Maedica 1 2017

Under the Auspice of “Carol Davila” University of Medicine and Pharmacy, Bucharest Volume 12 (15) No.
1 2017
Editor-in-Chief: Mircea Cinteza
Maedica JCM, 2017, 12: 20
www.maedica.org
EDITORIAL
• The antibodies: what a Universe!
ORIGINAL PAPERS
• Caesarean birth in Romania: safe motherhood between ethical, medical and statistical
arguments
• The mirage of long term vital benefice – risk for the beginning of life?
• Concomitant lung and liver hydatid cyst managed as one-stage surgery
• Unusual entities of appendix mimicking appendicitis clinically – emphasis on diagnosis and
treatment
• Combined anatomic anterior cruciate ligament and anterolateral ligament reconstruction
• Uterine artery Doppler flow indices in pregnant women during
the 11 weeks + 0 days and 13 weeks + 6 days gestational ages: a study of 168 patients
STATE OF THE ART

• Newborn skin: common skin problems
• Cutaneous toxicities of molecular targeted therapies
• Correlation between idiopathic nephrotic syndrome and atopy in children – short review
• Chronic venous insufficiency: a frequently underdiagnosed and undertreated pathology
CASE REPORT
• A case report of 9p deletion syndrome associated with partial trisomy of 1q42
• Thyroid association ophtalmopathy in Hashimoto’s thyroiditis: a case report
ISSN 1841-9038 Publisher

Volume 12 No. 1 2017
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Mædica - a Journal of Clinical Medicine
Contents
EDITORIAL POINT OF VIEW
Mircea CINTEZA The antibodies: what a Universe! 3
ORIGINAL PAPERS
Anca A SIMIONESCU, Erika MARIN Caesarean birth in Romania: safe motherhood 5
between ethical, medical and statistical arguments
Ramona MOHORA, Decebal HUDITA, The mirage of long term vital benefice – risk for 13
Silvia-Maria STOICESCU the beginning of life?
Usha DALAL, Ashwani Kumar DALAL, Concomitant lung and liver hydatid cyst managed 19
Rikki SINGAL as one-stage surgery
Rikki SINGAL, Muzzafar ZAMAN, Unusual entities of appendix mimicking 23

Bhanu Pratap SHARMA appendicitis clinically – emphasis on diagnosis and
treatment
Stefan MOGOS, Bogdan SENDREA, Combined anatomic anterior cruciate ligament 30

Ioan Cristian STOICA and anterolateral ligament reconstruction
Voicu DASCAU, Gheorghe FURAU, Uterine artery Doppler flow indices in pregnant 36
Cristian FURAU, Cristina ONEL, women during the 11 weeks + 0 days and
Casiana STANESCU, Liliana TATARU, 13 weeks + 6 days gestational ages: a study of
Cristina GHIB-PARA, 168 patients
Cristina POPESCU, Luminita PILAT,
Maria PUSCHITA
STATE-OF-THE-ART
Zekayi KUTLUBAY, Ali TANAKOL, Newborn skin: common skin problems 42
Burhan ENGİN, Ersin SİMSEK,
Server SERDAROGLU, Yalçın TUZUN,
Erkan YILMAZ, Bülent EREN
Dana Lucia STANCULEANU, Cutaneous toxicities of molecular targeted 48

Daniela ZOB, Oana Catalina TOMA, therapies
Bogdan GEORGESCU,
Laura PAPAGHEORGHE,
Raluca Ioana MIHAILA
Elena Camelia BERGHEA, Correlation between idiopathic nephrotic 55

Mihaela BALGRADEAN, syndrome and atopy in children – short review
Ionela-Loredana POPA
Marilena SPIRIDON, Chronic venous insufficiency: a frequently 59

Dana CORDUNEANU underdiagnosed and undertreated pathology
Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017 1

CONTENTS
CASE REPORTS
Ali VAHABI, Filiz HAZAN, Isa Abdi RAD A case report of 9p deletion syndrome associated 62
with partial trisomy of 1q42
Deepak JAIN, Sudhir MOR, Thyroid association ophtalmopathy in Hashimoto’s 65

Hari Krishan AGGARWAL, thyroiditis: a case report
Pulkit CHHABRA, Promil JAIN
Instructions for authors 68

Peer reviewer team 74
2 Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017

MAEDICA – a Journal of Clinical Medicine
2017; 12(1): 3-4
E DITORIAL P OINT OF V IEW
The Antibodies: What a Universe!

Mircea CINTEZAa,b
a
Department of Cardiology, Emergency University Hospital, Bucharest, Romania
b
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
In the initial group of patients treated aggressive-

ly with classical methods, the rate of complete
response is only 8% and the median survival is
6.6 month. Axicabtagene Ciloleucel is the name
of the therapeutic agent by which the patient’s
T cells are transformed to express an antigen re-
ceptor to the antigen CD19, which is a protein
on the surface of B-cell lymphomas and leuke-
mia (2). The research team uses it in ZUMA-1
Phase 2 Study in both diffuse large B-cell lym-
phoma, primary mediastinal B-cell lymphoma
and transformed follicular lymphoma. The trial is
ongoing with great promise.
The concept of using antibodies in cancer
”…we are entering a new era of immune in- therapy is complex and developed in two main
terventions for cancer” – Adrian Bot, senior re- directions (3, 4). The first direction is to identify
searcher in cancer therapy, stated in 2011, when antigens on the cancer cells enough specific for
he was appointed in a key position of an impor- that cancer tissue. The second direction is more
tant research team in the field. complex: firstly, to understand why the immune
And the results did not retard (1). The team in system of the host is weaker than normal (some-
which Dr. Bot works has recently shown that times the weakness is induced by the cancer
such a therapy had outstanding results in the cells themselves – by which mechanisms?) and
therapy of resistant diffuse large B cell lympho- secondly, to create antibodies against the speci-
ma, a deadly Non-Hodgkin disease when not fic cancer antigens or to reprogram the immune
responding to last line of chemotherapy or re- system of the host to recognize those antigens
lapsing in 1 year after autologous stem cell trans- and to destroy their host – the cancer cell (3, 4)
plant. In recent presented series of 7 patients, 4 The field of pathology where antibodies play
had complete response (57%) and 5 overall re- already, or may play, a therapeutic role is much
sponse (71%) (1). 3 of the patients are in a com- larger than cancer: inflammatory diseases, such
plete response status after a 12+ month survey. as systemic lupus erythematosus, rheumatoid ar-
Address for correspondence:

Mircea Cinteza, Department of Cardiology, Emergency University Hospital, 169th Independentei Avenue, 5th District, Bucharest, Romania
E-mail: mirceacinteza@gmail.com
Article received on the 23th of March 2017. Article accepted on the 24th of March 2017.

CARDIOVASCULAR RISK PREDICTION: GREAT CHANGES ARE EMERGING
thritis, eosinophilic asthma or even chronic obs- SPIRE-1 and SPIRE-2 studies with bococizumab.
tructive pulmonary disease, and antiviral agents, And: big surprise!! After such human and finan-
antibodies against B virus hepatitis and even cial investment, the drug was retired from the
against HIV. Many therapies are developed and market because… because inflammation deve-
some are already used in clinical trials (5). loped at the site of injection. An immune reac-
Another field in which antibodies are already tion of the host against the foreign antibody pro-
approved for human use is the therapy of dyslipi- voked this reaction (7). However, the other 2
demia. The PCSK9 inhibitors are antibodies that competitors, as well as others on the pipeline
block the receptor of PCSK9, an enzyme which promise to be a family of therapies as important
occupies the LDL-C receptor on the hepatocyte as the outstanding family of statins was several
and other membranes. This decreases dramati- decades before.
cally the uptake of the LDL-C from the blood We may say that this moment is as important
and, in consequence, high levels of LDL-C will for medicine as the moment of antibiotic disco-
circulate, favoring the development of athe- very. And even more. The fact that antibodies
rosclerotic plaques. may cure a much wider field of diseases than
Blocking the PCSK9 by an antibody, LDL-C is infections may contribute essentially to the thera-
removed from the circulation and its concentra- py of the strongest enemy of medicine – cancer
tion is reduced in a significant degree, compara- – and may also help diagnosis in fields where the
ble with the amount reduced by statins (6). disease is not yet recognized in time to begin
Two antibodies which inhibit PCSK9 are al- therapy.
ready approved for clinical use in the USA and
Europe: alirocumab and evolocumab. But a third
one was that which accomplished the largest Conflicts of interest: none declared.
clinical trials: more than 26 000 patients in Financial support: none declared.
R#$#%#&'#*
1. Locke FL, Neelapu SS, Barle" NL, et al. cancer immunotherapy: discovering biomarkers, and novel targets.
Phase 1 results of ZUMA-1: a multicenter novel targets and reprogramming the Intern Rev Immunology 2016; 35:291-293.
study of KTE-C19 Anti-CD19 CAR T cell immune system. Intern Rev Immunol 6. Evere" BM, Smith RJ, Hia" WM.
therapy in refractory aggressive 2015;34:101-103. Reducing LDL with PCSK9 Inhibitors –
lymphoma. Molecular Therapy 4. Grizzi F, Mirndola L, Qehajaj D, et al. the clinicall benefit of lipid drugs.
2017;25:285-295. Cancer-Testis Antigens and immuno- N Engl J Med 2015; 373:1588-1591.
2. Business Wire, 2017, Feb 28, h!p://www. therapy in the light of cancer complexity. 7. Husten L. Pfizer ends development of its
businesswire.com/news/ Intern Rev Immunology 2015;34:143-153. PCSK9 Inhibitor. www.cardiobrief.
home/20161206005667/en/ 5. Bot A, Kumar H. Translational opportu- org/2016/11/01
3. Chiriva-Internati M, Bot A. A new era in nities for antibodies: therapeutics,

2017; 12(5): 5-12
O RIGINAL PAPER
Caesarean Birth in Romania:

Safe Motherhood Between Ethical,
Medical and Statistical Arguments
Anca A SIMIONESCUa, Erika MARINb
a
”Carol Davila” University of Medicine, Filantropia Hospital, Bucharest, Romania
b
Department of Statistics and Econometrics, University of Economic Studies
Bucharest, Romania
ABSTRACT
The number of caesarean sections increased significantly in Romania. In 2012, caesarean sections
accounted for 41.2% of total births, according to a study of the Romanian National School for Public Health.
This estimation is in agreement with the statistical data on caesarean sections recorded in one of the most
important hospitals in Bucharest, Romania, Filantropia Hospital.
Many factors have influenced the large number and sharply increasing trend of caesarean sections, from
the historical ones, with roots in the communist regime, when abortions were outlawed, to current day
doctors’ medical practices and mothers’ beliefs and fears related to the process of labor and the newborn’s
health.
This paper aims to examine the pros and cons for caesarean birth. The analysis is presented from three
perspectives: expressed by the doctor/medical caregiver, the patient/mother and some of the third parties
indirectly involved in the medical decision: the foetus/newborn, the hospital/medical unit and the society as
a whole, knowing that ethics is beyond the legal, economic or administrative frames.
Keywords: caesarean section, Romania, ethics, autonomy, maternal decision
INTRODUCTION was promulgated, outlawing abortion and use of

contraception; at that time, prohibiting caesare-
I
n the last two decades, Romania has been
an surgery was considered to help increase the
facing a significant decrease in fertility and
number of births. These negative trends number of births, in line with the demographic
originate from the communist period that policy of the communist party.
left a strong mark on the health care system. As a result, between 1966 and 1989, a num-
One of Nicolae Ceausescu’s goals was the growth ber of 9,542 maternal deaths as a consequence
of the Romanian population up to 30 million of illegal abortions or birth-related complications
persons. In this vain, in 1966, the Decree 770 was reported (1). Information about contracep-
Anca A Simionescu, MD, PhD
Filantropia Hospital, 11-13 Ion Mihalache Bvd, District 1, Bucharest, Romania
Email: contact@ancasimionescu.com
Article received on the 20th of December 2016 and accepted for publication on the 14th of March 2017.

CAESAREAN BIRTH IN ROMANIA: SAFE MOTHERHOOD BETWEEN ETHICAL, MEDICAL AND STATISTICAL ARGUMENTS
tive methods and reproductive life were taboo, In the last decade, information provided by
although officially, the family was considered mass-media, internet, friends’ family or other pa-
“the vital cell of society”. Contraceptive methods tients’ acquaintances has become an important
were not available in any medical facility. assisting tool in deciding on a method of birth.
In the ‘80s, according to the local official sta- The increase in caesarean birth rate is associ-
tistics (Romanian National Institute for Statistics), ated with various aspects ranging from medical
the number of pregnant women and newborns and financial ones to moral and ethical ones.
followed a negative trend, decreasing from a These discussions are mainly involving the field
maximum of 526,000 births registered in 1966, of caesarean sections on request, without an ob-
down to an average of 400,000 births . stetrical indication, performed at the mother’s
In hospitals (all public), patients were able to request or sometimes at the doctor’s recommen-
choose their doctor and natural births were as- dation without a strong medical motivation.
sisted by midwifes and doctors on call during The modern structure of medical ethics con-
early labor. In rural areas, some of the patients siders autonomy, beneficence, non-maleficence
gave birth at home only with midwifes when no and justice when referring to a patient. When
medical care was available nearby. divergences occur between doctors and patients
The number of newborns continued to drop
with respect to the choice of the delivery me-
significantly after the change of the political re-
thod, conflict may arise between the mother’s
gime in 1989. A historical minimum was reached
autonomy (and the respect for her own views,
in 2013, when according to the Romanian Na-
interests, beliefs and values) and the doctor’s au-
tional Institute for Statistics, the number of births
tonomy (related to medical knowledge, risks in-
in Romania dropped to 198,216 – a decline by of
volved, medical recommendations and clinical
63% compared to the maximum reach after the
promulgation of the 1966 Decree. guides).
Some important structural shifts were recor- This paper aims to explain the recent trends
ded as well, regarding the mother’s age and the in caesarean sections in Romania from three per-
geographic area (rural versus urban). The clinical spectives: expressed by the doctor/medical care-
recording and examination of pregnancies giver, the patient/mother and some of the third
changed too. In 1970, the clinical recording of parties indirectly involved in the medical deci-
pregnant women was compulsory and 460,509 sion: the foetus/newborn, the hospital/medical
pregnant women were recorded. Currently, this unit and the society as a whole, knowing that
number is significantly lower, following the de- ethics is beyond the legal, economic or adminis-
mographic trend described above; thus, in 2011 trative frames.
only 130,756 pregnant women were clinically re-
corded by the Romanian National Institute for STATISTICAL CONSIDERATIONS
Statistics (2) .
Pregnant women’s age followed the European The available official data on caesarean sec-
trend and women have become more career- tions in Romania are quite limited. The WHO
oriented. At present, unmarried couples and reports covers only a few years (the latest avai-
single women are having babies. Women who lable value is for the year 2010).
work abroad or those who have financial possi- National statistics on caesarean sections are
bilities can choose to give birth in Western coun- not currently available. Therefore, we had to use
tries. only data from published studies and articles. For
Another important structural change was re- example, a study of the Romanian National
gistered in the mode of delivery, from mainly School for Public Health reported that, in 2012,
vaginal births before 1990 to an important in- caesarean births accounted for 41.2% of the total
crease in caesarean sections in the last two de- births in the public hospitals. To have a more re-
cades. According to WHO (World Health Orga- alistic view on the issue, the number of caesare-
nization) data, in 1999, in Romania, caesarean an sections performed in private clinics (not offi-
sections represented 11% of the total number of cially reported), where the caesarean section
births, whereas in 2010 they accounted for rate is estimated to be around 60% (4), should be
30.4% of the total number of births (3). added to the aforementioned figure.

FIGURE 3. Live-births in Romania by assistance at

FIGURE 1. Comparative evolution of the number of vaginal births vs birth, 2013
caesarean deliveries in Filantropia Hospital, 2003-2013. Data source: National Institute for Statistics, Romania,
Data source: Filantropia Hospital, Bucharest TEMPO database
public and private units) as it provides Level III

neonatal intensive care. Although the clinic of-
fers specialised medical assistance for cases of
extreme premature children as well as foetal pa-
thologies, it does not perform caesarean sections
on request, but only based on medical docu-
ments and obstetrical indications.
In conclusion, even if there are no official sta-
tistical data collected on the same methodologi-
cal principles, empirical evidence shows a con-
sistent increase in the number of caesarean
FIGURE 2. Evolution of caesarean section percentage in total births, section deliveries and the fact that more than
Filantropia Hospital, Bucharest, Romania, 2003-2013. two out of five Romanian children born in the
Data source: Filantropia Hospital, Bucharest, Romania last few years are delivered through caesarean
section, while WHO recommends that the cae-
sarean section should represent around 15% of
These values are similar to those registered in
the total births (5).
one of the largest hospitals in Bucharest – Filan-
tropia University Hospital (the oldest Maternity
OBSTETRICAL CONSIDERATIONS
in Romania). Here, in the last 10 years, caesarean
sections accounted for about 40% of the total In Romania, most of the deliveries are per-
births. formed by obstetricians and in 95% of the cases
Figure 1 presents the evolution of births in doctors are present either alone or with a mid-
Filantropia Hospital, showing the contribution of wife (Figure 3).
vaginal births and caesarean sections. The evolu- For university hospitals, the general proce-
tion slightly oscillates from year to year in terms dure for caesarean section with indication is usu-
of number of births and mode of delivery. ally obtained by getting the Head of Depart-
The weight of caesarean section delivery ment’s approval based on medical indications.
varied from a minimum of 31.6 % of total births When patients’ request to receive caesarean
in 2003 up to 47.2% in 2014, as showed in section surgery is refused, many of them go to
Figure 2. private hospitals that respect their birth choice.
The caesarean section rate in Filantropia Ma- The caesarean section was introduced as a
ternity is explained by the large numbers of high failure of natural birth due to special obstetrical
risk pregnancies referred by other hospitals (both conditions: placenta praevia, cephalo-pelvic dis-

proportion, transversal presentation. Due to the that finalizes with failure of vaginal birth and
electronic fetal monitoring during labor, given an emergency caesarean section, surgery technique
uncertain foetal status, emergency caesarean and length, anaemia, previous infections, obesi-
surgery is performed to save the foetus and in the ty, and diabetes.
mother’s best interest. Instrumental extractions There is a slight risk increase in women who
are usually indicated for bradycardia and pro- had 2 or more scare uterus: uterine rupture, risk
longed foetal distress, as a correctly applied and of abnormal placentation (accreta), urinary blad-
assisted extraction using forceps has been pro- der wounds and more laborious and sometimes
ven to protect the foetus against perinatal hypo- haemorrhagic surgical interventions. The Ameri-
xia. Emergency caesarean section during expul- can College of Obstetricians and Gynaecologists
sion would have a higher risk of neonatal (ACOG) do not recommend caesarean on de-
convulsions compared to instrumental extrac- mand to mothers who wish to have more than
tions (5). one child because of the increased surgery risk
In 2005, WHO showed that the risk of mater- involved in subsequent pregnancies (10).
nal death as a result of caesarean section surgery In Nigeria, Rukewe et al. found that 10.5% of
is 3- to 5-fold higher than that involved by natural a pregnant women population in a University
birth; similarly, the risk of hysterectomy is two Hospital had complications related to anaesthe-
times higher than that involved by natural birth sia (due mainly to general anaesthesia) (11).
as well the risk to be admitted in the intensive Lactation is starting later after caesarean sec-
care unit for more than 7 days (6).
tion birth and mothers need more days to re-
Compared to caesarean section on demand,
cover and take care of the newborn compared to
without medical indication, performed on the
natural birth.
39th week of pregnancy, caesarean surgery for
For the foetus, natural birth and spontaneous
either obstetrical reasons or performed during
labor seem to have fewer complications com-
labor would have more complications due to the
pared to caesarean section. In a randomised
obstetrical pathology that indicated it (for exam-
study of 116 pregnant women with one child,
ple, the risk of uterine atony or postpartum
under 37 weeks of pregnancy, who entered into
haemorrhage is higher for placenta praevia).
There are as well some debatable obstetrical in- premature labor, Alfirevic et al. compared foetal
dications for caesarean section such as foetal and maternal complications after natural birth to
macrosomia for preventing shoulder dystocia, those after caesarean section and found no sig-
but there is no scientific evidence that caesarean nificant differences in Apgar scores at 5 minutes,
section performed at the beginning of labor perinatal mortality, respiratory distress syndrome,
would be more efficient in this case (7). ischemic encephalopathy and asphyxia at birth.
Caesarean section increases the risk of infec- There were reports on accidental knife injuries of
tions (fever, endometritis, puerperal sepsis), soft spots in caesarean section surgery and one
haemorrhage, thrombophlebitis, thrombosis, and case of bruising at a vaginal birth, but no signifi-
embolism. A retrospective analysis on a repre- cant differences were recorded in the 5-minute
sentative sample of 26,356 patients with no risk Apgar score. Likewise, no significant differences
at their delivery due/planned date (either natural in maternal complications were reported (12).
or via caesarean section) showed a significantly In time, natural birth can have some compli-
lower risk of chorioamnionitis, postpartum haem- cations related to urinary and anal incontinence
orrhage, uterine atony and prolonged rupture of or sexual dysfunctions, with a notable impact on
membranes in the planned births with caesarean family and socio-economic life. Some studies are
section compared to natural birth (8). In a meta- associating these complications with multi-parity
analysis on 13,000 women, Smaill FM et al. and large weight of the child at birth (13). Handa
proved that caesarean section increased the risk et al. found a higher risk of urinary incontinence
for infection and infectious morbidity 20 times in patients with epidural analgesia, due to the
compared with vaginal birth and recommends prolonged expulsive efforts. As well, a correla-
antibiotic-prophylaxis (9). tion was found between urinary incontinence
The factors associated with increased risks for and instrumental extractions and spontaneous
infection are those correlated to prolonged labor lacerations, but not with episiotomy (14).

Some authors suggest that pregnancy for pa- relationship, and doctors recommend a caesare-
tients over 30 years is considered to be a risk an section as a response to their patient’s desire,
factor for urinary incontinence and pelvic floor guided by the principle that providing a service
dysfunction, but regardless whether delivery was to their “client’s satisfaction” means keeping ‘the
by caesarean section or vaginal (15). client’. Such a way of working is abnormal not
In conclusion, medical research, statistical only for the patient, who has to wait for the doc-
data and findings from randomised studies show tor to deliver the baby in case of natural delivery,
less medical risks for babies delivered vaginally but also for the doctor, because it is impossible to
and more complications in caesarean section for answer all calls at all times.
obstetrical indication for both the mother and For obstetricians, the major disadvantage of
the newborn. practicing caesarean sections without medical
indication will be the lack of practical experience
THE DOCTOR’S PERSPECTIVE in obstetrical maneuvers (breech presentation,
shoulder dystocia, instrumental extraction) and
The decision making process for the choice of difficult foetal extraction even during caesarean
delivery should be made together by the doctor surgery – when the extractions are made simi-
and the mother. One of the most important ethi- larly to vaginal births (for example, femoral frac-
cal dilemmas for choosing a caesarean section tures, incorrect extractions in case of transversal
relates to a proper understanding of the informed presentation).
consent (16, 17). Doctors would like to act on their autonomy
In Romania, the informed consent was intro- and make or not recommendations for caesarean
duces in 2003; the Law 95/2006 on health care based on their medical knowledge, involved
system reform stipulates that patients above 18 risks, medical recommendations and clinical
years are obliged to sign an agreement form. The guides, which is sometimes in conflict with the
patient has the right to be informed on the risks mother’s autonomy to make her own choice on
associated to the clinical investigations and treat- the delivery method.
ments. Information is provided during a personal
consult by the doctor (18). MOTHER’S PERSPECTIVE
The patient has the right to either express his/
her consent during hospitalisation or withdraw it The patients’ degree of satisfaction during
after receiving the information from the medical pregnancy and labor is intrinsically linked to their
team. Dima et all showed that 46% of the Roma- own value system, trust in their doctor, medical
nian patients are only concerned by the main care provided by the hospital and the health sys-
aspects of the medical procedures which they tem, in general. For example, in a Romanian
want to be explained in an understandable man- dedicated setting for mothers there is the follo-
ner (19). wing statement: “In Filantropia Hospital, most of
Sometimes, detailed medical information on the doctors performing ultrasound for prenatal
the benefits and limitations of each of the deli- diagnosis are competent due to their training
very methods, tailored for the patient’s level of stages abroad”.
understanding, cannot be offered because doc- Patients expect to play an active part in deci-
tors are overloaded and may be not too inte- sion making regarding the mode of delivery; in
rested in providing detailed information to the many cases, a caesarean section is preferred be-
patient. cause mothers are afraid of a prolonged and
Given the fear of legal consequences that painful labor, or not having permanent assistance
might appear as a result of complications during from the medical staff during their labor, or many
labor, doctors could recommend a caesarean (yet improbable) medical complications (from
section even in the absence of medical indica- episiotomies to the nuchal cord entanglement
tions. When acting this way, they have in mind and foetus suffocation), or medical problems as
their own time management, as the caesarean a result of the use of a forceps or vacuum device.
section allows scheduling of birth at a chosen In most cases, these fears are explained by the
date. Also, as a reminiscence of the communist mothers’ poor or insufficient understanding of
past, the patient is a client in the patient-client the medical aspects related to vaginal delivery

and caesarean section surgery, which is related should have a full understanding of the risks and
not only to the insufficient communication be- benefits involved by each delivery method.
tween health professionals and patients but also
to the patient’s level of medical education. More- THE THIRD PARTY PERSPECTIVE
over, in Romania there are still disparities in the
available medical information provided by doc- The two major actors in making the decision
tors, which amplifies mothers’ confusion (e.g., about the method of delivery are the mother
information about foetal suffocation by nuchal (patient) and the doctor. Other actors can as well
cord entanglement or the use and results of for- indirectly influence the decision making process.
ceps that may handicap the baby). One of the third parties is the hospital, with
Nuchal cord is common. It may lead to peri- its own policies and procedures. In Romania, the
natal asphyxia during labor, but the medical team health care system is under-financed, and the
National Health Insurance House allocates two
can notice any changes in the electronic foetal
to three times more money for caesarean section
heart rate during labor (20). It does not require
compared to vaginal birth (depending on compli-
prenatal screening and involves no medical rea-
cations). This might determine some hospitals to
sons for caesarean section before labor (21). An
encourage caesarean sections as opposed to
experienced, board-certified obstetrician is
vaginal births.
skilled to identify these cases and perform a
Hospital under-financement also encourages
quick and safe instrumental extraction of a foetus
private medicine to be practiced in public set-
with bradycardia. A loose nuchal cord can be
tings, raising several issues such as medical res-
easily slipped over the baby’s head to decrease
ponsibility or improvement of medical care qual-
traction during delivery of the shoulders.
ity, and not clientele.
Therefore, the fear of nucal cord as well as
For the health system, a large number of cae-
other medical conditions is mainly based on pre-
sarean sections will put financial pressure and
judgments, and not on medical evidence.
will deplete the funds from other healthcare ser-
Pregnant women’s perception is that surgery
vices. To decrease the number of unnecessary
is superior to vaginal birth. If complications ap-
caesarean sections, Romania has just introduced
pear, the doctor is capable of solving them (not
the co-payment system for caesarean sections on
necessarily true for all doctors). In Romania, pa-
demand, but it still needs to be enforced. Medi-
tients with caesarean section believe they re-
cal indications for caesarean section have to be
ceived better medical care than women with
standardized at national level and a robust sys-
vaginal delivery. The level of pain is considered
tem to ensure the application of recommenda-
lower and easier to control, as no pain is felt du-
tions should be implemented.
ring the operation and pain medication can be
Another party who is directly affected by the
used postoperatively.
result of birth method decision is the foetus/new-
As the pregnant women tend to be older,
born. This party cannot express his/her own
some patients feel they are ’too old’ for a poten-
choice directly but as shown previously, in most
tially long labor. In many cases, those with in vitro
of the cases, in the absence of medical indica-
fertilization who receive anticoagulant therapy or
tions, vaginal birth is more beneficial for the
recurrent abortion are asking for a caesarean sec- newborn as opposed to caesarean section.
tion. Therefore, it is important that both the mother
A traumatic experience with complications at and the doctor act together in the best interest of
the first/ previous vaginal delivery is also a cause the foetus/newborn, as the latter cannot use his/
of demanding a caesarean section. her right to personal autonomy. q
Time management is also important especial-
ly for career-oriented mothers who need to have CONCLUSION
a rigorously planning of the birth (22).
Patients requiring caesarean sections are sup- The number of caesarean sections increased
porting their option by using a lot of arguments, all over the world, but in Romania some evi-
but their level of medical understanding is often dence shows that more than 40% of the children
inappropriate. To exert their autonomy, mothers are delivered through caesarean section.

