sex ratios (female/male) were 4/8, 0/4, and 9/1; the median [firstquartile point (Q1), third quartile point (Q3)] ages were 79.00 [74.25, 84.25], 75.50 [73.00, 78.50] and73.50 [70.25, 75.00] years old; the median MMSE points [Q1, Q3] were 21.50 [20.75, 22.00], 25.00[25.00, 25.25] and 26.50 [24.50, 27.75]; the median HDS-R points [Q1, Q3] were 18.00 [14.00, 19.00],
23.00 [19.50, 26.25] and 29.00 [28.25, 30.00].
There was a significant group difference of sex ratio among the AD, MCI, HC groups (p＝0.002,
Fisher s exact tests). There were fewer male participants in the HC group compared to AD and MCI
group.
The AD group were significantly older than HC group (H＝2.40, p＝0.044). The median age of the
MCI group was not significantly different compared to the AD (H＝0.86, p＝0.668) and HC (H＝1.28, p＝0.403) group.

The AD group had significantly lower MMSE scores than both the MCI group (H＝2.78, p＝0.015)
and HC group (H＝3.21, p＝0.004). There was no significant MMSE score difference between the MCI
and HC groups (H＝1.00, p＝0.576).
The AD group had significantly lower HDS-R scores than the HC group (H＝3.98, p＜0.001). MCI
group tended to have lower HDS-R scores than HC group (H＝2.30, p＝0.056).

- 17 -

Maruta et al

Figure 2. Score correlation between robot scores and neuropsychological examinations. Abbreviations: AD,
Alzheimer s disease; MCI, mild cognitive impairment; HC, healthy control; MMSE, Mini-Mental Scale Examination;and HDS-R, Hasegawa Dementia Scale Revised.

Table 2. ‌Average scores of each question of robot test
Question (max point)

Average score±SD

p value

AD

MCI

HC

Q1. Birthday (1)1.00±0.00

1.00±0.00

1.00±0.00

NaN

Q2. Age (1)0.83±0.39

1.00±0.00

1.00±0.00

0.308

Q3. Repeating 3 words (3)2.33±0.78

2.75±0.50

2.40±0.84

0.649

Q4. Digits backward (2)0.92±0.79

1.25±0.96

1.30±0.67

0.488

Q5. Calculation (2)1.42±0.67

2.00±0.00

1.50±0.71

0.298

Q6. Recalling 3 words (6)0.25±0.62

3.00±2.58

5.30±1.06＜0.001Q7. Immediate recall of short story (5)0.08±0.29

3.00±1.41

2.80±1.40＜0.001Q8. Conceptualization (3)2.00±1.04

2.25±0.96

2.90±0.32

0.055

Q9. Orientation to time (3)0.67±0.98

2.00±0.00

3.00±0.00＜0.001

Q10. Orientation to place (1)0.50±0.52

0.75±0.50

1.00±0.00

0.028

Q11. Delayed recall of short story (5)0.00±0.00

1.75±1.71

1.70±1.95

0.015

Q12. Recall robot s name (1)0.00±0.00

0.00±0.00

0.10±0.32

0.467

Total (33)

10.00±2.63

20.75±4.35

24.00±4.19＜0.001

P values represent group differences among AD, MCI, and HC groups with the Kruskal-Wallis test. Abbreviations:
AD, Alzheimer s disease; HC, healthy control; HDS-R; Hasegawa Dementia Scale Revised; MCI, mild cognitive
impairment; MMSE, Mini-Mental Scale Examination; NaN, not a number; and SD, standard deviation.

Robot scores
Figure 2 shows score correlations between the robot test and the neuropsychological examinations
MMSE and HDS-R. There was a significant correlation between the robot scores with the MMSE (rho- 18 -

Can Robots Detect Poor Cognitive Function?
＝0.814, p＜0.001) and the HDS-R scores (rho＝0.855, p＜0.001).

Robot scores in the AD group (median, 11.0) were significantly lower than those in the MCI group(median, 21.5; H＝2.93, p＜0.001) and HC group (median, 24.0; H＝3.97, p＝0.009). There was no
significant difference in robot scores between the MCI and HC groups (H＝1.28, p＝0.407).
Table 2 shows the average scores of each question of the robot test. There were significant groupdifferences in Q6 (recalling 3 words), Q7 (immediate recall of short story), Q9 (orientation to time),
Q10 (orientation to place) and Q11 (delayed recall of short story). All participants in the 3 groups
answered Q1 (birthday) correctly. Only HC participants answered Q12 correctly.

Discussion
We performed a pilot study for the use of a general-purpose interactive robot to screen for
dementia. The robot conducted a modified HDS-R, which was completed by all participants. There
were significant correlations between the robot scores and MMSE and HDS-R scores conducted by ahuman psychologist. Previous studies have supported the usefulness of the MMSE and HDS-R as
screening tests for Alzheimer s disease11,16). Moreover, robot scores of 14 or less were obtained only inpatients with dementia and not in those with MCI or HC. These results suggest our robot scores areuseful to detect poor cognitive functioning in healthy and cognitive impaired elderly participants.
Therefore, our novel robot was able to talk to and get the necessary information from elderly patientsto make such a detection.
It is worth noting that there were no dropouts in the robot test despite some of the participants
included having mild to moderate AD. This supports the idea that patients with mild to moderate AD
can accept a general-purpose interactive humanoid robot in well-structured interactions as aninterviewer. Furthermore, although the robot represents an inspector, it appears that there was no
psychological burden that would make psychological examination difficult to complete in this study.
However, because our study focused on screening and was not targeted at patients with severe
dementia, it is still unclear whether a patient with severe dementia could communicate with ourrobot. A previous study has shown that a humanoid robot can be used with institutionalized patientswith advanced dementia, but in that study, unlike here, the robot was remotely operated17).
In the robot test, the breakdown of the subject s score was comparable to that of the conventional
test. The loss of recent memory (Q6, recalling 3 words; Q11, delayed recall of short story) andorientation (Q9, orientation to time; Q10, orientation to place) was striking while short-term memory
loss (Q3 repeating 3 words; Q4, digits backward) was relatively preserved in AD and MCI patients.
This preservation of short-term memory is in line with previous studies showing that short-time
memory is intact in patients with a damaged medial temporal lobe, such as AD patients 18,19).
There are three important tasks revealed by this study regarding our modified HDS-R, and it will
be necessary to improve the content of the questions for future research. First, the administration
time may be long. In this study, we tested various types of questions to investigate what kind ofquestion is best suited for a robot. Therefore, the robot test can be shortened in the future. Second,
internal consistency could be improved. Some questions (Q1-5, Q12) were either too easy or too
difficult to distinguish AD or MCI participants from HC. Third, participants in the MCI and HC
groups could not be clearly differentiated by our robot test. The cause of this could be the small
sample size of the experiment, or the difficulty of the robot test. The difficulty of the robot test was
designed using HDS-R as a reference, which is designed to screen for dementia, not MCI. Therefore,- 19 -

Maruta et al

the robot test was considered to be too easy to distinguish MCI from HC.
Compared to the Montreal Cognitive Assessment (MoCA), which has been reported as a usefulscreening tool for MCI20), our test lacks a trail making test because our robot can only interact
verbally in this study. When MMSE and a trail making test were combined, the accuracy andprecision of mild dementia screening was reported to improve21). Similarly, to accurately screen for
MCI we might need to include a trail making test in future studies. Some commercially available
robots such as PEPPER (Soft Bank Corp., Tokyo, Japan) have touch panels to aid in communication,and therefore could easily incorporate a trail making test into our test.
There are three advantages to our robot test compared to the paper based conventional test. First,
no expert is required to conduct the cognitive function tests. Second, we can standardize the methodof conducting cognitive function tests. Third, since the recorded interviews are scored, laborassociated costs are minimized. Bearing in mind privacy issues, recorded interviews can be sent
electronically and scored anonymously at a centralized location. Considering that SOTA has beenstudied for use as a recreational robot in nursing homes, we believe that our robot is better suited tosupport dementia screening in nursing homes that lack the necessary human resources.
This study has several limitations that should be considered when interpreting the data. First,
the number of participants was small. There was no precedent for the application of an interactive
robot to a neuropsychological examination. Therefore, we considered that the number of cases wasappropriate as an initial pilot study aimed at optimizing the protocol for future studies. Second, thesex ratio and age of participants was biased, and it is possible that sex and age may inﬂuence scoresin the robot test. However, strong correlations between robot scores and the MMSE (or HDS-R)
suggests that the robot scores are not affected by the sex and age of the examinee. Third, responses
to the robot were not quantified, therefore we could not demonstrate a statistical association between
the severity of dementia and the responses to the robot. Finally, there is a possibility that thelearning effect occurred, because MMSE and HDS-R were performed before the robot test. It is
possible that the task was performed appropriately as a result of having experienced the MMSE andHDS-R, even if the instruction by the robot was inadequate. However, most of the instructions in the
robot test were modified for the robot conversation from original HDS-R. Furthermore, to minimize
learning effects, we modified questions relating to delayed recall and changed the starting number forthe serial sevens. Therefore, we assume the learning effect did not significantly affect the robot scoreor the interactions between participants and robot in this study.
Conclusions
Even though the interviewer is a general-purpose interactive robot, our novel robot was able totalk to and get the necessary information from elderly participants to detect poor cognitive functioning.
Our pilot study suggests that a general-purpose interactive robot could be a promising support toolfor dementia screening. Although our robot currently requires human scoring, it can still reduce
human cost because a non-specialized human can effectively score recorded interviews from robot
tests in their spare time. We expect that in the future, interactive robot tests will become a valid andreliable tool for clinicians when screening for dementia in nursing homes that lack appropriate
human resources.
Acknowledgements
All authors have no COI to declare regarding the present study.

- 20 -

Can Robots Detect Poor Cognitive Function?

We would like to thank Editage (www.editage.jp) for English language editing. We are also
grateful to Mai Horimoto, Yukiho Watai, and Masayo Kobayashi for conducting neuropsychiatry
examinations.
References
1. Atri A. Effective pharmacological management of Alzheimer s disease. Am J Manag Care 2011;17:S346-355.
2. Brodaty H, Low LF, Gibson L, et al. What is the best dementia screening instrument for general practitioners
to use? Am J Geriatr Psychiatry 2006;14:391-400.
3. Kobayashi S. Neuropsychological test using personal computer. Japanese Journal of Neuropsychology 2002:18:
188-193. (In Japanese)
4. Tsuji M, Higashi Y, Iwase Y, et al. Neuropsychological examination of elderly subjects with dementia andmentally healthy elderly using a touch panel of a personal computer. Journal of Life Support Engineering 2009;21:158-163. (In Japanese)
5. Onoda K, Yamaguchi S. Revision of the cognitive assessment for dementia, iPad version (CADi2). PLoS One
2014;9:e109931.
6. Gustafsson C, Svanberg C, Müllersdorf M. Using a robotic cat in dementia care: a pilot study. J Gerontol Nurs
2015;41:46-56.
7. McGlynn S, Snook B, Kemple S, et al. Therapeutic robots for older adults: investigating the potential of Paro.
HRI 14 Proceedings of the 2014 ACM/IEEE international conference on Human-robot interaction. ACM, NY,
USA, 2014. pp. 246-247.
8. Petersen S, Houston S, Qin H, et al. The utilization of robotic pets in dementia care. J Alzheimers Dis 2017;55:
569-574.
9. D Onofrio G, Sancarlo D, Raciti M, et al. MARIO project: validation and evidence of service robots for older
people with dementia. J Alzheimers Dis 2019;68:1587-1601.
10. Kuwahara N. Assessing the use of communication robots for recreational activities at nursing homes.
European Union Digital Library 2016;16(7):e4.
11. Imai Y, Hasegawa K. The Revised Hasegawa s Dementia Scale (HDS-R) - Evaluation of its usefulness as ascreening test for dementia. Hong Kong Journal of Psychiatry 1994;4:20-24.
12. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on
Alzheimer s Disease. Neurology 1984;34:939-944.
13. Folstein MF, Folstein SE, McHugh PR. Mini-mental state . A practical method for grading the cognitive stateof patients for the clinician. J Psychiatr Res 1975;12:189-198.
14. Artero S, Petersen R, Touchon J, et al. Revised criteria for mild cognitive impairment: validation within alongitudinal population study. Dement Geriatr Cogn Disord 2006;22:465-470.
15. Kanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow
Transplant 2013;48:452-458.
16. Kim KW, Lee DY, Jhoo JH, et al. Diagnostic accuracy of mini-mental status examination and revised
Hasegawa Dementia Scale for Alzheimer s disease. Dement Geriatr Cogn Disord 2005;19:324-330.
17. Valentí Soler M, Agüera-Ortiz L, Olazarán Rodríguez J, et al. Social robots in advanced dementia. Front Aging
Neurosci 2015;7:133.
18. Baddeley AD, Warrington EK. Amnesia and the distinction between long- and short-term memory. Journal of
Verbal Learning and Verbal Behavior 1970;9:176-189.
19. Milner B. Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 1972;19:421446.
20. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening
tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695-699.
21. Wouters H, Appels B, van der Flier WM, et al. Improving the accuracy and precision of cognitive testing inmild dementia. J Int Neuropsychol Soc 2012;18:314-322.

