oman medical journal
Volume 30 | Issue 1 | January 2015
www.omjournal.org
Indexed in SCOPUS and listed in PubMed Central
Editorial
- Stem Cell Research and Ethics: An Update
Review
- Excessive Daytime Sleepiness and Unintended Sleep Episodes Associated with
Parkinson’s Disease
Original articles
- Quality of Diabetes Care at Outpatient Clinic, Sultan Qaboos University Hospital
- The Relationship between Body Mass Index and Periodontitis in Arab Patients
with Type 2 Diabetes Mellitus
ISSN: 1999-768X (print); 2070-5204 (electronic)
Oman Medical Journal
Indexed and listed in PubMed, Scopus, Index Medicus for the Eastern Mediterranean Region,
SCImago Journal & Country Rank
E D I TO R I A L B OA R D
•
editor-in-chief
Dr. Ibrahim Al-Zakwani
• associate editor
• statistics editor
Dr. Asya Al-Riyami
Dr. Ahmed Al-Qasmi
Dr. Medhat Kamal El-Sayed
• editorial board members
Dr. Abdulaziz Al-Mahrezi
Dr. Abdulhakeem Al-Rawahi
Dr. Abdullah Al-Mujaini
Dr. Abdullah Al-Maniri
Dr. Adhra Al-Mawali
Dr. Amna Al-Futaisi
Dr. Khalid Al-Rasadi
Dr. Kurien Thomas
Prof. Mahmoud El-Aty
Dr. Murtadha Al-Khabori
Prof. Neela Al-Lamki
Dr. Nihal Al-Riyami
Dr. Raad Al-Mehdi
Dr. Rashid Al-Abri
Dr. Reem Abdwani
Dr. Saif Al-Yaarubi
Dr. Waad-Allah Mula-Abed
Prof. Yasser Wali
Editorial Assistants
Ms. Bishara Al-Mahruqi
Mrs. Jenny Manoguid
Mrs. Charie Ricafort
Ms. Rabha Al-Abdulsalaam
Mrs. Iman Al-Busaidi
Technical Editor/Web Designer
Mr. Amir Hussain
• editorial office
Medical Editor
Dr. Ayshe Ismail
international advisory board members
Prof. A G Pusalkar, Lilaviti Hospital, India
Prof. Kichu Nair, University of South Wales, United Kingdom
Prof. Gordon Ferns, University of Surrey, United Kingdom
Dr. Thomas Harle, Wake Forest University Medical School, United States
Dr. Kenneth Mattox, Baylor College of Medicine, United States
Dr. Celia Rodd, McGill University, Canada
Dr. Helen Batty, University of Toronto, Canada
Dr. Bassem Saab, American University of Beirut Medical Center, Lebanon
Prof. Walter Rosser, Queens University, Canada
Dr. Mary-Ann Fitzcharles, McGill University, Canada
Dr. Michael Shevell, McGill University, Canada
Dr. Khalid Al-Jabri, Al Mufraq Hospital, United Arab Emirates
Professor Dirk Deleu, Weil Cornell Medical College, Qatar
Dr. Murtada Shabrawi, Cairo University, Egypt
Dr. Mahfooz Farooqi, National Guard Hospital, Saudi Arabia
Dr. Amy Young, Baylor College of Medicine, United States
Dr. Mustafa Afifi, Ministry of Health, United Arab Emirates
Prof. Thomas Walsh, Yale University, United States
Prof. Dimitri Mikhailidis, University College London, United Kingdom
© copyright
All articles published represent the opinions of the authors and do not reflect official policy of the journal. All rights are reserved to
Oman Medical Journal. No part of the journal may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or via any storage or retrieval system, without written permission from the journal.
issn: 1999-768X (print); issn: 2070-5204 (electronic)
CONTENTS
VOLUME 30, ISSUE 1, JANUARY 2015
cas e r eport s editor ia l
Stem Cell Research and Ethics: An Update
1
Ayshe Ismail
Hughes-Stovin Syndrome and Massive
Hemoptysis: A Management Challenge
3
Extrahepatic Biliary Cystadenoma: A Rare
Cause of Biliary Obstruction
11
17
26
31
36
42
Asma Al-Shidhani, Samia Al-Rashdi, Hamdan Al-Habsi
and Syed Rizvi
Sawsan Al-Sinani, Ali Al-Mamari, Nicolas Woodhouse,
Omaiyma Al-Shafie, Fatima Amar, Mohammed AlShafaee, Mohammed Hassan and Riad Bayoumi
Localized Acral Hypertrophy
70
l et t er to edi tor Allergic Rhinitis in Oman and Malaysia: The
Similarities and Differences
72
Irfan Mohamad and Ramiza Ramli
Manal Awad, Betul Rahman, Haidar Hasan and
Houssam Ali
Quality of Diabetes Care at Outpatient
Clinic, Sultan Qaboos University Hospital
c l i n ica l q u i z Saifullah Khalid, Samreen Zaheer, Sabarish
Narayanasamy, Faisal Jamal, Mohd Faizan and Tausif
Ahmad
Mohammed Al-Abri, Abdullah Al-Asmi, Aisha
Al-Shukairi, Arwa Al-Qanoobi, Nandhagopal
Rmachandiran, Povothoor Jacob and Arunodaya Gujjar
Impact of Acne on Quality of Life of
Students at Sultan Qaboos University
69
Abdulrasheed Ibrahim and Sunday Ajike
Asim Al-Balushi, Hamood Al-Kindi, Hamood Al-Shuaili,
Suresh Kumar and Salim Al-Maskari
The Relationship between Body Mass Index
and Periodontitis in Arab Patients with Type
2 Diabetes Mellitus
66
on l i n e cas e r eport
Congenital Symmetrical Lower Lip Pits:
Van der Woude Syndrome
Catherine Norrish, Mark Norrish, Uwe Fass, Majid
Al-Salmani, Ganji Shiva Lingam, Fiona Clark and
Hebal Kallesh
Frequency of Obstructive Sleep Apnea
Syndrome Among Patients with Epilepsy
Attending a Tertiary Neurology Clinic
63
Adli Metussin, Pemasari Telisinghe, Kenneth Kok and
Vui Chong
Mojgan Rahmanian, Mehri Leysi, AliAkbar Hemmati,
and Majid Mirmohammadkhani
Adolescents and Adults with Congenital
Heart Diseases in Oman
Post-aural Nodular Fasciitis
Mohammed Al-Rahbi, Hunaina Al-Kindi and Salma
Al-Sheibani
or igi na l a rt icl e s
The Cystic Fibrosis Symptom Progression
Survey (CF-SPS) in Arabic: A Tool for
Monitoring Patients’ Symptoms
59
Khalfan Al-Zeedy, B. Jayakrishnan, Dawar Rizavi and
Juma Al-Kaabi
Fatai Salawu and Abdulfatai Olokoba
The Effect of Low-Dose Intravenous
Ketamine on Postoperative Pain Following
Cesarean Section with Spinal Anesthesia:
A Randomized Clinical Trial
55
Wael Abuzeid, Hatim Al-Lawati and Neil Fam
r e v i ew art icl e
Excessive Daytime Sleepiness and
Unintended Sleep Episodes Associated with
Parkinson’s Disease
Acute Myocardial Infarction after Switching
from Warfarin to Dabigatran
48
Instructions to authors73
Oman Medical Journal
Listed and indexed in PubMed Central
Oman Medical Journal is an open access international journal, which intends to engage
and inform doctors, researchers and other health professionals by publishing a wide range of
peer-reviewed articles. The journal is published bi-monthly by the Oman Medical Specialty
Board. It is distributed free to all medical doctors and allied health professionals in various
institutions locally and internationally.
Edito
ria
ls
w
vie es
Reticl
ar
Clin
noteical
s
to
ter
r
t
o
Leedit
Submit your
Manuscript
icasl
n
i
e
Cluizz
q
Or
ar igin
t
i
c
leas l
se
Caorts
p
re
com Bri
m
u
n
icaef
t
i
o
ns
submit your manuscript at www.omjournal.org
For more information please contact:
Oman Medical Journal, Oman Medical Specialty Board, Way #9993, Block 3,
Al-Khoudh, Seeb, Muscat, Sultanate of Oman
 (+968) 2418 1050/1082/1186;  omj@omsb.org;  http://www.omjournal.org/
editorial
Oman Medical Journal [2015], Vol. 30, No. 1: 1–2
Stem Cell Research and Ethics: An Update
Ayshe Ismail
Oman Medical Journal, Oman Medical Specialty Board, Muscat, Oman
A RT I C L E I N F O
Article history:
Received: 6 January 2015
Accepted: 22 January 2015
Online:
DOI 10.5001/omj.2015.01
S
tem cell therapies are not new. Bone marrow
stem cell transplants have been performed
for decades with much of the general public
unaware that this is, in fact, a stem cell therapy.
While the use of adult-derived stem cells and
storage of cord blood has caused little debate, it is
only since 19981 when researchers first learnt how
to remove stem cells from human embryos that
controversy has ensued.
Embryonic stem (ES) cells, being pluripotent,
have the potential to form all types of cells, and,
therefore, have a huge potential in curing human
disease. Research using human ES cells could help
to better understand early human development, be
used to research possible toxic effects of drugs (drugscreening) and, most importantly, be used in the
field of regenerative medicine in the development of
cell replacement therapies. However, both political
and religious leaders have discussed the moral
implications of destroying human embryos.
In 2001 in the US there was a restriction on
funding for ES cell research by President George
Bush. President Bush stated that federal funds could
only be used for research on human embryonic stem
cell lines that had already been established, preventing
researchers from creating more. However, this did not
inhibit researchers receiving private funding. President
Barack Obama went on to lift the ban in 2009.
At the core of the ES cell issue is the question:
when does life begin?2 This question closely links
to debates over abortion and with the “pro-life”
movement. However, even this debate is not uniform
as while some oppose abortion and the use of human
ES cells, others oppose abortion but support stem
cell research using frozen embryos that remain
after a woman or couple has completed infertility
treatment, citing the “lesser of two evils” argument.
The debate about stem cells is also a religious
one. As Rana Dajani3 explained in her editorial,
*Corresponding author:  ayshe.i@omsb.org
discussions in Jordan concluded that stem-cell
research is permissible in Islam providing it is carried
out to improve human health, since Muslim scholars
consider life to start 40–120 days after conception.
Denominations of the Christian faith, including
Roman Catholics and Orthodox Christians, believe
that the embryo has a status of a human individual
from conception and therefore any decisions/
interventions not in favor of the embryo violates
the right of the embryo to life.4 Understandably,
such conclusions are not easy to reach, and such
theological debate is beyond the scope of this article.