As current medical evidence proves that va- nefits/risks involved and trust in the healthcare
ginal birth involves less risk for both mother and system can have a considerable impact on safe
newborn, the increase in the number of caesa- motherhood in Romania.
rean section raises some medical, ethical and fi- Autonomy – women’s right to make and act
nancial concerns. according to their own decision – is a complex
Mothers’ autonomy is an important issue too, concept. The mother’s decision should be based
but one the other hand, caesarean section with- on correct medical information, and not on pre-
out medical indication could lead to maternal conception or biased information from family
and foetal medical risks linked to anaesthesia members or the internet. Doctors and midwifes
and surgical process. have an important role as they are implementing
The doctor and the mother should decide to- the informed consent. They also have autonomy
gether on the choice of birth. The decision based on their medical knowledge, but their rec-
should be fully informed, as mothers have to ommendation should be clearly explained to
clearly know and understand which are the be- mothers. Only a full understanding of the main
nefits and risks of caesarean section surgery both benefits and risks of each delivery method can
for themselves and their newborn. lead to a real enactment of the autonomy prin-
In Romania, the enforcement of the newly ciple. q
introduced co-payment system for caesarean
sections on demand, based on standardization Conflict of interests: none declared.
of medical indications for caesarean section, Financial support: none declared.
might reduce their number. Public hospitals as Acknowledgements: This paper was partially
well as private clinics should have the same cli- supported (for A.A. Simionescu) by the grant
nical indications and some control should exist 20062/24.07.2014 from “Carol Davila”University of
to prevent abusive medical indications. Medicine and Pharmacy, Bucharest, Romania.
Change in the current – somehow distorted Special thanks to Professor Gheorghe Peltecu for
– perceptions and beliefs of Romanian women providing access to statistical data regarding
based on understanding of the real medical be- Filantropia Hospital.
R#$#%#&'#*
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2017; 12(1): 13-18
O RIGINAL PAPER
The Mirage of Long Term Vital

Benefice – Risk for the Beginning of
Life?
Ramona MOHORAa,b, Decebal HUDITAa, Silvia-Maria STOICESCUa,b
a
”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
b
”Alessandrescu-Rusescu” National Institute of Mother and Child Health,
Bucharest, Romania
If we must care for life, than it must not depend on any preconception that we have of it, of importance being the fact that life is what makes
all other values achievable, in so that life must be defended, promoted, sustained, helped, respected, accepted and tutored. To care for life is
to take an impartial moral stand, to perceive the ontological last resorts of life as a divine gift, and to translate that into the community by
ethical and normative manner, through which you can highlight it’s immunity and the responsibility of every individual for their own life
and for the life of others (1).
Iuvenalie Ion Ionascu, Arhim. Dr. Paroh
ABSTRACT
Introduction: Cord blood is the “life” of the fetus until birth. After delivery, the newborn is “single” and
forced to adapt to live using the latest resources provided by the mother. Those who believe that a newborn
is just a miniature independent adult are just trusting one of the illusions of secular medicine.
Cord blood contains precious cells, stem, red and white blood cells. T cells as a part of white blood cells
prevent infections and other illnesses. Cochrane Database 2013 published a study reporting the role of
delayed umbilical cord clamping for the benefit of infants. Harvesting of stem cells increases early clamping.
So, is prevention better than treatment, speaking about possible pathologies that can occur throughout life?
Material and methods: A prospective study of newborns in “Alessandrescu-Rusescu” National Institute
for Mother and Child Health, Bucharest, Romania, was monitored by their adaptation to extrauterine life,
depending on time and technique of clamping. The impact of harvesting stem cells after birth was explored.
Results: Of all babies, 8.23% were premature. Maternal pathology (arterial hypertension, diabetes
mellitus, infections, thrombophilia) was present in 31.76% of cases. Of the 85 newborns with harvested
stem cells, 47% needed assistance in the neonatal intensive care unit (NICU). Birth asphyxia (SA≤7) was
present in 10.58% of cases.
Conclusion: Two protocols with strong recommendations about umbilical cord clamping and harvesting
stem cells, respectively, are necessary.
Keywords: delayed clamping, early clamping, stem cells, term newborn, preterm infant,
extrauterine life transition.

Ramona Mohora
Str. Gheorghe Polizu nr. 38-52, sector 1, Bucuresti
Email:mohoraramona@yahoo.com
Phone: 0765 818 029
Article received on the 01st of February 2017. Article accepted on the 11th of March 2017.

THE MIRAGE OF LONG TERM VITAL BENEFICE – RISK FOR THE BEGINNING OF LIFE?
INTRODUCTION Confirmed by
To be confirmed (4)
studies (4)
M
odern societies have the duty to
Respiratory distress
choose from technologies that Chronic lung disease
syndrome
offer them support and the
chance to improve their lives (2). Anemia of prema-
Retinopathy of prematurity
turity
In 1997, the cloning of Dolly
opened up “the debating of cloning” for discus- Intraventricular Ulcerative necrotizing
haemorrhage enterocolitis
sion. At the present time we have shifted the dis-
cussion towards “debating stem cells” (3). Periventricular Ductus arteriosus
Stem cell therapy is a way towards regenera- leukomalacia Childhood anemia (9)
tive medicine. Hypoxic-ischemic encefa-
Normally a skin cell remains a skin cell forev- lopathy (9)
er, a nervous cell remains a nervous cell until it Cerebral palsy (9)
dies, and so on (4). Mental deficiency (9)
Stem cells can transform into different types
Cognitive and behavioral
of cells such as cardiac, nervous, muscle cells,
impairments (9)
etc. They play a crucial part in the development
and maturing of many systems and organs (e.g., TABLE 1. Neonatal affections induced by the
delayed adaptation to extrauterine life and by the
the nervous, respiratory, cardiovascular, hemato- immaturity of systems and organs
logic, endocrine and immune systems) long be-
fore birth (5-7).
The concentration of stem cells in circulating The placenta and the umbilical cord can con-
blood is higher during the fetal period than in tain up to 200 mL of blood carrying hematopo-
any other period of the life course (8). They are etic stem cells and important supplies of iron
able to be “instructed” towards certain functions, (10). According to a UC Davis study carried out at
which makes them useful in treating some median obstetrics hospital in Mexico City, a two min-
cal ailments (3). ute delay in clamping the umbilical cord increas-
The first stem cells transplant – the nature’s es a child’s iron store by 27-47 mg of iron, which
transplant – occurs at birth when the placenta is equivalent to approximately two months of in-
fant iron requirements. This fact could help pre-
and the umbilical cord begin contracting and
vent iron deficiency anemia until the age of 6
pumping blood towards the newborn. After the
months (10).
blood has been distributed to all the compart-
After the placenta has finished transferring
ments, blood flow stops and the cord also stops
blood to the child, it is difficult to collect even a
pulsing. The process occurs in most mammals,
few milliliters of blood to determine the blood
and this blood transfusion is allowed to end type. The large umbilical vessels are empty and
physiologically in most species, except in human blood in the small vessels begins to coagulate.
beings (8). The latter manipulate the transition The minimum necessary for collecting umbilical
from intrauterine to extrauterine life through the cord blood is 45 mL (11).
moment when the umbilical cord is clamped. If it The blood from the umbilical cord represents
occurs untimely, the first stem cells transplant is „the life” of a baby until birth. It contains a lot of
reduced quantitatively, depriving the newborn of valuable cells such as stem cells, red blood cells
the cells that belong to him (4). and leukocytes, including T cells (12).
The etiology of many affections in the neona- “Most of the transplants performed by using
tal period is linked to a delayed adaptation to privately banked blood are done for the donor’s
extrauterine life and to immaturity (4). Moreover, siblings”, explains Morey Kraus (13).
the maturation of each system and organ contin- Regarding harvesting stem cells after birth, a
ues after birth (Tables 1 and 2). In this context, volume of approximately 150 mL of blood is col-
depriving a newborn of the cells that are actually lected from the umbilical cord. In this purpose,
his (hers) could have an impact on subsequent clamping must take place immediately after birth
development. (first seconds), so that about 50 mL of blood still

remain in the placenta. Therefore, stem cell har- lymphomas or autoimmune disorders. Any other
vesting can be done only by depriving the child purposes are speculative (12).
of one third of his blood volume (9). Considering this, the question arises why
Immediate clamping of the umbilical cord is would we deprive a child of these cells at birth as
the equivalent of removing one third of an adult’s long as there are extremely small chances to re-
blood, such a process being classified as severe ceive them back?
hemorrhage (9). Another question may be whether there is a
From a newborn weighing 3.6 kg, with a connection between the deprival of stem cells at
blood volume of approximately 280 mL, a maxi- birth and the occurrence of certain illnesses for
mum of 14 mL could be collected from the um- which we use stem cells treatment.
bilical vessels. The lowest blood quantity which Delayed umbilical cord clamping has a great
is acceptable for collecting is 45 mL, whereas the immediate value and stem cells from umbilical
highest limit is 215 mL (11). cord blood can provide long term protection for
the newborn.
The main benefits of delayed umbilical cord
clamping are (12):
– higher levels of iron
– lower risk of anemia
– fewer blood transfusions
– lower incidence of intraventricular
bleeding.
Iron is an essential trophic needed in process-
es that depend on oxygen consumption. There-
fore, it plays a key role in the function of vital
cells. Compared to other organs, the brain has
the highest oxygen consumption, oligodendro-
cytes being the predominant iron-containing
FIGURE 1. Infant blood volume
cells. The importance of iron in myelin produc-
(h!p://exaltbirthservices.com/empowering-choices/ tion has been demonstrated by studies that show
delayed-cord-clamping/) the connection between low amount of iron and
low myelinisation (14).
A “vampire midwife” declares that, in the ma- Up to 50% of children from developing
jority of the cases, she filled at least half of a countries become anemic until the age of 1, a
blood container (i.e., 90 mL). It is suggested that, negative situation in which impairments on
in this situation, parents must be adequately in- psychomotor-development could be an irrever-
formed if they are to make the decision of col- sible effect (15). Therefore, prevention is certain-
lecting stem cells by drawing a significant amount ly more efficient than treating the infant, and
of blood from their child’s blood volume (11). it will be better while keeping what is rightfully
They have to weigh the advantages of collect- his.
ing whole blood at birth compared to a possible According to the European Group on Ethics in
treatment for a slightly probable future disease. Science and New Technology, there are several
The blood from the umbilical cord is the infant’s essential ethical principles which can be consid-
blood (11). One of the first treatments applied to ered relevant:
a newborn requiring neonatal intensive care is – the principle of respect for human dig-
intravenous infusion of a bolus of saline solution nity and integrity, that state/declare the
0.9% or blood. We consider that it is desirable to principle of non trading the human
let the nature do its own transfusion (Figure 1). body;
According to Dr. Sarah Buckley, the probabi- – the principle of autonomy or the right
lity that the newborns would need their own of self-determination on the basis of
cells stored was estimated at 1:20.000. complete and correct information;
The blood from the autologous umbilical cord – the principle of justice and solidarity in
is suitable for infants who develop solid tumors, rightfull healthcare accesibility;

– the principle of beneficence, or the ob-

ligation to do good, especially in health
care protection;
– the principle of nonmaleficence, or ob-
ligation to do no harm, including the
obligation to protect vulnerable groups
and persons, in order to respect the
confidentiality and their private lives;
– the principle of proportionality, that re-
quires a balance between means and FIGURE 2. Term versus preterm infants
objectives. q
METHOD
T he study analyzed the infants whose stem

cells were harvested between 1 January and
31 March 2014, in ”Alessandrescu-Rusescu” Na-
tional Institute for Mother and Child Health. We
watched the evolution of pregnancy and moni-
tored labor, delivery, type of newborns and their
transition to extrauterine life. Umbilical cord FIGURE 3. NICU admission from cells harvested infants
clamping was done below 30 seconds after deliv-
ery and 100-120 mL of placental blood were har- globin and hematocrit level (Figure 4). Anemia
vested. The Apgar score was given at 1 minute was considered when haemoglobin level fell un-
after birth and neonatal resuscitation was initiat- der 14 g% and the hematocrit was <45%, hypo-
ed before 1 minute. q glycemia when blood sugar level was <40 mg%,
and hypocalcemia <8 mg/dL or <1.1 mmol/L.
RESULTS
I n all cases with stem cells harvested, the um-

bilical cord was clamped below 30 sec. Of
3094 births (2013-year previous to this study),
16.58% were harvested stem cells. The first three
months of 2014 (January 1 to March 31) stem
cells were harvested to 12.46% (682) of all births;
maternal age was mainly 31-35, with no signifi-
cant differences between primiparous vs. mul-
tiparous, and 78.82% of all mothers where from
urban areas.
There were 8.23% preterm infants (Figure 2)
and the distribution by gender was roughly equal.
Maternal pathology (arterial hypertension – FIGURE 4. Newborn outcome
1.17%, diabetes mellitus – 1.17%, infections –
32.94%, thrombophilia – 8.23%) was present in Of all newborns, 15.29% had arterial hypo-
31.76% of these births. The delivery mode was tension requiring volume replacement with NS
67.05% by caesarean section. Birth asphyxia (Ap- 0.9%.
gar score ≤7) was present in 10.58% of cases. The risk of infection was mostly increased by
Of the 85 newborns in which stem cells were labor with ruptured membranes from 16 hours
harvested, 40 (47%) needed NICU hospitalisa- and presence of pathogens in maternal cultures
tion (Figure 3). (vagina, urine) during the last trimester (Figure 5).
We monitored extrauterine transition of new- Birth asphyxia and anemia was registered in
borns by heart rate, oxygen saturation, haemo- the first 24 hours (Figure 6).

DISCUSSION
rupture of mebmranes
≥16 H
I n the selected group explored by us, the um-
bilical cord was clamped below 30 seconds in
all cases with stem cells harvested to obtain more
streptococcus B milliliters of blood. This procedure has been seen
more often lately. In the three months of our
escherichia coli study, stem cells were harvested in 75% of the
total harvested in the previous year.
staphylococcus aureus The mothers aged 31 to 35 years were mainly
from urban areas (78.82%), with no significant
differences between the primiparous and mul-
FIGURE 5. Maternal infectious risk tiparous ones.
31.76% of the mothers presented pathology
(arterial hypertension 1.17%, diabetes mellitus 1.17%,
infections 32.94%, and thrombophilia 8.23%).
Of the 32.94% women with infectious risk,
we found out that the risk was mostly induced by
labor with ruptured membranes more than
16 hours and presence of pathogens in maternal
cultures (vagina, urine) in the last trimester (Strep-
tococcus B 34.48%; Escherichia coli 44.82%;
Staphylococcus aureus 6.89%).
Most infants were at term, 8.23% were pre-
mature, and the distribution by gender was
roughly equal.
The caesarean section was performed in
FIGURE 6. The incidence of neonatal anemia and asphyxia in pre- 67.05% cases; 10.58% of them were with birth
term and term infants asphyxia (Apgar Score ≤7).
Anemia was registered in the first 24 hours
The following findings show the pathology of and was present in 1.28% of term infants and
newborns described in literature. 28.57% of preterm infants.
Neonatal intensive care unit admission was
Confirmed by studies To be confirmed required in 47% of cases and the treatment con-
sisting in termic neutral point, oxygenotherapy,
Respiratory Distress
Anemia 8.23% treatment of hypovolemia was taolored to the
Syndrome 4.70%
needs of each newborn.
Hypoxic-ischemic encephalopathy
Anemia of prematurity 1.17% Newborn outcome was mainly dominated by
2.35%
early infectious signs. Clinical assessment reveled
TABLE 2. Neonatal diseases induced by delay in adapting to presence of metabolics disorders (hypoglicemia
extrauterine life and immaturity of systems and organs in the cases 10.58%, hypocalcemia 23.52%) and cardiocircu-
studied in our clinic
latory signs (arterial hypotension 15.29%, brady-
cardia 8.23%).
Although anemia is diagnosed in the first 24 Newborns with arterial hypotension requiring
hours, probably consecutive to harvesting the volume replacement with NS 0.9% were 15.29%.
stem cells, at discharge only 1.17% of the neo- The literature showed that the delay in transi-
nates have anemia of prematurity, showing that tion to extrauterine life and immaturity of sys-
good nutritional care has been provided. tems and organs could be expressed in neonates
The neonatal resuscitation team should know by respiratory distress syndrome (RDS) and ane-
that stem cells have been harvested, so that they mia of prematurity. In our study, we found 4.70%
should have an effective emergency intervention of cases with the RDS and 1.17% with anemia of
for correction of hypovolemia. q prematurity. q

CONCLUSION The harvesting was done predominantly at

cesarean section because that was the predomi-
H arvesting stem cells is a common practice in

developed countries; the statistical analysis
shows that it can become more common in
nant way of delivery (67.05%) for both term and
preterm newborns.
A well-prepared neonatal resuscitation team
Romania as well. is required every time a stem cell harvesting pro-
Early clamping of the umbilical cord is usually cedure is performed. As a result, we can antici-
done no later than 30 seconds after birth, even pate that the chance of the newborn requiring
though there is no protocol to implement this neonatal resuscitation is needed.
practice. The parents have to be informed about the
47% of all newborns who had stem cells har- potential complication of stem cells harvesting
vested needed NICU assistance for arterial hypo- procedure before practicing it.
tension induced or correlated with anemia and More investigations are necessary to explain
asphyxia accompanied by bradycardia. the high incidence of anemia in preterm group
We believe that hypotension was determined compared with term infants.
by correlating several factors (anemia, perinatal Current evidence is insufficient to decide
asphyxia and bradycardia). Anemia, perinatal as- whether the long-term potential benefits of this
phyxia and bradycardia are evidence of cardiac practice outweigh the short-term damage done
impairment and required volume expander and by blood deprivation. q
oxygen. A particularity of this group was that
31.76% of newborns came from risk pregnancies
(arterial hypertension, diabetes mellitus, infec- Conflict of interests: none declared.
tions, thrombophilia). Financial support: none declared.
R#$#%#&'#*
1. Iuvenalie Ion Ionașcu, Arhim. Dr., mental pathways and specification of confessions of a vampire-midwife,
Paroh al Comunității Ortodoxe Romane intrapulmonary stem cells. h!ps://midwifethinking.com/2015/09/16/
“Sf. Ioan Casian” din Roma și protopop Pediatr Res2006;59:84R–93R. cord-blood-collection-confessions-of-a-
al comunităților ortodoxe române din 7. Bhandoola A, von Boehmer H, Petrie vampire-midwife/ 2015.
Italia Centrală și Meridională. Îngrijirea HT, et al. Commitment and develop- 12. Kelly Winder, Delayed Cord Clamping-
vieții umane – principiu fundamental în mental potential of extrathymic and whay you should demand it, h!p://
bioetică. Revista Romana de Bioetică. 2015:3. intrathymic Tcell precursors: plenty to www.bellybelly.com.au/birth/cord-
2. Holland S, Lebacqz K, Zoloth L. The choose from. Immunity 2007;26:678–689. clamping-delaying-cord-clamping#.
Human Embryonic stem cell debate. 8. Mark Sloan. Common Objections to U2KAfYGSxn1 2016 available from:
Science, ethics and public policy. 2001. delayed cordon clamping-what’s the h!p://news.nationalgeographic.com/
3. Amin Abboud. The Stem Cell Debate evidence say? h!ps://www.scienceand- news/2006/04/0406_060406_cord_blood.html
available from: h!p://www.lifeissues. sensibility.org/p/bl/et/ 13. Erica Lloyd. Umbilical Cord Blood: The
net/writers/edi/edi_06stemcelldebate. blogid=2&blogaid=526 2012. future of stem cell research?
html 9. Hilary Butler. The ethics of cord National Geographic News 2006.
4. Tolosa JN, Park D-H, Eve DJ, Klasko clamping and stem cell collection, h!p:// 14. Todorich Bozho, Pasquini Juana M,
SK, Borlongan CV, Sanberg PR. Stem www.beyondconformity.co.nz/ Garcia Corina I, Paez PM, Connor JR.
Cells Review Series, Mankind’s first hilarys-desk/the-ethics-of-cord-clamp- Oligodendrocytes and myelination:
natural stem cell transplant. ing-and-stem-cell-collection 2008. The role of iron. 3 OCT 2008 DOI: 10.1002/
J Cell Mol Med 2010;14:488-495. 10. Americord, Delayed Cord Clamping: A glia.20784.
5. Merkle FT, Alvarez-Buylla A. Neural guide to research and options, h!p:// 15. Cord Blood banking vs. Delayed cord
stemcells in mammalian development. cordadvantage.com/delayed-clamping- clamping, h!p://wellroundedbirthprep.
Curr Opin Cell Biol 2006;18:704–709. cord-blood-banking.html 2013. blogspot.ro/2011/08/cord-blood-banking-
6. Borok Z, Li C, Liebler J, et al. Develop- 11. Rachel Reed. Cord Blood Collection: vs-delayed-cord.html 2011.

2017; 12(1): 19-22
O RIGINAL PAPER
Concomitant Lung and Liver

Hydatid Cyst Managed as One-Stage
Surgery
Usha DALALa, Ashwani Kumar DALALa, Rikki SINGALb
a
Department of Surgery, Government Medical College and Hospital, Sector -32,
Chandigarh, Punjab, India
b
Department of Surgery, Maharishi Markandeshwar Institute of Medical Sciences and
Research, Mullana (Distt-Ambala) Haryana, India
ABSTRACT
Objective: Over the world, hydatidosis is endemic in many countries. It is more prevalent in Turkey. We
came across with concomitant hydatidosis of the lung and liver and reviewed the management.
Material and Methods: This is a prospective study that was carried out in the Government Medical
College and Hospital, sector-32, Chandigarh, India, between 2004 and 2010, in the Department of Surgery.
A total of five patients diagnosed with concomitant liver and pulmonary hydatid disease underwent surgery.
They were operated by thoracotomy and laparotomy in the same sitting.
Results: Hydatid cysts located in the lungs were managed by means of cystotomy and capitonnage. For
liver cysts, cystotomy and inversion of the cavity with sutures was the surgical method of choice, and a drain
was left in place. Excessive biliary drainage occurred in one patient who was managed successfully.
Conclusions: We believe that simultaneous management of pulmonary and hepatic cysts through the
thoracic route and by laparotomy is convenient and should be encouraged in patients because this approach
decreased morbidity and mortality by deferring second operation. Needle aspiration can be applied only for
liver cysts but it is absolutely contraindicated in lung hydatid cysts.
Keywords: lung, liver, hydatid cyst, single-stage surgery
INTRODUCTION Isolated hydatid disease of the spleen is very ex-

ceptional especially in the hilum region. Human
H
ydatid disease as parasitosis
hydatid disease can involve the liver (66%), lung
caused by Echinococcus granulo-
sus remains a widespread health (5–15%), spleen (less than 2%) and rarely other
problem in endemic areas, inclu- parts of the body (2).
ding the Middle East, Mediterra- This disease is quite prevalent in Turkey. It is
nean countries and Central Asia. Concomitant characterized by round lesions in lungs and liver.
pulmonary and liver hydatid disease may occur A considerable number of patients with lung hy-
in 4% to 25% of patients with hydatidosis (1). datid cysts also have liver cysts (3). Peripheral or-
Professor Dr Rikki Singal, C/o Dr Kundan Lal Hospital, Ahmedgarh, Dis$-Sangrur, Pin code-148021, Punjab, India
Phone: 09996184795; fax: 01731304550
Email: singalsurgery@yahoo.com
Article received on the 16th of December 2016. Article accepted on the 10th of March 2017.