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Osaka City Med. J. Vol. 66, 23-29, 2020

Efficacy of Practical Training Using a Simulator for
Auscultation of Lung Sounds
YOSHIHIRO TOCHINO1,3), KANAKO SATO2), KENJI SAWA2), SACHIKO OKU3),
KAZUTO HIRATA2), and TAICHI SHUTO1,3)
Departments of Medical Education and General Practice1) and Respiratory Medicine2),
Osaka City University Graduate School of Medicine; andOsaka City University Hospital, Skills Simulation Center3)

Abstract
BackgroundAuscultation training using a simulator before professors rounds has been performed in fifth-year
medical students since 2012. The objective of the present study was to assess whether students could
differentiate abnormal lung sounds in patients and whether their performance improved during
professors rounds after simulation-based training.
Methods
Fifth-year medical students were divided into a simulation-based training group (Group S) and anon-simulation training group (Group N). In Group S, auscultation training using a simulator was
performed just before professors rounds. In Group N, students listened to recordings of four
abnormal lung sounds. The students auscultated lung sounds in patients and mentioned theidentified lung sounds. Teachers assessed the students attitudes and auscultation skills.
Results
There were nine students in Group S and nine in Group N. The accurate response rate for norales was significantly higher in Group S than in Group N (p＝0.003). With regard to fine crackles
and coarse crackles, the accurate response rates tended to be higher in Group S than in Group N (p＝0.056 and p ＝0.053, respectively). Standard precautions, communication, and enthusiasm as
students attitudes showed no significant differences between Group S and Group N. On the other
hand, auscultation skills were significantly better in Group S than in Group N (p＜0.05).
Conclusions
Auscultation training using a simulator helped medical students differentiate abnormal lungsounds in patients. This training also improved auscultation skills but did not improve the attitudesof medical students during professors rounds.
Key Words: Auscultation; Simulation-based education; Lung sounds

Received September 18, 2019; accepted November 26, 2019.
Correspondence to: Yoshihiro Tochino, MD, PhD
Department of Medical Education and General Practice, Osaka City University Graduate School of
Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3797; Fax: +81-6-6645-3796
E-mail: m1152721@med.osaka-cu.ac.jp- 23 -

Tochino et al

Introduction
Chest auscultation is an important, simple, and non-invasive skill among medical workers, which
provides clinical information about lung structure and function. Therefore, medical students shouldbe able to auscultate patients accurately before graduation.
Simulation-based education has recently been adopted worldwide, as well as in Japan1-3). Miller
presented the assessment of clinical skills as a pyramid with the following four levels: knows, knows
how, shows how, and does4). Simulation is a shows how level and is before the does level, which is
performed before clinical practice. The efficacy of the lung sound simulator Mr. Lung ® has beenreported, and it has been assessed whether medical students could differentiate abnormal lungsounds from the simulator5,6). However, there are few reports on whether auscultation training ispractically effective for differentiating abnormal lung sounds in patients.
Auscultation training using a simulator before professors rounds has been performed in fifth-year
medical students since 2012 at Osaka City University7). We previously reported that self-assessmentof auscultation with regard to abnormal lung sounds after auscultation training using a simulator
improved the confidence of students to differentiate lung sounds when compared with the findings
before simulation training. However, our previous report did not clarify whether the students could
differentiate abnormal lung sounds in real patients.
The objective of this study was to assess whether students could differentiate abnormal lungsounds in patients and whether their performance improved during professors rounds after
simulation-based training. We hypothesize that auscultation training using a simulator helps
medical students differentiate abnormal lung sounds in patients, and also improves the auscultation
skills or attitudes of medical students during professors rounds.

Methods
Clinical clerkship of fifth-year students in Osaka City University involves division of students into
groups (four or five students) and rotation around 18 departments of Osaka City University Hospitalfor 2 weeks each. The present study was performed between November 2017 and February 2018, andit enrolled four student groups. The participants were fifth-year medical students who provided
consent for study inclusion. They were divided into a simulation-based training group (Group S) anda non-simulation training group (Group N). The four student groups were alternately included inthese two training groups.
In Group S, auscultation training was performed using a simulator for 1 hour just before
professors rounds, and it was attended by students, doctors, and nurses. The Mr. Lung ® (Kyoto
Kagaku, Kyoto, Japan) simulator was used. Four abnormal sounds, including fine crackles, coarse
crackles, wheezes, and rhonchi, were auscultated in the simulator using a stethoscope, with
explanations from teachers who were respiratory specialists. During simulation training, theteachers also provided information about standard precautions, communication, and favorable
attitudes for professors rounds. In Group N, students listened to recordings of the four abnormallung sounds and received explanations from the same teachers, who provided explanations to GroupS, for 1 hour just before professors rounds. In this group, the teachers also provided information
about standard precautions, communication, and favorable attitudes for professors rounds.
During professors rounds, all participants auscultated lung sounds in patients who agreed to thisstudy, and they mentioned the identified lung sounds in assessment sheets (Fig. 1). Additionally, the- 24 -

Efficacy of Simulator Training for Auscultation

Figure 1. Assessment sheet. Students mentioned the lung sounds on the top, and teachers mentioned the attitudes
and auscultation skills of the students at the bottom of the sheet.

teachers mentioned the attitudes of the students during professors rounds and their auscultation
skills in the same assessment sheets.
The study protocol was approved by the appropriate Institutional Ethics Committee (Osaka City
University, Graduate School of Medicine; approval no.: 2865).
Statistical analysis
Statistical analyses were performed with JMP (version 10; SAS Institute, Inc., Cary, NC, USA).
Non-parametric analysis was performed for comparison of the two groups. The Mann-Whitney U test
was used to compare abnormal lung sounds, students attitudes during professors rounds, andstudents auscultation skills. A p-value ＜0.05 was considered significant.

Results
In this study, nine students were included in Group S and nine were included in Group N. In
Group S, four students auscultated two patients and five students auscultated four patients. In
Group N, eight students auscultated three patients and one student auscultated four patients.
Differentiation of abnormal lung sounds was better in Group S than in Group N
The results of accurate responses for lung sounds in Group S and Group N are presented in Figure
2. Both groups did not listen to wheezes and rhonchi, and thus, we presented graphs of fine crackles,
coarse crackles, and no rales (normal lung sounds). The accurate response rate for no rales was
significantly higher in Group S than in Group N (p＝0.003). With regard to fine crackles and coarse
crackles, the accurate response rates tended to be higher in Group S than in Group N (p＝0.056 and- 25 -

Tochino et al

Figure 2. Results of lung sounds in Group S and Group N. Group S is a simulation-based training group and GroupN is a non-simulation training group. Both groups did not listen to wheezes and rhonchi. The accurate response rate
for no rales is significantly higher in Group S than in Group N (graphs on the right). With regard to fine crackles andcoarse crackles, the accurate response rates tend to be higher in Group S than in Group N (graphs on the left and in
the middle, respectively).

p＝0.053, respectively).
Simulation-based training improved students auscultation skills but not their attitudes
during professors rounds
Students attitudes during professors rounds are presented in Figure 3, and their auscultation
skills during professors rounds are presented in Figure 4. Standard precautions, communication,and enthusiasm with regard to students attitudes were not significantly different between Group S
and Group N. On the other hand, auscultation skills were significantly better in Group S than inGroup N (p＜0.05). As of auscultation skills, eight students were good and one student was notgood in Group S, while five students were good and four students were not good in Group N.

Discussion
The findings of the present study indicate that auscultation training for lung sounds using asimulator might help students accurately differentiate abnormal lung sounds. Arimura et al reported
the efficacy of auscultation training for lung sounds using a simulator among medical students6).
They assessed whether students could differentiate four abnormal lung sounds in a lung soundsimulator and not in patients. Our study assessed students auscultation skills in patients; however,- 26 -

Efficacy of Simulator Training for Auscultation

Figure 3. Results of students attitudes during professors rounds in Group S and Group N. Group S is a simulationbased training group and Group N is a non-simulation training group. There are no significant differences between
the two groups.

Figure 4. Results of students auscultation skills during professors rounds in Group S and Group N. Group S
is a simulation-based training group and Group N is a non-simulation training group. The auscultation skills are
significantly better in Group S than in Group N. Eight students were good and one student was not good in Group S,
while five students were good and four students were not good in Group N.

- 27 -

Tochino et al

only two abnormal lung sounds (fine crackles and coarse crackles) and normal lung sounds (no rales)
were evaluated. Although further research involving other abnormal lung sounds is needed, thefindings of our study indicate that simulation-based training might improve the ability of students to
auscultate lung sounds in the clinical setting.
Although simulation-based training improved auscultation skills, it did not improve the attitudesof medical students during professors rounds. In auscultation training using a simulator, students
auscultated sounds from the simulator with a stethoscope. The use of a stethoscope might havehelped improve their auscultation skills. Mangione et al reported that patient revisits were
important for medical students and residents to improve their auscultation skills8). Therefore, in thepresent study, simulation-based training might have improved the auscultation skills of the students
in Group S. On the other hand, simulation-based training did not improve their attitudes, including
standard precautions, communication, and enthusiasm. Abe et al recently reported about theeducational benefits associated with the use of a robotic patient simulation system for thedevelopment of clinical attitudes9). The robotic patient was similar to a real patient, which might
have helped improve students attitudes. To improve students attitudes with our simulation-based
training, we need to adopt conditions that represent real clinical settings and patients.
An important limitation of this study was the difference in patients between Group S and GroupN. Clinical clerkship of fifth-year students was performed every 2 weeks; therefore, few patientswere the same for Group S and Group N. Nevertheless, a professor from the Department ofRespiratory Medicine auscultated the lung sounds from the patients and confirmed the lung sounds
before professors rounds; therefore, patients in this study appear to have been selected appropriatelyby the professor. One more limitation of this study is small number of students. The accurate
response rate for fine crackles and coarse crackles tended to be higher in Group S than in Group N,
therefore to increase number of students enrolled may lead to statistically significant of them.
We concluded that auscultation training using a simulator helped medical students differentiate
abnormal lung sounds in patients. This training also improved auscultation skills but did not
improve the attitudes of medical students during professors rounds.
Acknowledgement
All authors have no COI to declare regarding the present study.
References
1. Issenberg SB, McGaghie WC, Hart IR, et al. Simulation technology for health care professional skills training
and assessment. JAMA 1999;282;861-866.
2. Bradley P. The history of simulation in medical education and possible future directions. Med Educ 2006;40;
254-262.
3. Ishikawa K, Sugawara A, Kobayashi G, et al. A 2012 nationwide survey on the application of simulation-based
education in medical schools in Japan. Igaku Kyoiku/ Medical Education (Japan) 2013;44;311-314. (InJapanese)
4. Miller GE. The assessment of clinical skills/competence/performance. Acad Med 1990;65;S63-S67.
5. Yoshii C, Yamauchi H, Kaneko H, et al. Experience with the lung-sound auscultation simulator "Mr. Lung".
Igaku Kyoiku/ Medical Education (Japan) 2004;35;343-347. (In Japanese)
6. Arimura Y, Komatsu H, Yanagi S, et al. Educational usefulness of lung auscultation training with an
auscultation simulator. Nihon Kokyuki Gakkai Zasshi 2011;49;413-418. (In Japanese)
7. Tochino Y, Yoshimoto N, Oku S, at al. Educational effects of practical training of auscultating lung sounds
using simulator for fifth-year medical students. Osaka City University Journal of Higher Education Studies- 28 -