As a result of the discussions in Jordan, in January
2014 the country passed a law to control research and
therapy using human ES cells. The regulation was
the first in the Arab and Islamic region. It highlights
the recognition that Jordan has for the potential of
stem cell therapy and provides a framework for other
countries in the region to follow. The law specifically
bans private companies from using human ES cells,
limiting research or therapies to government, and
publically funded organizations/institutions, which
have higher levels of transparency and are supervised
by the health ministry and a specialized committee.
Although there is no published record of ES cell
research in Oman, stem cell transplantation (bone
marrow, peripheral blood, and cord blood) has been
carried out at Sultan Qaboos University Hospital
(SQUH) since 1995.5 More recently, researchers
at SQUH established the first national voluntary
cord blood bank in the country. This caters for
parents who have a child with a disorder that would
normally be cured by bone marrow transplantation
and who wanted their newborn baby’s cord blood
to be collected and processed for a possible matched
related transplant for their offspring.5
Adult-derived stem cell sources are also available.
Adult stem cells are multipotent, meaning that they
are capable of producing multiple (but not all)
2
Ayshe Ism ail
cell types. These are found in a variety of tissues,
including the fetus. Initially researchers believed
that adult stem cells could only form the cell types
of the organ from which they were derived, but the
cells have shown more versatility than this.6,7
The first transplanted human organ grown
from adult stem cells was performed in 2008 by
researchers from the University of Padua, the
University of Bristol, and Politecnico di Milano.8
They harvested a section of trachea from a donor
and stripped it of all cells, leaving a cartilage scaffold
which was seeded with stem cells taken from the
recipient patient’s bone marrow. The new section
of trachea was then grown in the laboratory over
four days and transplanted into the patient. Four
months later their research, which was published
in The Lancet, reported that the patient’s immune
system showed no signs of rejection.
Other breakthroughs, such as the ability to
induce pluripotency in adult cells (iPS cells) may
bring the debate over ES cells to an end. However,
it will not remove the ethical concerns over the use
of human ES cells. iPS cells are not exactly the same
as human ES cells, which will be needed to act as
the control for measuring the “stemness” of other
cells.9 As yet, the cells that will be the most useful for
cell replacement therapies has not been determined,
which warrants the study of all stem cell types.
An additional ethical consideration is that iPS
cells have the potential to develop into a human
embryo, in effect producing a clone of the donor.
However, many nations are already prepared for this,
having legislation in place that bans human cloning
for various purposes, although there is no consensus
around the world on these policies.10
r ef er ences
1. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield
JW, Donovan PJ, et al. Derivation of pluripotent stem cells
from cultured human primordial germ cells. Proc Natl Acad
Sci U S A 1998 Nov;95(23):13726-13731.
2. de Wert G, Mummery C. Human embryonic stem
cells: research, ethics and policy. Hum Reprod 2003
Apr;18(4):672-682.
3. Dajani R. Jordan’s stem-cell law can guide the Middle East.
Nature 2014 Jun;510(7504):189.
4. Origins, ethics and embryos: the sources of human
embryonic stem cells. From eurostemcell.org. Accessed
January 2015.
5. Alkindi S, Dennison D. Umbilical Cord Blood Banking
and Transplantation: A short review. Sultan Qaboos Univ
Med J 2011 Nov;11(4):455-461.
6. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas
R, Mosca JD, et al. Multilineage potential of adult
human mesenchymal stem cells. Science 1999 Apr;284
(5411):143-147.
7. Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E,
Karlström H, et al. Generalized potential of adult neural
stem cells. Science 2000 Jun;288(5471):1660-1663.
8. University of Bristol. “Adult Stem Cell Breakthrough: First
Tissue-engineered Trachea Successfully Transplanted.”
ScienceDaily. ScienceDaily, 19 November 2008. <www.
sciencedaily.com/releases/2008/11/081119092939.htm>.
9. The Stem Cell Debate: Is It Over? From learn.genetics.utah.
edu. Accessed January 2015.
10. Pattinson SD, Caulfield T. Variations and voids: the
regulation of human cloning around the world. BMC Med
Ethics 2004 Dec;5:E9.
review article
Oman Medical Journal [2015], Vol. 30, No. 1: 3–10
Excessive Daytime Sleepiness and Unintended
Sleep Episodes Associated with Parkinson’s Disease
Fatai Salawu1* and Abdulfatai Olokoba2
Department of Medicine, Federal Medical Centre, Yola, Nigeria
Department of General Internal Medicine, University of Ilorin Teaching Hospital, Ilorin. Nigeria
1
2
A RT I C L E I N F O
Article history:
Received: 31 December 2012
Accepted: 7 December 2014
Online:
DOI 10.5001/omj.2015.02
Keywords:
Parkinson Disease; Sleep;
Dopamine Agonists;
Pedunculopontine Nucleus.
A B S T R AC T
This article looks at the issues of excessive daytime sleepiness and unintended sleep
episodes in patients with Parkinson’s disease (PD) and explores the reasons why patients
might suffer from these symptoms, and what steps could be taken to manage them. During
the last decade, understanding of sleep/wake regulation has increased. Several brainstem
nuclei and their communication pathways in the ascending arousing system through the
hypothalamus and thalamus to the cortex play key roles in sleep disorders. Insomnia is
the most common sleep disorder in PD patients, and excessive daytime sleepiness is also
common. Excessive daytime sleepiness affects up to 50% of PD patients and a growing
body of research has established this sleep disturbance as a marker of preclinical and
premotor PD. It is a frequent and highly persistent feature in PD, with multifactorial
underlying pathophysiology. Both age and disease-related disturbances of sleep-wake
regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also
contribute to excessive daytime sleepiness. Effective management of sleep disturbances and
excessive daytime sleepiness can greatly improve the quality of life for patients with PD.
S
leep disturbances in the late stages of
Parkinson’s disease (PD) were recognized by
James Parkinson1 in his classic monograph
noting that: “The sleep becomes much
disturbed. The tremulous motions of the limbs
occur during sleep, and augment until they awaken
the patient, and frequently with much agitation
and alarm…..and at the last, constant sleepiness,
with slight delirium”. The diagnosis of PD requires
the identification of its cardinal features, which are
motor symptoms. Diagnosis is impossible without
them, but recognition of the importance of nonmotor features has increased over the past years.2
Non-motor features (which include autonomic
nervous system dysfunction, disorders of cognition
and mood, psychosis, pain, loss of smell, and
fatigue) affect nearly all PD patients, appear early
in the course of PD, and contribute to excessive
daytime sleepiness (EDS). All of these symptoms
have significant adverse effects on the quality of life
(QoL) of both patients and caregivers and require
proper identification and treatment.3-7
Clinical presentation of sleep disturbance
Sleep-related problems in PD can be divided
into disturbances of sleep and disturbances of
wakefulness. Disturbances of sleep include insomnia,
*Corresponding author:  dr_abdulsalawu@yahoo.com
restless leg syndrome (RLS), rapid eye movement
sleep behavior disorder (RBD), sleep apnea, and
parasomnias. Disturbances of wakefulness include
EDS, and sleep attacks. With normal aging, there
is disruption of normal sleep architecture and
alterations in the normal circadian rhythm leading to
impaired nocturnal sleep and EDS.8,9 These problems
are accentuated in PD patients, with 60% to 90%
having some form of sleep disturbance, particularly
in the advanced stages of the disease.3,6,10-12
Epidemiology of sleep disturbance in
Parkison’s disease
The prevalence of sleep disturbance in PD is difficult
to ascertain due to the heterogeneity of patients and
different criteria used to categorize sleep disturbances.
There is paucity of data on the role of gender in sleep
disturbances. Smith and colleagues,13 studied 153
patients and their spouses, and reported that sleep
disturbances occurred more frequently in females
with PD (41%) than in men (25%). However, there
was no sex difference for difficulty initiating sleep.
Van Hilten and colleagues,14 observed that female
patients experienced more difficulty maintaining
sleep (87.5%) and excessive dreaming (68.4%)
than males (64% and 31.6%, respectively). Sleep
dysfunction in PD usually manifests by difficulty
4
Fatai Sal awu, et al.
in initiating sleep, fragmented sleep, reversal of the
sleep cycle, and EDS.15,16 EDS was assessed using
the Epworth scale in 101 patients with PD and 100
age-matched controls.17 EDS was detected in 76%
of patients with PD compared to 47% of controls
(p<0.050). Nearly a quarter (24%) of patients with
PD had scores in the diagnostic range of narcolepsy,
compared to only 5% of controls (p<0.001).
Sleep disturbances in PD are numerous and there
may be different combinations.6,14,18-23 The cause of the
disturbances are multifactorial and may be related to
aging, Parkinsonian motor dysfunction, dyskinesia,
pain, nocturia, nightmares, dopaminergic and nondopaminergic medications, cognitive impairment,
and a variety of specific sleep disorders, including
RLS, periodic limb movements of sleep (PLMS),
RBD, and sleep apnea. Collectively, they contribute
to the increase in daytime sleepiness frequently
found in PD patients.24 EDS and RBD may be
harbingers of PD and other synucleinopathies,
such as multiple system atrophy,25 and thus already
present in the premotor phase of the disease. It
is also clear that dopaminergic medications and
particularly dopamine agonists can have a complex
effect on sleep. Sometimes these medications
cause insomnia, and their sedative properties may
contribute to daytime sleepiness.17,26-30 In other
situations, they improve the quality of sleep by
improving nocturnal immobility. 31,32Therefore,
dopaminergic medications can either improve or
worsen sleep in PD patients.
Neuroanatomy of sleep in Parkinson’s
disease
The anatomical basis of sleep disturbances in
PD is not fully understood, but it likely involves
degeneration of both dopaminergic and nondopaminergic systems. Sleep disturbances are
primarily due to the progressive disease process
impairing thalamocortical arousal and affecting
sleep-regulating centers in the brainstem. Secondary
causes are nocturnal disease manifestations,
and side effects of pharmacological treatment.
Mesocorticolimbic dopamine neurons that project
from the ventral tegmental area (VTA) targeting
the thalamus, hippocampus, and cerebral cortex are
thought to be involved in the arousal mechanism.33
Dopamine plays a complex role in state control,
specifically maintains the wake state, and regulates
sleep homeostasis. 34 These dopamine-mediated
arousal functions are independent from the
nigrostriatal dopaminergic system. Subsequently,
the responsible mesolimbic dopaminergic
system may also degenerate later than the
nigrostriatal system.34
Aetiology of sleep disturbance in Parkinson’s
disease
Non-dopaminergic neurons have also been
implicated in sleep dysfunction in PD. Reduced
levels of hypocretin in the cerebrospinal fluid are
an established biomarker in narcolepsy, and PD
patients show narcolepsy-like sudden onset sleeps
during the daytime, suggesting similar hypocretin
action in these patients. Braak and his colleagues35
hypothesis of ascending brainstem degeneration
proposes early disease involvement of several
other non-dopaminergic brainstem nuclei, such
as the cholinergic pedunculopontine nucleus
(PPN), serotonergic tegmental area, nucleus
magnocellularis, and noradrenergic locus cereleus
(LC). Degeneration of neurons in these sleep-wake
related pathways (the flip-flop switch), which are
associated with thalamocortical arousal, could
contribute to the development of sleep dysfunction
in PD.36 The PPN has attracted particular attention
because it is intimately related to the anatomic
control of sleep, and is thought to play a critical
role in mediating inhibition of voluntary muscles
during REM.16,37 This hypothesis has propelled
our understanding of sleep dysfunction in PD.