CONCOMITANT LUNG AND LIVER HYDATID CYST MANAGED AS ONE-STAGE SURGERY
gan hydatidosis is much less common, as few

embryos can escape the capillary filtrating sys-
tems of the liver and lung (4).
Here we evaluate our patients with lung and
liver cysts and present our experience. Also, we
discuss the principles of treatment for hydatid
disease. q
MATERIAL AND METHODS
T his study was carried out in the Department

of Surgery, Government Medical College and
Hospital, sector-32, Chandigarh, India, from 2004
to 2010. A total of five patients were diagnosed FIGURE 2. Computed tomography (CT) scans of
with concomitant hepatic and pulmonary hyda- the same patient showing bilateral lung cysts and
an additional liver cyst just to the right side of the
tid disease. They underwent a successful single- falciform ligament
stage surgery. There were 3 males, one female
and one child, whose ages ranged from 8 to RESULTS
67 years, with a median age of 43. The cysts
were located on the diaphragmatic surface of the
right and left lobes of the liver. Thoracotomy
with laparotomy was the method of approach.
I n the single-stage surgery for lung and liver
cysts, a posterolateral thoracotomy was done
through the 5th intercostal space – on the right
All the five patients with concomitant lung side in two patients, bilateral thoracotomy in one
and liver cysts had subphrenic location (100%); patient, and left sided thoracotomy in two pa-
one of them had a cyst in the right lung (20%), tients. Lung cysts were operated first in supine
two in the left lung (40%), and two had bilateral position with a sand bag on the back on opposite
cysts (40%). In one case, chest X-ray revealed a side. After posterolateral thoracotomy, the lung
cyst on both sides and a ruptured cyst on the left was freed from all adhesions to the chest wall.
side (Figure 1). Then, the edges of the wound and the surface of
the lung other than the cyst surface were co-
vered with sponges soaked in saline solution and
diluted (10%) povidone-iodine solution to pre-
vent inadvertent implantation of scolices or a
daughter cyst.
While the lungs were kept inflated by Bar-
rett’s technique, a large needle connected to the
suction tip was inserted into the cyst. An anti-
scolicidal agent was not injected into the cystic
cavity before needle aspiration. When the cyst
was aspirated and its fluid evacuated, the most
prominent part of the cyst was opened (cystoto-
my), and the cyst membranes were removed
FIGURE 1. Bilateral cysts, X-ray showing left lung with sponge holding forceps. Then the cavity was
cyst (ruptured) irrigated with saline solution and cleaned with
sponges moistened with diluted povidone-io-
On admission, all patients had either other dine. The bronchial openings were sutured.
parenchymatous lesions of the lung or pleural The residual cavity starting from the deepest
complications, including pneumothorax and level, with a space of 1.5 to 2 cm left between
pleural effusions. Empyema was found in one each layer, was obliterated with absorbable
patient. In the patient with empyema, the opera- purse-string sutures (polygalactin 3 0, Vicryl;
tion was delayed until his recovery after drainage Ethicon, capitonnage), and then laparotomy was
of the empyema. q done for liver cyst. Cystotomy was performed to

remove the germinative membrane. Only one of ways in which infection spreads have been sug-
the five patients had bile leakage; no bile leak gested to explain the escape of liver and lung
occurred in the other four patients. The inner involvement through lymphatics or through ve-
surface of the cyst, the cavity and the remaining novenous shunts within the liver and in the space
pericystic liver tissue were inverted with sutures of Retzius (8).
and filled with omentum. The subdiaphragmatic Hepatic cysts can be reached by the transdia-
area was drained with a portex tube drain below phragmatic route during right thoracotomies for
the diaphragm. In one case, bile drainage existed pulmonary cysts in synchronous right pulmonary
on the inner surface of the cyst, the biliary ope- and subdiaphragmatic hepatic cysts and the two
nings were sutured first, and the cavity was inver- separate procedures may be performed in just
ted. Then the subdiaphragmatic area was drained one stage (7). With their enlargement, they might
below the diaphragm with a latex drain. If there cause abdominal pain, discomfort, and a palpa-
was combined biliary drainage and pus in the ble mass. In cases of pulmonary cysts, patients
cavity, a latex drain was placed after the biliary might have dyspnea and non-productive cough.
openings had been sutured, and the cavity was Some patients might have blood-streaked spu-
inverted. The subdiaphragmatic area was also tum and thoracic pain. Vigorous coughing and
drained. Generally, no matter how big the cysts expectoration of membranes are the symptoms
were, we preferred not to put an external drain of ruptured hydatid disease (5). Plain chest radio-
in the cystic cavity for the liver, except for the graphs and ultrasonography are the diagnostic
case of suppuration. Only the subphrenic region tools for hydatid disease. Computed tomography
was drained, and the drain is frequently removed also plays an important role to reach for diagno-
on the third day. sis and management in both intact and ruptured
In the post-operative period, albendazole cysts (9). Air fluid level or floating membranes
(10-20 mg/kg) was given. The drug was given as may be seen in some cases giving the characte-
three sequential, 28-day courses, with 21-day in- ristic appearance of water lily sign, crescent sign,
tervals between courses. The postoperative serpent sign, or air-bubble sign, which may be
course in all the patients was uneventful. Only a found in cases of ruptured hydatid cysts or com-
small number of complications occurred. Exces- plicated cysts with superadded infection (9).
sive biliary drainage occurred in one patient. Surgical treatment is advocated for pulmo-
There were no perioperative deaths. All patients nary and hepatic cysts and in whom medical
were followed-up for a period of 2 weeks to 5 management has not been successful (10). For
years. No recurrence was noticed for the cysts lung cysts, various surgical procedures have been
located in the liver and lung hydatid. q described in the literature such as conservative
resections, cystotomy with or without capiton-
DISCUSSION nage, or radical resections, such as segmentec-
tomy or lobectomy (2-4). In our experience with
H ydatid disease has been known since the

time of Hippocrates and Galen, and the
term hydatid cyst was used to describe echino-
5 patients, we have seen that even in giant liver
cysts (size >10 cm), laparotomy is convenient
and has good results when lung and liver cysts
coccosis in 1808 by Rudolphi. Hydatidosis is a are situated on opposite sides. For hepatic cysts,
parasitic disease caused by the larval growth of obliteration of the residual cavity with a subdia-
the tapeworm (Echinococcus granulosus) (5). The phragmatic drain leads to good results. For pa-
dog-sheep cycle is the paradigm for the life cycle tients with concomitant bilateral liver and lung
of the parasite. People get involved in this cycle hydatid disease, a right or left thoracotomy ap-
as an intermediate accidental host by contact proach was applied. Because of the risks of me-
with infected dogs or consuming contaminated diastinitis and hepatobilliary fistula, none of our
vegetables (6). In adults, the most common site four patients with concomitant liver cysts under-
of infection is the liver, while in children it is the went median sternotomy. According to Gharbi’s
lung. Moreover, some patients might have he- classification, the management for class I and
patic cysts in addition to pulmonary cysts. Syn- class II liver hydatid cysts can be done by percu-
chronous pulmonary and hepatic hydatid dis- taneous needle aspiration. However, in patients
ease may occur in 4% to 25% of cases (7). Various with simultaneous right lung and liver hydatid

cysts, the transdiaphragmatic approach addres- quences, and psychological profile (12). When
ses the liver cysts, while opening for a right tho- cysts are cracked or broken on both sides, it is
racotomy saves the patient from undergoing a necessary to begin by operating first the lung
second interventional procedure. With this pro- which contains the most intact cysts. One-stage
cedure, many liver cysts can be reached and pa- surgery can be done either by double thoracoto-
tients may be prevented from undergoing a se- my or median sternotomy in order to reduce the
cond surgical procedure (7). cost and avoid second general anaesthesia. It is
In our opinion, medical treatment is of no mainly indicated for young, uncomplicated and
value in pulmonary hydatid disease. However, peripheral cysts (13, 14). q
various points of view concerning medical treat-
ment exist (2-4). A chance of anaphylactic reac- CONCLUSION
tion can develop if the cyst ruptures. Intraopera-
tive irrigation of 0.5% cetrimide, 15% hypertonic
saline, and 0.5% silver nitrate solution prior to S urgical intervention should be the primary
treatment for hydatid disease. Subphrenically
located liver cysts should be treated simulta-
cyst opening may kill daughter cysts and further
reduce the risk of dissemination and anaphylac- neously with the lung hydatid disease. In patients
tic reaction (11). Although multiple session sur- with coexisting liver cysts, phrenotomy may be
gery is used to decrease the risk of complications, convenient and may be applied to prevent a se-
contamination and infection in multiple or bila- cond operation, when lung and liver cysts are on
teral pulmonary hydatid cyst cases, or in patients the same side. q
with other organ involvement, single-session sur-
gery can be used in selected cases, taking into Conflict of interests: none declared.
account the operative trauma, financial conse- Financial support: none declared.
R#$#%#&'#*
1. Aghajanzadeh M, Aghajanzadeh G, 6. Singal R, Mi"al A, Garg M, et al. of hydatid disease of liver and lungs: The
Ebrahimi H, Jahromi SK, Maafi AA, Unusual location of primary hydatid cyst state of art. Khirurgiia (Mosk) 2012;12-17.
Massahnia S. One stage operation for diagnosed on aspiration cytology. 11. Singal R, Dalal U, Dalal AK, Singh P,
five giant hydatid cysts of both lungs J Cosmet Dermatol 2017; 00:1–3. Gupta R. Subcutaneous hydatid cyst of
and liver in a 20-year-old female. doi:10.1111/jocd.12316. the thigh. South Med J 2010;103:965-966.
Tanaffos 2012;11:52-54. 7. Yener Aydin, Mine Çelik, Ali Bilal Ulaş, 12. Türk F, Yuncu G, Karabulut N, Türk T,
2. Singal R, Goyal S, Goyal R, Mi"al A, Atila Eroğlu. Transdiaphragmatic Ozban M, Zümrütbas EA, Akdag B. A
Gupta S. Primary splenic hydatid cyst in approach to liver and lung hydatid cysts. single-center large-volume experience in
a young boy--an uncommon entity. West Turk J Med Sci 2012;42 (Sup.2):1388-1393. the surgical management of hydatid
Indian Med J 2011;60:374-376. 8. Dalal U, Dalal AK, Singal R, Naredi B, disease of the lung with and without
3. Gupta A, Singal RP, Gupta S, Singal R. Gupta S. Primary hydatid cyst masquer- extrapulmonary involvement.
Hydatid cyst of thigh diagnosed on ading as pseudocyst ofthe pancreas with World J Surg 2013;37:2306-2312.
ultrasonography - a rare case report. concomitant small gut obstruction-an 13. Achour K, Ameur S, Chaouche H.
J Med Life 2012;5:196-197. unusual presentation. Management of bilateral pulmonary
4. Singal R, Sandhu KS, Mi"al A, Gupta Kaohsiung J Med Sci 2011;27:32-35. hydatid cysts. National Academy of
S, Jindal G. A giant splenic hydatid cyst. 9. Goyal VD, Sood S, Rana S, Pahwa S. Surgery 2013;12:38-43.
Proc (Bayl Univ Med Cent) 2016;29:55–57. Single-stage management of large 14. Lahroussi M, Kha"abi WE, Souki N,
5. Sadrizadeh A, Haghi SZ, Masuom SF, pulmonary and hepatic hydatid cysts in Jabri H, Afif H. [Bilateral pulmonary
Bagheri R, Dalouee MN. Evaluation of pediatric age group: Report of two cases. hydatid cyst]. Pan Afr Med J 2016;24:280.
the effect of pulmonary hydatid cyst Lung India 2014;31:267-269. doi:10.11604/pamj.2016.24.280.7700.
location on the surgical technique 10. Chernousov AF, Musaev GK, eCollection 2016.
approaches. Lung India 2014;31:361-365. Abarshalina MV. The surgical treatment

2017; 12(1): 23-29
O RIGINAL PAPER
Unusual Entities of Appendix

Mimicking Appendicitis
Clinically – Emphasis on
Diagnosis and Treatment
Rikki SINGAL, Muzzafar ZAMAN, Bhanu Pratap SHARMA
Department of Surgery, Maharishi Markandeshwer Institute of Medical Sciences and
Research, Mullana (Distt-Ambala), Haryana, India
ABSTRACT
Background: Abdomen is considered a magic box or a Pandora box where you will get different,
unexpected pathologies along with rare entities. Appendicitis is the commonest emergency in surgery which
presents challenges to surgeons because of a myriad list of differential diagnosis including both medical and
gynaecological pathologies. Preoperative imaging plays an important role in diagnosis and management.
Aims and objectives: To study the rare atypical anatomical and surgical presentations of appendix in
patients with clinical features of appendicitis. We focus on the clinical features and the role of investigations
for the radiological part and management.
Material and methods: This study was done in M.M. Institute of Medical Sciences and Research,
Mullana, Ambala, from November 2014 to July 2016. This was a retrospective study. We found 168 cases
with the diagnosis of appendicitis, out of which 19 were with rare entities.
Results: Subjects of both genders were aged between 20 and 60 years. Out of 19, 15 were males and 4
females. Four patients were operated for inguinal hernia but incidentally we found appendix in the hernial
sac termed as Amyand’s hernia. Another patient presented with obstruction and appendix was forming
a band diagnosed as torsion of appendix. Two most interesting cases were diagnosed as appendicular
neuralgia and relieved by appendectomy. Out of 19 cases, 7 cases were operated for appendicitis diagnosed as
appendicolith. In all the cases appendectomy was done without encountering any complications. Symptom
free patients were operated for appendicular neuralgia. No malignancy was found in mucocele appendix at
follow up. There were no complications by the 6-month follow-up.
Conclusion: As we came across with different entities of appendix presented with appendicitis, patients
should be investigated before proceeding for surgery. In our study, there were incidental findings for which
surgeons were not aware of the diagnosis and even for the patient. In inguinal hernia, ultrasonography was
not done, diagnosis being made on clinical basis. Clinical and radiological investigations play an important
part in early diagnosis and management.
Keywords: appendix, perforation, inflammation, torsion, hernia, mucocele, neuralgia.

Rikki Singal, Professor (MS, FICS, FICS) C/o Dr Kundan Lal Hospital, Ahmedgarh, Dis$-Sangrur, Punjab, Pin Code-148021, India
Email – singalsurgery@yahoo.com
Phone: 09996184795, Fax: 01731304550
Article received on the 22nd of November 2016 and accepted for publication on the 10th of March 2017.

UNUSUAL ENTITIES OF APPENDIX MIMICKING APPENDICITIS CLINICALLY – EMPHASIS ON DIAGNOSIS AND TREATMENT
INTRODUCTION 2016. A total of 168 cases that were found retrospe-

ctively diagnosed as acute appendicitis were inclu-
A
ppendicitis is the commonest surgical ded in this study, and in 19 of them rare presenta-
emergency for which appendectomy tions were seen intraoperatively. All these patients
is the only option by either a laparosco- had complete history and underwent thorough cli-
pic or an open procedure. The appen- nical, radiological and haematological investigations. q
dicular neuralgia is a rare cause of chronic
right lower quadrant abdominal pain (RLQAP), even OBSERVATION AND RESULTS
though no objective disorder can be determined.
This condition can be described as chronic ap-
pendicitis or (neurogenic) appendicopathy. Van
Rossem et al included 10 patients with chronic
T he age range of our patients was 20-60 years.
Out of 19, 15 were males and 4 females. Five of
the male patients were operated for inguinal hernia
RLQAP who underwent an appendectomy. After and Amyand’s hernia was incidentally found; one
careful selection, elective appendectomy was male patient had torsion of appendix; two men
performed in their centre for this group of patients had mucocele. Two female patients in this series
(1). Mucinous cystadenoma is a rare cystic neo- had mucocele appendix. All patients underwent
plasm of appendix that develops as a result of pro- laparoscopic/open appendectomy (Table 1).
liferation of mucin-secreting cells in an appendix.
It is seen in 0.2–0.3% of resected appendices in Torsion of appendix
Europe and the United States. Even in benign di-
The patient admitted in emergency with ab-
sease such as cystadenoma, dissemination of mu-
dominal pain along with off and on intestinal ob-
cin-producing cells into the peritoneal cavity can
struction. Ultrasonography of the abdomen re-
cause pseudomyxoma peritonei (2). About 25%
vealed dilated intestinal loops and inflammed
of patients are asymptomatic and the condition is
appendix with small amount of collection in the
found incidentally on imaging or at the time of
right iliac fossa. In view of obstruction, surgery
surgery. Another rare entity, known as Amyand’s
planned. The midline incision made and a band
hernia, with an incidence of 0.07% to 0.13% of all
was overlying the small bowel loops originated from
cases of appendicitis, is an inguinal hernia with
the tip of the appendix. The tip of the appendix
appendix as the content of hernial sac (3). Radio-
was inflamed and formed a mass. This appendicu-
logical investigations play a major role in diagnos-
lar band was only causing obstruction by twisting to
ing the disease including appendicitis cases. It is
the ileal loops. The band measuring 8 cm in length
very rare to diagnose it preoperatively on Ultraso-
was coiled around the small bowel (Figure 1). There
nography (USG) as an inflamed appendix in the
was colour change in the bowel loops and append-
obstructed inguinal hernia (4). Prompt surgery is
ectomy was done by relieving the band. Hot packs
required to avoid the complications such as incar-
were given to the bowel loops and colour came to
ceration or strangulation and subsequent morbi-
normal, so the resection of the intestine was not
dity (5). Nowadays, diagnostic laparoscopy (DL) is a
performed. Appendectomy was done with preser-
valuable adjunct to the early diagnosis and mana-
vation of the bowel and gross resected specimen
gement of this often-confounding condition (6).
showed long appendix along with an inflamed
Regarding imaging as per ACR (American College
mass at the tip (Figure 1).
of Radiology), computed tomography is the most
accurate imaging study for evaluating suspected
Amyand’s hernia
acute appendicitis and alternative etiologies of right
lower quadrant pain. USG and contrast-enhanced Four cases were admitted with uncomplicated
computed tomography (CECT) help in the investi- inguinal hernia and were planned for surgery. After
gations to diagnose abdominal injuries (6-8). q identification of the spermatic cord, sac separated
and inside the sac hard structure felt. The sac
MATERIAL AND METHODS opened and to our surprise we found appendix ly-
ing in the hernial sac. The appendix was non-in-
T his study was done in M.M. Institute of Medical

Sciences and Research, Mullana, Ambala, In-
dia, in a single unit, from November 2014 to July
flamed, the tip was held and its base took out only
through the inguinal hernia incision site. There was
no inflammation or perforation of the appendix.

Sir Age and Operative findings and

Clinical features Diagnosis
no gender surgery
1 30 yrs / Presented with pain right lower quadrant, nausea, Torsion of appendix Open appendectomy
male anorexia with neutrophilic and fever since 2 days
2 42 yrs/ Swelling on right sided inguinal region Inguinal hernia right Hernioplasty with appen-
male sided, Amyand’s dectomy (as there was no
hernia infection)
3 38 yrs/male Swelling on right sided inguinal region Inguinal hernia right Hernioplasty with
sided, Amyand’s appendectomy (as there was
hernia no infection)
4 60 yrs/male Swelling on right sided inguinal region Inguinal hernia right Hernioplasty with
sided, Amyand’s appendectomy (as there was
5 20 yrs/ Swelling on right sided inguinal region Inguinal hernia right Hernioplasty with
male sided, Amyand’s appendectomy (as there was
6 57 yrs/male Presented with pain right lower quadrant with Mucocele appendix Open appendectomy with
fever, nausea and anorexia for 3 days; tenderness local washing was done.
was present in RLQ with rebound also; usg revealed
dilated luminal diameter of appendix with peri ap-
pendiceal fluid. Chest x-ray revealed bronchitis.
7 46 yrs/fe- Diabetic female presented with pain migrat- Mucocele appendix Open appendectomy
male ing from umbilical region to RLQ of abdomen.
Neutrophilic with pus cells in urine routine
examination was present. Usg revealed a positive
target sign with dilated appendicular lumen with
perforation at tip.
8 23 yrs/fe- Unmarried female came to emergency with recur- Mucocele appendix Open appendectomy
male rent a!acks of pain lower abdomen in past one
year; usg revealed features of acute appendicitis
with haematuria.
9 35 yrs/ Presented with pain abdomen, mild fever and Mucocele appendix Open appendectomy
male nausea for 3 days. There was rebound tenderness
in RLQ with usg revealed dilated appendicular lu-
men and peri appendiceal fluid. CT scan was done
10 45 yrs / Presented with dull ache pain (recurrent a!acks) Appendicular Lap appendectomy
male since last 3 years. Usg of the abdomen was nor- neuralgia
mal. Patient was a chronic smoker and was having
bad chest.
11 30 yrs / Presented with pain RLQ recurrent a!acks since Appendicular Lap appendectomy
male 1 year presented with dull pain umbilical region neuralgia
with nausea, vomiting and fever.
12 34 yrs / Presented with pain RLQ with nausea; patient Appendicolith Lap appendectomy
male had tenderness in RLQ with ultrasound showing
appendicitis with appendix perforated in middle.
13 28 yrs / Patient had high grade fever with localised peri- Appendicolith Lap appendectomy. A small
male tonitis features in RLQ had a history of 3- 4 days calculus/appendicolith was
on us; there was ruptured appendix with peri stuck at base of appendix and
appendiceal collection. appendix was ruptured at tip.
14 29 yrs/male Presented with constant dull ache pain in RLQ Appendicolith Lap appendectomy
with anorexia and malaise since 3 days received
analgesia at home. We revealed features of acute
appendicitis.
TABLE 1. Detailed presentation and operative findings

dectomy and hernioplasty. They were successfully

discharged on the 6th day after surgery without any
complications such as infection, hematoma or any
discharge from the wound site. Patients were fol-
lowed up for 6 months and there was no recurrence.
Mucocele appendix
Four cases were diagnosed as mucocele appen-
dix and one patient presented with pain abdomen
predominantly in the right iliac region. There was
no history of weight loss but fever was present off/
FIGURE 1. Operative section showing appendicular band. Arrows on. In two cases, a mass was felt in the right iliac
indicate: a) caecum; b) band covering the small bowel loops; c) fossa for which differential diagnosis was kept as
inflamed area at the tip of the appendix appendicular lump or lymphoma. In other two
cases, no mass was felt, except for tenderness in the
right iliac area. Abdominal ultrasonography sus-
pected the presence of a mass. On CECT scan a
mass was present arising from the appendix diag-
nosed as mucocele appendix most probably be-
nign (Figure 3). Open surgery planned to avoid the
spillage of the cells. On surgery, there was a large
whitish mass found in the right iliac area with
small nodules, which was involving the appendix
(Figure 4a). Base was clear, so appendectomy done
(Figure 4b). On histopathology, low-grade appendi-
FIGURE 2. Operative area revealed appendix in the hernial sac
(the sac is held with the artery forceps and the appendix with the ceal mucinous neoplasm was diagnosed (Figure 5).
Babcock’s forceps) At one year follow-up, the patient was well and had
no recurrence.
Appendicular neuralgia
Three cases presented with abdominal pain
along managed with off and on medication but not
relieved. Ultrasonography of the abdomen was
normal, so we proceeded with the computed to-
mography (CT) which was also normal, and even
magnetic resonance imaging (MRI) was done to
rule out the cause of abdominal pain, but MRI was
normal too. However, the patient was having ab-
dominal pain and the lower limb flexion test was
positive. We planned for diagnostic laparoscopy
and to our surprise, the tip of the appendix was ly-
ing on the psoas muscle, which explained the cause
of his pain. Laparoscopy appendectomy was done
and the patient had no longer abdominal pain after
FIGURE 3. Computed tomography showing giant lump in the iliac
surgery.
region
Appendicolith
So, we performed appendectomy, followed by Seven cases were diagnosed as appendicolith
meshplasty (Figure 2). In the postoperative period, and mostly presented with abdominal pain and fe-
patients were given third generation antibiotics ver. Ultrasonography revealed an inflamed appen-
along with metrogyl for five days, in view of appendix and in two cases, appendicolith was seen (Fi-

FIGURE 7. a) White arrow showed lith lying outside from

FIGURE 4. a) Operative section revealed whitish colour the perforated appendix; b) white arrow showed appendicolith
lump as mucocele appendix; b) gross specimen revealed and black arrow showing artery passed through the perforated
mucous in the appendix (base is hold by artery) lumen; c) black arrow showed perforation in appendix and
white arrow showed dilated appendix
gure 6a). Laparoscopic appendectomy was done in

two cases (Figure 6b). On surgery, the appendico-
lith with 7–8 cm in size and perforation was present
in the middle of the appendix. In three cases, lapa-
roscopic appendectomy was performed to avoid
large incisions (Figure 6c, d). In one case, appendi-
colith with 2x3 cm in size was firm in consistency,
with inflamed appendix, and it was lying outside of
the appendix through the perforation site of the ap-
pendix (Figure 7a). Surgery was successfully done
and the patient felt well, without any pain or fever
FIGURE 5. a) High power view showing the mucinous lining of the (Figure 7b). A drain in the form of Ryle’s tube was
appendix; b) section showing fla!ened mucosa of the appendix which
at places is lined by mucinous epithelium (H and E X 40X)
put in and removed in all patients on the 3rd or 4th
postoperative day. All patients had uneventful post-
operative recovery. q
DISCUSSION
M ucocele of the appendix was coined for the

first time by Karl Freiherr von Rokitansky in
1842. It is the condition of appendix in which it is
transformed into a mucus filled sac; its incidence
ranges from 0.07% to 0.63% and it affects both
genders between the 5th and 7th decades of life (9).
Mucocele of the appendix is a rare condition and
its pathological classification and management
strategy have not been standardized yet. A classifi-
cation of mucinous appendiceal neoplasia was de-
veloped, and it was agreed that “mucinous adeno-
carcinoma” should be reserved for lesions with
infiltrative invasion. The term “low-grade appendi-
ceal mucinous neoplasm” was supported and it
was agreed that “cystadenoma” should no longer
be recommended. A new term of “high-grade ap-
pendiceal mucinous neoplasm” was proposed for
lesions without infiltrative invasion but with high-
grade cytological atypia. It was agreed that low-
grade and high-grade mucinous carcinoma perito-
FIGURE 5. a) Ultrasonography revealed appendicolith in the
appendix; b) the operative area showed laparoscopic appendectomy nei should be considered synonymous with
and the cut area revealed appendicolith; c) and d) operative specimen disseminated peritoneal adenomucinosis and peri-
of appendectomy and appendicolith held with forceps toneal mucinous carcinomatosis, respectively (10).

Abdominal ultrasonography (US) and compute- Appendicolith is also another rare phenomenon
rized axial tomography scan (CT), respectively sus- also known as faecolith, coprolith, stercolith, en-
pected the diagnosis in only one case (9). If muco- terolith, or concretion and is composed of firm fae-
cele is benign, it is clinically dominated by acute or ces and some mineral deposits in the lumen of ap-
chronic pain in the right lower quadrant (11). In pendix. It contains fats (coprosterols), inorganic salts
our study, patients had no features of weight loss, (calcium phosphate) and organic residue (vegetable
except for abdominal pain in the right iliac fossa, or fibres) in a proportion of 50%, 25% and 20%, re-
were asymptomatic as in cases of Amyand’s hernia. spectively. Other causes of calcific areas of high at-
Differential diagnosis should be established with tenuation in the abdomen include dropped gall-
benign pathologies of the appendix like leiomyo- stones, calcified epiploic appendagitis, dropped
ma, neuroma, fibroma and lipoma and other con- surgical clips, and calcified mesenteric lymph nodes
ditions such as mesenteric cysts, hydrosalpinx, car- (16). The prevalence of faecoliths in the general
cinoid, lymphoma, intussusception, endometriosis population is 3%, and appendicoliths are seen in
and adenocarcinoma of the appendix (12). Tho- 10% of cases with acute appendicitis. However, gi-
rough histologic examination is essential and it pro- ant appendicoliths (>2 cm) are extremely uncom-
vides the final diagnosis of the appendiceal disease mon and the largest appendicolith found by us was
upon histologic examination of the appendectomy 2.3 cm (2 cm on CT) (17, 18). All reported cases of
specimen. giant appendicoliths have been managed by ex-
Another life threatening complication of the ap- traction, either surgically or endoscopically, mostly
pendicitis is the chronically inflamed appendix act- due to the presence or perceived risk of appendici-
ing as a tourniquet around a loop of the terminal tis (19). Singal R et al. (20) reported the case of an
ileum (13). The exact cause of torsion is unknown. inguinal hernial stone termed as herniolithiasis,
It may develop as a consequence of sudden rota- where a stone was found in the hernial sac. The
tion of the body, or it may be due to a long pedicle, stone contains calcium (60%) and phosphate (40%)
or the vein may be longer and more likely to twist to be the principal constituents without any
around its accompanying artery, or it may be amounts of oxalate, urate and cholesterol. X-ray of
caused by excess fat in the pedicles. It can also the stone showed radiopaque shadow (21). In our
cause intestinal obstruction by forming a band on study, we came across three cases diagnosed intra-
the abdominal wall or an adjacent loop of bowel operatively as appendicitis due to appendicolith.
and thus kink the bowel; or a loop of the small Laparotomy has been the most common approach,
bowel may be caught under the adherent band; but two cases of endoscopic extraction have been
another possibility is that it may initiate intussuscep- described in recent years (16).
tions (14). Although CT imaging is a highly effective Another very rare entity of the appendix was a
investigative modality in these cases, operative rare cause of chronic right lower quadrant abdomi-
treatment should not be delayed for a radiological nal pain (RLQAP) (1). The term “neurogenic appen-
investigation in the presence of abdominal perito- dicopathy” has been used for patients operated on
nism (13). Intraoperative findings revealed inflamed for acute appendicitis with their appendices lacking
appendix which was rotated around the ileum and signs of acute inflammation. They studied 40 cases
tip was forming a mass. diagnosed with neurogenic appendicopathy out of
Amyand’s hernia is defined as the occurrence of 121 cases. Appendix specimens were immunohis-
the appendix in an inguinal hernial sac and in case tochemically examined for the expression of S-100,
of appendicitis; its incidence is only 0.1%. If diagno- vasoactive intestinal polypeptide (VIP), and sub-
sis is made before surgery by CT, it is possible to stance P. VIP was more strongly expressed in con-
treat Amyand’s hernia laparoscopically (15). They trol specimens (p = 0.0211). Substance P was of no
reported three rare cases with different presenta- diagnostic value. Postoperative pain scores differed
tions and emphasize that USG and CT plays an im- significantly between the groups, favouring appen-
portant role in diagnosis and management. We dectomy (P = 0.005) (21). They observed that per-
came across with five cases diagnosed as Amyand’s sistent or recurrent lower abdominal pain can be
hernia, which was an incidental finding in cases treated by elective appendectomy with significant
where we performed inguinal hernia surgery. If ap- pain reduction in properly selected cases, despite
pendix in the hernial sac is not inflamed, then it the lack of abnormal histology in neurogenic ap-
should be removed and Meshplasty could be done. pendicopathy presented with chronic right lower