Efficacy of Simulator Training for Auscultation
2016;14;1-8. (In Japanese)
8. Mangione S, Nieman LZ. Pulmonary auscultatory skills during training in internal medicine and family
practice. Am J Respir Crit Care Med 1999;159;1119-1124.
9. Abe S, Noguchi N, Matsuka Y, et al. Educational effects using a robot patient simulation system for developmentof clinical attitude. Eur J Dent Educ 2018;22;e327-e336.

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Osaka City Med. J. Vol. 66, 31-37, 2020

Analysis of Gait in Stroke Patients with Hemiplegia
Using a Wearable Accelerometer
TAMOTSU NAKATSUCHI1), MITSUHIKO IKEBUCHI2,5), TOMOYA NISHIKAWA3), TETSUYA SUGAHARA3),
SHIGEYOSHI NAKAJIMA4), MASANOBU MORIMOTO3), and HIROAKI NAKAMURA5)
Tsuji-GEKA Rehabilitation Hospital1); Department of Rehabilitation medicine2),
Osaka City University Hospital; Yoshieikai Hospital3);
Department of Electric Information System4), Osaka City University
Graduate School of Engineering; and Department of Orthopedic Surgery5),
Osaka City University Graduate School of Medicine

Abstract
Background
Restoration of walking ability is the major goal of rehabilitation for stroke patients withhemiplegia. However, assessment methods are based on subjective evaluation, and no establishedobjective assessment method exists that is clinically feasible. This study aimed to determine whether
accelerometers could be used as clinically feasible objective assessment tools for predicting walking
ability in stroke patients with hemiplegia.
Methods
Participants included 36 stroke patients with hemiplegia who were able to walk (group C) and 40
healthy individuals (group N). Wearable accelerometers were attached at the seventh cervical (C7)and third lumbar vertebral (L3) levels. Acceleration, in three axial directions (mediolateral, vertical,
and anteroposterior), was measured during walking. Root mean square values were calculated andused as indices for cervical and lumbar sway. Associations between these values and the degree ofgait independence, measured using the Functional Ambulation Classification (FAC) score, were
evaluated.
Results
The cervical/lumbar sway significantly increased with decreasing degrees of gait independence(from groups with FAC5 to FAC4 and FAC3) in all three directions in group C. In group N, thecervical sway was smaller than the lumbar sway in all three directions. In group C, the cervical sway
increased with decreasing degrees of gait independence; however, in the group with FAC3, thecervical sway was greater than the lumbar sway, showing a reverse phenomenon.
Conclusions
These results revealed an association between body sway and degree of gait independence andReceived November 7, 2019; accepted April 14, 2020.
Correspondence to: Tamotsu Nakatsuchi, MD, phD.
Tsuji-GEKA Rehabilitation Hospital,
3-24 Ikutamamaemachi, Tennouji-Ku, Osaka 543-0072, Japan
Tel: +81-6-6771-0681; Fax: +81-6-6773-8647
E-mail: nakatsuchi@kankikai.com- 31 -

Nakatsuchi et al

demonstrated that evaluating cervical/lumbar sway using wearable accelerometers helped accurately
and objectively assess walking ability.
Key Words: ‌Accelerometer; Gait analysis; Hemiplegia; Functional Ambulation
Classification

Introduction
It is well-known that many stroke patients with hemiplegia have abnormal gait (i.e., an abnormal
walking pattern) even after they become capable of walking. Walking with an abnormal gait may
lead to joint deformity and an increase in risk of falls. Therefore, it is important for stroke patientswith hemiplegia to develop a normal or near-normal and stable gait as early as possible. To achievethis, an accurate and objective assessment of walking ability is needed; however, in the current
clinical setting, the assessment of walking ability is based on subjective evaluation techniques, suchas observation by the examiner.
In recent years, the method of using a wearable accelerometer has received attention as an
objective assessment tool to predict walking ability1). In this method, a wearable accelerometer istypically attached to the lumbar spine near the body s center of gravity, and acceleration of the body s
center of gravity is measured during walking and analyzed. However, few studies have evaluated theacceleration at regions other than the back. Although Sugawara et al reported correlations between
acceleration at the cervical and lumbar spine during walking and severity of hemiplegia (i.e.,
impairment) in patients with stroke2), to our knowledge, no studies have investigated the association
between the acceleration of the body s center of gravity during walking and the degree of gait
disturbance (i.e., disability).
This study aimed to evaluate the associations between cervical/lumbar sway during walking andwalking ability using a wearable accelerometer in stroke patients with hemiplegia, and to determine
whether the accelerometer could be used as a clinically feasible objective assessment tool to predict
walking ability in such patients.

Methods
Participants included 36 stroke patients with hemiplegia with no evidence of joint disorder in thelegs who were able to sufficiently understand the oral explanation and were able to walk along a
16-m straight course without assistance. Forty healthy individuals without gait disturbances werealso included as controls. This study was approved by the ethics committee of our institution(Approval Number #1). Informed consent was obtained from each participant after full written andoral explanation of the objectives of the study and the methodologies involved.
The stroke patients with hemiplegia (group C) consisted of 29 men and 7 women, with a mean ageof 69.9±9.1 years. The diagnoses were cerebral infarction in 25 patients and cerebral hemorrhage in
11 patients. Hemiplegia was right-sided in 26 patients and left-sided in 10 patients. The degree ofhemiplegia, based on the Brunnstrom Recovery Stages for the lower extremities, was Ⅳ (movement
deviating from basic synergies) in 8 patients, Ⅴ (movement independent of basic synergies) in 16
patients, and Ⅵ (near-normal coordinated movement) in 12 patients. The healthy individuals (groupN) consisted of 26 men and 14 women, with a mean age of 27.7±7.7 years.
The degree of gait independence was rated according to the Functional Ambulation Classification(FAC) score of the Hospital at Sagunto. The FAC is a tool to evaluate functional walking ability based- 32 -

Analysis of Gait in Stroke Patients
Table 1. Functional Ambulation Classification (FAC)
0: Nonfunctional Ambulator

Patient cannot ambulate, ambulates in parallel bars only, or requires supervisionor assistance from more than one person to ambulate safely outside parallel bars.

1: Ambulator-Dependent for
Physical AssistancePatient requires manual contact of no more than one person during ambulationon level surfaces to prevent falling. Contact is continuous and necessary tosupport body weight as well as to maintain balance or assist coordination.

2: Ambulator-Dependent for
Physical AssistancePatient requires manual contact of no more than one person during ambulationon level surfaces to prevent falling, consisting of continuous or intermittent lighttouch to assist balance or coordination.

3: Ambulator-Dependent forSupervision

Patient can ambulate without manual contact from another person but, for safety,
requires standby guarding of no more than one person because of poor judgement,
questionable cardiac status, or the need for verbal cuing to complete the task.

4: Ambulator-Independent,
Level surfaces only

Patient can ambulate independently on level surfaces, but requires supervision or
physical assistance to negotiate any of the following: stairs, inclines, or non-levelsurfaces.

5: Ambulator-Independent

Patient can ambulate independently on nonlevel and level surfaces, stairs andinclines.

Figure 1. A wearable accelerometer, IMU-Z (ZMP Inc.), with a sensor unit size of 42.0×52.5×20.5 mm and a weightof 35g, was attached to the cervical and lumbar spine of each participant.

on observation, using a 6-point scale ranging from 0 to 5, with greater numbers indicating betterwalking ability 3) (Table 1). The degree of gait independence in group C was FAC3 in 6 patients (group
FAC3), FAC4 in 11 patients (group FAC4), and FAC5 in 19 patients (group FAC5).
A wearable accelerometer, IMU-Z (ZMP Inc.), with a sensor unit size of 42.0×52.5×20.5 mm and aweight of 35g, was attached to the cervical and lumbar spine of each participant, and the acceleration
during walking at the cervical and lumbar spine were measured. The measurements were uploaded
to a computer (the host terminal) via Bluetooth, thereby allowing for a real-time measurement ofacceleration without interfering with walking (Fig. 1).
The accelerometer was attached to the neck at the level of the seventh cervical vertebra (C7) andto the hip at the level of the third lumbar vertebra (L3). C7 was chosen because it is easy to identify- 33 -

Nakatsuchi et al

this vertebra tactually. L3 was chosen because it is closer to the body s center of gravity and moves
in parallel with the body s center of gravity, with minimal horizontal rotation4). Each accelerometer
was fixed using an elastic belt, and the absence of potential influence of the elastic belt on
performance was confirmed by asking participants about the presence of a feeling of restraint whileattaching the device every time. Participants wore their own comfortable shoes and were allowed touse a lower extremity orthosis, if needed, during the walking test; however, they were not allowed touse a cane. During the test, all obstacles that might interfere with walking were removed from theenvironment so that participants could concentrate on walking. In addition, for security purposes,
another therapist (non-examiner) stood by the participant during the test in case of unexpected
accidents. Participants walked at their preferred speed.
The walking course included two 3-m sections, each for warm-up and cool down, and a 10-m
course for speed measurements, with a total of 16 m. Root mean square (RMS) values were
calculated from the acceleration data in the three axial directions obtained during steady-state
walking on the 10-m course. The RMS indicates the mean amplitude of the signal waveforms, andthe RMS calculated from the acceleration data during walking indicates the degree of body sway
during walking; higher values reportedly indicate greater sway 5-7). The RMS value obtained from theaccelerometer attached to C7 was used as the index of cervical sway, while that obtained from theaccelerometer attached to L3 was used as the index of lumbar sway. The RMS value is known to be
proportional to the square of walking speed, which may result in greater values. Therefore, theinﬂuence of walking speed was eliminated by dividing the obtained RMS by the square of walking
speed8). Furthermore, the influence of body height was eliminated by dividing the value by bodyheight.
Statistical analysis of the relationship between the degree of gait independence and the cervical/
lumbar RMS values was performed using analysis of variance with a significance level of p＜0.05.
Statistical analyses were performed using statistical software [R].