Interestingly, direct evidence of a beneficial effect
of a normally functioning PPN has been given by
deep brain stimulation of this nucleus, confirming
that PPN promotes REM sleep and plays a role
in switching from one state to another. Thus,
low-frequency stimulation of the PPN increases
alertness and high-frequency stimulation induces
non-rapid eye movement sleep (NREM) sleep,
while sudden withdrawal of the stimulation
elucidates REM sleep.38-40
Excessive daytime sleepiness
EDS is defined as a chronic state of inability to stay
awake during the day. A score greater than 10 on
the Epworth Sleepiness Scale (ESS), or a mean sleep
latency less than eight minutes on the Multiple
Sleep Latency Test (MSLT) 30,41,42 is considered
inappropriate sleepiness during waking hours and
has been under-recognized in PD. EDS was initially
5
Fatai Sal awu, et al.
considered a side effect of non-ergot dopamine D2D3 agonists,43 but it is not restricted to a specific class
of dopaminomimetic agents and may have other
causes. Because of the many potential problems that
can interfere with nocturnal sleep in patients with
PD and the tendency of dopaminergic medications
to induce sedation, EDS is a common problem.44,45
Epidemiology
One study found no increase in the prevalence
of EDS in untreated PD patients compared with
an age-matched healthy control group. EDS was
more frequent in treated patients, suggesting that
either the progression of the disease, the treatment,
or a combination of both, may be critical in the
development of this symptom.46 Another study
found that progression of the disease, before
initiation of dopaminergic treatment, was associated
with increased sleepiness. 47 Polysomnographic
recordings indicate that the average patient with PD
obtains only four to five hours of documented sleep
per night instead of the approximately eight hours
that are normally required.19,48 In one study, 76% of
consecutive PD patients reported EDS, compared
with 47% of age-matched controls (p<0.050)
and 24% had sleep scores in the range of patients
with narcolepsy, compared to only 5% of controls
(p<0.001).17 EDS is common in PD,6,14 however, it
is a multifaceted phenomenon not solely related to
dopaminergic medication. Next to dopaminergics,
disease severity, “wearing-off ”, and sleep
disordered breathing have been shown to influence
PD-related EDS.41
Putative biological markers
The notion of PD-related EDS is supported by the
fact that magnetic resonance imaging (MRI) brain
morphometry demonstrated that in PD patients
EDS was related to atrophy of the medial cerebellar
peduncle (PD with EDS (mean+SD) 16.08+0.93mm
vs. PD without EDS 17.82+0.80mm; p=0.010),
leading the authors to suggest the involvement of
degeneration of the pontomedullary respiratory
centers in the development of PD-linked EDS.49 In
one study,14 no significant difference was found in
the degeneration of the pontomedullary respiratory
centers between PD patients (44.4%) and control
patients (31%). The diurnal pattern was similar
with a peak in the early afternoon. The authors
concluded that no relationship existed between PD
and EDS, and that EDS was probably a consequence
of aging, as reported previously by Carskadon50
and Morewitz.51 EDS was noted in patients with
Parkinsonian syndromes in early descriptions52 and
spontaneous dozing during the daytime occurred in
nearly half of PD patients in one study.6 However,
EDS has only received increasing attention since the
controversially discussed report of “sleep attacks” in
PD patients on dopaminergic therapy. These case
reports first involved patients taking non-ergoline
dopamine agonists 43 and were subsequently
supplemented by case reports for virtually all other
dopamine agonists and levodopa.
Clinical presentation
Patients with EDS have a tendency to fall asleep
in unintended situations. Typically, these occur in
relatively benign situations that are conducive to
falling asleep such as while watching television or
reading. However, in extreme situations patients
may fall asleep during a meal, while in conversation,
and in potentially dangerous situations such as while
driving. Previous studies reported sleepiness with
varying frequencies (42%14 and 49%6).
Diagnostic tools
To identify sleepiness in an individual patient, it
may be necessary to use sleep questionnaires such as
the Epworth Sleepiness Scale (ESS),5 which do not
rely on subjective estimates of sleepiness, but rather
on a measure of the propensity of the patient to fall
asleep. The ESS is a set of eight questions, quick and
easy to use for the patient and carer, and does not
require technical measurements or the involvement
of a sleep laboratory. The ESS has been shown to
correlate with more cumbersome, expensive, and
time-consuming tests such as the Multiple Sleep
Latency Test (MSLT) in patients with sleep apnea.5
It is the sum of eight items that ask for ratings on
the tendency to doze in a variety of situations. The
ratings are scaled from zero (no chance of dozing) to
three (high chance of dozing) for each item. Higher
scores indicate greater sleepiness as indicated by
a higher likelihood to fall asleep during daytime
activities. The ESS has been translated into different
languages throughout the world. A validated
Arabic ESS questionnaire was just as good as
its English counterpart.53
The importance of addressing EDS in PD
was highlighted by a report of eight patients who
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
6
Fatai Sal awu, et al.
suddenly fell asleep while driving a motor vehicle.43
These episodes were termed “sleep attacks” by the
author because they seemed to have occurred without
warning, and were attributed to dopamine agonists
because they disappeared when the drugs were
withdrawn. This report generated intense interest
in the nature and frequency of sleep disturbances in
PD and a debate as to how these episodes are related
to the use of dopamine agonists. It is generally
thought that EDS in PD patients results from
impaired nocturnal sleep. However, not all studies
confirm this concept. The FAST TRACK study
evaluated daytime sleepiness using the MSLT. In 27
PD patients, the MSLT scores did not correlate with
the quantity and quality of the previous night’s sleep
or other sleep architecture measures, such as sleep
stage percentage, and total sleep time.54 Similarly,
in another study, no correlation was found between
MSLT score and total sleep time, sleep efficiency,
arousal index, apnea-hypopnea, or periodic leg
movement indices.55 These studies suggest that
the quality of nighttime sleep may not be the only
factor responsible for daytime sleepiness. Whatever
the mechanism, EDS (defined as being sleepy most
of the day) is present in a large number of PD
patients. Varying estimates have been reported,
ranging from 15% to 75%.17,56-63 The most widely
used tools are the ESS, MSLT, Scales for Outcomes
in PD (SCOPA-SLEEP), Parkinson’s Disease Sleep
Scale (PDSS), and Polysomnography (PSG). The
possibility that dopaminergic medications, and
especially dopamine agonists, may aggravate EDS
has attracted considerable attention, again driven by
the observation by Frucht and colleagues43 that all
patients who fell asleep while driving were receiving
high doses of dopamine agonists. PSG studies have
similarly demonstrated that total dopaminergic
dose, rather than the specific dopaminergic agent,
was the best predictor of EDS, as MSLT scores of
patients on different dopaminergic therapies were
similar to one another.55 EDS may occur with
use of other PD medications, including levodopa
and carbidopa. Seventy percent of dysautonomic
patients with PD reported sleep attacks compared
to 17.8% of nondysautonomic patients with PD.29
Sleep attacks (unintended sleep episodes)
A sleep attack is described as “an event of
overwhelming sleepiness that occurs without
warning or with a prodrome that is sufficiently short
or overpowered to prevent the patient from taking
appropriate protective measure”.43 Others have
suggested that sleep attacks in PD patients are more
likely to represent an extreme form of EDS due to the
combination of a sleep disturbance and the sedative
effects of dopaminergic medication.28 Sleep attacks
in which patients fall asleep without an antecedent
warning of sleepiness are not known to occur either
physiologically or in association with pathologic
conditions.5 For this reason, the concept of a sleep
attack has been abandoned even in narcolepsy.64
It was proposed that sleep attacks represent an
extreme form of sedation in patients who were
sleep deprived and on sedative medications, and
would be better termed unintended sleep episodes
(USE). The term sleep attack re-emerged in 1999
when Frucht et al,43 described sudden episodes of
falling asleep that caused driving accidents. Some
experts have suggested that the term USE is a more
appropriate description of these events, arguing that
the word “attack” fails to recognize the background
of sedation that may precede the onset of sleep.28,65
Patients experiencing sleep attacks may fall asleep
because they are continuously sleepy, and fall asleep
in situations where resistance to sleep is decreased.66
The concept of a sleep attack implies that the events
are inevitable and occur without any warning
whatsoever. The notion of USE implies that atrisk individuals can be identified and the episodes
prevented by instituting appropriate treatment
measures. Prodromes of sleepiness include yawning,
blinking, or tearing.
Prevalence and risk factors
A prospective survey of 236 patients with PD found
that 72 (30.5%) reported sudden sleep episodes.29
Another study, which used structured telephone
interviews in 2,952 patients with PD, found that
177 patients (6%) had sleep attacks.67 Ninetyone patients had at least one sleep attack without
a warning sign, while 86 patients always had a
warning sign prior to a sleep attack. Although sleep
attacks were initially described in patients receiving
pramipexole and ropinirole, it is clear that sedative
effects and USE can be seen with any dopaminergic
agents, including levodopa, 68-71 and that these
effects are dose related, occurring with greater
frequency in patients taking relatively high doses.
Thus, somnolence is more likely to occur in patients
taking higher doses of dopaminergic medications
7
Fatai Sal awu, et al.
and is greatest when a given dose reaches its
maximal concentration. The package insert for
pramipexole in the US recommends that patients
must be informed that they should not drive a
vehicle or engage in potentially dangerous activities
until they have enough experience to determine
whether pramipexole adversely affects their mental
performance.72 Sleep experts have criticized the term
sleep attacks saying it is inappropriate as sleepiness is
not adequately perceived, specifically in chronically
sleepy patients, and electrophysiological signs of
sleepiness precede sleep onset even in patients who
are not aware of it.73,74 This was confirmed when 47
somnolent PD patients underwent MSLT, and after
each nap they were asked whether they had slept
or dozed. Thirty-eight percent of the PD patients
did not perceive at least one PSG-confirmed nap.
These patients also showed a lower score on the
subjective ESS. However, sleep-state misperception
was no more frequent than in control subjects who
had other hypersomnias or sleep apnoea.75 These
findings demonstrate that sleep misperception is
a factum in PD patients as it is in individuals with
chronic sleepiness due to other conditions.73
Management approaches
Recent years have seen several disappointments in
neuroprotective therapy and it remains an important
challenge to understand why very promising drugs
have failed in human trials. Overall, sleep problems
in PD remain a major therapeutic challenge.