quadrant pain as seen in our three cases. In these CONCLUSION

cases, even radiological tests also remain in dilem-
ma to reach to diagnose and surgeons remain in We came across with different and rare intra-
confused state. But we advised in such cases, pa- operative pathological entities in the appendix in
tient should undergo appendicectomy as we had patients who presented in emergency with clinical
good results in appendicular neuralgia treated with and radiological features of appendicitis and re-
appendicectomy. Laparoscopic appendicectomy ceived timely surgical treatment.
(LA) has become popular nowadays, especially “Abdomen is like magic; you don’t know when
among laparoscopic surgeons, due to the benefits it may reveal a surprise finding or/how much time it
of minimal invasive surgery and the simplicity of this will take to finish; so, always fill your stomach and
technique. LA has been shown to be advantageous empty your bladder”. By Rikki Singal. q
compared with OA with regard to early postopera-
tive parameters such as postoperative pain and re- Conflict of interests: none declared.
covery of bowel function (22, 23). q Financial support: none declared.
R#$#%#&'#*
1. Van Rossem CC, Treskes K, Loeza DL, 9. Rabie ME, Al Shraim M, Al Skaini MS, Biomedical Research 2015;6:65-70.
van Geloven AA. Laparoscopic et al Mucus containing cystic lesions 17. Kim DJ, Park SW, Choi SH, et al. A case
appendectomy for chronic right lower “mucocele” of the appendix: the of endoscopic removal of a giant
quadrant abdominal pain. unresolved issues. Int J Surg Oncol 2015. appendicolith combined with stump
Int J Colorectal Dis 2014;29:1199-1102. doi:10.1155/2015/139461 appendicitis. Clin Endosc 2014;47:112–114.
2. Yoshida Y, Sato K, Tada T, et al. 10. Carr NJ, Cecil TD, Mohamed F, et al 18. Singhal S, Singhal A, Mahajan H, et al.
Two Cases of Mucinous Cystadenoma A consensus for classification and Giant appendicolith: Rare finding in a
of the Appendix Successfully Treated pathologic reporting of pseudomyxoma common ailment. J Minim Access Surg
by Laparoscopy. peritonei and associated appendiceal 2016;12:170-172.
Case Reports in Gastroenterology 2013;7:44-48. neoplasia: the results of the Peritoneal 19. Singal R. A case of inguinal hernia stone
3. Singal R, Gupta S. Amyand’s Hernia Surface Oncology Group International alongwith diabetes and pathophysiology.
– Pathophysiology, Role of Investigations (PSOGI) Modified Delphi Process. Presse Med 2013;42:1540-1541.
and Treatment. Maedica J Clin Med Am J Surg Pathol 2016;40:14-26. 20. Partecke LI, Thiele A, Schmidt-Wankel
2011;4:321-327. 11. Akagi I, Yokoi K, Shimanuki K, et al. F, et al. Appendicopathy--a clinical and
4. Ali MS, Malik AK, and Al-Qadhi H. Giant appendiceal mucocele: report of a diagnostic dilemma. Int J Colorectal Dis
Amyand’s Hernia. Study of four cases case. J Nippon Med Sch 2014;81:110-113. 2013;28:1081-1089.
and literature review. 12. Srihari V, Jayaram J, Baleswari G, et al. 21. Roumen RM, Groenendijk RP, Sloots
Sultan Qaboos Univ Med J 2012;12:232–236. Mucinous cystadenoma of the appendix. CE, Duthoi KE, Scheltinga MR,
5. Singal R, Dalal U, Dalal AK, et al. J NTR Univ Health Sci 2015;4:182-184. Bruijninckx CM. Randomized clinical
Traumatic anterior abdominal wall 13. O’Donnell ME, Sharif MA, O’Kane A, trial evaluating elective laparoscopic
hernia: A report of three rare cases. Spence RA. Small bowel obstruction appendicectomy for chronic right
J Emerg Trauma Shock 2011;4:142. secondary to an appendiceal tourniquet. lower-quadrant pain. Br J Surg
6. Malik KA. Torsion of an Epiploic Ir J Med Sci 2009;178:101-105. 2008;95:169-174.
Appendix Pretending as Acute 14. Pogorelić Z, Stipić R, Druzijanić N, 22. Singal R, Zaman M, Mi"al A, Singal S.
Appendicitis. Oman Medical Journal et al. Torsion of epiploic appendage Evaluation of Intracorporeal Kno!ing and
2010;25:225-226. mimic acute appendicitis. Endoloop Closure in Laparoscopic
7. Lufti Incesu, Caroline R Taylor, Bernard Coll Antropol 2011;35:1299-1302. Appendicectomy. Hellenic Journal of
D Coombs, Eugene C. Lin appendicitis 15. Singal R, Mi” al A, Gupta A, et al. An Surgery 2016; 88:4:225-228.
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8. Singal R, Gupta R, Mi"al A, et al. cases and a review of the literature. Two port laparoscopic assisted
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2017; 12(1): 30-35
O RIGINAL PAPER
Combined Anatomic Anterior

Cruciate Ligament and Anterolateral
Ligament Reconstruction
Stefan MOGOSa, b, Bogdan SENDREAa, Ioan Cristian STOICAa, b
a
Foisor Orthopaedics Clinical Hospital, 35-37 Ferdinand Avenue, Bucharest, Romania
b
University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
ABSTRACT
Purpose: The purpose of the current paper was to report the surgical technique of combined anatomic
anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction as well as the short term
clinical results after this surgical procedure.
Material and Methods: The current prospective study included 32 patients (5 females and 27 males)
with combined ACL and ALL reconstruction performed between December 2015 and July 2016. The patients
were included in the study taking into consideration the following criteria: chronic ACL lesion, high grade
rotational instability (pivot shift grade II and III) and participation in high grade pivoting sports. Patient
evaluation followed an established clinical and imaging protocol both preoperatively and at 6 and 12 weeks
postoperatively. This included clinical knee stability testing (Lachman test, Pivot shift test), Rolimeter
differential laxity testing, subjective and objective IKDC scores and Lysholm score and Tegner score.
Results: Postoperative stability at 6 weeks and 12 weeks as tested with Lachman test (p=0.02 and 0.01,
respectively), pivot shift test (p=0.03 and 0.01, respectively) and the Rolimeter arthrometer (p=0.008
and 0.006, respectively) showed a statistically significant difference as compared to preoperative values.
Postoperative scores at 6 weeks and 12 weeks as measured using objective IKDC form (p=0.008 and 0.006,
respectively), subjective IKDC form (p=0.04 and 0.03, respectively) and Lysholm form (p=0.02 and 0.01,
respectively) were statistically significant improved as compared to preoperative values. All patients had a
negative Lachman test at 6 and 12 weeks postoperatively. One patient had a positive grade I pivot shift test
at 6 weeks postoperatively and two patients had a positive grade I pivot shift test at 12 weeks postoperatively.
Differential anteroposterior laxity as measured with the Rolimeter arthrometer improved from 7.19±1.96
mm preoperatively to 0.28±0.45 mm and 0.13±0.34 mm, at 6 weeks and 12 weeks postoperatively,
respectively. According to the objective IKDC form, 29 patients were normal or nearly normal (grade A and
B) at 6 weeks postoperatively and 31 patients were normal or nearly normal at 12 weeks postoperatively.
Subjective IKDC score improved from 47.72±17.18 preoperatively to 56.52±11.74 and 73.38±14.28 at
6 and 12 weeks postoperatively, respectively. Lysholm score improved from 63.44±23.01 preoperatively
to 80.41±11.94 and 90.47±8.22 at 6 and 12 weeks postoperatively, respectively. Improved Tegner activity
scores were present at 12 weeks postoperatively as compared with 6 weeks postoperatively, but still lower as
compared to pre-traumatic scores. No significant complications were present in the current study group.

Stefan Mogos, M.D.
Address: Bd. Ferdinand 35-37, Sect. 2, Bucuresti, Romania
Email: stefan.mogos@gmail.com
Phone: +40721 254 618
Article received on the 12th of January 2017 and accepted for publication on the 10th of March 2017.

COMBINED ANATOMIC ANTERIOR CRUCIATE LIGAMENT
COMBINED
ANDAANATOMIC ANTERIOR
NTEROLATERAL LIGAMENT
CRUCIATE LIGAMENT AND ANTEROLATERAL LIGAMENT RECONSTRUCTION
Conclusions: Combined ACL and ALL reconstruction is an effective surgical procedure, with improved
postoperative clinical results and no significant short term complications. Longer follow-up is necessary in
order to better evaluate the results of this procedure.
Keywords: anterior cruciate ligament, antero lateral ligament, anatomic reconstruction
INTRODUCTION cycling for two patients and other sports for the
rest of the patients.
A
nterior cruciate ligament reconstruc- Patients were included in the study taking into
tion (ACLR) is a commonly performed consideration the following criteria: chronic ACL
surgical procedure with very good lesion, high grade rotational instability (pivot shift
long term results. Yet, residual rota- grade II and III) and participation in high grade
tional instability may persist in some pivoting sports. Exclusion criteria were recurrent
cases and this may predispose to secondary ACL tears, knee dislocation and associated
meniscal and cartilage lesions, recurrent ACL tears ipsilateral extra-articular knee surgery (osteoto-
and difficulties in performing high level pivoting mies, associated ligamentous procedures). Patient
sports (1-3). Thus, a better control of rotational evaluation followed an established clinical and
instability, either by double bundle ACL recon- imaging protocol both preoperatively and at six
struction (4-6) or by adding a lateral extra-articular and 12 weeks postoperatively. This included
surgical procedure (6-8), may contribute to im- clinical knee stability testing (Lachman test, Pivot
proving the clinical results. Recent publications shift test), Rolimeter anteroposterior differential
demonstrated the presence of the anterolateral laxity testing, subjective and objective IKDC
ligament (ALL) as a distinct ligamentous structure scores and Lysholm score and Tegner score.
on the anterolateral side of the knee (9-12), ex- Written consent was obtained from the
tending from the femoral origin, in a region situ- patients. This study received instutional review
ated posterior and proximal to the lateral femoral board approval.
epicondyle to the tibial insertion, located halfway Postoperative rehabilitation protocol included
between the Gerdy’s tubercle and the tip of the progressive weight bearing as tolerated with two
fibular head. Biomechanical studies emphasized crutches without brace, range of motion training
the role of the ALL as an important stabilizer of without hyperextension and proprioception and
tibial internal rotation. Sectioning the ALL was muscle training starting from 4th postoperative
greatly associated with high grade pivot shift tes- week. A gradual return to sports program was
ting (13-15). established – non-pivoting sports started at three
The purpose of the current paper was to report months postoperatively, non-contact pivoting
the surgical technique of combined anatomic ACL sports at six months postoperatively and contact
and ALL reconstruction and the short term clinical pivoting sports at nine months postoperatively.
The paired t-test was used to compare the
results after this type of surgical procedure. Our
preoperative and postoperative numerical data.
hypothesis was that combined ACL and ALL
The Fisher exact test was used to compare the
reconstruction is associated with improved clinical
preoperative and postoperative Lachman and
results without any specific short term
pivot shift test results and IKDC objective score.
complications. q
The level of significance was established at
p<0.05.
MATERIAL AND METHODS
Surgical technique
T he current prospective study included 32
patients (5 females and 27 males) with
combined ACL and ALL reconstruction performed
Combined ACL and ALL surgical procedure is
meant to anatomically reconstruct the ACL using
between December 2015 and July 2016. The a triple stranded semitendious and gracilis
mean age at surgery was 28.8±7.53 years. The autograft and to replicate the triangular native
mean surgical time was 93.38±15.06 minutes. shape of the ALL by double-bundle reconstruction
The sport practiced was football for 22 patients, using the gracilis tendon.

COMBINED ANATOMIC ANTERIOR CRUCIATE LIGAMENT AND ANTEROLATERAL LIGAMENT RECONSTRUCTION
Patient positioning Preparing of the ALL reconstruction site

The patient is positioned supine with a padded Two stab incisions are used to prepare a
tourniquet applied in the proximal region of the V-shaped tibial tunnel, the first positioned at the
thigh. Two posts are attached to the surgical table, level of the Gerdy tubercle and the latter half-way
the first lateral to the proximal thigh and the latter between the Gerdy tubercle and the tip of the
as a foot roll in order to maintain a 90° knee peroneal head, in order to replicate the large
flexion (Figure 1). native tibial insertion of the ALL. A 2-cm incision
is centered over the lateral epicondyle and is
meant for ACL femoral tunnel drilling (Figure 3).
FIGURE 1. Patient positioning for combined ACL

and ALL reconstruction
Hamstring graft harvesting

Graft harvesting is performed using a 3-cm
skin incision located in the antero-medial region
of the proximal third of the leg. The semitendinous
tendon is kept attached in order to obtain a better FIGURE 3. Preparing of the ALL reconstruction
fixation and vascularization of the graft, while the site: (A) bony landmarks; (B) skin incisions;
gracilis tendon is whip-stitched with a traction (C) V-shaped tunnel drilling using a 5 mm drill bit;
suture, detached and used both for ACL and ALL (D) traction suture passage
graft preparation. Graft diameter measurement is
ACL tunnel drilling
performed during this surgical step (Figure 2).
Outside-in ACL femoral tunnel drilling is
performed with the lateral starting point located
posterior and proximal to the lateral epicondyle,
corresponding to the femoral insertion point of
the ALL (Figure 4). Tibial tunnel is drilled outside-
in using graft harvesting incision (Figure 5). Graft
length measurement is performed after this
surgical step (Figure 6).
FIGURE 2. Hamstring graft harvesting: (A) skin

incision; (B) sectioning of the sartorius muscle fascia; FIGURE 4. Femoral tunnel drilling: (A)
(C) exposing semitendinous and gracilis tendons; extra-articular view of the outside-in femoral guide;
(D) intraoperative aspect after graft harvesting (B) Intra-articular view of the outside-in femoral guide

ACL graft passage and fixation

ACL graft is pulled from distal to proximal and
fixation is performed with bioabsorbable screws
first on the tibial side and then on the femoral side
in 30° of flexion and posterior drawer (Figure 8).
FIGURE 5. Femoral tunnel drilling: (A) extra-articular

view of the outside-in femoral guide; (B) Intra-articular
view of the outside-in femoral guide
FIGURE 8. ACL graft passage and fixation in 30° of flexion and

posterior drawer
ALL graft passage and fixation
FIGURE 6. Graft length measurement
ALL graft is pulled deep to the fascia lata from
ACL and ALL graft preparation proximal to distal through the V-shaped tibial
tunnel and re-routed proximally to its femoral
The semitendinous tendon was tripled in order
origin, located at the lateral entry point of the
to reproduce the previously performed length
femoral tunnel (posterior and proximal to the
measurements and the gracilis tendon was sutured
lateral femoral epicondyle) (Figure 9). Fixation is
over the tripled semitendinous graft. Thus, the
performed using the ACL traction sutures in full
ACL graft was composed of three strands of semi-
extension and neutral rotation (Figure 10). q
tendinous tendon and one strand of gracilis
tendon, while the ALL graft consisted of the
remaining gracilis graft (Figure 7).
FIGURE 9. ALL graft passage: (A) ALL graft after

ACL fixation; (B) proximal to distal passage of the
ALL graft; (C) passage of the ALL graft through
FIGURE 7. ACL and ALL graft preparation: V-shaped tibial tunnel; (D) distal to proximal
(A) the semitendinous tendon is looped over 2 passage of the ALL graft
traction sutures. (B) the semitendinous tendon is
RESULTS
tripled for the preparation of the ACL graft and one
strand of gracilis tendon is added to the graft;
(C, D) final aspect of the ACL and ALL graft, with
the remaining gracilis tendon used as a graft for ALL P ostoperative stability at six weeks and 12 weeks
as tested with Lachman test (p=0.02 and 0.01,
respectively), pivot shift test (p=0.03 and 0.01,
reconstruction

POSTOPERA- POSTOPERA-
PREOPERA-
TIVELY TIVELY
TIVELY
6 WEEKS 12 WEEKS
LACHMAN Chronic lung
TEST disease
0 0 32 32
I 2 0 0
FIGURE 10. Fixation of the ALL graft using the
traction sutures of the ACL II 14 0 0
III 16 0 0
respectively) and the Rolimeter arthrometer
(p=0.008 and 0.006, respectively) showed a statis- PIVOT SHIFT
tically significant difference as compared to preope- TEST
rative values. Improved results as measured with 0 0 31 30
the Rolimeter arthrometer were present at 12 weeks I 5 1 2
postoperatively as compared with six weeks posto- II 18 0 0
peratively without statistical significance. All patients
III 9 0 0
had a negative Lachman test at six and 12 weeks
postoperatively. One patient had a positive grade I ROLIMETER 7.19±1.96 mm 0.28±0.45 mm 0.13±0.34 mm
pivot shift test at six weeks postoperatively and two TABLE 1. Results regarding clinical and instrumental knee stability
patients had a positive grade I pivot shift test at 12 POSTOPERA- POSTOPERA-
PREOPERA-
weeks postoperatively. Differential anteroposterior TIVELY TIVELY
TIVELY
laxity as measured with the Rolimeter arthrometer 6 WEEKS 12 WEEKS
improved from 7.19±1.96 mm preoperatively to OBJECTIVE IKDC
0.28±0.45 mm and 0.13±0.34 mm, at six weeks
A 0 15 26
and 12 weeks postoperatively, respectively (Table 1).
B 1 14 6
Postoperative scores at six weeks and 12 weeks
as measured using objective IKDC form (p=0.008 C 14 3 0
and 0.006, respectively), subjective IKDC form D 17 0 0
(p=0.04 and 0.03, respectively) and Lysholm form SUBJECTIVE
47.72±17.18 56.52±11.74 73.38±14.28
(p=0.02 and 0.01, respectively) showed statistically IKDC
significant improvement as compared to preopera- LYSHOLM
tive values. According to the objective IKDC form, 63.44±23.01 80.41±11.94 90.47±8.22
SCORE
29 patients were normal or nearly normal (grade A TEGNER SCORE 4.75±1.81 3.31±1.11 4.22±1.07
and B) at six weeks postoperatively and 31 patients
TABLE 2. Results regarding objective and subjective knee score
were normal or nearly normal at 12 weeks postop-
eratively. Subjective IKDC score improved from effective surgical procedure, with improved
47.72±17.18 preoperatively to 56.52±11.74 and stability (as measured with Rolimeter arthrometer,
73.38±14.28 at six and 12 weeks postoperatively, Lachman test and pivot shift test) and clinical
respectively. Lysholm score improved from scores (subjective and objective IKDC scores and
63.44±23.01 preoperatively to 80.41±11.94 and Lysholm score) early postoperatively as compared
90.47±8.22 at six and 12 weeks postoperatively, to preoperative status. The Tegner activity score
respectively. Improved Tegner activity scores were followed an ascending trend postoperatively. Yet,
present at 12 weeks postoperatively as compared at 3-month follow-up it didn’t reach the pre-
with six weeks postoperatively but they were still traumatic values. No significant short term
lower as compared to pre-traumatic scores (Table 2). complications were present in our study group.
No significant complications were present in ACLR is associated with very good clinical
the current study group. q results. Yet, residual rotational instability may still be
present postoperatively (1-3). Double-bundle ACL
DISCUSSION reconstruction was introduced aiming to better
control rotational instability, but it didn’t manage to
T he main finding of the current study is that

combined ACL and ALL reconstruction is an
provide an obvious clinical benefit. Moreover, it
was associated with increased incidence of

cyclops syndrome and more difficult ACL revision have an important role in controlling internal
surgery (3-6). Lateral extra-articular procedures, rotation of the tibia (9-18).
as lateral fascia lata tenodesis and more recently There are some limitations of the current study.
ALL reconstruction are expected to better control Although it is a prospective study, the follow-up is
rotational instability, by providing a better lever limited to three months. Longer follow-up is
arm for controlling internal rotation than intra- necessary to better evaluate the benefits and the
articular procedures (6-8). potential long term complications of this surgical
There is great literature confusion when procedure. A comparative study may be useful in
defining the antero-lateral structures of the knee. evaluating the results of this surgical procedure
The first publication dealing with the topic dates with respect to either single or double-bundle
from 1879, when Segond mentioned the presence isolated anatomic ACL reconstruction. q
of a fibrous band on the anterolateral side of the
knee. Many inconstant descriptions of the antero- CONCLUSION
lateral structure are present in the literature.
However, only recent publications by Claes et al.,
Helito et al., Pomajzl et al., Stijak et al., Dodds et C ombined ACL and ALL reconstruction is an
effective surgical procedure with improved
clinical results and no significant short term
al., Kennedy et al., Parsons et al. and Monaco et al.
managed to better anatomically describe the complications. Longer follow-up is necessary in
anterolateral ligament and emphasyze its role in order to better evaluate the results of this
controlling rotational instability of the knee and its procedure. q
role for reducing the pivot shift phenomenon. The
role of the anterolateral ligament is minimal in Conflict of interests: none declared.
controlling anteroposterior stability, but it may Financial support: none declared.
R#$#%#&'#*
1. Hughston JC, Andrews JR, Cross MJ, et al. 1589-7. ligament of the knee. Knee Surg Sports
Classification of knee ligament instabilities. 6. Ferre"i A, Monaco E, Labianca L, et al. Traumatol Arthrosc 2016;24:2083-2088.
Part II. The lateral compartment. Double bundle or single bundle plus 13. Dodds AL, Halewood C, Gupte CM, et al.
J Bone Joint Surg Am 1976;58:173-179. extra-articular tenodesis in ACL recon- The anterolateral ligament: Anatomy,
2. Chambat P, Vargas R, Fayard JM, et al. struction? A CAOS study. Knee Surg Sports length changes and association with the
Résultats des reconstructions de ligament Traumatol Arthrosc 2008;16:98. Segond fracture. Bone Joint J 2014;96-B:325-331.
croisé antérieur sous contrôle ar- 7. Sonnery-Co"et B, Thaunat M, Freychet B, 14. Monaco E, Maestri B, Conteduca F, et al.
throscopique avec un recul supérieur à 15 et al. Outcome of a Combined Anterior Extra-articular ACL Reconstruction and
ans. In: Le genou et le sport du ligament à la Cruciate Ligament and Anterolateral Pivot Shift: In Vivo Dynamic Evaluation
prothèse. Chambat P, Neyret P (Eds), Ligament Reconstruction Technique With With Navigation. Am J Sports Med
Montpellier, France: Sauramps Médical. a Minimum 2-Year Follow-up. Am J Sports 2014;42:1669-1674.
2008:147-152. Med 2015;43:1598-1605. 15. Spencer L, Burkhart TA, Tran MN, et al.
3. Stergiou N, Ristanis S, Moraiti C, et al. 8. Guenther D, Griffith C, Lesniak B, et al. Biomechanical analysis of simulated
Tibial rotation in anterior cruciate ligament Anterolateral rotatory instability of the clinical testing and reconstruction of the
(ACL)-deficient and ACL-reconstructed knee. Knee Surg Sports Traumatol Arthrosc anterolateral ligament of the knee.
knees: a theoretical proposition for the 2015;23:2909-2917. Am J Sports Med 2015;43:2189-2197.
development of osteoarthritis. 9. Claes S, Vereecke E, Maes M, et al. 16. Song GY, Hong L, Zhang H, et al. Clinical
Sports Med 2007;37:601-613. Anatomy of the anterolateral ligament of Outcomes of Combined Lateral Extra-
4. Meredick RB, Vance KJ, Appleby D, et al. the knee. J Anat 2013;223:321-328. articular Tenodesis and Intra-articular
Outcome of single-bundle versus 10. Helito CP, Demange MK, Bonadio MB, Anterior Cruciate Ligament Reconstruc-
double-bundle reconstruction of the et al. Anatomy and Histology of the Knee tion in Addressing High-Grade Pivot-Shift
anterior cruciate ligament: a meta-analysis. Anterolateral Ligament. Orthop J Sports Phenomenon. Arthroscopy 2016;32:898-905.
Am J Sports Med 2008;36:1414-1421. Med 2013;1:2325967113513546. 17. Kennedy MI, Claes S, Fuso FA, et al.
5. Zaffagnini S, Signorelli C, Lopomo N, 11. Pomajzl R, Maerz T, Shams C, et al. The Anterolateral Ligament: An Anatomic,
et al. Anatomic double-bundle and A review of the anterolateral ligament of Radiographic, and Biomechanical
over-the-top single-bundle with additional the knee: current knowledge regarding its Analysis. Am J Sports Med 2015;43:1606-1615.
extra-articular tenodesis: an in vivo incidence, anatomy, biomechanics, and 18. Parsons EM, Gee AO, Spiekerman C, et al.
quantitative assessment of knee laxity in surgical dissection. The biomechanical function of the
two different ACL reconstructions. Arthroscopy. 2015;31:583-591. anterolateral ligament of the knee.
Knee Surg Sports Traumatol Arthrosc. 2012 12. Stijak L, Bumbaširević M, Radonjić V, et al. Am J Sports Med 2015;43:669-674.
Jan;20(1):153-9. doi: 10.1007/s00167-011- Anatomic description of the anterolateral

2017; 12(1): 36-41
O RIGINAL PAPER
Uterine Artery Doppler Flow Indices

in Pregnant Women During
the 11 Weeks + 0 Days and 13 Weeks
+ 6 Days Gestational Ages:
a Study of 168 Patients
Voicu DASCAUa, Gheorghe FURAUa, Cristian FURAUa, Cristina ONELa,
Casiana STANESCUb, Liliana TATARUa, Cristina GHIB-PARAc, Cristina POPESCUd,
Luminita PILATe,
Maria PUSCHITAf
a
Department of Obstetrics and Gynecalogy, „Vasile Goldiş” Western University, Arad,
Romania
b
Department of Anatomy, „Vasile Goldiş” Western University, Arad, Romania
c
Department of Haematology, „Vasile Goldiş” Western University, Arad, Romania
d
Department of Life Sciences, „Vasile Goldiş” Western University, Arad, Romania
e
Department of Phsyology, „Vasile Goldiş” Western University, Arad, Romania
f
Department of Internal Medicine, „Vasile Goldiş” Western University, Arad, Romania
ABSTRACT
Objectives: Uterine artery Doppler flow studies during the 11th and 14th week of pregnancy are
important in the prediction of preeclampsia and intrauterine growth restriction in pregnant women as well
as in the prevention thereof.
Methods: Our study on Doppler flow indices of the uterine arteries involved 168 patients examined in
our clinic, with pregnancies ranging from 11 weeks + 0 days to 13 weeks + 6 days.
Results: There were 72 patients from 11 weeks + 0 days to 11 weeks + 6 days (42.86%), 43 from 12 weeks
+ 0 days to 12 weeks + 6 days (25.60%), and 53 from 13 weeks + 0 days to 13 weeks + 6 days (31.55%).
The mean values of the Doppler indices were PI 1.75±0.79, 1.88± 0.81, 1.71±0.81, and 1.58±0.72 and RI
0.72±0.14, 0.75±0.14, 0.71±0.14, and 0.70±0.14 for the entire group and for the three intervals, respectively.
There were 71 (42.26%), 33 (19.64%, with 18 cases or 54.55% on the right side), and 64 (38.10%) patients
with bilateral, unilateral and absent uterine artery notching, respectively. The mean Doppler indices for
the three aforementioned groups were 2.18±0.79, 1.63±0.72, and 1.33±0.57 for the PI, and 0.79±0.11,
0.71±0.14, and 0.66±0.14 for the RI, respectively. The indices for the 175 arteries with and 161 without

Dr. Voicu DASCAU
Address: Closca Street no 3A, 7 app, postal code 310017, Arad,, Romania
Email: drdascauvoicu@yahoo.com