Results
The mean RMS values in group N (Control) and group C (FAC 5, 4, 3) for the cervical and lumbar
spine were shown in the table 2: in the mediolateral (ML) direction, the vertical (V) direction, and theanteroposterior (AP) direction, respectively. The differences were statistically significant for all items
by analysis of variance (Table 2).
Furthermore, a comparison between cervical and lumbar RMS values showed that the former was
lower than the latter in all three axial directions in group N, and the differences were statisticallysignificant. In group C, the cervical RMS values increased with decreasing degrees of gait

Table 2. The RMS values in group N (Control) and group C (FAC 5, 4, 3) (mean±SD), and P values by analysis ofvariance.
ML (C7)ML (L3)

V (C7)V (L3)AP (C7)AP (L3)Control
FAC50.034±0.008
0.079±0.027

0.049±0.013

0.069±0.010

0.068±0.021

0.122±0.037

0.087±0.022
0.149±0.050

0.037±0.010

0.109±0.046

0.108±0.038

FAC4

0.203±0.091

0.203±0.067

0.238±0.102

0.267±0.099

0.069±0.027
0.151±0.176

FAC3

0.379±0.251

0.328±0.103

0.383±0.180

0.359±0.107

0.318±0.228

P value

3.06E-16

1.48E-21

3.29E-18

6.78E-20

2.46E-130.307±0.144
1.27E-15- 34 -

0.176±0.074

Analysis of Gait in Stroke Patients

Figure 2. RMS values in ML direction of representative case are intermediate between FAC4 and FAC5, and inparticular, the value of lumbar spine is close to the value of FAC4.

Table 3. FAC assessment for representative case by each therapist ( ＊ :standard)
Therapists (Years of experience)＊

FAC(30 years)(9 years)(6 years)(5 years)(3 years)(3 years)

4
4
5
5
5
5

G (2 years)
H (2 years)
I (1 year)

4
3
4

A
B
C
D
E
F

independence; and cervical RMS value was higher than the lumbar RMS value in group FAC3,
showing a reverse phenomenon.
Here, we report a representative case (Case 1). The patient was a 76-year-old man. He had righthemiplegia due to cerebral infarction and his Brunnstrom recovery stage for the lower extremities
was Ⅴ.
The mean RMS values for the cervical and lumbar spine obtained from the accelerometer in Case
1 were as follows: in the ML direction, 0.145 and 0.178; in the V direction, 0.162 and 0.256; and in the
AP direction, 0.079 and 0.133, respectively. A comparison of these values with the mean RMS valuesof group C (according to the FAC score) in all three axial directions showed that the RMS values ofCase 1 were within±1SD of the mean RMS of group FAC4; moreover, it was lower than that of group
FAC3, and outside the range of values of group FAC5. These findings suggested that the status ofCase 1 corresponded to that of group FAC4 (Fig. 2 : the result in ML direction).

- 35 -

Nakatsuchi et al

Furthermore, the degree of gait independence of representative case was evaluated by 10 physicaltherapists (the mean work experience duration was 6.2 years, ranging from 1 to 30 years) using the
FAC score. Although there were variations among therapists in terms of the results, the patient
status was rated as FAC4 by all physical therapists with sufficient experience. Thus, the result
obtained from the RMS values coincided with that obtained from physical therapists with sufficientexperience (Table 3).

Discussion
Walking is an extremely complex movement. Bipedal locomotion̶walking on two legs in an
upright position̶is a dynamic repetitive movement with a regular pattern, in which the lost balanceis restored by using two legs alternatively. To achieve walking, control of the trunk (central part ofthe body) is necessary; thus, stability of the trunk is important for achieving smooth movement of theupper and lower extremities. It is therefore considered that decreased trunk function leads todecreased walking ability. In addition, the anatomical structure for controlling trunk motion isextremely complex9).
The results of this study showed that body sway during walking (both cervical and lumbar spine)
significantly decreased with increasing degrees of gait independence in all three axial directions (ML,V, and AP). The findings showed an association between body sway during walking and walking
ability.
In group N, the cervical sway was significantly smaller than the lumbar sway in all three axial
directions. In group C, the cervical sway increased with decreasing degrees of gait independence;
moreover, in group FAC3, the cervical sway was greater than the lumbar sway, showing a reverse
phenomenon. The results showed that the characteristic features of body sway in group FAC3 weredifferent from those of healthy individuals. Increased cervical sway in group FAC3 was considered
one of the reasons for these patients requiring stand-by assistance.
FAC3 is described as follows: Patients can walk independently on level ground but require standby help from one person for security purposes (walking with stand-by assistance) 2). A study inhealthy elderly individuals using a motion sensor indicated a significant difference in thedisplacement range of body sway during walking between the lower part of the trunk and the head,
and that the trunk sway was attenuated in the process of its transmission to the head. The findings
support the notion that the higher cervical sway in comparison to the lumbar sway in group FAC3, in
contrast to the pattern observed in healthy individuals, was one of the reasons for these patientsrequiring stand-by assistance while walking.
Group FAC4/FAC5 showed smaller cervical/lumbar sway in comparison to group FAC3; moreover,in contrast to group FAC3, group FAC4/FAC5 showed smaller cervical sway than lumbar sway̶abody sway pattern similar to that of healthy individuals. We believe that the decrease in cervical/
lumbar sway, as well as the relative decrease in cervical sway compared with lumbar sway, leads toan improvement in safety and independence of gait.
In general, walking ability is assessed by observing walking behavior and by detecting thepresence/absence of abnormal gait pattern. Observational assessment of walking can yield acceptable
results if it is performed in a systematic manner; however, detailed measurements may be
inconsistent among examiners9); some researchers may consider that the inter-rater reliability is low
owing to the differences in observational perspective and subjective scale .

- 36 -

Analysis of Gait in Stroke Patients

This study showed that cervical/lumbar sway during walking, measured using a wearable
accelerometer, significantly differed according to the degree of gait independence. It wasdemonstrated that the evaluation of cervical/lumbar sway using the wearable accelerometer allows
accurate and objective assessment of walking ability, and the wearable accelerometer can be used asa clinically feasible, objective assessment tool.
Some limitations of the study must be considered while interpreting the study results. There wasa large difference in the mean age of group C (stroke patients with hemiplegia) and group N (healthy
individuals), which may have inﬂuenced the results. Walking ability, and dynamic and static balance
are reportedly reduced in older people compared with younger people10,11). Further studies using an
age-matched control group are needed. In addition, the time dependent changes in the degree of gait
independence in stroke patients with hemiplegia were not examined in this study, and further studyof this issue is also needed.
This study evaluated the associations between cervical/lumbar sway during walking and thedegree of gait independence using a wearable accelerometer in stroke patients with hemiplegia.
The cervical/lumbar sway significantly increased in all three axial directions (ML, V, and AP) withdecreasing degrees of gait independence [from group FAC5 (completely independent) to FAC4
(independent only on plain ground) and FAC3 (walking with stand-by assistance)] in both group C(stroke patients with hemiplegia) and group N (healthy individuals). Furthermore, the cervical sway
increased with decreasing degrees of gait independence; in addition, in group FAC3, the cervical sway
was greater than the lumbar sway, showing a reverse phenomenon.
The results from this study revealed associations between cervical/lumbar sway during walking
and the degree of gait independence, and demonstrated that the wearable accelerometer could be
used as a clinically feasible objective assessment tool for predicting walking ability.
Acknowledgements
All authors have no COI to declare regarding the present study.
References
1. Auvient B, Brrunt G, Touzard C, et al. Reference data for normal subjects obtained with an accelerometricdevice. Gait Posture 2002;16:124-134.
2. Sugahara T. The usefulness of accelerometer for analyzing the gait of patients with hemiplegic stroke.
Japanese Journal of Clinical Biomechanics 2017;38:319-323.(In Japanese)
3. Holden MK, Gill KM, Magliozzi MR, et al. Clinical gait assessment in the neurologically impaired. Reliability
and meaningfulness. Phys Ther 1984;64:35-40.
4. Moe-Nilssen R, Helbostad JL. Trunk accelerometry as a measure of balance control during quiet standing.
Gait Posture 2002;16:60-68.
5. Mentz HB, Load SR, Fitzpatrick RC. Age-related differences in walking stability. Age Ageing 2003;32:137-142.
6. Mentz HB, Load SR, Fitzpatrick RC. Acceleration patterns of the head and pelvis when walking on level andirregular surfaces. Gait Posture 2003;18:35-46.
7. Henriksen M, Lund H, Moe-Nilssen R, et al. Test-retest reliability of trunk accelerometric gait analysis. Gait
Posture 2004;19:288-297.
8. Moe-Nilssen R. A new method for evaluating motor control in gait under real-life environmental conditions.
Part2: Gait analysis. Clin Biomech (Bristol, Avon) 1998;13:328-335.
9. Jacquelin Perry. Gait Analysis‐Normal and Pathological Function‐second edition. New Jersey: Slack Inc;
2007.
10. Bohannon RW. Comfortable and maximum walking speed of adults aged 20-79 years: reference values anddeterminants. Age Aging 1997;26:14-19.
11. Duncan PW, Weiner DK, Chandler J, et al. Functional reach: a new clinical measure of balance. J Gerontol 1990;
45:M192-197.

- 37 -

Osaka City Med. J. Vol. 66, 39-48, 2020

Finite Time Span of High-intensity Signal on T1-weighted Magnetic
Resonance Imaging Produced by a Human Blood Clot Usinga Circulating Vessel Phantom System
SHOICHI EHARA1), KENJI MATSUMOTO1), DAISUKE KIMURA2), DAICHI TAKEMORI2),
EIJI YAMADA2), TAKAO ICHIDA2), and MINORU YOSHIYAMA1)
Department of Cardiovascular Medicine1), Osaka City University Graduate School of Medicine;and Radiology2), Osaka City University Hospital

Abstract
Background
Following the introduction of non-contrast T1-weighted imaging (T1WI) in magnetic resonanceimaging, using the inversion-recovery gradient-echo sequence, many researchers have shown thathigh-intensity signals (HISs) in carotid and coronary arterial walls indicate the presence of
intraplaque hemorrhage or intracoronary thrombus containing methemoglobin. However, the timespan of HISs generated by thrombus remains unknown. The aim of this study was to image acirculating vessel phantom with T1WI to determine if ﬂow disturbance causes artifacts, such as a
HIS and to perform serial observations of a human blood clot.
Methods
Vessel bifurcation models were created using Y-type tube joints made of polypropylene, with andwithout stenosis or occlusion with a human blood clot or non-magnetic material. Our circulating
vessel phantom consisted of five parts, namely, a non-pulsatile pump, a ﬂuid reservoir, silicone tubes,
a vessel surrounding a human myocardium-equivalent phantom, and human blood-equivalent ﬂuid.
We evaluated T1WI using this system.
Results
On T1WI, the areas surrounding the bifurcations with stenosis or occlusion with non-magnetic
material showed no HISs. However, a HIS was found at the site of occlusion with a blood clot. The
signal intensity of the blood clot increased, as compared with the baseline, at 1 and 3 months,
subsequently decreasing at 4 months and then disappearing at 5 months.
Conclusions
This phantom study showed that a human blood clot generated a HIS on T1WI without being
affected by blood ﬂow blood, and the presence of the signal was limited to a finite time span of ＜5months.
Received November 14, 2019; accepted April 14, 2020.
Correspondence to: Shoichi Ehara, MD.
Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Tel: +81-6-6645-3801; Fax: +81-6-6646-6808
E-mail: ehara@med.osaka-cu.ac.jp- 39 -

Ehara et al

Key Words: ‌Magnetic resonance imaging; Atherosclerotic plaque; Thrombosis;
Phantom; Coronary artery

Introduction
Advances in the field of magnetic resonance (MR) imaging have allowed for non-invasive, in vivo
assessment of human carotid1-5) and coronary atherosclerotic plaques6-14). Following the introduction of
non-contrast T1-weighted imaging (T1WI), using inversion-recovery gradient-echo sequence withblack-blood condition, many researchers have shown that high-intensity signals (HISs) in the carotidand coronary arterial walls indicate the presence of intraplaque hemorrhage or intracoronary
thrombus containing methemoglobin2-8,10) and relate to future cardiovascular events9,11,12). Furthermore,some studies have demonstrated that MR imaging can identify not only the presence of a thrombus
or hemorrhage but also its stage of development in patients with deep vein thrombosis15), pulmonary
embolism, and complex carotid plaques4,16). However, the time span of HIS generated by thrombus
remains unknown.
The T1WI MR technique overcomes many difficulties associated with conventional techniques thatgenerated a signal based on blood ﬂow. With T1WI, signal generation does not rely on ﬂowing blood
because it uses a non-slice-selective inversion recovery pulse for the black-blood method. Further,image interpretation requires only the detection of a high signal, rather than visualization of theunaffected vessel wall 17). Although theoretically the T1WI technique is considered to be unaffected byblood ﬂow, this supposition has not been verified with actual clinical images.
Understanding the progression of the HIS from thrombi will ultimately require serial observations
with T1WI in MR. A circulating vessel phantom system is useful for observing and monitoring thedevelopment and disappearance of HISs produced by thrombi. It can also be used for assessing theeffects of flowing blood on the HIS with T1WI. The aims of this study are to verify whether flow
disturbance causes artifact like an HIS and to perform a serial observation of human blood clots,
using a circulating vessel phantom system with T1WI in MR.