Management of PD is complex, has to target
underlying mechanisms, and comprises of nonpharmacological and pharmacological approaches.
The first step is to identify at-risk patients.76
To accomplish this, the physician or ancillary
personnel must inquire about EDS from both
the patient and carer, who might provide a more
objective assessment of the patient’s sleep habits
as patients may not recognize that they are sleepy
having become tolerant to the sensation of chronic
tiredness. Therefore, management options for EDS
and unintended sleep episodes include ensuring
correct diagnosis by ruling out syncope, seizures,
and cardiac disorder.
Non-pharmacological approaches can be the
mainstay of treatment for mild to moderate EDS. As
described, the use of a validated sleepiness scale, such
as the ESS, provides a quick and reliable assessment
of sleepiness based on the propensity of the patient
to fall asleep in unintended situations, and does
not rely on the patient’s subjective awareness of
whether or not they are sleepy. ESS scores greater
than 10 are considered to be in the sleepy range,
and such patients are at higher risk for experiencing
unintended episodes of falling asleep.76 Further
management options include introducing proper
sleep hygiene, eliminating unnecessary sedative
medications, using the lowest dose of dopaminergic
medication that provides satisfactory clinical
control, identifying and treating sleep disorders, and
counselling patients on risks of daytime sleepiness
and sudden sleep episodes.75 Patients with EDS
should not drive a motor vehicle until this problem
has been corrected. Indeed, European agencies have
suggested that patients with PD taking dopamine
agonists should not drive at all, although some
experts believe that this recommendation is too
harsh and that patients may safely drive, subject
to specific treatment guidelines. PSG is the “gold
standard” method used to evaluate sleep disorders
and provides detailed information about actual
sleep status. It can detect the co-occurrence of sleep
apnea, restless leg syndrome-periodic leg movement
in sleep (RLS-PLMS), and RBD. MSLT is helpful
to quantify the severity of EDS. Good sleep hygiene
is the cornerstone of effective management of any
sleep disorder.
The management of Parkinsonian motor
symptoms can be improved with the use of
dopaminergic agents. If alterations in dopaminergic
medications fail to help EDS, one can consider
adding a wakefulness promoting agent like
modafinil. Usually, mechanisms are multiple
and treatment multimodal. Modafinil is a nonamphetamine drug well-established as a first-line,
symptomatic treatment for EDS associated with
narcolepsy and, more recently, is proving to be a
useful agent in other medical conditions where
EDS is a symptom. Whilst its mode of action is
yet to be explained, modafinil appears to exert its
effects specifically on the hypothalamus sleep-wake
system, increasing wake promoting neuronal activity
in the tuberomammillary nucleus (TMN) and
decreasing sleep-promoting neuronal activity in the
ventrolateral preoptic area (VLPO), thus inducing
“calm wakefulness”.77 Early open-label reports were
promising,78,79 but double-blind controlled studies
showed only modest80,81 or no benefit.82 In the clinic,
the drug may be useful in treating EDS in individual
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
8
Fatai Sal awu, et al.
patients with PD. It should be started at a dose of
100mg and increased to 200–400mg per day as
necessary. Side effects include insomnia, head pains,
and depression. Depression should be evaluated and
treated accordingly. Sometimes reassurance with or
without supplementary psychotherapy is sufficient,
but most often antidepressant medications are
needed.
Further areas of research are now also focusing on
adenosine A2A receptor antagonistsodium oxybate
and caffeine to promote wakefulness. In the pursuit
of improved treatments for PD, the adenosine A2A
receptor was used as an attractive non-dopaminergic
target.83 This was based on compelling behavioral
pharmacology and selective basal ganglia expression
of this G-protein-coupled receptor. Its antagonists
crossed the threshold of clinical development as
adjunctive symptomatic treatment for relatively
advanced PD. Adenosine derived from the
degradation of adenosine triphosphate (ATP) or
adenosine monophosphate (AMP) function as a
signaling molecule in the nervous system through
the occupation of A1, A2, and A3 adenosine.84
Adenosine A2A receptors have a selective
localization to the basal ganglia and specifically to
the indirect output pathway, and as a consequence
offer a unique opportunity to modulate the output
from the striatum that is believed to be critical to
the occurrence of motor components of PD. Several
studies conducted worldwide report an inverse
association between caffeine/coffee consumption
and the risk of developing PD.85 The association
is strong and consistent in men, but uncertain in
women possibly because of an interaction with
hormone replacement therapy. 86 Palacios et al,86
found that consumption of decaffeinated coffee was
not associated with PD risk.
C O N C LU S I O N
Improving patients’ QoL is a key factor to consider
when reviewing PD treatment plans since more
than a half of PD patients report problems with
sleep disturbances more than the motor symptoms
of the disease, and EDS and unintended sleepiness
has a large impact on the QoL of PD patients as well
as their carers. There is no doubt that non-motor
aspects of PD are of unquestionable relevance. As
of today; however, options for their management
are very limited. Prompt diagnosis should become
standard in clinical practice, and management a
research priority. Advice on good sleep hygiene
is instrumental, as pharmacological approaches
have yet to provide consistent and reliable results
without significant adverse effects. The efficacy of
pharmacological treatment of EDS in PD using
wakefulness-promoting drugs, such as modafinil,
remains controversial. Sleep attacks have been
reported in patients taking dopamine agonists for
conditions other than PD.87
Disclosure
The authors declared no conflict of interest. No funding was
received for this work.
r ef er ences
1. Parkinson J. An Essay on the Shaking Palsy. London:
Whittingham and Rowland for Sherwood. Neely and
Jones, 1817.
2. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy
of clinical diagnosis of idiopathic Parkinson’s disease: a
clinico-pathological study of 100 cases. J Neurol Neurosurg
Psychiatry 1992 Mar;55(3):181-184.
3. Trenkwalder C. Sleep dysfunction in Parkinson’s disease.
Clin Neurosci 1998;5(2):107-114.
4. Pal PK, Calne S, Samii A, Fleming J A E. A review of
normal sleep and its disturbances in Parkinson’s disease.
Parkinsonism Relat Disord 1999 Apr;5(1-2):1-17.
5. Johns MW. A new method for measuring daytime
sleepiness: the Epworth sleepiness scale. Sleep 1991
Dec;14(6):540-545.
6. Factor SA, McAlarney T, Sanchez-Ramos JR, Weiner WJ.
Sleep disorders and sleep effect in Parkinson’s disease. Mov
Disord 1990;5(4):280-285.
7. Adler CH, Thorpy MJ. Sleep issues in Parkinson’s disease.
Neurology 2005 Jun;64(12)(Suppl 3):S12-S20.
8. Dinges DF. The influence of the Human Circadian
Timekeeping System on Sleep.in Principles and Practice of
Sleep Medicine. Kryger MH, Roth T, Dement WC, Eds.
552-558, Philadelphia, WB Saunders, 1989.
9. Freedom T. Sleep and Parkinson’s disease. Dis Mon 2007
May;53(5):275-290.
10. van Hilten B, Hoff JI, Middelkoop HA, van der Velde
EA, Kerkhof GA, Wauquier A, et al. Sleep disruption in
Parkinson’s disease. Assessment by continuous activity
monitoring. Arch Neurol 1994 Sep;51(9):922-928.
11. Oerlemans WG, de Weerd AW. The prevalence of sleep
disorders in patients with Parkinson’s disease. A selfreported, community-based survey. Sleep Med 2002
Mar;3(2):147-149.
12. Porter B, Macfarlane R, Walker R. The frequency and
nature of sleep disorders in a community-based population
of patients with Parkinson’s disease. Eur J Neurol 2008
Jan;15(1):50-54.
13. Smith MC, Ellgring H, Oertel WH. Sleep disturbances in
Parkinson’s disease patients and spouses. J Am Geriatr Soc
1997 Feb;45(2):194-199.
14. van Hilten JJ, Weggeman M, van der Velde EA, Kerkhof
GA, van Dijk JG, Roos R A C. Sleep, excessive daytime
sleepiness and fatigue in Parkinson’s disease. J Neural
Transm Park Dis Dement Sect 1993;5(3):235-244.
15. Comella CL. Sleep disturbances and excessive daytime
sleepiness in Parkinson disease: an overview. J Neural
9
Fatai Sal awu, et al.
Transm Suppl 2006;70(70):349-355.
16. Rye DR, Bliwise DB. Movement Disorders Specific to Sleep
and the Nocturnal Manifestations of Waking Movement
Disorders. In: Watts RL, Koller WC, eds. Movement
Disorders: neurologic Principles and Practice. New York:
McGraw Hill Inc; 1997, 687-714.
17. Brodsky MA, Godbold J, Roth T, Olanow CW. Sleepiness
in Parkinson’s disease: a controlled study. Mov Disord 2003
Jun;18(6):668-672.
18. Nausieda PA, Weiner WJ, Kaplan LR, Weber S, Klawans
HL. Sleep disruption in the course of chronic levodopa
therapy: an early feature of the levodopa psychosis. Clin
Neuropharmacol 1982;5(2):183-194.
19. Aldrich MS. Parkinsonism. In, Kryger MH, Roth T,
Dement WC, Eds. Principles and Pracitice of Sleep
Medicine. Philadelphia, PA: WB Saunders Company,
1994, 783-789.
20. Dowling GA. Sleep in older women with Parkinson’s
disease. J Neurosci Nurs 1995 Dec;27(6):355-357, 360362.
21. Lees AJ, Blackburn NA, Campbell VL. The nighttime
problems of Parkinson’s disease. Clin Neuropharmacol
1988 Dec;11(6):512-519.
22. Menza MA, Rosen RC. Sleep in Parkinson’s disease. The
role of depression and anxiety. Psychosomatics 1995 MayJun;36(3):262-266.
23. Neusieda PA. Sleep disorders. In, Koller WC, Eds.
Handbook of Parkinson’s disease. New York: Marcel
Dekker, 1987. 371.
24. Tandberg E, Larsen JP, Karlsen K. Excessive daytime
sleepiness and sleep benefit in Parkinson’s disease: a
community-based study. Mov Disord 1999 Nov;14(6):922927.
25. Postuma RB, Gagnon JF, Vendette M, Fantini ML,
Massicotte-Marquez J, Montplaisir J. Quantifying the
risk of neurodegenerative disease in idiopathic REM sleep
behavior disorder. Neurology 2009 Apr;72(15):1296-1300.
26. Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig
H, Stern M, et al. A multicenter double-blind placebocontrolled trial of pergolide as an adjunct to Sinemet in
Parkinson’s disease. Mov Disord 1994 Jan;9(1):40-47.