UTERINE ARTERY DOPPLER FLOW INDICES IN PREGNANT WOMEN
notching, taken separately, in all patients, as well as for the uterine arteries with and without notching in
patients with unilateral notching only were 2.16±0.76, 1.30±0.54, 2.08±0.66, and 1.17±0.43 for the PI, and
0.79±0.11, 0.65±0.14, 0.79±0.11, and 0.63±0.12 for the RI, respectively
Conclusions: The mean uterine artery PI and RI decrease from 11 weeks + 0 days-11 weeks + 6 days to
13 weeks + 0 days-13 weeks + 6 days. They also decrease from patients with bilateral uterine artery notching
to those without notching. The frequency of uterine artery notching decreases with increasing gestational
age. Our results are similar to those in literature.
Keywords: pregnancy, gestational age, uterine artery notching, Doppler indices, pulsatility
index, resistivity index, preeclampsia, intrauterine growth restriction
INTRODUCTION administration of low-dose aspirin and, if needed,

antihypertensive medication, and early delivery in
P
re-eclampsia (PE) remains one of the selected cases (3-5).
leading causes of maternal and perina- In clinical setting, reference ranges for UtA
tal mortality and morbidity, with an es- Doppler ultrasound during pregnancy are
timated 10-15% of all maternal deaths recommended and used for the appropriate
being due to hypertensive diseases in analysis of impedance to blood flow. In this regard,
pregnancy. The prediction of patients at high risk pulsatility index (PI) has been advocated as the
for PE has been a focus of research and, at pres- best Doppler index in several studies (6).
ent, the first trimester is considered to be the Transvaginal approach was used at 11–14 weeks
preferred gestational period for PE screening (1). of gestation, while transabdominal ultrasound was
The prophylactic use of low-dose aspirin begin- used at 15–41 weeks. After comparing the
ning in early pregnancy (prior to 16 weeks) is reproducibility of UtA Doppler PI in the first and
able to reduce the prevalence of PE by as much second trimesters of pregnancy using both
as 50% and significantly decrease rates of perina- transvaginal and transabdominal ultrasound scan,
tal death (1). Although no single efficient scree- it has been concluded that PI was evenly
ning procedure for predicting PE has been adop- significantly higher in both trimesters using
ted in clinical practice, uterine artery Doppler is transvaginal approach (2, 7-9).
the most widely studied clinical test available for First and second trimester uterine artery
this particular purpose, becoming a useful meth- Doppler blood flow assessments have high
od for the indirect assessment of uteroplacental predictive value for clinical outcome (especially in
circulation in early pregnancy (11–14 weeks). If the prediction of preeclampsia and IUGR) (10). In
combined with examination of maternal history, studies which have correlated Doppler velocimetry
mean arterial pressure (MAP) and certain bio- and clinical outcomes, a rather wide range of
chemical markers (pregnancy-associated plasma specificity and sensitivity values were found for
protein A or PAPP-A and placenta growth factor subsequent pregnancy complications (10).
or PIGF), uterine artery Doppler may be regard- For a correct and clinically significant uterine
ed as an adjunct screening tool for predicting PE artery PI measurement, the gestational age must
and intrauterine growth restriction (IUGR). Ab- be between 11+0 and 13+6 weeks. Transabdo-
normal uterine artery Doppler results have been minal ultrasound should be used to obtain a
shown to be strongly correlated with several midsagittal section of the uterus and cervical
types of adverse maternal and perinatal out- canal, and the internal cervical os should be
comes (1, 2). identified; afterwards, the transducer should be
Early identification of pregnant patients at risk gently tilted from side to side in each paracervical
of developing PE and IUGR is more likely to region, using color flow mapping to identify the
facilitate targeted antenatal surveillance and uterine arteries as aliasing vessels coursing along
possibly an efficient early intervention. It would the side of the cervix and uterus. Pulsed wave
also potentially avoid the development of serious Doppler with the sampling gate set at 2 mm to
complications, through interventions such as cover the whole vessel and an angle of insonation

PI RI
Group Value 5 th
95th
Value 5th 95th
All (168 patients) 1.75±0.79 0.55 3.58 0.72±0.14 0.41 0.95
11 weeks + 0 days to 11 weeks + 6 days (72 patients) 1.88± 0.81 0.72 3.34 0.75±0.14 0.50 0.91
12 weeks + 0 days to 12 weeks + 6 days (43 patients) 1.71±0.81 0.79 2.71 0.71±0.14 0.52 0.87
13 weeks + 0 days to 13 weeks + 6 days (53 patients) 1.58±0.72 0.75 2.76 0.70±0.14 0.49 0.89
Bilateral uterine artery notching (71 patients) 2.18±0.79 1.12 3.58 0.79±0.11 0.62 0.93
Unilateral uterine artery notching (33 patients) 1.63±0.72 0.81 2.57 0.71±0.14 0.53 0.86
Absent uterine artery notching (64 patients) 1.33±0.57 0.59 2.36 0.66±0.14 0.43 0.86
Uterine artery with notch (n=175) 2.16±0.76 1.12 3.56 0.79±0.11 0.60 0.93
Uterine artery without notch (n=161) 1.30±0.54 0.58 2.36 0.65±0.14 0.41 0.87
Uterine artery with notch in unilateral notch patients
2.08±0.66 1.29 3.16 0.79±0.11 0.62 0.91
(n=33)
Uterine artery without notch in unilateral notch
1.17±0.43 0.63 2.04 0.63±0.12 0.44 0.81
patients (n=33)
TABLE 1. Mean PI±SD, mean RI±SD, 5th and 95th percentiles
<30° should be used to obtain flow velocity 0.36-1), 0.71±0.14 (range 0.40-0.96), and
waveforms from the ascending branch of the 0.70±0.14 (range 0.37-0.94) for the RI for the
uterine artery at the point closest to the internal entire group and for the three gestational age in-
os. When three similar consecutive waveforms are tervals, respectively.
obtained, the PI should be measured and the Our study revealed that 71 (42.26%), 33
mean PI of the left and right arteries calculated (19.64%), and 64 (38.10%) patients had bilateral,
(3, 4). q unilateral and absent uterine artery notching,
respectively (Figure 2). The Doppler indices for
MATERIAL AND METHODS the three aforementioned groups were 2.18±0.79
(range 0.72-4.33), 1.63±0.72 (range 0.55-3.55),
W e assessed the uterine artery Doppler flow

indices in 168 pregnant patients within
the 11 weeks + 0 days and 13 weeks + 6 days
and 1.33±0.57 (range 0.46-2.82) for the PI and
0.79±0.11 (range 0.46-1), 0.71±0.14 (range 0.40-
0.96), and 0.66±0.14 (range 0.36-1) for the RI,
gestational ages in our clinic during the 2014- respectively.
2016 period (both in and outpatients) by using a After assessing the uterine arteries in the study
Sonoscape SSI-6000 and a General Electric group according to the presence or absence of
Logiq e ultrasound devices. The Doppler flow notching, the indices for the arteries with (n=175,
was analyzed with a 2 mm window and an in- including 142 in 71 patients with bilateral notching
sonation angle of less than 30 degrees, according and 33 in 33 patients with unilateral notching) and
to existing guidelines. q without notching (n=161, including 33 in 33 pati-
ents with unilateral notching and 128 in 64 pati-
RESULTS ents without notching) in all 168 patients, as well
as for the uterine arteries with and without notching
A mong the 168 pregnant women in the group
we studied, there were 72 patients from 11
weeks + 0 days to 11 weeks + 6 days (42.86%),
in the 33 patients with unilateral notching, were
2.16±0.76 (range 0.72-4.33), 1.30±0.54 (range
43 from 12 weeks + 0 days to 12 weeks + 6 0.46-2.82), 2.08±0.66 (range 0.91-3.55), and
days (25.60%), and 53 from 13 weeks + 0 days 1.17±0.43 (range 0.55-2.09) for the PI and
to 13 weeks + 6 days (31.55%) gestational age 0.79±0.11 (range 0.46-1), 0.65±0.14 (range 0.36-1),
(Figure 1). The values of the Doppler indices 0.79±0.11 (range 0.52-0.96), and 0.63±0.12
were 1.75±0.79 (range 0.46-4.33), 1.88± 0.81 (range 0.40-0.86) for the RI, respectively
(range 0.46-4.33), 1.71±0.81 (range 0.55-4.29), Table 1 presents the mean, standard deviations
and 1.58±0.72 (range 0.49-3.93) for the PI and and the 5th and 95th percentiles for the pulsatility
0.72±0.14 (range 0.36-1), 0.75±0.14 (range and resistivity indices, while figures 3 and 4

11 weeks 12 weeks 13 weeks +

+ 0 days to + 0 days to 0 days to
Notching 11 weeks + 12 weeks + 13 weeks +
6 days 6 days 6 days
(n=72) (n=43) (n=53)
Bilateral 36 (50%) 17 (39.53%) 18 (33.96%)
Unilateral 16 (22.22%) 8 (18.60%) 9 (16.98%)
Absent 20 (27.78%) 18 (41.86%) 26 (49.06%)
TABLE 2. Distribution of frequency of different

types of uterine artery notching among the three
gestational age groups
FIGURE 1. Age group distribution
FIGURE 5. Distribution of frequency of different

types of uterine artery notching among the three
gestational age groups
FIGURE 2. Notch type distribution
FIGURE 3.
Mean PI±DS FIGURE 6. Distribution of types of uterine artery
notching among the three gestational age groups
present the means and the standard deviations

thereof.
Table 2 and Figure 5 show the frequency of
different types of uterine artery notching among
the three gestational age groups (a decrease in the
frequency of both can be observed), while Table 3
and Figure 6 present the distribution of types of
uterine artery notching among the three gestational
FIGURE 4. age groups (approximately half of the cases with
Mean RI±DS bilateral or unilateral artery notching are in the 11

Notching Bilateral (n=71) Unilateral (n=33) Absent (n=64)

11 weeks + 0 days to 11 weeks + 6 days (n=72) 36 (50.70%) 16 (48.49%) 20 (31.25%)
TABLE 3. Distribution of types of uterine artery notching among the three gestational age groups
Comparison p Comparison p
PI Total vs Bilateral notch <0.0000001 RI Total vs Bilateral notch <0.0000005
PI Total vs Unilateral notch NS RI Total vs Unilateral notch NS
PI Total vs Absent Notch <0.0000001 RI Total vs Absent Notch <0.00005
PI Bilateral notch vs Unilateral notch <0.000005 RI Bilateral notch vs Unilateral notch <0.00005
PI Bilateral notch vs Absent Notch <0.0000001 RI Bilateral notch vs Absent Notch <0.0000001
PI Unilateral notch vs Absent Notch <0.005 RI Unilateral notch vs Absent Notch <0.05
PI Total vs 11 - 11+6 NS RI Total vs 11 - 11+6 <0.05
PI Total vs 12 - 12+6 NS RI Total vs 12 - 12+6 NS
PI Total vs 13 - 13+6 <0.05 RI Total vs 13 - 13+6 NS
PI 11 - 11+6 vs 12 - 12+6 NS RI 11 - 11+6 vs 12 - 12+6 <0.05
PI 11 - 11+6 vs 13 - 13+6 <0.05 RI 11 - 11+6 vs 13 - 13+6 <0.05
PI 12 - 12+6 vs 13 - 13+6 NS RI 12 - 12+6 vs 13 - 13+6 NS
PI Present Notch vs Absent Notch <0.0000001 RI Present Notch vs Absent Notch <0.0000001
PI Present Notch vs Unilateral with RI Present Notch vs Unilateral with
NS NS
Present Notch Present Notch
PI Present Notch vs Unilateral with RI Present Notch vs Unilateral with
<0.0000001 <0.0000001
Absent Notch Absent Notch
PI Absent Notch vs Unilateral with RI Absent Notch vs Unilateral with
<0.0000001 <0.0000005
Present Notch Present Notch
PI Absent Notch vs Unilateral with RI Absent Notch vs Unilateral with
NS NS
Absent Notch Absent Notch
PI Unilateral with Present Notch vs RI Unilateral with Present Notch vs
<0.0000001 <0.0000005
Unilateral with Absent Notch Unilateral with Absent Notch
TABLE 4. Comparison of PI and RI
weeks + 0 days to 11 weeks + 6 days gestational with an RI of 1 and absent notching). A PI below
age group). 0.85 (12th percentile) yields a FPR (false positive
We used Student’s t-test to compare the PI rate), defined as a present uterine artery notch, of
and RI among different groups (all patients versus 2.5%; a PI above 2.77 (11th percentile) leads to a
different gestational age groups and versus groups FNR (false negative rate), defined as an absent
according to the presence or absence of notching, uterine artery notching, of 5.4%. As for the RI, the
as well as different groups between them, and the FPR for a value below 0.53 (11th percentile) was
indices of all uterine arteries with and without 8%, while the FNR for a value above 0.91 (94th
notching within the group), the results being percentile) was 10%. q
shown in table 4 (NS=non significant) (Table 4).
In the group we studied, uterine artery
DISCUSSION
notching was always absent in case of PI below
the 5th percentile and RI below the 4th percentile The frequency of bilateral uterine artery
and always present in case of PI above the 90th notching in our study is 42.26% and the frequency
percentile, while no such percentile could be of both bilateral and unilateral uterine artery
established for the RI (there were two patients notching decrease with increasing gestational age.

The results in our study are similar to those in CONCLUSION

literature:
– mean PI 1.79, 1.68, 1.58, and 1.49 at
11, 12, 13 and 14, with the 95th T he mean uterine artery PI and RI and the fre-
quency of bilateral and unilateral uterine ar-
tery notching decrease from 11 weeks + 0 days-
percentile at 2.70, 2.53, 2.38, and
2.24 weeks, respectively (11); 11 weeks + 6 days to 13 weeks + 0 days-13
– PI 1.96±0.6, 1.83±0.53, 1.71±0.47, weeks + 6 days. They also decrease from preg-
and 1.58±0.41, with the 95th nant patients with bilateral uterine artery no-
percentile at 3.13, 2.88, 2.63, and tching to those without notching.
2.38 at 11, 12, 13, and 14 weeks, Our aim is to screen, as much as possible, all
respectively (12); pregnant patients between 11 and 14 weeks of
– PI 1.6±0.5, 1.5±0.6, 1.4±0.4, and pregnancy who are referring to our clinic of
1.3±0.4 at 11, 12, 13, and 14 weeks, pregnancy by uterine artery Doppler ultrasound,
respectively (1); in order to discover bilateral notching as soon as
– RI 0.7±0.1, 0.7±0.1, 0.6±0.1, and possible for specific prophylactic treatment, according
0.6±0.1 at 11, 12, 13, and 14 weeks, to existing guidelines and recommendations, to
respectively (1); be started. q
– PI 2.32 ± 0.79 and RI 0.83 ± 0.07
with notching, 1.61 ± 0.78 and 0.71
± 0.16 without notching (13);
– 95th percentile of RI at 11-14 weeks at
0.85 (14);
– the frequency of bilateral notching
48.6%, 47.9%, 30.6%, and 28.4% at 11, 12, Conflict of interests: none declared.
13, and 14 weeks, respectively (12). q Financial support: none declared.
R#$#%#&'#*
1. Alves JA, Silva BY, de Sousa PC, Maia SB, Ultrasound Obstet Gynecol 2013;41:491-499. Artery Doppler Velocimetry and Placental
Costa Fida S. Reference range of uterine 6. Ferreira AE, Mauad Filho F, Abreu PS, Bed Histopathology. Int Sch Res Notices
artery Doppler parameters between the Mauad FM, Araujo JuniorE, Martins WP. 2014;13;2014.
11th and 14th pregnancy weeks in a The reproducibility of first and second 11. Gómez O, Figueras F, Fernández S, et al.
population sample from Northeast Brazil. trimester uterine artery pulsatility index by Reference ranges for uterine artery
Rev Bras Ginecol Obstet 2013;35:357-362. transvaginal and transabdominal ultra- mean pulsatility index at 11–41 weeks of
2. Peixoto AB, Da Cunha Caldas TM, Tonni sound. Ultrasound Obstet Gynecol gestation. Ultrasound Obst Gyn
G, De Almeida Morelli P, Santos LD, 2015;46:546-552. [CrossRef] 2008;32:128-132.
Martins WP, Araujo Júnior E. Reference J Turk Ger Gynecol Assoc 2016;17:16-20. 12. Gomez O, Figueras F, Martinez JM, et al.
range for uterine artery Doppler pulsatility 7. Scandiuzzi RM, de Campos Prado CA, Sequential changes in uterine artery blood
index using transvaginal ultrasound at Araujo Júnior E, et al. Maternal uterine flow pa!ern between the first and second
20-24 weeks of gestation in a low-risk artery Doppler in the first and second trimesters of gestation in relation to
Brazilian population. trimesters as screening method for pregnancy outcome.
J Turk Ger Gynecol Assoc 2016;17:16-20. hypertensive disorders and adverse Ultrasound Obstet Gynecol 2006;28:802-808.
3. Poon LC, Syngelaki A, Akolekar R, Lai J, perinatal outcomes in low-risk pregnancies. 13. Gadelha da Costa AG, Spara Patricia,
Nicolaides KH. Combined screening for Obstet Gynecol Sci 2016;59:347-356. de Oliveira Costa T, Neto WRT. Uterine
preeclampsia and small for gestational age 8. Ghulmiyyah L, Sibai B. Maternal mortality arteries resistance and pulsatility indices at
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lowdose aspirin: a meta-analysis. between First and Second Trimester Uterine

2017; 12(1): 42-47
S TATE OF THE ART
Newborn Skin: Common Skin

Problems
Zekayi KUTLUBAYa, Ali TANAKOLa, Burhan ENGİNa, Ersin SİMSEKb,
Server SERDAROGLUa, Yalçın TUZUNa, Erkan YILMAZc, Bülent ERENd
a
Dermatology Department, İstanbul, Cerrahpasa Faculty of Medicine,
İstanbul University, Istanbul, Turkey
b
Private Family Physician, Istanbul, Turkey
c
Blood Bank, Tissue Typing Laboratory; İstanbul, Cerrahpasa Faculty of Medicine,
İstanbul University, Istanbul, Turkey
d
Council of Forensic Medicine of Turkey, Bursa Morgue Department, Bursa, Turkey
ABSTRACT
The newborn skin can be separated from adult’s skin in several ways. In dermatologic examination it can
be easily observed that it is thinner, less hairy and has less sweat and sebaceous gland secretions. These dif-
ferentiations present especially in preterm newborns. Their skin is exposed to mechanical trauma, bacteria
and weather, heat alterations. At birth, newborn skin is protected by the coverage of vernix caseosa, which
has lubricating and antibacterial features and its pH ranges from 6.7 to 7.4. Beneath the vernix caseosa the
skin has a pH of 5.5-6.0. In newborn dermatologic examination it is very important to distinguish transient
benign dermatoses and severe diseases, make early diagnosis and treat congenital skin disorders. Although
the benign cases are common in this life period, clinical presentations can be much more exaggerated, dra-
matic and cause a great deal of anxiety to parents. Therefore, as a doctor, knowing the dermatological, patho-
logical and non-pathological common skin rashes guides the family in the right direction, offers advice to
reduce uncertainty and time for the treatment of severe conditions and builds a confidential doctor-patient
relationship.
In this review, our aim is to provide a general overview to common skin rashes in newborn period.
Keywords: newborn, common skin rushes, innocent, pathologic, congenital
INTRODUCTION seases and sometimes malign tumors should be

taken into consideration. Neonatal skin lesions
R
ashes are extremely common in new- are common. Differentiation of the nonsignifi-
borns. During the first four weeks of cant conditions from more serious clinical enti-
life, the newborn period includes vari- ties is important (1, 2). Infants with unusual pre-
ous dermatologic skin problems. Most sentations or signs of systemic illness should be
of them are innocent and transient. evaluated for Candida, viral, and bacterial infec-
However, serious infectious, congenital skin ditions. Milia and miliaria result from immaturity of
Bülent Eren, MD, Pathologist, Forensic Medicine Specialist, Associate Professor, Director of Bursa Morgue Department,
Council of Forensic Medicine of Turkey Bursa Morgue Department, Esra Sok No: 4, Üçevler, Nilüfer 16120, Bursa, Turkey
Phone:+90 224 222 03 47, Fax:+90 224 225 51 70
Email: drbulenteren@gmail.com

NEWBORN SKIN: COMMON SKIN PROBLEMS
skin structures. Nearly all of these skin rashes are

a serious concern for parents and may result in
visits to the physician or questions during routine
newborn examinations.
Transient Vascular Phenomena

A central erythema can be inspected during
the first hours of life; the extremities tend to be
much redder. By crying or heat loss, acral parts
become symmetrically blue in color, without any
other cutaneous changes including edema. This
bluish discoloration named ‘Acrocyanosis’ fades
away characteristically with warming of the ex-
tremities or when the newborn stops crying. It FIGURE 2. Blue-gray macule on the sacral region is
should be differentiated from central cyanosis, characteristic for the Mongolian spot
which is associated with cardiovascular and respi-
ratory system diseases. Etiopathogenesis is related and can repeat in the first three weeks. According
to vasomotor instability and immaturity (1, 2). Cu- to position, pressure creates erythematous areas,
tis marmorata can be detected during the first 2-4 while the other parts are observed as pale. Harle-
weeks of life. It is also a physiological response to quin color change is also a benign entity and it is
temperature changes like acrocyanosis. The clini- more common in preterm neonates.
cal feature with red blue reticulated cyanosis of Neonatal desquamation is another common
trunk and extremities can help in diagnosis (Figure 1). skin problem of the newborn that usually occurs
Pathogenesis is based on immature autonomic on hands, feet and ankles. If eruptions are wide-
control of the vascular plexus. Persistent cases are spread, it should be distinguished from ichthyosis
together with trisomy 18, Down syndrome, hypo- vulgaris and continual peeling syndrome. This be-
thyroidism, Cornelia de Lange Syndrome and nign condition is also accompanied by post matu-
congenital heart disease. Both patterns did not set rity. The Mongolian spot is mostly blue gray or
on after 1 month of age. Cutis marmorata is more blue green congenital patch over the sacrogluteal
common in preterm infants, although acrocyano- area (Figure 2). A specific therapy is not required
sis is rare in preterm newborns (1). Harlequin and lesions fade in 3-5 years, while they expand
color change is a transient erythema covering half in the first year of life. The etiology is not com-
of the newborn’s body surface with a vertical pro- pletely understood, but the melanocytes migra-
nounced demarcation line and usually occurs in tion from the neural crest through the epidermis
the first week of life, continues up to 20 minutes crest is interrupted (1, 2). Salmon Patch is another
innocent rash occurs as a result of capillary vascu-
lar malformation. It is named either ‘Angel Kiss’ or
‘Stork Bite’ according to location – on the fore-
head or nape, respectively. The lesions fade in
early childhood. A further laser therapy can be
used if the lesions persist into adulthood (1).
Erythema Toxicum Neonatarum

Erythema toxicum neonatorum is a benign,
self-limited, asymptomatic skin condition that
only occurs during the neonatal period. It is one of
the most common innocent and self-limited skin
rashes mainly in full-term newborns. The condi-
tion affects 30-70% of the newborns. The typical
FIGURE 1. Pinkish blue marbled macules are seen newborn with erythema toxicum neonatorum has
on the left lower limb an average birth weight and is born at term (6).

The etiology of erythema toxicum neonatorum phase, pruritus is the main complaint. The etiolo-
remains unknown. Increased, ground-substance gy remains unknown, but the scabies infestation
viscosity in neonatal skin, with associated trauma may trigger the onset of the lesions in some infants
can lead to eosinophilic inflammation within the (1). Many cases of infantile acropustulosis are pre-
skin. Self-limited, acute, cutaneous, graft-versus- ceded suspected scabies infestation, and a scabies
host reaction caused by maternal lymphocytes in id reaction has been suggested (16). Bacterial and
the relatively immunosuppressed fetal circulation viral culture results are consistently negative. The
can also be lamed in aetiopathogenesis (7). Ery- most recently recognized cause of infantile pustu-
thematous lesions with central papule or pustule losis is a deficiency of interleukin 1 receptor an-
tend to locate on the face, trunk and proximal ex- tagonist, resulting in unopposed action of inter-
tremities. The lesions are usually surrounded by a leukin 1 and life-threatening systemic inflammation
distinctive diffuse, blotchy, erythematous halo (8). (17). Children are irritable, and obviously uncom-
Clinical findings are mostly enough for the diagno- fortable, but otherwise healthy. Children have been
sis. However, histopathological research is re- empirically treated with antiscabies ointments
quired sometimes. Pathologic specimen includes prior to presentation (18). Treatment is often un-
eosinophils and 15-20% of patients have circula- necessary because of the self-limited nature of the
ting eosinophils in the peripheral blood (1, 9, 10). condition. Topical corticosteroids and oral dapsone
The condition requires no treatment. It typically have been used successfully. Oral antihistamines
resolves within two weeks after birth. If it does not may be useful in severe itching diseases (17, 18).
follow the usual course, prompt consultation with
a pediatric dermatologist is advised. Neonatal Acne
Neonatal acne presents within the first 30 days
Transient Neonatal Pustular Melanosis
of life. It is generally a transient benign statement.
Transient neonatal pustular melanosis is a be- However in severe cases, which do not resolve,
nign idiopathic skin condition. This transient skin an androgenic excess should be taken in consi-
disorder occurs especially in black newborns and deration. Etiology based on androgen effect that
occurs at birth. The eruptions locate on the fore- causes sebaceous gland hyperplasia. Neonatal
head, neck, upper chest, sacrum, chest and thighs acne must be distinguished from infantile acne.
(11). On the skin they appear as small vesicles, Infantile acne tends to be more pleomorphic and
superficial pustules, and pigmented macules inflammatory than the neonatal one (19). Recent
which disappear by five days of age and resolute studies show that the colonization of Malassezia
with fine white collarets of scale. In mostly post spp. can be related to neonatal acne. It typically
mature infants, there are only pigmented macules consists of closed comedones on the forehead,
without any vesicles or pustules (12). The pigmen- nose and cheeks, although other locations are also
ted macules disappear approximately up to three possible. Open comedones, inflammatory papu-
months (1, 13). Transient neonatal pustular mela- les, and pustules can also develop. A treatment is
nosis is a self-limited skin eruption with no associ- not especially recommended, but infants can be
ated mortality or morbidity. No systemic symp- treated with a 2.5% benzoyl peroxide lotion if le-
toms are associated with the skin lesions of sions are extensive and persist for several months
transient neonatal pustular melanosis. No specific (20). Severe neonatal acne accompanied by other
therapy is necessary for transient neonatal pustu- signs of hyperan-drogenism should prompt an in-
lar melanosis (14). vestigation for adrenal cortical hyperplasia, virili-
zing tumors. The lesions fade away within 1-3
Acropustulosis of Infancy months (10, 13).
Acropustulosis of infancy or infantile acropus-
Milia
tulosis is a recurrent, self-limited, pruritic, vesico-
pustular eruption of the palms and the soles oc- Common skin rush in newborn is seen with
curring in young children. Palms and soles are the yellow/white small superficial cysts. Milia occur in
main localizations of the disease (15). Lesions nearly half of healthy newborns and are typically
continue typically 1-3 weeks prior to remission present at birth, although their onset may be de-
period which lasts 1-3 weeks. During the active layed in premature neonates (21). Milia are be-

nign, keratin-filled cysts. Milia arise on facial skin

bearing vellus hair follicles and arise from the
lower infundibular sebaceous collar of the vellus
hair (22). Milia affect 40-50% of healthy new-
borns. Infants born prematurely are less common-
ly affected. No racial predilection is observed.
Physical examination shows tiny papules on new-
born facial skin. This lesion originates from the
pilosebaceous unit, keratin retention being the
main cause. Normally lesions resolve within first
few weeks, but they sometimes last and spread
throughout the whole body. These cases are re-
lated to the oral-facial-digital syndrome and he- FIGURE 3. Crusted erythematous papules and
reditary trichodysplasia (Marie Unna hypotricho- plaques are noticed on the diaper region
sis). Multiple lesions occurring on the trauma
Diaper Dermatitis
areas such as hands knees and feet are important
for the mild variant of scarring epidermolysis The term diaper dermatitis includes all erup-
bullosa as a miscellaneous diagnosis (1, 2, 5). tions that occur in the area covered by the diaper.
Milia are easily diagnosed on clinical findings It generally refers to irritant chronic contact der-
alone. Histologic examination reveals small cysts matitis (26). Diaper dermatitis, considered the
lined by stratified squamous epithelium and cen- most common skin disorder of infancy in the
tral keratinous material. Treatment of milia is not United States, accounts for more than one million
necessary as these lesions have a tendency to clinic visits per year (27). There are several causes
spontaneously resolve (23). for maceration of the skin such as urine enzymes,
wiping, rubbing and stool. The most important
Miliaria factor is wetness of the diaper area. Due to wet-
ness, barrier function of the skin is destroyed and
The keratinous plugging of the eccrine ducts
penetration of irritants becomes easier. Candida
causes the rupture of the duct and leakage of
albicans may be isolated in up to 80% of infants
sweat into epidermis and dermis. Both milia and
with perineal skin irritation. Infection occurs gene-
miliaria result from the immaturity of skin struc-
rally 48-72 hours after irritation (28). Diaper der-
tures, but they are clinically distinct entities. Mili-
matitis is a mostly self-limited disorder that disap-
aria affects up to 40% of infants and usually ap-
pears within three days. Irritant contact dermatitis
pears during the first month of life (24). Clinical
begins as acute erythema on the convex skin sur-
findings are correlated with the level of obstruc-
faces of the pubic area and buttocks, with sparing
tion. The most common type in newborns is mili-
of the skin folds, reflecting the areas of the body
aria crystalline, which is characterized by tiny
in most contact with the diaper (26). The clinical
non-inflammatory vesicles in the eccrine gland
findings are red macules papules, plaques and
ducts at the level of stratum corneum degree; its
vesicles in the warm moist areas especially inside
major localizations are the intertriginous areas such
the diaper (Figure 3). Resistant rushes are related
as the neck axillae cloth-covered truncal areas re-
to chronic irritants or secondary infection with
gions. It consists of 1 to 2 mm vesicles without
yeast or bacteria (1). When bacterial infection is
surrounding erythema. Each vesicle evolves with
superimposed, superficial erosions, yellow crusts
rupture followed by desquamation, and may per-
and impetiginization are seen. The first treatment
sist for hours to days. Miliaria rubra is characteri-
step is to use a barrier with minimal ingredients to
zed by the small secondary inflammatory papules
avoid potential irritants or sensitizers. Topical anti-
and pustules. Obstruction in this type of miliaria
fungal agents can be used too (26).
occurs in mid epidermis. Clinical findings are
mostly on the forehead, upper trunk, volar aspects
Dimpling
of the arms and covered parts of the skin. In order
to avoid sweat retention, minimizing of overhea- One of the most commonly seen minor ano-
ting is the best prevention method (5, 13, 25). malies occurs on the sacral skin region. Generally,

dimpling is a cosmetic problem. However, when Desquamation prompts to thermal regulation dif-
deep dimples or sınus tracts involve the lumbosa- ficulties and secondary infections. 60-70% of the
cral spine, further visualizing methods – such as cases tend to develop congenital ichthyosiform
ultrasound during the first six months, followed by erythroderma. As differential diagnosis, harlequin
magnetic resonance imaging and computed to- baby should be thought. It is a severe variant of
mography – should be used to exclude malforma- ichthyosis with thickened stratum corneum with
tions (1). deep cracks and fissures (1).
Umbilical Granulomas Neonatal Pemphigus