Methods
The study was approved by the Osaka City University Hospital s ethics committee.
Production of vessel bifurcation models with stenosis or occlusion
Four types of vessel bifurcation models were created with Y-type tube joints made of polypropylene(width 3.2×inner diameter 0.65×height 5.0 cm; #PP-PY-S: AS ONE Co., Osaka, Japan). The firstmodel consisted of a bifurcation with total occlusion with human venous blood clot in one side branch,using blood obtained from a volunteer and coagulated at room temperature (Fig. 1A). The second
model consisted of occlusion formed by resin (non-magnetic material) in one side branch (Fig. 1B).
The third model involved severe stenosis formed by resin in one side branch (Fig. 1C), and the fourthcontained no stenosis or occlusion (Fig. 1D). Silicone tubes were connected to each end of thecoronary bifurcation models and then passed through the plastic container (diameter: 167 mm;
capacity: 3.2 liters) (Fig. 1).
Preparation for human blood-equivalent fluid and human myocardium-equivalent phantom
For MR imaging, the recognized T1 and T2 values in a 1.5T are approximately 1500 ms and 200
ms for the blood18), and around 950 ms and 50 ms for the myocardium19), respectively.
In our study, we first prepared a human blood-equivalent fluid. To prepare 10000 mL of- 40 -

Time Span of High-intensity Signal by Blood Clot

Figure 1. Four types of vessel bifurcation models with and without concentric stenosis or occlusion. A, Total occlusion
using a human blood clot in one side branch. B, Total occlusion formed by non-magnetic material in one side branch.
C, Severe stenosis formed by non-magnetic material in one side branch. D, No stenosis or occlusion. E, Silicone
tubes were connected to each end of the coronary bifurcation models. F, These tubes were passed through a plastic
container. G, A human myocardium-equivalent phantom, consisting of the dissolved agarose solution, was poured into
the prepared plastic container, and cooled to room temperature for solidification.

circulating fluid to approximate the relaxation times of blood, we mixed 1000 mL of Manganese
Chloride Tetrahydrate (Bothdel Oral Solution 10; Meiji Dairies Co. and Kyowa Hakko Kirin Co., Ltd,Tokyo, Japan) into 9500 mL of saline.
We then created a human myocardium-equivalent phantom using agarose powder (Type 1, low
EEO, #A-6013: SIGMA-ALDRICH, St. Louis, USA) as a gelling agent, Meglumine Gadopentetate(Magnevist; Bayer HealthCare, Berlin, Germany) as the T 1 modifier, Manganese Chloride
Tetrahydrate (Bothdel Oral Solution 10; Meiji Dairies Co. and Kyowa Hakko Kirin Co., Ltd, Tokyo,
Japan) as the T 2 modifier, NaN3 (Katayama Chemical, Osaka, Japan) as an antiseptic, andphysiological saline. To prepare a 3800g myocardium-equivalent phantom, we used 39.2g of agarose
powder (1.15%), 0.5 mL of Meglumine Gadopentetate, 357.9 mL of Manganese Chloride Tetrahydrate,
1.13g of NaN3 (0.03%), and 3400 mL of saline, as described in a previous report20,21). These ingredientswere mixed in a stainless steel pot and constantly stirred, while heated using an induction heating
apparatus. The heating continued until the agarose powder was dissolved, and a clear solution was
obtained. The agarose powder dissolved at 40℃ for 70 min, and heating continued for 80 min andthen stopped. The maximum temperature of the solution reached 70℃, and stirring continued until- 41 -

Ehara et al

Figure 2. Circulating vessel phantom system.

100 min.
Finally, the agarose solution was slowly poured into the prepared plastic container, equipped withthe previously mentioned coronary bifurcation models, and cooled to room temperature for solidification(Fig. 1).
Circulating vessel phantom system
Our circulating vessel phantom system consisted of five parts forming a closed circuit: a nonpulsatile pump, a ﬂuid reservoir, 8-mm inner diameter silicone tubes, a vessel phantom surrounding
a human myocardium-equivalent phantom, and human blood-equivalent fluid (Fig. 2). The mean
velocity of the human blood-equivalent ﬂuid was adjusted to 15-17 cm/s within the circulating vessel
phantom system, using a non-pulsatile pump22). This phantom was preserved in room air.
MR image acquisition
Phantom MR imaging was performed using a 1.5-T MR system (Philips Healthcare, Best, The
Netherlands) with a 32-elements cardiac coil. Images were obtained at baseline and once monthly for
up to eight months after collection of the human blood sample. Initial survey images were focusedaround the phantom, and reference images were then obtained to assess the sensitivity of parallel
imaging. First, a phase-contrast turbo gradient echo technique (Q-FLOW) was used to measure ﬂow
velocity within the circulating vessel phantom system23). Next, to confirm the ﬂow status through the- 42 -

Time Span of High-intensity Signal by Blood Clot

stenosis or occlusion, steady-state free precession three-dimensional MR angiographic images wereacquired (repetition time, 3.7 ms; echo time, 1.8 ms; ﬂip angle, 80°; SENSE factor, 2.0; number of
excitations, 1; acquisition trigger delay, 632 ms; field of view, 250×250×53 mm; acquisition matrix,
202×202; reconstruction matrix, 480×480×105, resulting in an acquired spatial resolution of 1.25×
1.25×1.5 mm, reconstructed to 0.52×0.52×0.75 mm). Then, black-blood images at baseline wereobtained using a three-dimensional T1WI inversion-recovery gradient-echo sequence with a Look
Locker sequence, fat-suppressed and radial k-space sampling in Y-Z plane (repetition time, 4.4 ms;
echo time, 2.0 ms; flip angle, 20°; SENSE factor, 2.5; number of excitations, 2; TFE pre-pulse
consisted of non-selective and adiabatic inversion pulses; TFE prepulse inversion time, 400 ms;
acquisition trigger delay, 600 ms; field of view, 250×250×42.5 mm; acquisition matrix, 187×187;
reconstruction matrix, 448×448×85, resulting in an acquired spatial resolution of 1.34×1.34×1.7mm, reconstructed to 0.56×0.56×0.85 mm)8,10,12). As these sequences need to recognize R waves, thephantom was imaged at a cardiac frequency of 60 bpm, using a simulated electrocardiogram. From
one month after the collection of the human blood sample onward, imaging of the surrounding humanmyocardium-equivalent phantom without circulating human blood-equivalent fluid was performed
using a three-dimensional T1WI inversion recovery gradient-echo sequence, fat-suppressed andlinear k-space sampling in Y-Z plane (repetition time, 7.9 ms; echo time, 3.6 ms; flip angle, 12°;SENSE factor, 2.0×2.0; number of excitations, 1; TFE prepulse, invert; TFE prepulse inversion time,1100 ms; field of view, 220×220×220 mm; acquisition matrix, 220×220; reconstruction matrix, 432×
432×220, resulting in an acquired spatial resolution of 1.0×1.0×1.0 mm, reconstructed to 0.51×0.51
×1 mm).

Measurements of the T1 and T2 relaxation times for the blood-equivalent ﬂuid and the humanmyocardium-equivalent phantom were made by MIXED sequence24).
MR signal intensity analysis
The areas around the bifurcations with stenosis and total occlusion were analyzed. When an HIS
was visually confirmed on T1WI, signal intensity at the proximal and distal parts of the signal wasmeasured.
The target area within the vessel model-to- myocardial phantom signal-intensity ratio, defined as
the highest signal intensity of the target area within the vessel model divided by the signal intensityof the myocardial phantom, was calculated by placing a freehand circular region of interest on astandard console of the clinical MR system6-14).

Results
Using a 1.5T MR scanner, the T1 and T2 values of the blood-equivalent ﬂuid were 1342 ms and
183 ms, and those of the human myocardium-equivalent phantom were 962 ms and 130 ms,
respectively. These values were similar to recognized values in the literature. Figure 3 shows thebaseline MR angiography and T1WI for each vessel bifurcation model. Vessel occlusion or stenosis
within the bifurcation models was confirmed by MR angiography. On T1WI, the areas around thebifurcations with stenosis or total occlusion formed by resin show no HISs (Figs. 3B-3D). However, a
HIS was found at the site completely occluded with a human blood clot (Fig. 3A).
Table 1 shows the time course of signal intensity from the proximal and distal parts of the humanblood clot and myocardial phantom during the follow-up period. The signal intensity of the humanblood clot at one and three months increased compared with that at baseline, and subsequently- 43 -

Ehara et al

Figure 3. Baseline MR angiography and T1WI for each vessel bifurcation model.

Table 1. ‌Time course of signal intensity of the proximal and distal parts of the human blood clot andmyocardial phantom
Proximal partThrombus

Myocardial
phantom

Distal part
Signal-intensity
ratio

Thrombus

Myocardial
phantom

Signal-intensity
ratio

Baseline

163.40115.671.41

146.33114.65

1.28

1 month
3 month4month5 month
6 month
7 month
8 month

163.41
196.12
119.65
4.94
4.35
3.59
3.35

106.85103.5495.09
109.66123.89121.41
120.11

1.53
1.89
1.26
0.05
0.04
0.03
0.03

234.13
192.83163.08
3.44
2.50
4.58
3.11

118.99119.76122.49146.51
154.67147.52151.92

1.97
1.61
1.33
0.02
0.02
0.03
0.02

decreased at four months. The signal disappeared at five months after the collection of the humanblood sample, and remained at low levels. In contrast, the signal intensity of the myocardial phantom
slightly increased during the follow-up period. As shown in Figure 4, an increase in the human blood
clot-to-myocardial phantom signal-intensity ratio was observed at one month compared with that at
the baseline. The signal then decreased at four months, and disappeared completely by five months
at both the proximal and distal parts (proximal part; baseline: 1.41, one month: 1.53, three months:
1.89, four months: 1.26, five months: 0.05, six months: 0.04, seven months: 0.03, and eight months:
0.03, distal part; baseline: 1.28, one month: 1.97, three months: 1.61, four months: 1.33, five months:
0.02, six months: 0.02, seven months: 0.03, and eight months: 0.02).

- 44 -

Time Span of High-intensity Signal by Blood Clot

Figure 4. Time course of the human blood clot-to-myocardial phantom signal-intensity ratio in the proximal anddistal parts.