27. Parkinson Study Group. Safety and efficacy of Pramipexole
in early Parkinson’s disease: a randomized dose-ranging
study. JAMA 1997 July;278(2):125-130.
28. Olanow CW, Schapira AH, Roth T. Waking up to
sleep episodes in Parkinson’s disease. Mov Disord 2000
Mar;15(2):212-215.
29. Montastruc JL, Brefel-Courbon C, Senard JM, Bagheri H,
Ferreira J, Rascol O, et al. Sleep attacks and antiparkinsonian
drugs: a pilot prospective pharmacoepidemiologic study.
Clin Neuropharmacol 2001 May-Jun;24(3):181-183.
30. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C,
Jankovic J. Daytime sleepiness and other sleep disorders in
Parkinson’s disease. Neurology 2001 Oct;57(8):1392-1396.
31. Reuter I, Ellis CM, Ray Chaudhuri K. Nocturnal
subcutaneous apomorphine infusion in Parkinson’s disease
and restless legs syndrome. Acta Neurol Scand 1999
Sep;100(3):163-167.
32. Askenasy JJ, Yahr MD. Reversal of sleep disturbance
in Parkinson’s disease by antiparkinsonian therapy: a
preliminary study. Neurology 1985 Apr;35(4):527-532.
33. De Keyser J, Ebinger G, Vauquelin G. Evidence for a
widespread dopaminergic innervation of the human
cerebral neocortex. Neurosci Lett 1989 Oct;104(3):281285.
34. Trotti LM, Rye DB. Neurobiology of sleep: the role of
dopamine in Parkinson’s disease. In Nonmotor symptoms
in Parkinson’s disease, Chaudruri KR, Tolosa E, Schapira
A, Poewe W, Eds., 165-76, Oxford University Press, 2009.
35. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen
Steur EN, Braak E. Staging of brain pathology related to
sporadic Parkinson’s disease. Neurobiol Aging 2003 MarApr;24(2):197-211.
36. Saper CB, Chou TC, Scammell TE. The sleep switch:
hypothalamic control of sleep and wakefulness. Trends
Neurosci 2001 Dec;24(12):726-731.
37. Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL.
The pedunculopontine nucleus in Parkinson’s disease. Ann
Neurol 1989 Jul;26(1):41-46.
38. Arnulf I, Ferraye M, Fraix V, Benabid AL, Chabardès
S, Goetz L, et al. Sleep induced by stimulation in the
human pedunculopontine nucleus area. Ann Neurol 2010
Apr;67(4):546-549.
39. Alessandro S, Ceravolo R, Brusa L, Pierantozzi M, Costa
A, Galati S, et al. Non-motor functions in parkinsonian
patients implanted in the pedunculopontine nucleus:
focus on sleep and cognitive domains. J Neurol Sci 2010
Feb;289(1-2):44-48.
40. Amara AW, Watts RL, Walker HC. The effects of deep
brain stimulation on sleep in Parkinson’s disease. Ther Adv
Neurol Disord 2011 Jan;4(1):15-24.
41. Poryazova R, Benninger D, Waldvogel D, Bassetti
CL. Excessive daytime sleepiness in Parkinson’s
disease: characteristics and determinants. Eur Neurol
2010;63(3):129-135.
42. Shpirer I, Miniovitz A, Klein C, Goldstein R, Prokhorov T,
Theitler J, et al. Excessive daytime sleepiness in patients with
Parkinson’s disease: a polysomnography study. Mov Disord
2006 Sep;21(9):1432-1438.
43. Frucht S, Rogers JD, Greene PE, Gordon MF, Fahn S.
Falling asleep at the wheel: motor vehicle mishaps in
persons taking pramipexole and ropinirole. Neurology
1999 Jun;52(9):1908-1910.
44. Arnulf I. Excessive daytime sleepiness in parkinsonism.
Sleep Med Rev 2005 Jun;9(3):185-200.
45. Kales A, Ansel RD, Markham CH, Scharf MB, Tan TL.
Sleep in patients with Parkinson’s disease and normal
subjects prior to and following levodopa administration.
Clin Pharmacol Ther 1971 Mar-Apr;12(2):397-406.
46. Fabbrini G, Barbanti P, Aurilia C, Vanacore N, Pauletti C,
Meco G. Excessive daytime sleepiness in de novo and treated
Parkinson’s disease. Mov Disord 2002 Sep;17(5):1026-1030.
47. Carter J, Carroll VS, Lannon MC, Vetere-Overfield B,
Baker R. Sleep disruption in untreated Parkinson’s disease.
Neurology 1990;40(supplement 1):220.
48. Sharf B, Moskovitz C, Lupton MD, Klawans HL. Dream
phenomena induced by chronic levodopa therapy. J Neural
Transm 1978;43(2):143-151.
49. Gama RL, Távora DG, Bomfim RC, Silva CE, de Bruin
VM, de Bruin PF. Sleep disturbances and brain MRI
morphometry in Parkinson’s disease, multiple system atrophy
and progressive supranuclear palsy - a comparative study.
Parkinsonism Relat Disord 2010 May;16(4):275-279.
50. Carskadon MA. Sleep and alertness. New York, Raven
Press, 1989; 53-69.
51. Morewitz JH. Evaluation of excessive daytime sleepiness
in the elderly. J Am Geriatr Soc 1988 Apr;36(4):324-330.
52. Wein A, Golubev V, Yakhno N. Polygraphic analysis of sleep
and wakefulness in patients with Parkinson’s syndrome.
Waking Sleeping 1979 Jan;3(1):31-40.
53. Al-Abri M, Al-Hamhami A, Al-Nabhani H, Al-Zakwani I.
Validation of the arabic version of the epworth sleepiness
scale in oman. Oman Med J 2013 Nov;28(6):454-456.
54. Rye DB, Bliwise DL, Dihenia B, Gurecki P. FAST TRACK:
daytime sleepiness in Parkinson’s disease. J Sleep Res 2000
Mar;9(1):63-69.
55. Arnulf I, Konofal E, Merino-Andreu M, Houeto JL,
Mesnage V, Welter ML, et al. Parkinson’s disease and
sleepiness: an integral part of PD. Neurology 2002
Apr;58(7):1019-1024.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
10
Fatai Sal awu, et al.
56. Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J,
Fleming J. Excessive daytime sleepiness and sudden-onset
sleep in Parkinson disease: a survey by the Canadian
Movement Disorders Group. JAMA 2002 Jan;287(4):455463.
57. Razmy A, Lang AE, Shapiro CM. Predictors of impaired
daytime sleep and wakefulness in patients with Parkinson
disease treated with older (ergot) vs newer (nonergot)
dopamine agonists. Arch Neurol 2004 Jan;61(1):97-102.
58. Stevens S, Cormella CL, Stepanski EJ. Daytime sleepiness
and alertness in patients with Parkinson disease. Sleep 2004
Aug;27(5):967-972.
59. Ferreira JJ, Desboeuf K, Galitzky M, Thalamas C, BrefelCourbon C, Fabre N, et al. Sleep disruption, daytime
somnolence and ‘sleep attacks’ in Parkinson’s disease: a
clinical survey in PD patients and age-matched healthy
volunteers. Eur J Neurol 2006 Mar;13(3):209-214.
60. Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D,
Larsen JP. Excessive daytime sleepiness in Parkinson
disease: is it the drugs or the disease? Neurology 2006
Sep;67(5):853-858.
61. Dhawan V, Dhoat S, Williams AJ, Dimarco A, Pal S,
Forbes A, et al. The range and nature of sleep dysfunction
in untreated Parkinson’s disease (PD). A comparative
controlled clinical study using the Parkinson’s disease sleep
scale and selective polysomnography. J Neurol Sci 2006
Oct;248(1-2):158-162.
62. Amick MM, D’Abreu A, Moro-de-Casillas ML, Chou KL,
Ott BR. Excessive daytime sleepiness and on-road driving
performance in patients with Parkinson’s disease. J Neurol
Sci 2007 Jan;252(1):13-15.
63. Ghorayeb I, Loundou A, Auquier P, Dauvilliers Y, Bioulac
B, Tison F. A nationwide survey of excessive daytime
sleepiness in Parkinson’s disease in France. Mov Disord
2007 Aug;22(11):1567-1572.
64. American Sleep Disorders Association. International
Classification of Sleep Disorders Revised: Diagnostic and
Coding Manual. Rochester, MN: American Sleep Disorders
Association, 1997.
65. Bliwise DI, Borchert LD, Cantor C, et al. Excessive daytime
sleepiness (EDS) in Parkinson’s disease (PD) patients
with unintended sleep episode (USE) while treated with
dopaminergic agents. Parkinsonson and Related Disorders
2001 Supplement 1, S52.
66. Manni R, Mazzarello P. Hallucinations, REM sleep,
and Parkinson’s disease: a medical hypothesis. (Letter).
Neurology 2001 Oct;57(7):1350-1351.
67. Paus S, Brecht HM, Köster J, Seeger G, Klockgether
T, Wüllner U. Sleep attacks, daytime sleepiness, and
dopamine agonists in Parkinson’s disease. Mov Disord 2003
Jun;18(6):659-667.
68. Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep
attacks and Parkinson’s disease treatment. Lancet 2000
Apr;355(9212):1333-1334.
69. Schapira AH. Sleep attacks (sleep episodes) with pergolide.
Lancet 2000 Apr;355(9212):1332-1333.
70. Roth T, Rye DB, Borchert LD, Bartlett C, Bliwise DL,
Cantor C, et al. Assessment of sleepiness and unintended
sleep in Parkinson’s disease patients taking dopamine
agonists. Sleep Med 2003 Jul;4(4):275-280.
71. Hauser RA, Gauger L, Anderson WM, Zesiewicz TA.
Pramipexole-induced somnolence and episodes of daytime
sleep. Mov Disord 2000 Jul;15(4):658-663.
72. Möller JC, Stiasny K, Hargutt V, Cassel W, Tietze H, Peter
JH, et al. Evaluation of sleep and driving performance in six
patients with Parkinson’s disease reporting sudden onset of
sleep under dopaminergic medication: a pilot study. Mov
Disord 2002 May;17(3):474-481.
73. Aldrich MS. Sleepiness and sleep deprivation. In Aldrich
MS. Sleep Medicine. New York: Oxford University Press,
1999; 111-126.
74. Poewe W, Hogi B. Sleep and Parkinson’s disease. Editorial
review. Curr Opin Neurol 2000;13:423-426.
75. Merino-Andreu M, Arnulf I, Konofal E, Derenne JP,
Agid Y. Unawareness of naps in Parkinson’s disease and
in disorders with excessive daytime sleepiness. Neurology
2003 May;60(9):1553-1554.
76. Olanow CW, Stern MB, Sethi K. The scientific and
clinical basis for the treatment of Parkinson disease (2009).
Neurology 2009 May;72(21 Suppl 4):S1-S136.