Umbilical granulomas occurs in the first weeks Neonatal pemphigus is a rare autoimmune
of life after the umbilical cord detaches. Normally blistering disease (31). It is characterized by flaccid
umbilical cord area heals with epithelization with- blisters on the skin and, in contrast to pemphigus
out any excessive scar tissue. Granulation tissue vulgaris, rarely mucous membranes (32). Pemphi-
may persist at the base of the umbilicus after cord gus vulgaris patients receiving severe treatments
separation; the tissue is composed of fibroblasts rarely become pregnant, so neonatal pemphigus
and capillaries and can grow to more than 1 cm. is an unusual condition. On the other hand, pem-
However, moisture and secondary infections cre- phigus vulgaris is usually seen in patients with an
ate an excessive granulation tissue that can be re- older age. Direct immunflourescence shows trans-
duced by Silver nitrate cauterization or repeated placental IgG autoantibodies against Desmo-
isopropyl alcohol application; they produce vari- glein-3 that is considered to be the main reason of
able amounts of drainage that can irritate the sur- neonatal pemphigus (33). Some cases were re-
rounding skin (29). An umbilical polyp is brighter ported as stillborn (34).
red as compared to a granuloma and represents A further treatment was not necessary. Within
retained intestinal or gastric mucosa from the vi- three weeks the eruption fades away (35). q
telline duct. It is important to distinguish umbilical
granuloma from the umbilical polyps which deri- CONCLUSION
vate from the omphalomesenteric duct or ura-
chus, and surgical separation should be per-
formed (1). Small umbilical granulomas usually M iscellaneous diagnosis of common skin rush-
es of newborns are congenital disorders, in-
fectious diseases, which are mostly recognized by
respond to silver nitrate application. One or more
applications may be needed. Care must be taken dermatologists. Hence, the first step in clinical ex-
to avoid skin contact. Silver nitrate can cause amination should be the recognition of benign
painful burns. Large umbilical granulomas or cases, which are transient, but distress parents. In
those that persist after Silver nitrate treatment re- order to create a reliable doctor-patient relation-
quire surgical excision (30). ship, detailed advice that includes transient inno-
cent cases is required. Subsequently, if there is any
Collodion Baby doubt about an abnormal condition, dermatology
consultation is the best option. q
Collodion babies are often premature and
transparent thick membrane encasing the new- Conflict of interests: none declared.
born presents at birth that peels within 2-3 weeks. Financial support: none declared.
R#$#%#&'#*
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Eisen AZ, Wolff K, Austen KF, Goldsmith 1995;263-347. 7. Bassukas ID. Is erythema toxicum
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cutaneous graft-versus-host-reaction from acropustulosis revisited: history of scabies 26. Serdaroglu S, Ustunbas TK. Diaper
maternal-to-fetal lymphocyte transfer? Med and response totopical corticosteroids. Dermatitis (Napkin Dermatitis, Nappy
Hypotheses 1992;38:334-338. Pediatr Dermatol 1998;15:337-341. Rash). J Turk Acad Dermatol 2010;4:04401r.
8. Tarang G, Anupam V. Incidence of 17. Minkis K, Aksentijevich I, Goldbach- 27. Nield LS, Kamat D. Prevention, diagnosis,
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neonates. J Dermatol Case Rep 2011;5:58-63. antagonist deficiency presenting as infantile Pediatr 2007;46:480-486.
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temporary skin symptoms. Pediatric Dermatol- psoriasis. Arch Dermatol 2012;148:747-752. Etiologic factors in diaper dermatitis: the
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S, Çokuğraş H, Tüzün B, Mat MC. 1. Ed. tulosis in infancy. Int J Dermatol 1997;36:688-691. 29. Pomeranz A. Anomalies, abnormalities,
İstanbul, Nobel Kitabevi, 2005;43-52. 19. Serna-Tamayo C, Janniger CK, Micali G, and care of the umbilicus.
10. PekcanYaşar Ş, Mansur T. Newborn skin Schwar; RA. Neonatal and infantile acne Pediatr Clin North Am 2004;51:819-827.
physiological findings. Türkiye Klinikleri J vulgaris: an update. Cutis 2014;94:13-16. 30. Nagar H. Umbilical granuloma: a new
Pediatr 2005;14:184-192. 20. O’Connor NR, McLaughlin MR, Ham P. approach to an old problem.
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1997;14:131-143. Dermatol Venereol Leprol 2002;68:334-337. Dermatology, 7th ed, Blackwell Science,
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2017; 12(1): 48-54
S TATE OF THE ART
Cutaneous Toxicities of Molecular

Targeted Therapies
Dana Lucia STANCULEANUa, b, Daniela ZOBa, Oana Catalina TOMAc,
Bogdan GEORGESCUc, Laura PAPAGHEORGHEd, Raluca Ioana MIHAILAc
a
Medical Oncology Department, “Prof. Dr. Al. Trestioreanu” Institute of Oncology,
Bucharest, Romania
b
Oncology Department, ”Carol Davila” University of Medicine and Pharmacy,
Bucharest, Romania
c
Medical Oncology Department, “Prof. Dr. Al. Trestioreanu” Institute of Oncology,
Bucharest, Romania
d
Dermatology Department, Coltea Clinical Hospital, Bucharest, Romania
ABSTRACT
Antineoplastic targeted therapies, such as EGFR inhibitors, tyrosine kinase inhibitors and BRAF
inhibitors, frequently lead to systemic and cutaneous side effects, significantly affecting patient’s quality
of life. Patients with new targeted therapies have an increased risk of developing skin reactions. The new
molecular target therapies developed in the last decades can induce severe skin reactions, which may require
dose reduction or discontinuation of treatment and consequently, a decrease in patient’s quality of life.
The present paper describes toxic cutaneous reactions associated with the most frequently used molecular
therapies (epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, BRAF-inhibitors),
frequency of occurrence and methods of diagnosis and treatment, in order to offer a clinically efficient
management for maintaining a good quality of life, with compliance to treatment and good therapeutic
efficacy.
Knowledge of cutaneous adverse reactions in new therapies is mandatory in order to have a proper
management of oncologic patients. Recognizing target therapy toxicities by both oncologists and
dermatologists, understanding therapeutic mechanisms and choosing optimum treatments for oncologic
patients are critical. A correct evaluation of skin toxicity can allow for an adequate decision regarding
treatment dose or discontinuation, impacting therapy response and patient survival.
Keywords: targeted therapies, epidermal growth factor receptor inhibitors, tyrosine kinase
inhibitors, BRAF inhibitors, toxic cutaneous reactions, patient quality of life

Dana Lucia Stanculeanu, MD, PhD
Institute of Oncology, Bucharest, Sos. Fundeni, No. 252, 022338 Bucharest, Romania
Phone: (0040) 744327992
Email: dlstanculeanu@gmail.com
Article received on the 13th of February 2017 and accepted for publication on the 14th of March 2017.

CUTANEOUS TOXICITIES OF MOLECULAR TARGETED THERAPIES
INTRODUCTION cancer, colorectal, breast, pancreas and head and

neck cancers). Such therapies – monoclonal
A
ntineoplastic therapies have numerous antibodies targeting the tyrosine kinase
side effects, both systemic and extracellular domain of EGFR (Cetuximab,
cutaneous. Patients treated with either Panitumumab), with intravenous administration,
classical chemotherapeutic agents or or small molecule tyrosine kinase inhibitors
with new targeted therapies have an targeting the intracellular domain of EGFR, with
increased risk of developing skin reactions. oral administration (Gefitinib, Erlotinib, Lapatinib,
Classical chemotherapy induces well known Afatinib) – are generally well tolerated and do not
skin reactions. These include infusion reactions, have significant systemic reactions. Given the fact
diffuse or localized cutaneous pigmentary that EGFR is expressed in skin structures, hair
changes, radiation dermatitis, hand-foot follicles and gastro-intestinal tract, EGFR inhibitors
syndrome, nail changes (changes in pigmentation, are frequently associated with skin toxicities
onycholysis, paronychia), mucosal changes, (acneiform reactions, xerosis, paronychia,
stomatitis, alopecia, photosensitivity, cutaneous eczemas, fissures, telangiectasias, maculopapular
erythematosus lupus, drug rashes, exfoliative reactions, mucositis and post-inflammatory
dermatitis, erythema multforme. Some agents hyperpigmentations) (1, 4).
may also cause severe skin reactions: Stevens The most frequent cutaneous reaction is the
Johnson syndrome, toxic epidermal necrolysis, dose-dependent acneiform rash, located on the
ulcers, Raynaud’s syndrome, reactive dermato- face, scalp and upper trunk, with a prevalence of
myositis paraneoplastic skin syndromes – pemfigus 49-67% of patients treated with Erlotinib (Figure 1)
like, porphyria, reactivation of varicella zoster and 75-91% of patients treated with Cetuximab
virus. (Figure 2). Skin lesions usually appear in the first
The new molecular target therapies developed two weeks of treatment, diminishing in intensity
in the last decades (epidermal growth factor in the following two weeks. Most commonly they
receptor inhibitors, tyrosine kinase inhibitors, occur after the administration of monoclonal
monoclonal antibodies, BRAF-inhibitors) can antibodies. Acneiform reactions consist of erythe-
induce severe skin reactions, which may require matous papules, pustules and nodules, located
dose reduction or discontinuation of treatment predominantly on seborrheic areas, and may be
and consequently, a decrease in the patient’s associated with pruritus, pain, stinging and irrita-
quality of life (1-3). tion. Pruritus may affect more than 50% of patients,
The correct diagnosis of an adverse reaction leading to major discomfort. Comedos, a distinc-
secondary to antineoplastic agents requires a tive mark of acne vulgaris, are absent (1, 4-6).
differential diagnosis with other drug reactions,
specific dermatological entities, cutaneous meta-
stases and paraneoplastic syndromes. A multidis-
ciplinary approach, with oncologists and dermato-
logists, aims to improve quality of life and
treatment adherence.
The present paper describes toxic cutaneous
reactions associated with the most often used
molecular therapies, frequency of occurrence and
methods of diagnosis and treatment, in order to
offer a clinically efficient management for main-
taining a good quality of life, with compliance to
treatment and good therapeutic efficacy.
Epidermal growth factor receptor inhibitors

(anti EGFR)
Molecular therapies targeting epidermal FIGURE 1. Skin rash consisting of erythematous
growth factor receptors (EGFR) have proved their papules and pustules after anti EGFR therapy
efficacy in treating multiple types of cancer (lung (Cetuximab)

worsening of a cutaneous rash and an alteration of

the clinical status (4, 10).
Skin rashes secondary to anti-EGFR therapy
could have a negative impact on disease-related
quality of life and may influence the efficacy and
duration of treatment. Available therapies for such
reactions include empirical topical and systemic
antibiotic therapies. Testing for specific bacterial
colonization is not mandatory, unless patients
exhibit worsened symptoms or reactions that
become refractory to treatment. The management
of cutaneous drug reactions implies preventive
and specific dermatologic therapies, customized
FIGURE 2. Skin rash consisting of erythematous for each patient, according to lesion type, location
violaceous papules and pustules, with fine scales,
and severity. The collaboration between
yellow crusts and telangiectasias after anti EGFR
therapy (Cetuximab) oncologists and dermatologists is advisable for
most patients.
PRIDE syndrome comprises the most frequent Preventive measures include adequate
reactions associated with anti-EGFR reactions hydration of dry areas (non-alcoholic emollients,
(papules, pustules, paronychia, hair growth urea creams), decrease in sun exposure, avoiding
disorders, pruritus, skin and mucosal xerosis). prolonged skin contact with water, irritants and
Unfortunately, some patients can develop solvents. Topical agents may be used to reduce
severe acneiform reactions that may lead to dose the reaction severity. Mild reactions may receive
reduction or treatment discontinuation. Some clindamycin and hydrocortisone based creams or
studies show a positive correlation between ointments. A study published by Yamazaki et al.
acneiform rash severity and treatment response. offers objective evidence to support the use of
„Correlation Between the Severity of Cetuximab- topical agents in cutaneous reactions after anti-
Induced Skin Rash and Clinical Outcome for EGFR TKI therapies, early use permitting further
Head and Neck Cancer Patients: The RTOG anti-EGFR treatment (7).
Experience”, a study with 602 enrolled patients, Oral antibiotics can be prophylactically use
demonstrated a higher survival rate for patients (such as minocycline 100 mg/day, tetracycline
with grade 2-4 cutaneous reactions after treatment 500 mg/day), leading to a decrease in pruritus and
with Cetuximab, probably due to the decrease of erythema intensity, consequently reducing skin
distant metastases (7). Two meta-analyses, irritation. Moderate reactions may be treated with
published in 2012 and 2013, have demonstrated hydrocortisone, clindamycin, erythromycin,
that skin toxicity is a predictive and independent pimecrolimus, along with oral antibiotics
survival factor, and patients who developed therapies, including cyclins (doxycycline 50-100
moderate to severe cutaneous reactions had a mg/day). Tetracycline is widely used in cutaneous
higher treatment response rate. Further studies are reactions because of its anti-inflammatory
needed to demonstrate if dermatotoxicities can properties, inhibiting lymphocyte proliferation,
represent a reliable criteria for treatment response neutrophil migration and interleukin-6 synthesis,
monitoring regarding anti-EGFR therapies (8, 9). as well for its antibacterial properties.
Other cutaneous and mucosal reactions due Using these methods, 80% of anti-EGFR
to anti-EGFR therapy include oral and nasal therapy-related reactions can be easily managed.
aphthosis, ulcerations, mucositis, stomatitis and Most often, modifying treatment dose will not be
photosensitivity. Rarely, exfoliative dermatitis, necessary. If cutaneous toxic effects are not
Stevens-Johnson syndrome, toxic epidermal reduced in 2-4 weeks, despite correct topical and
necrolysis, ocular complications (dry eye syn- oral treatment, then treatment dosage may be
drome, corneal erosions), vasculitis, purpura, and reduced or anti-EGFR therapy may be ceased. In
anaphylactoid reactions may develop (1). severe reactions (grade 2 or higher), if a rash
Bacterial infection, most often with infection is suspected or if skin reactions are
Staphylococcus aureus, may determine a sudden refractory to topical treatment, systemic corticoid

therapy, such as Prednisone (12-25 mg/day, one direct extravasation in skin and mucosae, both
week, with dose tapering), should be initiated. molecules displaying the same types of toxicities
Recommended systemic antibiotherapy is tetra- (1, 16, 17).
cycline, doxycycline and minocycline. Doxy- Hand-foot syndrome (Figure 3) is the most
cycline doses may range from 50-100 mg/day, frequently encountered cutaneous adverse
lower doses having mainly an anti-inflammatory reaction in patients undergoing treatment with
effect, in order to reduce the incidence of tyrosine kinase inhibitors. Reaction severity is
antibiotherapy resistance and digestive adverse dose-dependent. It presents as painful vesicles
effects. Higher doses of doxycycline (100 mg that subsequently transform in hyperkeratosis on
twice daily) are reserved for severe reactions. areas exposed to friction or traumas (heals, soles,
Studies showed that doxycycline did not reduce toes, interphalangeal joints, elbows, knees). Lesi-
adverse reactions related to anti-EGFR therapies; ons usually appear after 2-4 weeks of treatment
however, they significantly reduced their severity. (Figure 4). Associated symptoms (tingling, pares-
If the rash is worse despite treatment or persistent, thesias, burning sensation and pain) significantly
a bacterial superinfection should to be evaluated. affect patient’s quality of life, leading to either
Retinoids represent another therapeutic option, treatment cessation or dose reduction. This may
because of their anti-inflammatory effects; negatively impact primary disease management.
however, patients may face a worsening of Hand-foot syndrome pathogenesis is unknown
mucosal and cutaneous dryness due to anti-EGFR (1, 16, 17).
therapies. Higher retinoid doses are associated Other adverse reactions include stomatitis
with desquamation, paronychia and photo- (with an early onset), alopecia, hair fragility,
sensitivity. Minimal therapeutic doses must be hyperpigmentation (Sorafenib) or depigmentation
prescribed to avoid these side effects. New (Sunitinib), which is reversible one month after
therapies that are currently under investigation treatment cessation, proliferative lesions
include the vitamin K3 analogue, menadione (squamous cell carcinomas, keratoachantomas
(1, 4-6, 10-12). Xerosis, desquamations and skin and inflamed actinic keratosis), facial and scalp
fissures require ammonium lactate 12%, salicylic erythema (similar to seborrheic dermatitis), facial
acid 6% and 20% urea based emollients. Pruritus edema and yellow skin pigmentation (for
may be alleviated using topical corticosteroids, Sunitinib), which are reversible. Cutaneous
menthol, oral antihistamines, and in severe cases hemorrhages, periungal erythema, erythema
gabapentin and pregabalin can be used. Studies multiforme, dysesthesia and Stevens-Johnson
show that concomitant antineoplastic therapies syndrome are less frequent (1, 16, 17).
(radiotherapy and chemotherapy and Cetuximab) Preventive measures against hand-foot
do not produce a higher risk for mucositis, syndrome include limitation of hot water usage
acneiform reactions or post-radiotherapy dermatitis
impacting quality of life (13-15).
Small molecule tyrosine kinase inhibitors

Sorafenib and Sunitinib are tyrosine kinase
inhibitors that stop angiogenesis and tumor
proliferation by blocking the vascular endothelial
growth factor receptor (VEGFR), platelet derived
growth factor receptor (PDGFR) and cytokinic
receptor (KIT). Sunitinib is approved for renal
cancers, gastrointestinal stromal tumors, pancreatic
neuroendocrine tumors, whereas Sorafenib,
which inhibits RAF kinase, is used in renal, hepatic
and thyroid cancer. Patients may present adverse FIGURE 3. Up: vesicles and tension bullae on a well
defined erythematous background on soles (HFS);
effects such as arterial hypertension, diarrhea and
lower left: well defined erythemato-squamous plaques
cutaneous reactions by inhibiting PDGFR and on elbows; lower right: well defined erythematous
VEGFR, and direct vascular injury, determining plaques on soles

FIGURE 4. Erythema on the palmar and dorsal

aspects of hands, including the fingers and nail folds,
with desquamation, hyperkeratosis and fissures
for hands and feet, cooling with cold water or a

cold damp towel, avoiding heat generators,
saunas, sun exposure, use of thick socks or gloves,
avoiding contact with chemical substances (e.g., FIGURE 5. Upper left: periocular papillomas;
laundry detergent, domestic cleansing products) upper right: erythema multiforme-like lesions, soft
and limiting any physical strain that may lead to bullae with serous fluid content, surrounded by and
pressure or friction on palms and soles. erythemato-edematous ring, on a red-violaceous
background (targetoid lesions); lower left and right:
Topical agents are used for grade 1-2 reactions,
small, slightly erythematous papules and nodules,
whereas topical associated with oral therapies are (metastases versus dermatofibromas)
used for grade 3 reactions. Hyperkeratotic areas
can be treated with daily applications of 10-20%
cell proliferation, differentiation, survival, stress
urea based creams or 0.1% tazarotene creams,
response and apoptosis (1, 21).
while 0.05% clobetasole propionate is used on
Vemurafenib is a strong BRAF mutation inhi-
erythematous areas. Urea is a keratolytic agent,
bitor. Dabrafenib is a reversible, ATP-competitive,
increasing skin moisture by softening the dry or
selective BRAF inhibitor. Both are approved for
rough layers of the skin. Tazarotene is a topical
the treatment of V600 BRAF positive metastatic
retinoid that reduces cutaneous proliferation and
melanoma. Both Vemurafenib and Dabrafenib
inflammation. Topical agents must be used at
are generally well tolerated. Adverse reactions are
most twice daily. Excessive use may lead to
due to a paradoxical activation of MAPK pathway
irritation. Other options include salicylic acid and
(22-25).
ammonium lactate. Topical corticotherapy or
Cutaneous reactions due to BRAF inhibitors
anesthetics (lidocaine creams or patches) can be
are papular eruptions, photosensitivity, xerosis,
used on painful vesicles or areas on palms and
pruritus, paronychia, alopecia and hair changes,
soles. Non-steroidal anti-inflammatory drugs
hyperkeratotic lesions. Vemurafenib and Dabrafenib
(ibuprofen, naproxen and celecoxib), pregabalin
patients can develop warts, seborrheic keratoses,
or codeine are oral analgesics used in severe
hypertrophic actinic keratoses, eczemas, hand-foot
cases. Such cases warrant a reduction in Sunitinib/
syndrome, papillomas, keratoachantomas and
Sorafenib dose or even temporary treatment
squamous cell carcinomas, most of which are
discontinuation. Studies show that patients exhi-
related to Vemurafenib. Dabrafenib is an appro-
biting adverse reactions to Sunitinib and Sorafenib
priate therapeutic option in patients that do not
have a higher treatment efficacy. Such correlations
tolerate Vemurafenib (Figure 5). Trametinib is a
may lead to identifying patient groups that benefit
MAPK inhibitor approved for inoperable melano-
more from treatment with small molecule tyrosine
mas with V600E BRAF or V600K mutations.
kinase inhibitors (1, 16-20).
Cutaneous adverse reactions are less frequent and
comprise acneiform eruptions, pruritus and
BRAF inhibitors
xerosis. Squamous cell carcinoma secondary to
Approximately 40-60% of melanoma patients Trametinib administration is uncommon com-
have a BRAF mutation, that leads to the activation paring to BRAF inhibitors. Dabrafenib plus
of a signaling cascade in the MAP kinase pathway Trametinib and Vemurafenib plus Cobimetinib
(mitogen-activated protein kinases) involved in associations have similar efficacy, but with a lower

incidence of skin toxicities or either malignant or treatment dose or discontinuation, impacting

hyperproliferative disorders. This is due to the therapy response and patient survival. Today,
paradoxical activation of the MAPK pathway. dose modifications are made using the adverse
Addition of a MEK inhibitor leads to the inhibition reactions criteria according to the National Cancer
of RAS signaling in MAPK pathway, which prevents Institute’s CTCEA.
cellular proliferation. Fever is the most important Although useful and widely accepted, this
adverse reaction of the Dabrafenib plus Trametinib system is yet to be validated. Therefore, patient
combination and may lead to dose reduction or evaluations can be subjective. Other possible
treatment discontinuation (1, 21-25). methods to describe cutaneous toxicities are:
An interdisciplinary collaboration between DERETT journal (DErmatologic REaction Targeted
oncologists and dermatologists is necessary. Therapy–Patient Symptom Experience Diary),
Knowledge of cutaneous adverse reactions in new where patients take notes of adverse reactions,
therapies is mandatory in order to have a proper using the FACT-EGFRI-18 scale for anti-EGFR
management of oncologic patients. As such, therapies, HFS-14 (The Hand-Foot Syndrome 14)
patients receiving BRAF inhibitors must be exa- for hand-foot syndrome. These instruments used
mined on a regular basis by a dermatologist since in order to measure the impact of dermatological
an early diagnosis and adequate treatment can adverse events on quality of life, together with
improve patient quality of life and overall survival medical criteria, can deliver important data in
rates (1, 21, 22). q order for adequate decisions to be made for
optimal antineoplastic therapy dosing and
CONCLUSION maintaining a good quality of life. Recognizing
target therapy toxicities by both oncologists and
Antineoplastic targeted therapies such as EGFR dermatologists, understanding therapeutic me-
inhibitors, tyrosine kinase inhibitors and BRAF chanisms and choosing optimum treatments for
inhibitors frequently lead to dermatologic adverse oncologic patients is critical for both oncologists
reactions, which significantly affect patient’s and dermatologists. q
quality of life. This may determine unwanted dose
modifications. A correct evaluation of skin toxicity Conflict of interests: none declared.
can allow for an adequate decision regarding Financial support: none declared.
R#$#%#&'#*
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Cacciapuoti S. Acneiform Rash Induced Cancer Patients: The RTOG Experience. failure of first-line chemotherapy: A
by EGFR Inhibitors: Review of the International Journal of Radiation Oncology randomized, open-label trial. Journal of the
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Appendage Disorders 2015;1:31-37. 8. Petrelli F, Borgonovo K, Barni S. The 2016;74:1077-1085.
doi:10.1159/000371821 predictive role of skin rash with cetuxi- 12. Petrelli F, Borgonovo K, Barni S.
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2017; 12(1): 55-58
S TATE OF THE ART
Correlation Between Idiopathic

Nephrotic Syndrome and Atopy
in Children – Short Review
Elena Camelia BERGHEAa, Mihaela BALGRADEANa, b, Ionela-Loredana POPAa
a
”Marie Curie” Emergency Children’s Hospital, Bucharest, Romania
b
”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
ABSTRACT
The idiopathic nephrotic syndrome is a common chronic kidney diseases in children defined by the associa-
tion of massive proteinuria and hypoalbuminemia in a relapsing/remission course, with histological aspect
of minimal changes (also called minimal change disease) in the majority of the cases, but its pathogenesis
remains not very well known. Clinical and immunological studies have consistently shown a relationship
between atopic diathesis, immunoglobulin E and cytokines involved in immunoglobulin E synthesis and
idiopathic nephrotic syndrome. Additional research is necessary to clarify this relationship and to explore
the contribution of allergic disease to the development of nephrotic syndrome and to identify potential new
strategies of diagnosis and treatment.
Keywords: idiopathic nephrotic syndrome, atopy, immunoglobulin E, children
INTRODUCTION sively discussed. There are reported cases of INS

induced or precipitated by allergy to foods, aero-
T
he idiopathic nephrotic syndrome (INS) allergens or insect venom and many of the chil-
is a common chronic kidney diseases in dren with INS show an elevated level of immu-
children, representing more than 90% noglobulin E (IgE), the immunoglobulin with a
of cases of nephrotic syndrome be- central role in allergic inflammation (1).
tween 1 and 10 years of age and 50% The purpose of this article is to review clinical
after 10 years of age (1, 2). INS is defined by the and experimental findings showing the involve-
association of the clinical features of NS (massive ment of the immune response and of immuno-
proteinuria and hypoalbuminemia in a relapsing/ globulin E in INS pathogenesis.
remission course) with renal biopsy findings of
diffuse foot process effacement on electron mi- INS pathogenesis
croscopy and in majority of cases, aspect of mi-
nimal changes (also called minimal change disease INS is currently classified as steroid-sensitive
– MCD) on light microscopy, but its pathogenesis idiopathic nephrotic syndrome (SSNS) and ste-
remains not very well known (2, 3). The associa- roid-resistant idiopathic nephrotic syndrome
tion of this disease with atopy has been exten- (SRNS) depending on the response to corticoste-

Dr. Camelia Berghea, “Marie Curie” Emergency Children’s Hospital, Bucharest, Romania
E-mail: bcamelia@gmail.com
Article received on the 9th of January 2017. Article accepted on the 16th of February 2017.