Discussion
This phantom study with T1WI in MR has three major findings. First, ﬂow disturbance did notcause an artifact HIS. Second, a human blood clot did generate an HIS. Finally, the HIS generated
from a human thrombus on T1WI was limited to a time span of less than several months.
MR technology enables assessment of the atherosclerotic plaque morphology in vivo. It has beenreported that HISs of the carotid and coronary arteries on T1WI indicate the presence of intraplaquehemorrhage or intracoronary thrombus containing methemoglobin2-8,10). Recently, we demonstrated
that intraluminal and intrawall HISs on T1WI in angina patients are related to the different types ofvulnerable plaque morphology10). Intraluminal HISs were associated with thrombus and intimal
vasculature assessed using optical coherence tomography, while macrophage accumulation andabsence of calcification were independent factors associated with intrawall HISs. Interestingly, thepercent diameter stenosis was significantly greater in lesions with intraluminal HISs than in nonHIS lesions. Recently, our different study investigated the association between the duration ofcoronary occlusion and HIS on T1WI in MR among patients showing total coronary occlusion on
angiography. We demonstrated that HISs were found frequently on the proximal edge of theocclusion14). From these data, we hypothesized that the HIS on T1WI might arise not only frommethemoglobin but also from static or turbulent blood ﬂow in severely stenotic or occluded coronary
lesions. The T1WI technique is theoretically unaffected by blood ﬂow, because it uses a non-selective
inversion-recovery pulse for a black-blood condition. The inversion time for a null blood condition
using a Look Locker sequence was determined by adjusting the ﬂow of blood. The HIS may haveresulted from a gap in a null point, since the longitudinal magnetization of stagnant blood is lessthan that of ﬂowing blood. We now developed a circulating phantom system to verify whether ﬂow
disturbances cause artifact like an HIS. Our results show that the areas around bifurcations with- 45 -

Ehara et al

stenosis or total occlusion formed by non-magnetic material show no HISs on T1WI. These findings
lead us to conclude that the T1WI technique is not affected by various blood flow patterns inaccordance with a previous report17).
Furthermore, studies have demonstrated that the presence of an HIS on non-contrast T1WI had
the potential to predict the stage of a thrombus in vivo4,15,16). Kelly et al reported that red blood cells
containing methemoglobin produced T1 shortening in proportion to the amount of methemoglobin17).
They also supposed that this signal persists for several weeks, though the overall period is less thansix months. Our recent MR study regarding coronary total occlusion revealed that the frequency ofan HIS within the occlusion site was significantly higher in short duration occlusions, estimated to beless than six months, than in long duration occlusions14). In this phantom study, the HIS on T1WI
generated from a human blood clot was limited to a span of less than several months. These in vivo
data, together with our present in vitro findings, support the conclusion that the HIS on T1WI was
associated with the presence of a recent thrombus, and the signal would be limited to a finite timespan.
Such information on thrombus age may have several novel clinical implications in the field ofcoronary intervention, including the prediction of slow-ﬂow/no-ﬂow phenomena or the determinationof the age of a chronic total occlusion. The precise assessment of recent plaque thrombosis or
hemorrhage could be useful in the identification of lesions at high-risk for no-reﬂow to deploy distal
protection devices and may inﬂuence procedural success rates for chronic total occlusion, which could
lead to more appropriate risk-stratification and treatment25,26). Additionally, Noguchi et al reported
that statin therapy reduced the coronary plaque-to-myocardium signal-intensity ratio, as well as lowdensity lipoprotein cholesterol and high-sensitivity C-reactive protein levels13). If statin therapy not
only modifies plaque morphology and makes it more stable, but also accelerates the degradation ofmethemoglobin, it could be invaluable in treatment strategies for atherosclerosis.
This study has several limitations. First, in our circulating vessel phantom system, the nonpulsatile pump and human venous blood were used. Degeneration of blood clot depends on various
intraplaque environments in vivo, such as temperature, surrounding tissue, and oxygen pressure.
Methemoglobins are formed by oxidization of deoxyhemoglobins in a suitable oxygen pressure.
Therefore, the human clot formed and preserved at room temperature in vitro might have a different
appearance or time course on MR than intraplaque hemorrhage or juxtaluminal thrombus in vivo.
Second, the human myocardium-equivalent phantom made of gel may degenerate in months, and therelaxation times of that may change at each observational point.
This circulating vessel phantom study showed that a human blood clot generated a HIS on T1WI,
without being affected by ﬂowing blood, and this signal was limited to a finite time span less thanseveral months. This circulating vessel phantom system was useful for serial observation andmonitoring of the development or disappearance of HIS produced by thrombi and for verification of
the effect of ﬂowing blood on HIS with T1WI.
Acknowledgements
All authors have no COI to declare regarding the present study.
We are grateful to Mitsuyo Matsumoto at Philips Electronics Japan, Ltd for assistance with MR
image acquisition. Philips Electronics Japan, Ltd did not have any inﬂuence on the execution of thisstudy, analysis of the data, nor on the writing of this manuscript. The authors of this manuscript- 46 -

Time Span of High-intensity Signal by Blood Clotdeclare no relationships with any companies, whose products or services may be related to the subject
matter of the article.
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2. Yuan C, Mitsumori LM, Beach KW, et al. Carotid atherosclerotic plaque: noninvasive MR characterization andidentification of vulnerable lesions. Radiology 2001;221:285-299.
3. Cai JM, Hatsukami TS, Ferguson MS, et al. Classification of human carotid atherosclerotic lesions with invivo multicontrast magnetic resonance imaging. Circulation 2002;106:1368-1373.
4. Moody AR, Murphy RE, Morgan PS, et al. Characterization of complicated carotid plaque with magnetic
resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003;107:3047-3052.
5. Murphy RE, Moody AR, Morgan PS, et al. Prevalence of complicated carotid atheroma as detected by magnetic
resonance direct thrombus imaging in patients with suspected carotid artery stenosis and previous acutecerebral ischemia. Circulation 2003;107:3053-3058.
6. Kawasaki T, Koga S, Koga N, et al. Characterization of hyperintense plaque with noncontrast T(1)-weighted
cardiac magnetic resonance coronary plaque imaging: comparison with multislice computed tomography andintravascular ultrasound. JACC Cardiovasc Imaging 2009;2:720-728.
7. Jansen CHP, Perera D, Makowski MR, et al. Detection of intracoronary thrombus by magnetic resonanceimaging in patients with acute myocardial infarction. Circulation 2011;124:416-424.
8. Ehara S, Hasegawa T, Nakata S, et al. Hyperintense plaque identified by magnetic resonance imaging relates
to intracoronary thrombus as detected by optical coherence tomography in patients with angina pectoris. Eur
Heart J Cardiovasc Imaging 2012;13:394-399.
9. Noguchi T, Kawasaki T, Tanaka A, et al. High-intensity signals in coronary plaques on noncontrast T1-weighted
magnetic resonance imaging as a novel determinant of coronary events. J Am Coll Cardiol 2014;63:989-999.
10. Matsumoto K, Ehara S, Hasegawa T, et al. Localization of coronary high-intensity signals on T1-weighted MR
imaging: relation to plaque morphology and clinical severity of angina pectoris. JACC Cardiovasc Imaging
2015;8:1143-1152.
11. Hoshi T, Sato A, Akiyama D, et al. Coronary high-intensity plaque on T1-weighted magnetic resonance imaging
and its association with myocardial injury after percutaneous coronary intervention. Eur Heart J 2015;36:19131922.
12. Matsumoto K, Ehara S, Hasegawa T, et al. Prediction of the filter no-reflow phenomenon in patients withangina pectoris by using multimodality: magnetic resonance imaging, optical coherence tomography, andserum biomarkers. J Cardiol 2016;67:430-436.
13. Noguchi T, Tanaka A, Kawasaki T, et al. Effect of intensive statin therapy on coronary high-intensity plaquesdetected by noncontrast T1-weighted imaging: the AQUAMARINE pilot study. J Am Coll Cardiol 2015;66:245256.
14. Matsumoto K, Ehara S, Hasegawa T, et al. Association between duration of coronary occlusion and highintensity signal on T1-weighted magnetic resonance imaging among patients with angiographic total
occlusion. Eur Radiol 2017;27:3896-3903.
15. Tan M, Mol GC, van Rooden CJ, et al. Magnetic resonance direct thrombus imaging differentiates acuterecurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood 2014;124:623-627.
16. Chu B, Kampschulte A, Ferguson MS, et al. Hemorrhage in the atherosclerotic carotid plaque: a highresolution MRI study. Stroke 2004;35:1079-1084.
17. Kelly J, Hunt BJ, Moody A. Magnetic resonance direct thrombus imaging: a novel technique for imaging
venous thromboemboli. Thromb Haemost 2003;89:773-782.
18. Barth M, Moser E. Proton NMR relaxation times of human blood samples at 1.5 T and implications forfunctional MRI. Cell Mol Biol (Noisy-le-grand) 1997;43:783-791.
19. Piechnik SK, Ferreira VM, Lewandowski AJ, et al. Normal variation of magnetic resonance T1 relaxation
times in the human population at 1.5 T using ShMOLLI. J Cardiovasc Magn Reson 2013;15:13.
20. Kato H, Yoshimura K, Kuroda M, et al. Development of a phantom compatible for MRI and hyperthermia
using carrageenan gel: relationship between dielectric properties and NaCl concentration. Int J Hyperthermia
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21. Yoshida A, Kato H, Kuroda M, et al. Development of a phantom compatible for MRI and hyperthermia using
carrageenan gel: relationship between T1 and T2 values and NaCl concentration. Int J Hyperthermia 2004;20:- 47 -

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22. Oe H, Hozumi T, Murata E, et al. Arachidonic acid and docosahexaenoic acid supplementation increases
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23. Nagel E, Thouet T, Klein C, et al. Noninvasive determination of coronary blood flow velocity withcardiovascular magnetic resonance in patients after stent deployment. Circulation 2003;107:1738-1743.
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25. Limbruno U, Micheli A, De Carlo M, et al. Mechanical prevention of distal embolization during primaryangioplasty: safety, feasibility, and impact on myocardial reperfusion. Circulation 2003;108:171-176.
26. Olivari Z, Rubartelli P, Piscione F, et al. Immediate results and one-year clinical outcome after percutaneous
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Osaka City Med. J. Vol. 66, 49-57, 2020

Identification of Factors Predicting the Onset of Gallbladder Cancer
Complicated with Pancreaticobiliary Maljunction
MASAKI HORIIKE1), YOSHIKI MOROTOMI2), SHIGEKAZU TAKEMURA3), SHOGO TANAKA3),
HIROJI SHINKAWA3), TOSHIHIKO SHIBATA1), and SHOJI KUBO3)
Departments of Pediatric Surgery1) and Hepaticobiliary-Pancreatic Surgery3),
Osaka City University Graduate School of Medicine; andDepartment of Pediatric Surgery2), Kitano Hospital

Abstract
BackgroundPancreaticobiliary maljunction (PBM) is a congenital anomaly in which bile and pancreatic juice
ﬂow into each other and is well known to promote carcinogenesis. Further, carcinogenesis has a wide
age range, from early childhood to old age. It is believed that differences in the conﬂuence form, suchas the junction angle θ between the bile duct and pancreatic duct, and the cross-sectional area of eachlumen is strongly affected. We aimed to identify predictive factors of carcinogenesis.
Methods
We measured several confluence form parameters and examined differences between patientswith and without gallbladder (GB) cancer who underwent surgery at our hospital.
Results
The cosine of θ (cosθ), junctional bile duct cross sectional area (Cb), and shape of the common bile
duct {ratio of the maximum diameter of the congenital biliary dilatation to the diameter of the bile
duct [MCBD/Db]} significantly differed between the groups.
Conclusions
We defined several cut-offs predicting the carcinogenesis of GB cancer as follows:(1) cosθ≧0.84, (2) Cb≧8.0, and (3) MCBD/Db≦4.3.
While it is impossible to measure the degree of reciprocal ﬂow of bile and pancreatic juice in vivo,
these cutoff values can be important indicator of the risk of GB carcinogenesis in PBM cases.
Key Words: ‌Biliary tract neoplasms; Carcinogenesis; Pancreatic juice; Common bileduct; Pancreatic ducts