77. Stahl SM. Awakening to the psychopharmacology of sleep
and arousal: novel neurotransmitters and wake-promoting
drugs. J Clin Psychiatry 2002 Jun;63(6):467-468.
78. Happe S, Pirker W, Sauter C, Klösch G, Zeitlhofer J.
Successful treatment of excessive daytime sleepiness
in Parkinson’s disease with modafinil. J Neurol 2001
Jul;248(7):632-634.
79. Nieves AV, Lang AE. Treatment of excessive daytime
sleepiness in patients with Parkinson’s disease with modafinil.
Clin Neuropharmacol 2002 Mar-Apr;25(2):111-114.
80. Högl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Seppi
K, et al. Modafinil for the treatment of daytime sleepiness
in Parkinson’s disease: a double-blind, randomized,
crossover, placebo-controlled polygraphic trial. Sleep 2002
Dec;25(8):905-909.
81. Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J.
Randomized trial of modafinil for treating subjective
daytime sleepiness in patients with Parkinson’s disease. Mov
Disord 2003 Mar;18(3):287-293.
82. Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for
daytime somnolence in Parkinson’s disease: double blind,
placebo controlled parallel trial. J Neurol Neurosurg
Psychiatry 2005 Dec;76(12):1636-1639.
83. Xu K, Bastia E, Schwarzschild M. Therapeutic potential
of adenosine A(2A) receptor antagonists in Parkinson’s
disease. Pharmacol Ther 2005 Mar;105(3):267-310.
84. Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB,
Chen JF. Adenosine, adenosine A 2A antagonists, and
Parkinson’s disease. Parkinsonism Relat Disord 2009
Jul;15(6):406-413.
85. Postuma RB, Lang AE, Munhoz RP, Charland K, Pelletier
A, Moscovich M, et al. Caffeine for treatment of Parkinson
disease: a randomized controlled trial. Neurology 2012
Aug;79(7):651-658.
86. Palacios N, Gao X, McCullough ML, Schwarzschild MA,
Shah R, Gapstur S, et al. Caffeine and risk of Parkinson’s
disease in a large cohort of men and women. Mov Disord
2012 Sep;27(10):1276-1282.
87. Gouraud A, Millaret A, Descotes J, Vial T; French
Association of Regional Pharmacovigilance Centres.
Piribedil-induced sleep attacks in patients without
Parkinson disease: a case series. Clin Neuropharmacol 2011
May-Jun;34(3):104-107.
original article
Oman Medical Journal [2015], Vol. 30, No. 1: 11–16
The Effect of Low-Dose Intravenous Ketamine on
Postoperative Pain Following Cesarean Section with
Spinal Anesthesia: A Randomized Clinical Trial
Mojgan Rahmanian1, Mehri Leysi1, Ali Akbar Hemmati2, and Majid
Mirmohammadkhani3*
Department of Gynecology, Semnan University of Medical Sciences, Semnan, Iran
Department of Anesthesiology, Semnan University of Medical Sciences, Semnan, Iran
3
Research Center for Social Determinants of Health Community Medicine Department, Semnan University of Medical
Sciences, Semnan, Iran
1
2
A RT I C L E I N F O
Article history:
Received: 14 July 2014
Accepted: 19 December 2014
Online:
DOI 10.5001/omj.2015.03
Keywords:
Cesarean Section; Ketamine;
Pain, Postoperative;
Anesthesia, Spinal.
A B S T R AC T
Objectives: Low-dose ketamine has been considered a good substitute for opioids for
controlling postoperative pain. The purpose of this study was to determine the effect
of low-dose intravenous ketamine following cesarean section with spinal anesthesia
on postoperative pain and its potential complications. Methods: One hundred and
sixty pregnant women volunteered to participate in this randomized controlled trial.
Participants were randomly divided into two groups (n=80 for each group). Five minutes
after delivery, the experimental group received 0.25mg/kg ketamine while the control
group received the same amount of normal saline. Results: There was a significant
difference between the two groups in the severity of pain at one, two, six, and 12 hours
following surgery. Postoperative pain was significantly less severe in the experimental
group. Compared to the control group, the experimental group felt pain less frequently
and therefore asked for analgesics less often. On average, the number of doses of analgesics
used for the participants in the experimental group was significantly less than the number
of doses used for the control group. Analgesic side effects (including nausea, itching, and
headache) were not significantly different between the two groups. However, vomiting
was significantly more prevalent in the control group and hallucination was more
common in the experimental group. Conclusion: We conclude that administration of
low doses of ketamine after spinal anesthesia reduces the need for analgesics and has
fewer side effects than using opioids. Further studies are required to determine the proper
dose of ketamine which offers maximum analgesic effect. Furthermore, administration of
low-dose ketamine in combination with other medications in order to minimize its side
effects warrants further investigation.
E
veryday millions of people around the
world undergo surgical operations and
subsequently experience postoperative
pain. Postoperative pain has numerous
side effects, including (but not limited to)
atelectasis, thrombosis, myocardial ischemia, cardiac
arrhythmia, electrolyte imbalance, ileus, and urinary
retention.1-3 The aforementioned underscores the
significance of effective control of postoperative
pain. Cesarean section is one of the most common
types of surgeries in the world.4 Over the past century,
cesarean section has significantly reduced the rate of
neonatal deaths and has saved the lives of millions
of new mothers.5 Cesareans can negatively affect
the physical domains of quality of life for a woman
*Corresponding author:  mirmohammadkhani@razi.tums.ac.ir
after delivery6 and postoperative pain is one of the
most significant side effects of cesarean section. Pain
is an unpleasant sensory and emotional experience
associated with actual or potential tissue damage.5
Controlling postoperative pain and getting the new
mother out of bed and moving as early as possible
following the surgery will reduce the respiratory,
cardiovascular, urinary, and digestive side effects
of surgery. There are numerous medications for
controlling postoperative pain. Based on the pros
and cons of each medication, as well as the patient’s
preference, physicians choose the most suitable
medication for each patient. Opioids, such as
morphine and pethidine, are the most commonly
used medications for postoperative pain. However,
12
Mojgan R ahm an i an, et al.
opioids have numerous side effects including
addiction, respiratory depression, drug resistance,
nausea, and vomiting. Therefore, surgeons generally
prefer the use of non-opioid analgesics for reducing
postoperative pain.4
Numerous studies have examined the effect of
different doses of ketamine in combination with
other medications in reducing postoperative pain.4,7-17
However, the results have been contradictory. While
some studies have shown that ketamine reduces the
pain score and consequently the need for opioids
following surgery8,13,17 others have not found such
results.9,12 Spinal anesthesia can be done using different
drug combinations including bupivacaine alone,
bupivacaine and fentanyl, bupivacaine and fentanyl
and morphine. The effect of ketamine on postoperative
pain following spinal anesthesia using different drug
combinations has also been investigated.9
In this study we examined the effect of lowdose intravenous ketamine on postoperative pain
and the need for analgesics, including opioids,
following cesarean section with spinal anesthesia
using bupivacaine.
M ET H O D S
One hundred and sixty pregnant women who
were admitted to the Amiralmomenin Hospital in
Semnan, Iran, between April 2013 and March 2014
for elective cesarean section volunteered to participate
in this randomized controlled clinical trial (registry
number IRCT2012100611019N1).
Women with singleton term pregnancy who were
scheduled to undergo elective cesarean section were
included in the study. Exclusion criteria were: history
of drug abuse, chronic diseases such as diabetes,
history of previous cesarean section or any other
abdominal surgery, abnormal bleeding during and/
or following the surgery, allergic reaction to ketamine,
psychological disorders, high blood pressure, high
intracranial pressure, history of seizure, and history
of hallucination following taking ketamine. Women
with contraindications to spinal anesthesia were also
excluded from the study.
All participants were informed about the
experimental procedure and the potential side effects
of the medications used in the study before signing a
consent form. All procedures were approved by the
Office of Research Ethics of the Semnan University
of Medical Sciences.
Participants were randomly divided into equal
groups (n=80 in each group). All participants had
spinal anesthesia using bupivacaine. The dose of the
drug, as well as the method of injection was identical
for all individuals; 12.5mg or 2.5cc 0.5% solution, in
the L4-L5 space using needle 25, midline, with the
patient in a sitting position. The duration of block
was considered as the duration between inducing
anesthesia at T4 level to back of sensation at umbilicus
level. The upper dermatome level was T4 in all
patients. Duration of surgery in all participants was
recorded. Five minutes after delivery, women in the
experimental group received 0.25mg/kg intravenous
ketamine via bolus dose, while the control group
received the same amount of normal saline. A
researcher blind to the aforementioned grouping
and the nature of treatment received by each group
monitored the participants and recorded if and when
the participants felt any pain and asked for sedatives.
A numeric pain rating scale was used to record the
participants’ pain score at one, two, six, and 12 hours
following surgery. Participants were asked to rate the
intensity of their pain in the scale of one (no pain at
all) to 10 (very intense and unimaginable pain). If the
patient asked for analgesics, she was given a 100mg
rectal diclofenac suppository. If the pain persisted the
patient was given another 100mg rectal diclofenac
suppository every six hours, with a maximum of
four suppositories in 24 hours. In cases where the
pain score was greater than five and the pain was
persistent and could not be controlled by diclofenac
suppositories, pethidine (50mg, intramuscular
injection) was prescribed. A maximum of three doses
of pethidine were prescribed during the first 24 hours
following surgery, with a minimum six hour interval
between the two consecutive injections. Participants
were monitored for common side effects, such as
nausea, vomiting, headache, hallucination, and
itching, and the prevalence of such side effects was
recorded.
The pain scores, time to first request for analgesia,
and the number of diclofenac suppositories and
pethidine injections used in the first 24 hours
following the surgery were compared between the
two groups using t-tests and Mann-Whitney U test.
Chi-squared and Fisher’s exact test were used to
compare the frequency of side effects. The statistic
software SPSS was used for all statistical analysis.
For all analyses, a p-value of less than 0.050 was
considered to be significant.
13
Mojgan R ahm an i an, et al.
Table 1: Characteristics of participants for the
control and experimental groups.
Characteristic
Control
group
(n=80)
Experimental
group
(n=80)
p-value
Age
27.6±4.4
27.4±4.8
0.700
Weight
Duration of
surgery (minutes)
77.7±10.8
39.8±3.2
78.5±11.9
40.2±3.8
0.600
0.500
R E S U LT S
There was no significant difference between the
experimental and control groups in participants’ age
(mean ± standard deviation (SD)=27.4 ±4.8 years
and 27.6 ±4.4 years, respectively; p=0.700) and their
weight (78.5±11.9 and 77.7±10.8; p=0.600). The
mean ± SD for duration of surgery was 40.0±3.5
minutes (the minimum time was 35 minutes and
the maximum time was 59 minutes) while there was
no significant difference between the two groups in
term of duration of surgery (p=0.500) [Table 1]. All
of the participants were primigravida.