CORRELATION BETWEEN IDIOPATHIC NEPHROTIC SYNDROME AND ATOPY IN CHILDREN – SHORT REVIEW
roids. There are now two hypotheses concerning Researchers have tried to identify the circula-
the mechanisms of INS. One of them is that the ting factors released from T-cells that increase the
proteinuria is induced by a primary glomerular glomerular permeability to serum proteins. Be-
defect due to a mutation of a gene coding for cause cytokines are small proteins that function as
podocyte structures or for glomerular basement inflammatory mediators in a paracrine and auto-
membrane proteins resulting in podocyte efface- crine mode, they were believed to be the most
ment. The older one is that INS results from a dis- likely pathogenic soluble factors (6). Increased
order of T-cell function resulting in increased plas- levels of IL-2 (12), soluble IL-2 receptor (13), inter-
ma levels of lymphocyte-derived permeability feron-gamma (12, 13), IL-4 (14, 15), IL-12 (16), IL-
factor affecting podocyte shape and function (2). 13 (17), IL-18 (17), tumor necrosis factor (TNF)-α
(18), and vascular endothelial growth factor
Podocyte disorder (VEGF) (19) were associated with MCD relapse
(6). The specific effect of a cytokine on the devel-
In 1998 a mutations in the gene NPHS1, which
opment of proteinuria was not studied extensively.
encodes the podocyte-expressed immunoglobu-
However, it was shown that IL-13 can experimen-
lin superfamily protein nephrin, was identified as
taly induce nephrotic proteinuria in IL-13 trans-
a cause of congenital nephrotic syndrome in hu-
fected rats, but the role of IL-13 in the pathogen-
mans (4). Mutations of genes encoding several
esis of the nephrotic syndrome is not yet clarified
other podocyte proteins can explain cases of in-
(20). There are other diseases like asthma and
herited nephrotic syndrome.
psoriazis, associated with high levels of IL-13, and
In addition, it was shown that podocytes ex-
not with proteinuria (6). Remission of renal lesions
press a T-cell costimulatory, known as CD80 or
after treatment with infliximab, a monoclonal an-
B7.1, that can be induced by direct activation of
tibody anti-TNF-α, suggests a role for this cytokine
podocytes, independent of T cells action, or by cy-
in nephrotic syndrome (21). However, due to the
tokines such as interleukin (IL)-13 (5) and is associ-
complex interactions among cytokines, it is very
ated with proteinuria (6). The underlying mecha-
difficult to determine the role of each cytokine.
nism is unknown but it is believed that the increased
Another molecule proposed by the investigators
expression of CD80 on podocytes leads to shape
as circulating factor that increases glomerular per-
change and proteinuria. MCD is associated with
meability is the nuclear transcription factor called
pronounced expression of CD80 on podocytes,
NF-κB, that controls the expression of several cy-
and increased urinary excretion of CD80 (7, 8).
tokines and cellular adhesion molecules and it
The expression of CD80 is regulated by cytokines
was shown that its activity is higher in patients
such as CTLA-4, IL-10, and TGF-β, all produced by
with INS (22). Another factor involved in INS
Tregs cells. Disfunctional Tregs in INS unable to pro-
pathogenesis is an imbalance of subtypes of T
duce these cytokines, induce persistent expression
lymphocytes. Here are some suggestive data: re-
of CD80 and persistent proteinuria (6).
mission of INS after treatment with cyclosporin-A
due to reduction of IL-2 levels, a cytokine pro-
T-cell disfunction and lymphocyte-derived
duced by T lymphocytes (23), association of INS,
permeability factors
severity with decreased activity of regulatory T
The pathophysiological role of a circulating cells (24), INS worsening after TCD4+ cells deple-
factor affecting the podocyte structure and function (25), high expression of mRNA for IL-13 on
tion was suggested by cases of massive proteinuria TCD4+ and TCD8+ lymphocytes of children
in patients with nephrotic syndrome after trans- with INS and overexpression of receptors for IL-4
plantation of a kidney from a healthy donor, by and IL-13 in glomeruli of mice transfected with
the successful treatment of some of those patients IL-13 (26), although it has not been definitively
by plasma exchange (9), by the disappearance of established that MCD was a Th2-dependent dis-
nephrotic syndrome when kidneys affected by order (27).
MCD were transplanted into patients without ne-
phrotic syndrome (10) or the development of Association with atopy
neonatal nephrotic syndrome by placental trans-
Atopy is defined as a personal and/or familial
fer of proinflammatory cytokines from a mother to
tendency, usually in childhood or adolescence, to
her newborn (11).

become sensitized and produce IgE antibodies in whom the major role in IgE synthesis it is accom-
response to ordinary exposure to allergens, usu- plished by IL-4 (27). Serum levels of IL-5 (cyotkine
ally proteins (28). MCD is frequently associated important în eosinophilic inflammation character-
with allergic symptoms and an elevated serum IgE istic for asthma and allergic disesases) and IL-13
level (29). Some authors mentioned that higher are higher in patients with steroid-sensitive NS
serum IgE levels can be related to poor outcome before compared with after treatment (29).
with frequent relapses or poor response to corti- Recently, were published the results of a popu-
costeroids of INS in children (30, 31). There are lation-based cohort study having as topic the inci-
data showing that, in atopic children with INS, se- dence and risk of INS in children with atopic der-
rum IgE levels are higher when they were in re- matitis (AD) compared with non-AD controls in
mission than in non-atopic patients. Both atopic Chinese population (1). AD is a chronic and re-
and non-atopic nephrotic children develop high lapsing inflammatory skin disease whith onset in
levels of IgE during relapses compared with remis- first months or years of life, that precedes other
sion (29). Very early information about specific allergic disorders in early childhood (35). The re-
sensitization to an allergen and its impact on ne- sults obtained by the authors support the relation-
phrotic syndrome dates from 1959, when ship between pre-existing AD and the subsequent
Hardwicke et al. (27, 32) reported seasonal pro- risk for INS. The incidence of INS was two-fold
teinuria in patients with pollen hypersensitivity. higher in the AD cohort than in the non-AD co-
Subsequent studies have shown a higher inci- hort, and the risk increased with the severity of
dence of allergic diseases in children with ne- AD symptoms (1). q
phrotic syndrome, but the exact correlation be-
tween IgE specific sensitization and the CONCLUSION
pathogenesis of proteinuria is not understood. It is
debatable whether the very frequent association
between high levels of IgE and INS is indicative for I diopathic nephrotic syndrome is a complex di-
sease with more than one causal factor. Clinical
and immunological studies have consistently
atopic state or just uncover pathogenetic mecha-
nism affecting lymphocyte regulation of immuno- shown a relationship between atopic diathesis
globulin synthesis during nephrotic relapses, simi- and INS (1), and according to older data, atopy is
lar to those found in atopy (27). Some authors associated with up 30% of INS cases (36). The sig-
suggest that a humoral immune perturbation seen nificantly increased risk of INS development in
in patients with INS relapses is responsible for the children with AD supports an important correla-
increased IgE synthesis (33). tion between allergic diseases and INS pathogen-
Evidence suggesting common pathways in- esis. In the future, additional research is needed
clude: increased expression of IL-13 mRNA on T into both the factors that are known to modulate
cells CD4+, CD8+ în children with INS relapses IgE synthesis and the cytokine-regulating network
(35), IL-13 experimentally induced proteinuria of serum IgE in order to clarify the relationship
(26), a significantly higher expression of CD23, between IgE production and INS, explore the
the type II IgE receptor, on B cells from active contribution of allergic disease to the develop-
MCD patients (34), correlated with greater IL-4 ment of nephrotic syndrome and identify poten-
activity. IL-4 and IL-13 are known regulators of B tial new strategies of diagnosis and treatment. q
cell IgE production in atopic patients. It was shown
that in MCD patients, IL-13 can spontaneusly in- Conflict of interests: none declared.
duce IgE synthesis, in contrast to atopic patients in Financial support: none declared.
R#$#%#&'#*
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6. Kaneko K, Tsuji S, Kimata T, et al. minimal change nephrotic syndrome. 27. Cheung W, Wei CL, Seah CC, et al.
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nephrotic syndrome: a paradigm shift 17. Matsumoto K, Kanmatsuse K. Elevated steroid-responsive nephrotic syndrome.
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World J Pediatr 2015;11:21. nephrotic patients. 28. Johansson SGO, Bieber T, Dahl R,
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Araya C, Segal M, et al. Urinary CD80 18. Suranyi MG, Guasch A, Hall BM, nomenclature for allergy for global use:
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J Am Soc Nephrol 2009;20:260-266. syndrome in humans. Organization, October 2003.
8. Garin EH, Mu W, Arthur JM, Rivard CJ, Am J Kidney Dis 1993;21:251-259. J Allergy Clin Immunol 2004;113:832-836.
Araya CE, Shimada M, et al. Urinary 19. Matsumoto K, Kanmatsuse K. Elevated 29. Salsano ME, Graziano L, Luongo I,
CD80 is elevated in minimal change vascular endothelial growth factor levels Pilla P, Giordano M, Lama G. Atopy in
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Kidney Int 2010;78:296-302. Clin Nephrol 2001;55:269-274. 30. Yap HK, Yip WC, Lee BW, Ho TF, Teo J,
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2017; 12(1): 59-61
S TATE OF THE ART
Chronic Venous Insufficiency:

a Frequently Underdiagnosed
and Undertreated Pathology
Marilena SPIRIDONa, Dana CORDUNEANUb
a
Department of Cardiology, “St. Spiridon” Clinical Emergency Hospital, Iasi,
Romania
b
Department of Internal Medicine, “St. Spiridon” Clinical Emergency Hospital, Iasi,
Romania
ABSTRACT
The article describes the medical approach of a frequent pathology, chronic venous insufficiency.
Chronic venous insufficiency requires early diagnosis as well as an evaluation of the associated risk fac-
tors; also, patients need to understand the disease and its treatment, and to become compliant with all their
physician’s recommendations. Importantly, the physician should correctly evaluate the disease and decide
the best option for the patient.
These days, it is crucial that the patient benefits from optimal treatment choice in order to prevent com-
plications.
CVI is a potentially severe pathology that has been underdiagnosed and undertreated for a long time and
requires patience from the patient as well as care from the physician.
BACKGROUND mally occurs during exercise, resulting in venous

hypertension. In addition, poor function or failure
C
hronic venous insufficiency (CVI) is a of the calf muscle pump due to inactivity, immo-
common but underdiagnosed cause bility or abnormal gait may contribute to venous
of leg pain and swelling, and it is fre- hypertension. Chronic venous hypertension
quently associated with varicose causes abnormalities in the capillaries within the
veins. It is a consequence of the dys- leg tissues that make them more permeable. This
function of the valve of the veins, associated with allows fluid, proteins and blood cells leak into the
an impaired circulation of blood in the leg veins (1). tissues. Venous hypertension may also be associ-
Valve failure may occur due to a weakening of ated with an increased inflammatory response,
the valves as a result of varicose veins, or damage changes in the structure of the microvasculature
to the deep veins secondary to venous thrombo- and reduced skin and tissue oxygenation (2). It
sis, trauma or venous obstruction. The failure of has been postulated that valvular dysfunction
the valves allows the blood to flow back down causing reflux was the initial pathological change
(reflux) into the section of vein below. This pre- in CVD. The existing evidence seems to favour
vents the reduction in venous pressure that nor- pre-existing weakness in the wall, which produces

Dr Marilena Spiridon, MD
Phone: 0745 651 642
Mailing adress: marilena_spiridon@yahoo.com
Article received on the 28th of November 2016 and accepted for publication on the 11th of March 2017.

CHRONIC VENOUS INSUFFICIENCY: A FREQUENTLY UNDERDIAGNOSED AND UNDERTREATED PATHOLOGY
dilation and causes secondary valvular incompe- CVI; stockings are non-invasive, safe and
tence (3). Overall, these effects cause changes in can be sufficient in treating uncomplica-
the skin and subcutaneous tissues such as oede- ted venous disease
ma, hyperpigmentation, lipodermatosclerosis, at- Compression therapy systems applied exter-
rophe blanche and varicose eczema, and contri- nally to the lower leg increase pressure of the skin
bute to a greater skin fragility, increasing the risk of and underlying structures to counteract the force
leg ulceration and delayed healing (2). of gravity. This can help to relieve the symptoms in
the lower limb by acting to the venous and lym-
Risk factors for CVI phatic systems to improve removal of fluid (blood
and lymph) from the limb (2).
• Family history Compression therapy has two mechanisms of
• Increasing age over 30 action: a static effect or resting pressure and a dy-
• One or more blood clots in superficial or namic effect due to the changing circumference
deep veins of the leg during walking. Applying external pres-
• Female gender; varicose veins occur sure will increase pressure in the limb; this will be
nearly as commonly in men distributed evenly, according to Pascal’s law. The
• Prolonged standing greater the pressure increase in the lower limb, he
• Heavy lifting greater the force that pushes the fluid out of the
• Multiple pregnancies limb (2).
• Limited physical activity Bandages with a high SSI – static stiffness index
• High blood pressure – (inelastic) are able to remain rigid due to their
• Obesity (1) lack of extensibility. This allows them to generate
intermittent high working pressures and low res-
Diagnosis of CVI ting pressures, improving both comfort and effec-
Clinical examination is the first step for diag- tiveness of calf muscle pump (2).
nosing CVI. The accuracy of the diagnosis can be Bandages with a low SSI provide constant
increased by using a hand-held instrument called pressure, maintaining a therapeutic level of com-
Doppler that allows the examiner to listen to the pression a rest, but with less marked changes in
blood flow. The most accurate exam is a venous pressure during exercise (2).
duplex ultrasound scan, that provides an accurate Compressive stockings are a required treat-
image of the vein, so that any blockage caused by ment component during travel in patients who
blood clots or improper vein valve function can
be detected. To exclude other causes of leg swel-
ling, an MRI or CAT scan can be used (1).
Treatment of CVI
The treatment of CVI consists of both medical
and surgical approaches and involves additional
conservative therapeutic methods, as illustrated in
Figure 1:
• diet and lifestyle
• avoidance of prolonged standing or sitting
• structured exercise such as walking or
strengthen calf muscles may improve calf
muscle function
• elevation of the feet above the tights when
sitting and above the heart when lying
down, three to four times a day, to reduce
swelling (1)
• compression stocking use – a very impor-
tant part of the conservative treatment in FIGURE 1. Algorhythm for diagnosing and treating CVI (6)

CHRONIC VENOUS INSUFFICIENCY: A FREQUENTLY UNDERDIAGNOSED AND UNDERTREATED PATHOLOGY
Category Pressure storing the endothelial glycocalix structures. Sev-

Mild <20 mmHg
eral studies have also demonstrated the anti-in-
flammatory properties of sulodexide (5).
Moderate ≥20-40 mmHg
Studies on drug interactions with sulodexide
Strong ≥40-60 mmHg have shown that its oral administration in cardio-
Very strong ≥60 mmHg vascular disease, metabolic disorders and in pre-
TABLE 1. Categorisation of compression bandage vention and treatment of thrombosis does not in-
systems (2) terfere with the pharmacological interactions of
other routinely used agents (5).
require surgical interventions and in those with The efficacy of sulodexide has been shown in
advanced CVI (>C4 disease). In patients with re- several clinical trials in patients with peripheral
solution of symptoms under compliant compres- vascular disease, peripheral arterial occlusive di-
sive stocking use, surveillance at every 6 months is sease, coronary disease, cerebral vascular is-
recommended. If the patient develops break- chemia, myocardial infarction, post-thrombotic
through symptoms or if physical examination find- syndrome, intermittent claudication and vascular
ings deteriorate, the patient must be counselled complications of diabetics (5).
for intervention (4).
Surgical treatment
Pharmaceutical treatment
It is reserved for patients whose symptoms re-
Sulodexide is an agent with polypharmaco- main uncontrolled or worsen despite initial con-
logical actions which targets several sites involved servative treatment, and may consist of ligation
in the pathogenesis of CVD. The chemical com- with stripping, simple ligation and division, sclero-
position of sulodexide consists of 80% fast-moving therapy, stab evulsion, radiofrequency ablation,
heparine and 20% dermatan sulphate (5). endovenous laser therapy. q
The pharmacological effects of sulodexide dif-
fer substantially from other glycosaminoglycans CONCLUSION
and are mainly characterized by a prolonged half-
life, profibrinolytic properties and reduced effects
on both the coagulation cascade and bleeding pa-
rameters. The dual thrombin inhibitory action via
T hese days, it is very important that the patient
benefits from optimal choice of treatment in
order to prevent complications.
both antithrombin and heparin cofactor II gives CVI is a potentially severe pathology that has
sulodexide its potent antithrombotic effect with a been underdiagnosed and treated for a long time
low hemorrhagic profile (5). and that requires patience from the patient and
Sulodexide has endothelial protective effects care from the physician. q
by inducing the over expression of growth factors
that are important in the protection and repair of Conflict of interests: none declared.
several organs. It is capable of maintaining and re- Financial support: none declared.
R#$#%#&'#*
1. What is Chronic Venous Insufficiency ulcers. Wounds International. 2013. Venous Insufficiency. Supplement of
(CVI)? Vascular Disease Foundation. 3. Perrin M, Ramelet AA. Pharmacological Endovascular Today. 2011:12-15.
h!p://vasculardisease.org/flyers/ Treatment of Primary Chronic Venous 5. Hoppenstead DA, Fareed J.
chronic-venous-insufficiency-flyer.pdf Disease: Rationale, Results and Pharmacological profile of sulodexide.
2. Principles of compression in venous Unanswered Question. International Angiology. 2014;33:229-235.
disease: a practitioner’s guide to Eur J Vasc Surg 2011;41:117-125. 6. h!p://circ.ahajournals.org/
treatment and prevention of venous leg 4. Jennifer Heller. Treatment of Chronic content/130/4/333.

2017; 12(1): 62-64
C ASE REPORTS
A Case Report of 9p Deletion

Syndrome Associated with Partial
Trisomy of 1q42
Ali VAHABIa, Filiz HAZANb, Isa Abdi RADc
a
Assistant Professor of Medical Genetics, Department of Medical Genetics,
Motahrai Hospital, Urmia University of Medical Sciences, Iran
b
Assistant Professor of Medical Genetics, Department of Medical Genetics,
Dr. Behcet Uz Children’s Hospital, Izmir, Turkey
c
Professor of Neurogenetics, Department of Medical Genetics, Motahrai Hospital,
Urmia University of Medical Sciences, Iran
ABSTRACT
We report a case of partial deletion of 9p with partial trisomy of 1q42 syndrome, which is a rare clinical and cytogenetic report.
The dysmorphic features of the patient include microcephaly, plagiocephaly, trigonocephaly with metopic ridge, arched eyebrows,
hypertelorism, down-slanting palpebral fissure, ptosis, blepharophimosis, unilateral left epicanthic fold, long eyelashes, low-set
and posteriorly rotated ears, long philtrum, anteverted nares, retrognathia and unilateral undescended testis. Chromosomal
analysis revealed partial monosomy of 9p24 associated with partial trisomy of 1q42→qter.
Keywords: 9p deletion, trisomy of 1q42, mental retardation, microcephaly, trigonocephaly
INTRODUCTION tients with terminal deletion of the short arm of

chromosome nine, either pure 9p deletion or as-
D
eletion 9p syndrome was firstly re- sociated with some other chromosomal rearrange-
ported by Alfi et al in 1973 (1). In ment (3-7). In 1988, Huret et al reported 11 cases
1976, he described six cases of pa- of deletion 9p of which seven had pure 9p deletion
tients with terminal deletion of the and four had 9p deletion associated with another
9p22 that was associated with men-
chromosome rearrangements (8). The reported as-
tal retardation, trigonocephaly, upslanting palpe- sociated unbalanced chromosome segment in un-
bral fissure, wide flat nasal bridge, anteverted nos- related patients were trisomy 13q (four cases), tri-
trils, long upper lip, short neck, and long digits (2). somy 12q (three cases), trisomy 10q (three cases),
Thereafter, there were many reports describing trisomy 2q (two cases), trisomy 5p (two cases), tri-
birth defects and cerebral maldevelopment in pa- somy 5q (two cases), trisomy 7q (two cases), and
Isa Abdi Rad MD, PhD
Professor of Neurogenetics
Medical Genetic Department, Motahari Hospital
Urmia University of Medical Sciences, Iran
Email: ali.vahabi@hotmail.com
Phone: 0098 +44 32240166
Article received on the 25th of November 2016 and accepted for publication on the 10th of March 2017.

A CASE REPORT OF 9p DELETION SYNDROME ASSOCIATED WITH PARTIAL TRISOMY OF 1q42
two trisomy 16q (two cases) (8). Our patient had

partial trisomy of 1q42. q
CASE REPORT
A 3-year-old boy was referred to our clinical

Genetic Department because of psychomotor
developmental handicap. Following an unevent-
ful pregnancy, he was born via normal vaginal
delivery at term to a non-consanguineous mar- FIGURE 1. The front and lateral view of our case with partial trisomy
of 1q42→qter, and partial monosomy of 9p24. There are some distinct
riage. The patient’s birth weight and length were
dysmorphic features, including plagiocephaly, trigonocephaly with
normal (3000 grams and 51 cm, respectively). metopic ridge, arched eyebrows, hypertelorism, down-slanting
He had a normal head size at birth with head palpebral fissure, ptosis, blepharophimosis, unilateral left epicanthic
circumference (HC) of 36 cm, that is, the 75 per- fold, long eyelashes, long philtrum, anteverted nares, retrognathia, and
centile for sex and age. However, according to low-set posteriorly rotated ears.
the health chart records, there was a regression
of HC after 8 months of age. He was unable to sit
till two years of age. At the time of visit (3 years
of age), his physical examination was remarkable
for marked microcephaly (HC: 46 cm, that is,
under -2 SD for sex and age), plagiocephaly,
trigonocephaly with metopic ridge, arched eye-
brows, hypertelorism, down-slanting palpebral
fissure, ptosis, blepharophimosis, unilateral left
epicanthic fold, long eyelashes, low-set and pos-
teriorly rotated ears, long philtrum, anteverted
nares, retrognathia and left unilateral undescen-
ded testis (Figure 1). The palmar dermatoglyphics
pattern was normal. He had no seizure and his FIGURE 2. The karyotype of the patient has revealed derivative
vision and hearing were normal. chromosome 9
His neurologic examination revealed pro-
found developmental handicap, with inability to
walk. He was unable to utter even a single word.
His brain MRI showed chronic bilateral fronto-
temporal subdural hematoma with mild frontal
atrophy. His metabolic screening was normal.
GTG banding karyotype carried out on the
patient revealed derivative chromosome 9, that
is, 46,XY,der(9) (Figure 2). Consequently, a chro-
mosomal study was done on both parents to de-
termine the origin of the rearrangement. His fa-
ther’s karyotype was normal (46,XY) but his
mother’s showed translocation between chro-
mosomes one and nine [46,XX,t(1;9)(q24;p23)]
(Figure 3). Accordingly, we concluded that the FIGURE 3. The mother karyotype showed translocation between
patient had partial monosomy for 9p24 and par- chromosomes one and nine [46,XX,t(1;9)(q24;p23)]
tial trisomy for 1q42→qter. q
our case has postnatal-onset syndromic micro-
DISCUSSION cephaly due to chromosomal abnormality. Be-
sides microcephaly, distinct dysmorphic findings
C onsidering the time of onset, associated dys-

morphic features, and cytogenetic finding,
in our patient included arched eyebrows, hyper-
telorism, down-slanting palpebral fissure, ptosis,