Introduction
Pancreaticobiliary maljunction (PBM) is a congenital anomaly in which the pancreatic and bile

Received October 29, 2019; accepted June 9, 2020.
Correspondence to: Masaki Horiike, MD.
Department of Pediatric Surgery, Osaka City University Graduate School of Medicine,
1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Tel: +81-6-6645-3841; Fax: +81-6-6646-6057
E-mail: masakihoriike1031@gmail.com- 49 -

Horiike et al

ducts merge outside the duodenal wall, and bile and pancreatic juice ﬂow into each other because thesphincter of Oddi does not control the junction1). The reﬂux of pancreatic juice into the biliary tract
provokes higher rates of biliary tract cancer2-5) and is its most important prognostic factor. According
to the results of a nationwide survey6), bile duct and gallbladder cancers were found in 6.9% and13.4% of adult patient with PBM, respectively. Biliary tract cancers develop about 15-20 years earlier
in patients with PBM than in individuals without PBM. The carcinogenesis of biliary tract cancer
accompanying PBM is considered to involve a hyperplasia-dysplasia-carcinoma sequence induced bychronic inﬂammation caused by bile and pancreatic juice ﬂow into each other, which is different fromthe adenoma-carcinoma sequence or the de novo carcinogenesis associated with biliary tract cancers
in patients without PBM. It is well known that the time of carcinogenesis varies widely from earlychildhood to old age7-9). This suggests that there are important factors controlling the appearance of
carcinogenesis. Since PBM is a conﬂuence phenomenon of the biliary tract and pancreatic duct, it isappropriate to quantify it with hydrodynamic considerations. However, to our knowledge no previous
study has used a ﬂuid dynamics approach to understand PBM.
Furthermore, biliary tract cancer has poor prognosis, and it is very useful to predict carcinogenesis
in cases of PBM and to start treatment before carcinogenesis. We therefore studied PBM using a
conﬂuence model that considers two viscous ﬂuids, bile and pancreatic juice, as a new hydrodynamics
approach10,11）, and we aimed to identify predictive factors of carcinogenesis.

Methods
Patients
Among 91 patients with PBM who underwent hepaticojejunostomy between September 1990 and
September 2017 at our hospital, we studied 37 patients for whom clear medical image findings andtest results were available. We focused on the carcinogenesis of gallbladder (GB) cancer, and patientswere grouped by whether they had GB cancer or not.
The clinical records, laboratory test results, and clear medical image findings of magnetic
resonance cholangiopancreatography and abdominal computed tomography, which are pressure-free
images of the biliary tract, were reviewed.
The local ethics committee approved this study (authorization number, 4013).
Parameter calculations
To consider PBM as a conﬂuence of two viscous ﬂuids, the key points to explain the phenomenon
precisely are the ﬂow quantity (including the lumen cross-section), junction angle, and lumen form.
We set the following parameters to examine the conﬂuence of PBM: diameters of the bile duct andpancreatic duct at the junction site, length of the common channel, maximum diameter of thecongenital biliary dilatation (MCBD), and the ratio of MCBD to bile duct diameter at the junction site
(MCBD/Db). Figure 1 visually illustrates these parameters. Additional parameters included in themodel were the angle (θ) formed from the lines extending from the pancreatic and bile ducts, crosssections of the pancreatic and bile ducts at the junction site, and amylase in the gallbladder (AMY).
The bile duct cross-sectional area (Cb) and pancreatic duct cross-sectional area (Cp) were
calculated as follows:
Cb ＝ π (Db / 2)2, Cp ＝ π (Dp / 2)2,
Where Db and Dp are the diameters of the bile and pancreatic ducts at the junction site,
respectively.

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Gallbladder Cancer Complicated with Pancreaticobiliary Maljunction

Figure 1. Parameters chosen to examine the confluence of pancreaticobiliary maljunction. MCBD, maximum
diameter of the congenital biliary dilatation; Db, diameter of the biliary duct; Dp, diameter of the pancreatic duct; andLc, length of the common channel.

The trigonometric function cosθ was calculated as follows:(1) We draw a line crossing both extension lines from the bile duct and pancreatic duct, and make a
triangle.
(2) We define the lengths of the triangle forming θ as a and c, and the length of the intersection isdefined as b.
(3) We measure each length five times and calculate the average.
(4) Using the average values from step (3), we calculated cosθ as follows:cosθ ＝ (a2 ＋ c2 − b2) / 2ac (−1≦cosθ≦1)
Figure 2 visually illustrates θ and cosθ to make them easier to understand, and the parameters
mentioned above for the conﬂuence of two viscous ﬂuids are summarized in Table 1.
It is believed that free reﬂux of pancreatic juice into the biliary tract and gallbladder can induce
chronic damage to them, and eventually cause biliary carcinogenesis. Because AMY is representativeof the reﬂuxing pancreatic enzymes, we were interested in the relationship between AMY and otherparameters at the conﬂuence of PBM. Therefore, we performed a correlation analysis between them.
Statistical analysis
Normally distributed continuous data were expressed as the mean±standard deviation (SD).
Continuous variables were examined using the Mann-Whitney U test. Differences were consideredsignificant at the level of p＜0.05.
Spearman s rank correlation coefficient test was used to examine correlations between parameters,
while the GB carcinogenic rate for each type was analyzed using the Chi-square test for independence.

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Horiike et al

Figure 2. Visual illustration of θ, cosθ and three side lengths of the triangle a, b, and c.

Table 1. Parameters characterizing the fluid junction
Parameter

Abbreviation

Bile duct diameter

Db

Pancreatic duct diameter at juntion
Angle formed from the two extension lines
Trigonometric function for θ

Dp
θ
cosθ

Length of common channel
Bile duct cross section

Lc
Cb [ ＝ π ( Dc /2 )2 ]Pancreatic duct cross section

Cp [ ＝ π ( Dp /2 )2 ]Widest diameter of the choledochal cyst
Proportion of the choledochal cyst
Amylase in the gall bladder

MCBD
MCBD/Db
AMY

Data were analyzed using JMP, version 13 (SAS Institute Inc. Cary, NC, USA).

Results
Of 37 cases, there were 10 cases with GB cancer and 27 without. Table 2 presents the clinicalcharacteristics between the groups. There was no significant difference except surgical age. Elevencases were type Ⅰa, 15 were type Ⅰc, and 11 were Ⅳ-A, according to the Todani classification1).
Figure 3 shows the age distribution of each type. The surgical age range was wide, and all types wereobserved in patients with GB cancer. Figure 4 shows the average surgical age for patients without
GB cancer. There was no significant difference between types.
Figure 5 shows that the carcinogenic rate clearly differs between each type (p＝0.012). Table 3
presents the comparisons of these parameters between patients with and without GB cancer. For- 52 -

Gallbladder Cancer Complicated with Pancreaticobiliary Maljunction
Table 2. Comparison of patients' characteristics
GB cancer

YesNo(n＝10)(n＝27)

56±10

17±18

＜0.001

2:08

9:18

0.47

2/10 (20%)

11/27 (40.7%)

0.34

AST U/L

95±182101±167

0.79

ALT U/L109±23274±1070.53

γGTP U/L

206±367

142±240

0.36

ALP U/L

541±860719±151

0.34

T-Bil mg/dL

1.35±1.07

1.63±3.09

0.37

D-Bil mg/dL

0.65±0.89

0.51±0.92

0.5

LDH U/L

287±124396±2820.5

WBC /μL

6475±1817

8071±4239

0.37

Variable

Surgicalage

Male:female
Biliary calculus

p valueGB, gallbladder; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γGTP, gammaglutamyl transferase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin; LDH, lactate
dehydrogenase; and WBC, white blood cells.

Figure 3. Age distribution of each type in the Todani classification. GB, gallbladder.

Figure 4. Average surgical age of patients without gallbladder (GB) cancer for all types.

- 53 -

Horiike et al

Figure 5. Gallbladder (GB) cancer rate for each type.

Table 3. Comparison of each parameter between patients with and without GB cancer
GB cancer

YesNo(n＝10)(n＝27)Cb (mm2)

19.12±11.82

1.89±1.61＜0.01

Cp (mm2)

3.58±1.13

3.23±1.13

0.29

cosθ

0.87±0.15

0.35±0.47＜0.01

MCBD (mm)20.9±8.70

30.4±18.6

0.32

MCBD/Db

4.48±1.96

25.60±21.09＜0.01

20.38±4.04

15.82±6.490.15

1.32±1.05

1.81±1.64

0.81

VariableLc (mm)AMY (×10 U/L）
5

p valueGB, gallbladder; Cb, bile duct cross-sectional area; Cp, pancreatic duct cross-sectional area; θ, junction
angle between the pancreatic and bile ducts; MCBD maximum diameter of the congenital biliary dilatation;
Lc, length of the common channel; and AMY, amylase.

patients with and without GB cancer, the values were respectively 19.12±11.82 and 1.89±1.61 mm2
for Cb, 0.87±0.15 and 0.35±0.47 for cosθ, and 4.48±1.96 and 25.60±21.09 for MCBD/Db. These
parameters all significantly differed between groups (p＜0.05). On the other hand, Cp, MCBD, lengthof the common channel (Lc), and AMY were not significantly different.
Next, we generated scatter diagrams to determine which parameters are associated with the onset
age. Figure 6 shows that the Cb of patients with GB cancer was higher than that of patients without
GB cancer in all age groups. Figure 7 shows that cosθ had a wide range in the patients without GB
cancer, while the values were greater than 0.84 for all patients with GB cancer except one (cosθ＝0.5).
This exception was an advanced gallbladder cancer case, which had highly infiltrated the common
biliary tract. We suggest that the low value may not reflect the precise junction angle θ before
carcinogenesis. Figure 8 shows that MCBD/Db took a wide range of values in the patients without
GB cancer, while only low values were observed in patients with GB cancer. A low value indicatesthat the common bile duct is in a spindle-like or unexpanded form. Table 4 presents the examination
result of the correlation with AMY and other parameters. The correlation coefficient between AMY- 54 -

Gallbladder Cancer Complicated with Pancreaticobiliary Maljunction

Figure 6. Scatter diagram showing the relationship between junctional bile duct cross-sectional area (Cb) and onset
age.

Figure 7. Scatter diagram showing the relationship between cosθ and onset age.

Figure 8. Scatter diagram showing the relationship between the ratio of the maximum diameter of the congenital
biliary dilatation to the diameter of the bile duct (MCBD/Db) and onset age.

and cosθ was 0.50 (p＝0.02), and that between AMY and Lc was 0.47 (p＝0.046). The other parameters
were not correlated with AMY, showing that reﬂuxing pancreatic enzymes were inﬂuenced by cosθand Lc.