There was a significant difference between the two
groups in pain scores at one, two, six, and 12 hours
following surgery. The pain scores were significantly
greater for the control group than the experimental
group at all time intervals (p<0.001) [Table 2].
There were significant differences between the
two groups in the time to first request for analgesia
(p<0.001), time to the first use of diclofenac
suppository (p<0.001), and time to the first
pethidine injection (p<0.001). The time interval
between the surgery and when the patient first
complained of pain and requested analgesia was
significantly longer for the experimental group than
the control group. The time interval between surgery
and the first use of diclofenac suppository, and the
first pethidine injection were also significantly
Table 2: The mean and standard deviation of pain
scores for the two groups of participants at one, two,
six, and 12 hours following surgery.
Time interval
Control
group
(n=80)
Experimental
group
(n=80)
p-value
After one hour
4.95±1.2
3.55±0.31
<0.001
After two hours
5.38±1.06
3.92±1.33
<0.001
After six hours
After 12 hours
6.16±0.27
4.64±0.47
3.90±1.7
3.19±0.67
<0.001
<0.001
Table 3: The time interval (in hours) between the
surgery and the first complaint of pain and request
for and use of analgesia, and number of their use for
the two groups of participants.
Control
group
(n=80)
Experimental
group
(n=80)
p-value
First request for
analgesia**
1.36±0.48
2.76±1.28
<0.001
First diclofenac
suppository use**
1.48±0.6
2.89±1.33
<0.001
Diclofenac use
number***
3(1,4)
2(0,4)
<0.001*
First pethidine
injection**
Pethidine use
number***
4.10±2.85
6.12±3.79
<0.001
2(1,3)
0(0,2)
<0.001*
Time to
(hours)
*Mann-Whitney U test; ** mean±SD; *** median(range)
longer for the experimental group than the control
group [Table 3].
There was a significant difference between
the two groups in the mean number of doses of
diclofenac (p<0.001) and pethidine (p<0.001)
received. The mean ±SD of diclofenac received by
the experimental and control group were 1.79±2 and
2.86±3, respectively. The mean ±SD of pethidine
received by the experimental and control group were
0.44±0 and 1.62±2, respectively.
Everyone in the control group used diclofenac
suppositories; however, four participants from the
experimental group (5%) did not use diclofenac
suppositories at all. The majority of the participants
in the control group (n=45) required the first
diclofenac suppository during the first hour
following the surgery. On the contrary, the majority
of the participants in the experimental group who
used a suppository (n=23) took the first suppository
during the second hour after surgery. This suggests
that pain started later in the experimental group
than in the control group.
Only one participant from the control group
(1.2%) and 46 participants from the experimental
group (57.5%) did not require pethidine.
Participants in the control group who used pethidine
(n=36) required their first injection during the
first hour after surgery, whereas participants in the
experimental group who required pethidine (n=17)
received their first injection during the second hour
after surgery. These results further indicate that the
initiation of pain was delayed in the experimental
group compared to the control group. In total,
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
14
Mojgan R ahm an i an, et al.
Table 4: Frequency of side effects for the two
groups of participants.
Side effect
Control
group n(%)
Experimental
group n(%)
p-value
Nausea
25 (31.2%)
26 (32.5%)
0.865
Vomiting*
28 (35.0%)
15 (18.8%)
0.020
Headache
27 (33.8%)
21 (26.6%)
0.301
Hallucination*
Itching
8 (10.0%)
21 (26.2%)
18 (22.5%)
12 (15.0%)
0.032
0.079
*indicates significant difference between the two groups.
the experimental group received 143 diclofenac
suppositories and 35 doses of pethidine, while the
control group received 229 diclofenac suppositories
and 130 doses of pethidine.
Table 4 summarizes the frequency of common
side effects of surgery in the two groups. There was
no significant difference between the two groups in
the occurrence of nausea (p=0.865) and headache
(p=0.301). Although itching was more common in
the control group than the experimental group, the
difference was not significant (p=0.079). Vomiting
was significantly more common in the control group
than the experimental group (p=0.020). There was
a significant difference between the two groups in
hallucination (p=0.032), which was more common
in the experimental group than the control group.
DISCUSSION
Postoperative pain is one of the most significant
side effects of cesarean section.5 There are numerous
methods for controlling postoperative pain.
Opioids, such as morphine and pethidine, are the
most commonly used medications; however, they
usually cause multiple side effects.4 In an attempt to
avoid the side effects of opioids, many scientists4,18,19
have examined the effectiveness of different doses of
ketamine administered in a variety of methods as an
alternative approach for controlling postoperative
pain following cesarean section. We examined
the effect of low-dose intravenous ketamine
(0.25mg/kg ) on postoperative pain in women
undergoing caesarean section.
Our results showed that the pain scores were
significantly greater for the control group than the
experimental group at one, two, six, and 12 hours
following surgery indicating that participants in
the control group experienced a greater level of
postoperative pain than those in the experimental
group. This finding was similar to reports by Sen and
colleagues13 who showed that postoperative pain
scores were significantly lower in elective cesarean
section women who received low-dose intravenous
ketamine (0.15mg/kg) than those who received an
equal volume of normal saline intravenously (control
group) and those who received intrathecal fentanyl.
Arbabi and Ghazi-Saidi15 also reported less severe
pain in women who received low-dose ketamine for
postoperative pain following caesarean section.
In our study, the initiation of pain was delayed
in the experimental group, and therefore the time to
first request for analgesia was significantly longer in
this group than the control group. The longer time
to first request for analgesia in women who had
received low-dose intravenous ketamine has also
been previously reported.10,13,15 Furthermore, on
average participants in the experimental group used
fewer doses of analgesics than those in the control
group. This finding is in agreement with reports by
Arbabi and Ghazi-Saidi.15
Low-dose ketamine has been used to control
postoperative pain following other types of surgeries
too. Dahmani and colleagues20 showed that local
administration of ketamine during tonsillectomy
decreases the intensity of postoperative pain and
the need for analgesics. Adam et al,14 examined
the effect of low-dose intravenous ketamine in
combination with continuous femoral nerve
block on postoperative pain and rehabilitation
following total knee arthroplasty. The ketamine
group required significantly less analgesics than
the control group. They also reached 90° of active
knee flexion significantly sooner than the control
group. The authors concluded that ketamine
is a useful analgesic adjuvant in perioperative
multimodal analgesia and could contribute to
early knee mobilization.
Using a randomized, double-blind placebocontrolled design, Bauchat and colleagues 9
examined the effect of intravenous ketamine 10mg
administered during spinal anesthesia for cesarean
delivery on the incidence of breakthrough pain,
the pain that required supplemental postoperative
analgesia. Ketamine was used in addition to
intrathecal morphine and intravenous ketorolac.
The authors showed that the incidence of
breakthrough pain in the first 24 hours following
the surgery was not different between the
15
Mojgan R ahm an i an, et al.
experimental and the control groups. Furthermore,
the pain score in the first 24 hours and the number
of analgesics (acetaminophen/hydrocodone
tablets) administered during the first 24 or 72 hours
following surgery were similar for the two groups.
They concluded that low-dose ketamine offers
no additional benefit during cesarean delivery in
patients who received intrathecal morphine and
intravenous ketorolac. 9 The difference between
the results of our study and that of Bauchat et
al, might be due to the differences in the dose of
ketamine. While we used 0.25mg/kg ketamine,
Bauchat et al, used 10mg. Furthermore, we used
bupivacaine for spinal anesthesia. Bauchat et
al, however, used a combination of bupivacaine,
fentanyl, and morphine. The aforementioned
may have contributed to the diverse findings of
the two studies. Nonetheless, Bauchat et al, did
report lower pain scores in the group who received
ketamine compared to the control group at two
weeks postpartum.
In a study by Moshiri and colleagues 11
administrating a low dose of ketamine (0.15mg/kg)
did not affect the time to first request for analgesia
following cesarean section. Therefore, the authors
concluded that low-dose ketamine does not reduce
the postoperative pain following cesarean section.
Once again, the difference between the findings of
our study and that of Moshiri et al, might be due to
the differences in the dose of ketamine used, and the
sample size. In comparison to our study, Moshiri et
al, studied the effect of ketamine on a smaller group
of participants (n=120 vs. n=160 in our study),
and used a lower dose of ketamine (0.15mg/kg vs.
0.25mg/kg in our study).
The study performed by Kathirvel et al, 16 which
evaluated the effects of intrathecal ketamine added
to bupivacaine for spinal anaesthesia, showed that
the duration of motor blockade was shorter in
the ketamine group. However, significantly more
patients in the ketamine group had adverse events,
including sedation, dizziness, nystagmus, strange
feelings, and postoperative nausea and vomiting.
They concluded that the central adverse effects of
ketamine limited its spinal application. But in our
study using low dose ketamine has only one limit in
term of side effects, which was hallucination.
Reza and colleagues12 also reported that low-dose
ketamine has no effect on patients’ pain scores at
two, six, 12, and 24 hours following surgery or on the
prevalence of side effects. However, in comparison
with our study, they used a higher dose of ketamine
(0.5mg/kg vs. 0.25mg/kg in our study) in a smaller
sample (n=60 vs. n=160 in our study). Furthermore,
while we used spinal anesthesia using bupivacaine,
participants in their study underwent general
anesthesia using thiopental and succinylcholine. The
aforementioned differences might have contributed
to the different findings of the two studies.
Our study showed that ketamine had no
significant impact on the prevalence of side effects
such as nausea, headache, and itching. Similar results
were reported by Reza et al.12 In our study, vomiting
was significantly less common in patients that
received ketamine. However, in the study by Reza et
al, the occurrence of vomiting was similar between
the experimental and control group. The different
findings might be due to the fact that the participants
in our study received smaller doses of pethidine.
In our study, although hallucination was more
common in patients who received ketamine only
22.5% of these patients complained of hallucination.
In contrast, Arbabi and Ghazi-Saidi15 reported less
prevalence of hallucination in individuals who
received ketamine. The differences in the type
of anesthesia, sample size, dose of ketamine, and
the time ketamine was administered might have
contributed to the different findings. Arbabi and
Ghazi-Saidi studied the effects of 0.3mg/kg ketamine
administered before general anesthesia in a group of 60
parturient women.15 Sabzi and colleagues21 reported
that Midazolam effectively reduces ketamine-induced
postoperative hallucination.
The inevitable use of analgesics would affect the
pain score of patients and hide the presumptive effects
of ketamine, especially in the later measurements,
limiting the study.
C O N C LU S I O N
We conclude that administration of low-dose
intravenous ketamine following cesarean section
with spinal anesthesia reduces postoperative pain
and subsequently the need for analgesics. It also
reduced the prevalence of side effects.