A CASE REPORT OF 9p DELETION SYNDROME ASSOCIATED WITH PARTIAL TRISOMY OF 1q42
blepharophimosis, low-set posteriorly rotated ing where there was translocation between
ears, long philtrum, anteverted nares, retrogna- chromosomes one and nine.
thia and unilateral undescended testis. Chew and Thong reported two cases of par-
According to a review by Huret et al on 80 tial deletion 9p syndrome with trigonocephaly,
cases with different length of 9p deletion, it arching eyebrows, anteverted nares, long phil-
seems that dysmorphic features do not differ trum, abnormal ear lobules, congenital heart le-
with regard to the length of the deletion (8). All sions and digital anomalies (9). Trigonocephaly,
of 39 cases with pure 9p deletion described by arching eyebrows, anteverted nares and long
Huret et al were de novo and common dysmor- philtrum are in common with our patient’s dys-
phic features included trigonocephaly, upslan- morphic features.
ting palpebral fissures, and long philtrum (8). Monosomy of distal 9p has been shown to be
However, besides trigonocephaly and long phil- associated with a wide range of gonadal dysgene-
trum, our patient had down-slanting palpebral sis such as hypogonadism, streak gonads, crypt-
fissures. In our case, down-slanting palpebral fis- orchidism, hypoplastic testes, micro-genitalia,
sure is in contrast with other reports that de- and sex reversal (10, 11). Our patient also had
scribed upslanting palpebral fissures in 9p dele- unilateral cryptorchidism.
tion syndrome. To the best of our knowledge, our case is the
Huret et al have also reviewed 41 cases of del first report of association of 9p24 deletion syn-
(9p) with a partial trisomy, of which 38 were in- drome with 1q42 partial trisomy in a patient
herited from a carrier parent with balanced with constellation of congenital birth defects.
translocation (mother as a carrier in 25 cases, fa- Pilling up of clinical information of cases with
ther as a carrier in 13 cases). In 23 out of 38 similar chromosomal abnormalities, it would be
cases, the breakpoint occurred mainly at 9p24, helpful to understand the genetic basis of distinct
which has not been reported in cases with pure dysmorphic features. q
9p deletion. In pure 9p deletion, the most com-
mon breakpoint was at 9p22 (8). This break- Conflict of interests: none declared.
point, that is 9p24, is compatible with our find- Financial support: none declared.
R#$#%#&'#*
1. Alfi OS, Donnell GN, Crandall BF, Cytogenet Cell Genet 1976;17:296-297. Rethoret MO, Lejeune J. Eleven new
Derencsenyi A, Menon R. Deletion of the 5. Fryns JP, Pedersen JC, Duyck H, Fabry cases of del(9p) and features from 80
short arm of chromosome 9 (46, 9p-): A G, Van den Berghe H. Deletion of the cases. Journal of Medical Genetics
new deletion syndrome. short arm of chromosome 9; a clinically 1988;25:741-749.
Ann Genet 1973;16:17-22. recognisable entity. 9. Chew HB and Thong MK. Partial
2. Alfi OS, Donnell GN, Allderdice PW, Eur J Pediatr 1980;134:201-4. Deletion 9p Syndrome in Malaysian
Derencsenyi A. The 9p- syndrome. 6. Eden MS, Thelin JW, Michalski K, Children. Med J Malaysia 2010;65:215-217.
Ann Genet 1976;19:11-16. Mitchell JA. Partial trisomy 6p and 10. Monaghan HP, Howard NJ. Short stature
3. Allderdice PW, Heneghan WD, partial monosomy 9p from a de novo and microgenitalia in the 9p- syndrome.
Felismino ET. 9pter→ip22 deletion translocation 46,XY,-9,+der(9)t(6:9) Isr J Med Sci 1981;150:382-384.
syndrome: a case report. (p211:p24). Clin Genet 1985;28:375-384. 11. Vinci G, Chantot-Bastaraud S, El Houate
Birth Defects1976;12,:151-155. 7. Liberfarb RM, Atkins L, Holmes LB. A B, et al. Association of Deletion 9p, 46,XY
4. Breg WR, Aronson MM, Hill R, Greene clinical syndrome associated with 5p gonadal dysgenesis and autistic
AE, Coriell LL. Deletion in the short arm duplication and 9p deletion. spectrum disorder.
of chromosome 9 from a subject with Ann Genet (Paris) 1980;23:26-30. Mol Hum Reprod 2007;13:685-689.
congenital cerebral maldevelopment. 8. Huret JL, Leonardt C, Forestiert B,

2017; 12(1): 65-67
C ASE REPORTS
Thyroid Association Ophthalmopathy

in Hashimoto’s Thyroiditis:
a Case Report
Deepak JAINa, Sudhir MORb, Hari Krishan AGGARWALc, Pulkit CHHABRAb, Promil JAINd
a
Associate Professor, Department of Medicine, Pt.B.D.Sharma PGIMS, Rohtak, India
b
Resident, Department of Medicine, Pt.B.D.Sharma PGIMS, Rohtak, India
c
Senior Professor & Head Department of Medicine IV, Pt.B.D.Sharma PGIMS,
Rohtak, India
d
Assistant Professor, Department of Pathology, Pt.B.D.Sharma PGIMS, Rohtak, India
ABSTRACT
Thyroid associated ophthalmopathy is a constellation of symptoms caused by an autoimmune process involving the orbital
tissue. It is common in hyperthyroid patients due to Graves’ disease and also reported in euthyroid and hypothyroid Graves’
patients with positive thyroid receptor antibodies. But in Hashimoto’s thyroiditis, thyroid associated ophthalmopathy is a rarely
reported and poorly understood entity. Here we report thyroid associated ophthalmopathy in a patient with hypothyroidism
and negative thyroid receptor antibodies who showed heterogeneously hypoechoic thyroid gland on ultrasonography, diffuse
lymphocytic infiltrate on fine needle aspiration citology and reduced 99m Tc radioisotope uptake, supporting the diagnosis of
Hashimoto’s thyroiditis. The patient was treated with levothyroxine and artificial tear drops.
Keywords: Hashimoto’s thyroiditis, thyroid associated ophthalmopathy, Graves’ disease
INTRODUCTION are diagnosed as having euthyroid Graves’ disease

or hypothyroid Graves’ disease. But TAO in Hashi-
T
hyroid associated ophthalmopathy moto’s thyroiditis is a rare entity with very few
(TAO) is a constellation of symptoms cases reported until now. Pathogenesis of TAO in
caused by an autoimmune process in- Hashimoto’s thyroiditis is poorly understood, as
volving the orbital tissue. Ocular lesions TRAb hypothesis cannot explain it due to the usu-
in autoimmune thyroid diseases occur al negative TRAb status in these patients.
five times more often in women than in men (16 Here we report a case of TAO in a patient of
and 2.9 cases per 100000 annually, respectively) Hashimoto thyroiditis. q
(1). It generally occurs in hyperthyroid patients
due to Graves’ disease and sometimes also in eu- CASE REPORT
thyroid and hypothyroid patients (2). Most euthy-
roid and hypothyroid patients with TAO are thy-
roid receptor antibody (TRAb) positive, and they A 63-year-old non-smoker, non-alcoholic
male came to our hospital with complaint of

Dr. Deepak Jain Department of Medicine Pt. B.D. Sharma University of Health Sciences, ROHTAK-124001 (Haryana) INDIA, India
Phone: +91-9416147887
orcid.org/0000-0001-9476-3671
Article received on the 10th of Januuary 2017 and accepted for publication on the 14th of March 2017.

THYROID ASSOCIATION OPHTALMOPATHY IN HASHIMOTO’S THYROIDITIS: A CASE REPORT
fatigue. On general physical examination mild

pallor was present. No icterus, cyanosis, club-
bing or lymphadenopathy was noted. His blood
pressure and pulse rate were 116/78 mm Hg and
68/min, respectively. Ophthalmological exami-
nation showed bilateral proptosis, swelling of the
eyelids, conjunctival injection (Figure 1) and mild FIGURE 1. Physical features of the
adduction deficiency. The degree of exophthal- patient: bilateral proptosis, eyelid
mos on the Hertel exophtalmometer was 24 mm swelling, conjunctival injection
for the left eye and 20 mm for the right eye. In-
traocular pressure was normal in both eyes. Ten
point clinical activity score (CAS) was 2 (one
point each for swelling of eyelids and conjuncti-
val injection) and NOSPECS class 3 was found.
Laboratory data revealed the presence of
overt hypothyroidism with a thyrotropin (TSH)
level of 35.4 µIU/mL (normal range 0.35-4.94 by
chemiluminescent immunoassay), free 3,5,3’-tri- FIGURE 2. Magnetic resonance
iodothyronine (FT3) of 0.23 pg/mL (normal range imaging of orbits: mild bilateral
proptosis with mild increase in
1.71-3.71 by chemiluminescent immunoassay)
bulk of bilateral inferior recti with
and free thyroxine (FT4) of 0.45 ng/dL (normal sparing of anterior part of tendons
range 0.8-1.7 by chemiluminescent immunoas-
say). TRAb was 1.07 IU/L (normal value <1.75 euthyroid and hypothyroid Graves’ disease and
IU/L; by electrochemiluminescence immunoas- positive TRAb (2). When euthyroid and hypothy-
say), anti-thyroid peroxidase antibody (Anti TPO) roid patients with orbitopathy are TRAb nega-
titre was 591.8 IU/mL (normal range 0.08-8.0 tive, other diseases should be taken into consi-
IU/mL by chemiluminescent immunoassay). Anti deration, including cavernous carotid fistula,
thyroglobulin antibody (ATG) was 871.3 IU/mL sphenoid meningioma, orbital lymphoma, idio-
(normal value <65 IU/mL by chemiluminescent pathic orbital myositis and IgG4 related disease (3).
immunoassay). Ultrasonography (USG) of the Although it was initially thought that Graves’
thyroid showed heterogeneously hypoechoic disease and Hashimoto’s thyroiditis are separate
thyroid gland without any nodule. The right lobe entities, at present they both are considered to
was 17x15x32 mm and the left lobe 14x16x26 be autoimmune diseases and represent the op-
mm in size. The 99mTc scan revealed 0.1% up- posite sides of the same coin. A common factor
take at 20 minutes (normal range 0.3-3 %). Fine causing both thyroid disease and ocular abnor-
needle aspiration cytology (FNAC) showed dif- malities has been searched for a long time. The
fuse lymphocytic infiltrate. Magnetic resonance TSH-receptor antigen is shared between the thy-
imaging of orbits revealed mild bilateral propto- roid and the orbital tissues in Graves’ disease,
sis with mild increase in bulk of bilateral inferior thus explaining the extra thyroidal manifestation
recti (maximum thickness 6.5 mm) with sparing of the disease (4). Binding sites for both the TSH
of anterior part of tendons (Figure 2). and the TSH receptor antibodies exist on the or-
He was treated with levothyroxine replace- bital cells. Orbital tissues also possess TSH recep-
ment, artificial tear drops and ophthalmopathy tor variants (5). Expression of the TSH receptor
responded considerably to the treatment. Gluco- has been found to be increased in orbital pre-
corticoid therapy was not given as the clinical adipocytes (6). T cells reacting with TSH receptor
activity score was 2. q and various cytokines that stimulate fibroblast
proliferation has also been postulated as a pos-
DISCUSSION sible mechanism of Graves’ ophthalmopathy. In
Graves’ disease, TRAb is generally a stimulating
T hyroid associated ophthalmopathy is com-

mon in patients with Graves’s disease and
hyperthyroidism, and sometimes in those with
type, though the blocking type has been also de-
tected. Whether these blocking type TRAbs are a
significant cause of hypothyroidism in hypothy-

THYROID ASSOCIATION OPHTALMOPATHY IN HASHIMOTO’S THYROIDITIS: A CASE REPORT
roid Graves’ disease is unclear. In a study it was did not test our patient for these antibodies due
found that one third of patients with Graves’ di- to financial constraints.
sease who developed hypothyroidism after anti- We have reported TAO in a patient with hy-
thyroid medication had a blocking type TRAb pothyroidism and negative TRAb who showed
(7). On the contrary, Kasagi et al examined five heterogeneously hypoechoic thyroid gland on
cases of hypothyroid Graves’ disease and detec- USG, diffuse lymphocytic infiltrate on FNAC and
ted stimulating, not blocking type TRAb in all reduced 99m Tc radioisotope uptake, suppor-
patients (8). Hypothyroidism in these cases was ting the diagnosis of Hashimoto’s thyroiditis. The
not related to the presence of blocking type an- patient was managed with levothyroxine and ar-
tibodies. They considered that hypothyroidism tificial tear drops. Glucocorticoids need to be
in these cases may be associated with high anti- considered if ten point clinical activity score
body titres against thyroglobin and destructive (CAS) ≥ 3. Given that in our patient CAS was 2,
changes in the thyroid, which were demonstrated glucocorticoids were not used. q
by ultrasound and histological examination,
suggesting concomitant presence of Hashimoto’s DISCUSSION
thyroiditis.
Thyroid associated ophthalmopathy is rare in Thyroid associated ophthalmopathy can
patients with Hashimoto’s thyroiditis, and only sometimes occur in Hashimoto’s thyroiditis and
few cases have been reported (9-12). Pathogen- awareness of this atypical form is important, be-
esis of TAO in Hashimoto thyroiditis is poorly cause prompt recognition and treatment can
understood. Since patients with Hashimoto’s prevent corneal involvement and blindness due
thyroiditis test negative for TRAb, the TRAb hy- to optic nerve compression. q
pothesis does not explain the etiology of eye Financial statement: none declared.
signs in Hashimoto’s thyroiditis. An alternative Authorship statement: All authors agreed the
explanation for the ophthalmopathy in patients final version of the submitted manuscript.
with Hashimot thyroiditis is the presence of spe- Conflict of interests: none declared.
cific antibodies against eye muscle antigens such Patient consent obtained prior to the case
as calsequestrin, flavoprotein or G2s (13). We report study.
R#$#%#&'#*
1. Krassas GE, Wiersinga WM. Thyroid eye 1994;79:1234-1238. thyroiditis: a case report.
disease: current concepts and the 6. Valyasevi RW, Erickson DZ, Harteneck Pol Arch Med Wewn 2008;118: 318-321.
EUGOGO perspective. DA, et al. Differentiation of human orbital 10. Tomer Y. Unilateral ophthalmopathy in a
Thyroid International 2005;4:3-4. preadipocyte fibroblasts induces patient with Hashimoto’s thyroiditis.
2. Ponto KA, Binder H, Diana T, et al. expression of functional thyrotropin Thyroid 2000;10:99-100.
Prevalence, Phenotype, and Psychosocial receptor. J Clin Endocrinol Metab 11. Leo M, Menconi F, Rocchi R, et al. Role
Well-Being in Euthyroid/Hypothyroid 1999;84:2557-2562. of the underlying thyroid disease on the
Thyroid-Associated Orbitopathy. Thyroid 7. Tamai H, Kasagi K, Takaichi Y, et al. phenotype of Graves’ orbitopathy in a
2015;25:942-948. Development of spontaneous hypothy- tertiary referral center.
3. Cheuk W, Chan JK. IgG4-related roidism in patients with Graves’ disease Thyroid 2015;25:347-351.
Sclerosing Disease: A Critical Appraisal of treated with antithyroidal drugs: clinical, 12. Iyengar VS, Gosain V, Jagannatha K,
an Evolving Clinicopathologic Entity. immunological, and histological findings Ramegowda RB. Thyroid ophthalmopa-
Adv Anat Pathol 2010;17:303-332. in 26 patients. J Clin Endocrinol Metab thy in asymptomatic Hashimoto’s
4. Bartalena L, Wiersinga WM, Pinchera A. 1989;69:49-53. thyroiditis with hypothyroidism–An
Graves’ ophthalmopathy: state of the art 8. Kasagi K, Hidaka A, Nakamura H, et al. unusual presentation.
and perspectives. Thyrotropin receptor antibodies in J Assoc Physicians India 2016;64:101.
J Endocrinol Invest 2004;27:295-301. hypothyroid Graves’ disease. 13. Miller A, Arthurs B, Boucher A, et al.
5. Paschke R, Metcalfe A, Alcalde L, et al. J Clin Endocrinol Metab 1993;76:504-508. Significance of antibodies reactive with a
Presence of nonfunctional thyrotropin 9. Grzesiuk W, Szydlarska D, Pragacz A, 64 kDa eye muscle mem-brane antigen in
receptor variant transcripts in retroocular Bar-Andziak E. Thyroid-associated patients with thyroid autoimmunity.
and other tissues. J Clin Endocrinol Metab orbitopathy in patients with Hashimoto’s Thyroid 1992;2:197-202. .

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PEER REVIEWER TEAM
Peer reviewer team 2017

BABIUC Roxana Gastroenterology – Emergency University Hospital, Bucharest
BADILA Adrian Orthopedics – Emergency University Hospital, Bucharest
BADIU Catalin Vascular Surgery - Emergency University Hospital, Bucharest
BAJENARU Ovidiu Neurology – Emergency University Hospital, Bucharest
BERTEANU Mihai Medical Rehabilitation – Elias Emergency University Hospital, Bucharest
BOHILTEA Camil Genetics Department, “Carol Davila’ University of Medicine and Pharmacy, Bucharest
BOJINCA Violeta Reumatology – “Sf. Maria” Clinical Hospital, Bucharest
BOROS Cristian Anesthesia and Intensive Care – Emergency University Hospital, Bucharest
BUBENEK Serban Anesthesia and Intensive Care – “Prof. Dr. C.C. Iliescu” Cardiovascular Diseases Institute, Bucharest
BUMBACEA Dragos Pneumology – “Marius Nasta” Institute of Pneumophtisiology, Bucharest
CAPUSA Cristina Nephrology – “Carol Davila” Nephrology Clinical Hospital, Bucharest
CEAUSU Emanoil Infectious Diseases – “Dr. Victor Babes” Infectious and Tropical Diseases Hospital, Bucharest
CINTEZA Eliza Pediatrics – “Marie Curie” Emergency Children’s Hospital, Bucharest
CINTEZA Mircea Cardiology – Emergency University Hospital, Bucharest
CIOFU Carmen Pediatrics – “Alfred Rusescu” Institute for Mother and Child Health, Bucharest
CLATICI Victor Gabriel Dermatology – Elias Emergency University Hospital, Bucharest
CONDU Silvia Obstetrics and Gynecology – Emergency University Hospital, Bucharest
CONSTANTINESCU Tudor Pneumology – “Marius Nasta” Institute of Pneumophtisiology, Bucharest
CORLAN Alexandru Dan Statistics – Emergency University Hospital, Bucharest
CRISTEA Stefan Orthopedics – “Sf. Pantelimon” Emergency Clinical Hospital, Bucharest
DUICA Gabriela Obstetrics and Gynecology – “Marie Curie” Emergency Children’s Hospital, Bucharest
DRAGOI GALRINHO Ruxandra Cardiology – Emergency University Hospital, Bucharest
ENE Amalia Neurology – Emergency University Hospital, Bucharest
ENE Razvan Orthopedics and Traumatology - Emergency University Hospital, Bucharest
FILIMON-NEGREANU Ana Obstetrics and Gynecology – Emergency University Hospital, Bucharest
FLORESCU Maria Cardiology – Emergency University Hospital, Bucharest
GALOS Felicia Obstetrics and Gynecology – “Marie Curie” Emergency Children’s Hospital, Bucharest
GANGURA Gabriel Surgery – Emergency University Hospital, Bucharest
GHERGHICEANU Mihaela Infectious Diseases – “Dr. Victor Babes” Infectious and Tropical Diseases Hospital, Buchare
HORHOIANU Irina Obstetrics and Gynecology – Emergency University Hospital, Bucharest
IONESCU Gabriel Microbiology – “Dr. Ioan Cantacuzino” Clinical Hospital, Bucharest
JINGA Dan Oncology – Emergency University Hospital, Bucharest
JURCUT Ruxandra Cardiology – “Prof. Dr. C.C. Iliescu” Cardiovascular Diseases Institute, Bucharest
KLEIN Adriana Imagistics – Emergency University Hospital, Bucharest
LUPESCU Tudor Neurology – Emergency University Hospital, Bucharest
MAGDA Lucia Stefania Cardiology – Emergency University Hospital, Bucharest
MANDRUTA Ioana Neurology – Emergency University Hospital, Bucharest
MIHAILA Sorina Cardiology – Emergency University Hospital, Bucharest
MIHAI Vasile Neurology – Emergency University Hospital, Bucharest
MIRCESCU Gabriel Nephrology – “Dr. Carol Davila” Nephrology Hospital, Bucharest
MITROI Edi Orthopedics and Traumatology - Emergency University Hospital, Bucharest
MOLDOVAN Horatiu Cardiovascular Surgery – “Prof. Dr. C.C. Iliescu” Cardiovascular Diseases Institute, Bucharest
MURESIAN Horia Vascular Surgery - Emergency University Hospital, Bucharest
NASCUTIU Alexandra Microbiology – “Dr. Ioan Cantacuzino” Clinical Hospital, Bucharest
NEAGU Stefan Surgery – Emergency University Hospital, Bucharest
NEDELEA Florina Genetics – Filantropia Clinical Hospital, Bucharest
NEGREANU Lucian Gastroenterology - Emergency University Hospital, Bucharest
ONOSE Gelu Medical Rehabilitation – “Dr. Bagdasar Arseni” Clinical Hospital, Bucharest
PAVELIU Sorin Pharmacology – “Titu Maiorescu” University of Dental Medicine, Bucharest
PLAIASU Vasilica Genetics – “Alfred Rusescu” Institute for Mother and Child Health, Bucharest
POENARU Mircea Obstetrics and Gynecology – “Sf. Ioan” Emergency Clinical Hospital, Bucharest
POPA Gabriela Loredana Microbiology – “Carol Davila” University of Medicine and Pharmacy, Bucharest
POPA Liliana Gabriela Dermatology – Elias Emergency University Hospital, Bucharest
POPESCU Ileana Cardiology – Emergency University Hospital, Bucharest
RIMBAS Mihai Gastroenterology – Colentina Clinical Hospital, Bucharest
RIMBAS Roxana Cardiology – Emergency University Hospital, Bucharest
STOICESCU Claudiu Cardiology – Emergency University Hospital, Bucharest
SUCIU Victorita Medical Rehabilitation – Medical Rehabilitation National Institute, Bucharest
TOVARU Mihaela Dermatology – “Scarlat Longhin” Dermatology and Venerology Clinical Hospital, Bucharest
TRIFANESCU Raluca Endocrinology – “C.I. Parhon” Institute of Endocrinology, Bucharest
VASILE Dorina “Nicolae Kretzulescu” Medical Center, Bucharest
VASILE Danut Surgery - Emergency University Hospital, Bucharest
VINTILA Vlad Cardiology – Emergency University Hospital, Bucharest
VLADAREANU Radu Obstetrics and Gynecology – Elias Emergency University Hospital, Bucharest
ZAGREAN Leon Neurology - “Carol Davila” University of Medicine and Pharmacy, Bucharest
ZARNESCU Narcis Octavian Surgery - Emergency University Hospital, Bucharest

CME QUIZ
Maedica J Clin Med Medicine 2017;12(1)
MAEDICA - A JOURNAL OF CLINICAL MEDICINE

1. Antibodies are already used in the therapy of: c. The anterolateral ligament of the knee also has an
a. Cancer important role in controlling the anterolateral stability
b. Dyslipidemia of the knee
c. Myocardial ischemia d. The Lysholm score, Tegner score and Framingham
d. Rheumathoid arthritis score are used to evaluate knee stability
e. Eosinophilic asthma e. The rolimeter arthrometer is used to measure
differential anteroposterior laxity of the knee
2. In Romania, caesarian sections accounted for:
a. 11 % of total births in 1999 7. The following assertions regarding pre-eclampsia are
b. 15% of total births, as accounted by WHO, in 2004 true:
c. 30.4% of total births in 2010 a. Can be prevented by taking one of the new
d. 41.2% of total births in 2012 anticoagulants starting prior to the 16th week of
e. 70.3% of total births in 2015 pregnancy
b. Can be prevented by taking aspirin prior to the
3. The following assertions regarding placenta and 16th week of pregnancy
ombilical cord are true: c. Can be prevented by taking small doses of an ACEI
a. Stem cells can tansform into cardiac and nervous (angiotensin coverting enzyme inhibitor) drug during
cells the second and third trimesters of pregnancy
b. The first transplant appears when umbilical cord d. Can be prevented by taking small doses of a
pumps blood into the newborn hydrochlorothiazide during pregnancy
c. The placenta and umbilical cord can carry up to e. Contributes to the 10% maternal deaths due to
500 ml of blood hypertension in pregnancy
d. It is good to clamp the umbilical cord as early as
possible 8. The following skin disorders of the newborn have a
e. Neonatal affections induced by delayed benign evolution:
adaptation to extrauterine life include periventricular a. Acrocyanosis
leukomalacia and cerebral palsy b. Harlequin color change
c. Erythema toxicum neonatarum
4. The following assertions regarding hydatidosis are d. Transient neonatal pustular melanosis
true: e. Milia
a. In children, the most affected site of infection is
the lung 9. The following assertions regarding the cutaneous
b. In adults, the most affected organ is the liver reactions of new molecular target antineoplastic therapies
c. Multiple organ affection appears in more than are true:
50% of cases a. Patients who develop moderate to severe
d. The spleen is usually affected when the liver is cutaneous reactions have a bad response rate to
involved antineoplastic therapy
e. The water lilly sign is characteristic for hydatic cysts b. Gefitinib with intravenous administration may
produce xerosis
5. The following assertions regarding conditions related c. Stevens-Johnson syndrome may develop after
to appendicitis are true: anti-EGFR therapy
a. Appendicular neuralgia appears without an d. Preventive measures against skin rashes secondary
objective pathology to anti-EGFR therapy include reducing skin exposure
b. Mucinous cystadenoma is a neoplasm of the to either sun or water
appendix e. The therapy of skin rashes secondary to anti-GFR
c. Pseudomyxoma peritonei is asymptomatic in more therapy may include both antibiotics and prednisone
than half of the cases
d. Amyand’s hernia includes appendix in the hernial sac 10. The idiopathic nephrotic syndrome:
e. The tip of the appendix lying on the psoas muscle a. Represents more than 90% of nephrotic syndrome
may give pain which mimics appendicitis cases after the age of 10
b. May be precipitated by allergy to some types of
6. The following assertions regarding the reconstruction food
of knee ligaments are true: c. May be resistant to corticosteriods
a. Rotational instability may persist after isolated d. May be produced by a mutation in a gene
cruciate ligament reconstruction responsible for the final podocyte structure
b. The anterolateral ligament of the knee stabilizes e. May be produced by a lymphocyte B-cell
the tibial internal rotation dysfunction
Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017

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Dear readers,
Since 2006, when Mædica J Clin Med was initiated by Prof. Dr. Mircea Cinteza, the journal has been
constantly aiming at improving the quality of clinical practice in Romania by both its specialized
editorial content and the strong commitment of over 50 national and international reputed scientists
serving as its editorial board members, such as Prof. Dr. Mircea Cinteza (the editor-in-chief of
Mædica J Clin Med), Acad. Prof. Dr. Ioanel Sinescu – Rector of “Carol Davila” University of Medicine
and Pharmacy (UMF) in Bucharest, Prof. Dr. Dragos Vinereanu – Pro-Rector of “Carol Davila” UMF,
Prof. Dr. Mircea Beuran, Prof. Dr. Adrian Streinu-Cercel and many others.
Mædica J Clin Med appears four times a year, under the scientific auspices of the University of
Medicine and Pharmacy “Carol Davila” in Bucharest. It is accredited by the Romanian College of
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Under the Auspice of “Carol Davila” University of Medicine and Pharmacy, Bucharest Volume 12 (15) No.

Editor-in-Chief: Mircea Cinteza

Maedica JCM, 2017, 12: 20

STATE OF THE ART

ISSN 1841-9038 Publisher

Editor-in-chief Deputy Editors

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Publisher Editorial Assistant

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SUBSCRIPTIONS: abonamente@tarus.eu, contact@tarus.eu

Rikki SINGAL, Muzzafar ZAMAN, Unusual entities of appendix mimicking 23

Stefan MOGOS, Bogdan SENDREA, Combined anatomic anterior cruciate ligament 30

Dana Lucia STANCULEANU, Cutaneous toxicities of molecular targeted 48

Elena Camelia BERGHEA, Correlation between idiopathic nephrotic 55

Marilena SPIRIDON, Chronic venous insufficiency: a frequently 59

Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017 1

Deepak JAIN, Sudhir MOR, Thyroid association ophtalmopathy in Hashimoto’s 65

Instructions for authors 68

2 Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017

E DITORIAL P OINT OF V IEW

The Antibodies: What a Universe!

In the initial group of patients treated aggressive-

Address for correspondence:

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4 Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017

Caesarean Birth in Romania:

INTRODUCTION was promulgated, outlawing abortion and use of

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FIGURE 3. Live-births in Romania by assistance at

public and private units) as it provides Level III

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12 Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017

The Mirage of Long Term Vital

Address for correspondence:

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– the principle of beneficence, or the ob-

T he study analyzed the infants whose stem

I n all cases with stem cells harvested, the um-

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CONCLUSION The harvesting was done predominantly at

H arvesting stem cells is a common practice in

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Concomitant Lung and Liver

INTRODUCTION Isolated hydatid disease of the spleen is very ex-

Maedica A Journal of Clinical Medicine, Volume 12 No.1 2017 19

gan hydatidosis is much less common, as few

MATERIAL AND METHODS

T his study was carried out in the Department

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H ydatid disease has been known since the

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Unusual Entities of Appendix

Address for correspondence:

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