- 55 -

Horiike et al

Discussion
PBM is a single malformation in which the pancreatic and bile ducts join anatomically outside theduodenal wall, but there are several varieties in terms of their clinical courses and prognosis, owing
to differences between the various forms of confluence. Therefore, we chose parameters toquantitatively evaluate these conﬂuence forms, and then evaluated them as carcinogenic predictors.
Patients without GB cancer showed no differences in the surgical age between types (Fig. 4). In
addition, the carcinogenic rate clearly differed between each type (Fig. 5). If there had been a typewith a low surgical age, curative treatment would be completed before carcinogenesis, so the
carcinogenic rate would be expected to decrease. However, since we did not find such a difference insurgical age, it can be inferred that there is a wide range of carcinogenic risk within each type. Thismeans that variations in the connection between bile duct and the pancreatic duct strongly inﬂuences
GB carcinogenesis.
Next, when comparing each parameter between patients with and without GB cancer, Cb, cosθand MCBD/Db showed significant differences between patients with and without GB cancer (Table 3).
In addition, these parameters behaved differently between patients with and without GB cancer(Figs. 6-8). These findings indicated that these parameters play important roles in carcinogenesis.
Specifically, the Cb of all patients with GB cancer exceeded 8.0 mm2 (Fig. 6). We believe 8.0 mm2
is an important boundary value that promotes an increased reﬂux of pancreatic juices to the biliary
tract, and eventually contributes to carcinogenesis.
In addition, most values of cosθ in the patients with GB cancer were greater than 0.84 (Fig. 7),
which was correlated with AMY (Table 4). These findings indicate that pancreatic juices may moreeasily reﬂux to the biliary tract when the junction angle is smaller, and a value of 0.84 may be an
important boundary value that promotes the reﬂux of pancreatic juices to the biliary tract.
Finally, MCBD/Db reﬂects the degree of biliary tract dilatation and may be an indicator of thestagnation of bile and reﬂuxed pancreatic juices.
MCBD/Db had values less than 4.3 in all patients with GB cancer, while it ranged widely in thepatients without GB cancer MCBD/Db (Fig. 8). This different behavior of MCBD/Db seemed toindicate an important clue of carcinogenesis, and a value of 4.3 may be an important boundary valuethat controls the reﬂux of pancreatic juices to the biliary tract.
By examining the parameters listed above, we conclude that cosθ, Cb, and MCBD/Db can be
Table 4. Correlation between AMY and other parameters
Combination of parameters

Correlation coefficient

p value

AMY and Cb

−0.03

0.87

AMY and Cp

0.09

0.69

AMY and cosθ

0.50

0.02

AMY and MCBD

−0.08

0.75

AMY and MCBD/Db

−0.18

0.35

0.47

0.046

AMY and Lc

AMY, amylase; Cb, bile duct cross-sectional area; Cp, pancreatic duct crosssectional area; θ, junction angle between the pancreatic and bile ducts; MCBD
maximum diameter of the congenital biliary dilatation; Db, diameter of thebile duct; and Lc, length of the common channel.

- 56 -

Gallbladder Cancer Complicated with Pancreaticobiliary Maljunction

defined as carcinogenic predictors. In addition, from the results of Figures 6-8, the prediction criteria
for carcinogenesis are defined as follows.
(1) cosθ≧0.84(2) Cb≧8.0(3) MCBD/Db≦4.3
While it is impossible to actually evaluate the degree of reciprocal ﬂow of bile and pancreatic juicein vivo, the cutoff values above can be important indicators of the carcinogenic risk of GB cancer inpatients with PBM.
Because of the small number of cases, we could not use multiple logistic regression analysis on Cb,
cosθ, and MCBD/Db to determine which is the most useful parameter for carcinogenesis prediction.
We therefore plan to accumulate additional cases in the future and evaluate more appropriate
carcinogenesis prediction factors.
Acknowledgement
All authors have no COI to declare regarding the present study.
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Jikkyo shuppan;2009. pp. 145-182. (In Japanese)- 57 -

Osaka City Med. J. Vol. 66, 59-63, 2020

Crack and Pave and Intentional Protrusion of an Endoconduit
into the Terminal Aorta for Endovascular
Abdominal Aneurysm Repair
ATSUTAKA ARATAME, TAKASHI MURAKAMI, GOKI INNO, KENTA NISHIYA, YASUYUKI BITO,
MASANORI SAKAGUCHI, and TAKANOBU AOYAMA
Department of Cardiovascular Surgery, Osaka City General Hospital

Abstract

An unfavorable iliac artery anatomy is considered a surgical challenge in endovascular aortic
repair. The endoconduit technique was performed in an 83 year-old man with abdominal aortic
aneurysm with a severely calcified and stenotic iliac artery. The calcified iliac artery was cracked
before paving it with an 8 mm covered stent. The proximal 2 cm of the endoconduit was intentionallyprotruded into the terminal aorta, which was used for the distal landing of the contralateral limb of abifurcated stent graft. These technical modifications such as cracking before paving and protrusion
were successfully applied to this patient.
Key Words: ‌Endoconduit; Abdominal aortic aneurysm; Endovascular aortic repair

Introduction
The endoconduit technique is one of the alternative techniques used for a narrow and calcified
iliofemoral access route in endovascular aortic repair (EVAR). Here, we present a case of abdominal
aortic aneurysm (AAA) with an unfavorable iliac access for EVAR that was treated using the Viabahn
endoprosthesis (W. L. Gore & Associates, Newark, Delaware, USA) as an iliac endoconduit, which wasintentionally protruded into the terminal aorta.

Case Report
The report describes the case of an 83 year-old man with rapidly expanding AAA who wasrecommended EVAR. He had a treatment history of right aortofemoral artery bypass and left
femoropopliteal artery bypass.
Computed tomography (CT) angiography revealed a 4.7 cm AAA and an adequate proximal sealingzone. The left common iliac artery (CIA) and external iliac artery (EIA) were narrowed with heavy
calcification throughout their length, with the smallest diameter being 4.0 mm. The left internal iliac
artery (IIA) and right EIA were occluded, with the patent right aortofemoral artery bypass. Thus, theReceived October 9, 2019; accepted April 14, 2020.
Correspondence to: Atsutaka Aratame, MD.
Department of Cardiovascular Surgery, Osaka City General Hospital, 2-15-16
Miyakojima Hon-Dori, Miyakojima-ku, Osaka 534-0021, Japan
Tel: +81-6-6929-1221; Fax: +81-6-6929-0886
E-mail: atsutaka_aratame0113@yahoo.co.jp- 59 -

Aratame et al

Figure 1. Left figure; Preoperative reconstruction of computed tomography angiogram revealed the infrarenal
abdominal aneurysm and aortofemoral bypass. Right two figures; The multi-planar reconstruction computed
tomography showed the left iliac artery was narrowed with heavy calcification throughout its length.

patient was diagnosed with a rapidly expanding AAA and was recommended EVAR.
The operation involved creation of bilateral inguinal incisions under general anesthesia to expose
the left common femoral artery (CFA) and a prosthetic graft in the right groin. A sheath was placed
into each incision. Next, the right IIA was coil embolized with a 10 mm ×40 cm 3D Interlock-35
Fibered coil (Boston Scientific, Natick, MA) and 6 mm Tornado Embolization Coils (Cook Medical Inc,
Bloomington, Ind, US) through the left CFA access. After embolization, the left iliac artery waspredilated with an 8 mm semi-compliant balloon catheter (Wanda, Boston Scientific, Natick, MA,
USA), which led to the intentional rupture of the iliac artery. Then, a 8 ×100 mm Viabahn
endoprosthesis (JHJR081002J; W. L. Gore & Associates, Newark, Delaware, USA) was deployed. The
proximal 2 cm of this device was intentionally protruded from the common iliac artery to the terminal
aorta. Thereafter, we aggressively performed balloon dilatation using the same balloon catheter.
Vigorous high-pressure dilatation at the origin of the left CIA was carefully avoided because ruptureof this site would have been difficult to treat. During this procedure, the hemodynamics of thepatient remained stable. Thereafter, a 23×12×140 mm main body of the Excluder (RLT231214J;
W.L. Gore & Associates) was deployed through the right prosthetic graft, and the contra-gate wascannulated. A 16×10×70 mm iliac extension (PLL161007J; W.L. Gore & Associates) was selected as
the contralateral leg and was deployed inside the protruded portion of the Viabahn endoprosthesis
device. A 23×23×30 mm aortic cuff (PLA230300J; W.L. Gore & Associates) was added to treat a type1a endoleak. There was no type 1b or type 3 endoleak observed. The patient made an uncomplicatedrecovery. Postoperative CT angiography confirmed complete exclusion of the aneurysm sac and no
stenosis on the overlapping stent grafts.

- 60 -

EVAR by a Protruded “Crack and Pave” Endoconduit.

Figure 2. Intraoperative arteriogram after cracking the left iliac artery showed a sealed rupture.

Figure 3. Left figure; Postoperative reconstruction of computed tomography angiogram revealed no endoleak andpatency of the endoconduit. Right two figures; Sagittal section of computed tomography angiogram showed the mostproximal part of the endconduit was protruded about 2 cm into the aorta. There wass no stenosis in the overlapped
endoconduit.

- 61 -

Aratame et al

Discussion
Despite the recent development of low-profile devices that range from 6.1 to 7.5 mm in diameter, it
is extremely challenging to access severely calcified and advanced atherosclerotic iliac arteries. The
most common solutions to access such arteries are aortouniiliac grafting and cross-femoral bypass
when a unilateral iliac artery is suitable for the access1) and open iliac conduits2). Although bothprocedures are reliable, compared with the standard femoral approach, higher morbidity has beenreported for the aforementioned techniques1,2).
In various fields, the endoconduit technique has been reported to be a useful alternative accesswhen high-profile device passage is required3,4). This technique entails the deployment of a covered
stent in the unfavorable iliac arteries with dilation up to large diameters with a balloon catheter tocause controlled rupture. Compared with the retroperitoneal open iliac conduit technique, theendoconduit technique has been reported to be a more reliable and safer approach because of thelower incidence of iliofemoral complications 5). The midterm primary-assisted patency of an
endoconduit has also been reported to be high6).
Covered stents with a diameter of ≧10 mm have been used most often as endoconduits in the
past6). Recently, the development of low-profile devices has enabled the use of an endoconduit
measuring 8 mm in diameter for EVAR. In our case, the right CIA was narrow and continuously
calcified. Performing conventional EVAR could cause stent graft infold even if we use the minimum
diameter leg. Therefore, we considered an 8 mm Viabahn as an endoconduit was the best fit to the
distal landing to the 7 mm EIA.
The drawbacks of an oversized endoconduit include injury at the entry site of the CFA, injury to
the iliac artery by the distal edge of the endoconduit, and infolding 3,7). Therefore, the use of
endoconduits of a smaller size may reduce the incidence of these complications.
In the present case, we were concerned that complete rupture of the calcified iliac artery may not
be achieved with the 8 mm dilation with a balloon catheter after the deployment of the 8 mm
Viabahn, resulting in recoiling and persistent stenosis. Therefore, we performed dilatation before
endoconduit deployment to confirm reliable cracking, although this carried the risk of free ruptureand hemodynamic instability. If iliac rupture was not achieved, a larger balloon and non-compliant
balloon catheter were ready for use. In the most proximal part of the CIA, only mild predilatation
was performed because rupture of this area could not have been easily treated; however, mild stenosisof this lesion was acceptable. We planned to deploy the endoconduit in such a way that the mostproximal part was protruded 2 cm into the aorta to overlap the each stent graft. This allowed
complete opening of an 8 mm caliber lumen and performing a drastic balloon expansion in this area.
As a result, the iliac extender with a distal diameter of 10 mm could fit the completely dilated
Viabahn, even with the possibility of residual stenosis at the origin of the left CIA.
Acknowledgements
All authors have no conﬂicts of interest to declare regarding the present case report.
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EVAR by a Protruded “Crack and Pave” Endoconduit.
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