To fully understand the effect of ketamine
in postoperative pain following cesarean section
we recommend that future studies examine the
effect of different doses of ketamine, alone and in
combination with other medications to reduce
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
16
Mojgan R ahm an i an, et al.
its inevitable side effects (e.g., benzodiazepine to
control hallucination). Furthermore, we recommend
future studies use larger sample sizes to increase their
power in detecting the true differences between the
experimental and control groups.
Disclosure
The authors declared no conflict of interest. The article was
prepared based on a medical specialty degree thesis in the field
of obstetrics and gynecology supported by Semnan University
of Medical Sciences.
R ef er enc e s
1. Guyton AC, Hall JE. Somatic Sensation. Text Book of
Medical Physiology. Saunders; 2000. p. 699-720.
2. Kirby RR. Pain management. Clinical Anesthesia Practice.
Saunders; 2002. p. 1152-1159.
3. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I:
physiological pathways and pharmacological modalities.
Can J Anaesth 2001 Nov;48(10):1000-1010.
4. Madineh H, Rajaei M, Ghaheri H, Akhlaghi M, Ganji F. The
Effect of Intravenous Low Dose Ketamine on Postoperative
Pain. J Shahrekord Univ Med Sci 2005;7(2):29-34.
5. Walder B, Schafer M, Henzi I, Tramèr MR. Efficacy and
safety of patient-controlled opioid analgesia for acute
postoperative pain. A quantitative systematic review. Acta
Anaesthesiol Scand 2001 Aug;45(7):795-804.
6. Mousavi SA, Mortazavi F, Chaman R, Khosravi A. Quality
of life after cesarean and vaginal delivery. Oman Med J 2013
Jul;28(4):245-251.
7. Behdad S, Hajiesmaeili MR, Abbasi HR, Ayatollahi V,
Khadiv Z, Sedaghat A. Analgesic Effects of Intravenous
Ketamine during Spinal Anesthesia in Pregnant Women
Undergone Caesarean Section; A Randomized Clinical
Trial. Anesth Pain Med 2013 Sep;3(2):230-233.
8. Menkiti ID, Desalu I, Kushimo OT. Low-dose intravenous
ketamine improves postoperative analgesia after caesarean
delivery with spinal bupivacaine in African parturients. Int
J Obstet Anesth 2012 Jul;21(3):217-221.
9. Bauchat JR, Higgins N, Wojciechowski KG, McCarthy RJ,
Toledo P, Wong CA. Low-dose ketamine with multimodal
postcesarean delivery analgesia: a randomized controlled
trial. Int J Obstet Anesth 2011 Jan;20(1):3-9.
10. Ebong EJ, Mato CN, Fyneface-Ogan S. Pre-Incisional
Intravenous Low-Dose Ketamine Does Not Cause
Pre-Emptive Analgesic Effect Following Caesarean
Section under Spinal Anaesthesia. J Anesthe Clinic Res
2011;138(2):100-103.
11. Moshiri E, Norozi A, Pazoki S, Gazerani N, Choghayi M.
The effect of low dose Ketamine on postoperative pain after
spinal anaesthesia in cesarean section. Arak University of
Medical Sciences Journal 2011;14(2):81-88.
12. Reza FM, Zahra F, Esmaeel F, Hossein A. Preemptive
analgesic effect of ketamine in patients undergoing elective
cesarean section. Clin J Pain 2010 Mar-Apr;26(3):223-226.
13. Sen S, Ozmert G, Aydin ON, Baran N, Caliskan E.
The persisting analgesic effect of low-dose intravenous
ketamine after spinal anaesthesia for caesarean section. Eur
J Anaesthesiol 2005 Jul;22(7):518-523.
14. Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler
DI, Fletcher D. Small-dose ketamine infusion improves
postoperative analgesia and rehabilitation after total knee
arthroplasty. Anesth Analg 2005 Feb;100(2):475-480.
15. Arbabi S, Ghazi-Saeidi K. The Preemptive Effect of Low
Dose Ketamine on Postoperative Pain in Cesarean Section.
Journal of Iranian Society Anaesthesiology and Intensive
Care 2003;23(42):15-21.
16. Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo
P. Effects of intrathecal ketamine added to bupivacaine for
spinal anaesthesia. Anaesthesia 2000 Sep;55(9):899-904.
17. Ngan Kee WD, Khaw KS, Ma ML, Mainland PA, Gin T.
Postoperative analgesic requirement after cesarean section:
a comparison of anesthetic induction with ketamine or
thiopental. Anesth Analg 1997 Dec;85(6):1294-1298.
18. McCartney CJ, Sinha A, Katz J. A qualitative systematic
review of the role of N-methyl-D-aspartate receptor
antagonists in preventive analgesia. Anesth Analg 2004
May;98(5):1385-1400.
19. Kronenberg RH. Ketamine as an analgesic: parenteral,
oral, rectal, subcutaneous, transdermal and intranasal
administration. J Pain Palliat Care Pharmacother
2002;16(3):27-35.
20. Dahmani S, Michelet D, Abback PS, Wood C, Brasher
C, Nivoche Y, et al. Ketamine for perioperative pain
management in children: a meta-analysis of published
studies. Paediatr Anaesth 2011 Jun;21(6):636-652.
21. Sabzi F, Teimouri H, Nadri S. A comparison of effects
of Diazepam and Midazolam on Ketamine induced
postoperative Hallucination. Yafteh 2006;8(3):11-14.
original article
Oman Medical Journal [2015], Vol. 30, No. 7: 17–25
The Cystic Fibrosis Symptom Progression Survey
(CF-SPS) in Arabic: A Tool for Monitoring
Patients’ Symptoms
Catherine Norrish1*, Mark Norrish1, Uwe Fass1, Majid Al-Salmani1, Ganji Shiva
Lingam2, Fiona Clark2 and Hebal Kallesh2
Oman Medical College, Sohar, Oman
Sohar Regional Teaching Hospital, Sohar, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 14 September 2014
Accepted: 20 January 2015
Online:
DOI 10.5001/omj.2015.04
Keywords:
Cystic Fibrosis; Oman;
Survey; Disease progression;
Arabic.
A B S T R AC T
Objective: Our study aimed to develop a survey that could be used by nurses during
regular cystic fibrosis (CF) clinic visits, providing clinicians with a standardized means
of longitudinally assessing and monitoring symptom progression in their patients. In
addition, the use of this survey would provide an opportunity for patient engagement
and relationship building, thereby enhancing patient education and improving
adherence to treatment. This is the first such survey designed specifically for use in Arab
populations. Methods: The Cystic Fibrosis Symptom Progression Survey (CF-SPS) was
developed using previously published patient reported outcomes relating to pulmonary
exacerbations in CF. It contains 10 items that provide a patient-focused account of
symptoms. The survey was translated into Arabic and was completed by 12 patients on
139 occasions over 22 months. The psychometric properties of the survey were evaluated,
as was the relationship between the survey findings and other known clinical measures
of health status in CF. Results: The CF-SPS performs well as a psychometrically valid
clinical tool, with good internal consistency as determined by Cronbach’s alpha analysis.
Our results suggest that the CF-SPS is able to identify significant declines in health
status in line with routine clinical patient assessment (chest sounds, body mass index and
admissions). As such it is a useful tool that can support clinical decision making in the
care of Arabic speaking CF patients. Conclusion: We recommend the CF-SPSa (Arabic
version) as a valid tool for the longitudinal monitoring of symptom progression in CF in
Arabic speaking populations.
C
ystic Fibrosis (CF) is an autosomal
recessive disease and occurs in the
Caucasian population with a prevalence
of 1:25001 making it one of the most
common genetic disorders in this population.
CF affects mucus-producing organs and presents
predominantly with respiratory and gastrointestinal
symptoms.2 The disease is clinically characterized
by chronic airways infection and inflammation,
resulting in lung fibrosis and progressive loss of
pulmonary function. Lung disease is believed to be the
leading cause of 90% of deaths in patients with CF.3 A
failure to thrive is a result of pancreatic insufficiency
and subsequent malabsorption of nutrients,
resulting in reduced weight gain and difficulties in
maintaining body weight.4-8
Medical care concepts have advanced in Europe
and Northern America, where specialized CF
*Corresponding author:  norrishuk@gmail.com
centers provide holistic CF care. The advanced care
concepts, developed over the last four decades, have
contributed to an increase in life expectancy from
only six months in 1959 to around 30 years by 2003.
Where optimum CF care is available the predicted
median survival is now more than 50 years.9-11 Some
of these advances in CF care are yet to be realized in
Oman. The current average life expectancy for people
with CF in the North Al Batinah region was recently
reported as only 10.5 years.12 In addition, there is
limited research available on the perceived impact
of CF on daily life from the patients perspective, nor
is there research on the cultural/ethnic and socioeconomic factors that influence attitudes to health
and disease with respect to CF care in Oman.
A central part of CF care is the prevention,
diagnosis, and treatment of acute pulmonary
exacerbations (PEx). They are clinically characterized
18
Cat herin e Norrish, et al.
by a significant increase in respiratory symptoms such
as increased sputum production, increased cough,
and difficulty breathing as well as decreased appetite
and weight loss. These recurring episodes impact
significantly on health status.13 Liou et al,14 reported
that each PEx was found to significantly decrease
survival using a five-year survival prediction model.
It has been shown that lung function may not return
to baseline after a PEx suggesting overall decline
in lung health.3
In several studies the best predictors of a PEx were
signs and symptoms rather than physical examination
and laboratory results.15 Additionally, there appears
to be a move away from clinician-centered symptom
definitions of PEx, as described by Dakin et al,16
towards patient-reported outcomes (PROs) in order
to find a standardized patient-derived symptom
definition and exacerbation score.17-19 In one recent
study, the top triggers for seeking treatment for a
PEx, reported by adults, adolescents, and parents
of young children, were constant cough, increased
thick dark sputum, shortness of breath, fatigue,
chest pain, reduced activity, and poor appetite.18 This
symptom cluster is similarly reported by adults and
children with CF.20
PROs are now believed to be an essential
part of patient-centered care and have been used
to evaluate drugs, to assess and track the effects
and progress of a disease on different aspects of
patients functioning and for developing individual
treatment plans.21,22 A well-established PRO, the
Cystic Fibrosis Questionnaire-Revised Respiratory
Symptoms Scale (CFQ-RRSS), has recently been
used to evaluate respiratory symptoms in CF in
order to establish the efficacy of inhaled antibiotics
over 18 months.23 Jarad et al, developed a simple new
respiratory symptom scoring system for adults with
CF for assessing symptoms at the start and end of
each PEx, but this questionnaire only assesses four
respiratory symptoms, which may not capture
the full range of symptoms in CF.24 Another tool
for assessing respiratory symptoms in children,
adolescents, and adults is the 16-item Cystic
Fibrosis Respiratory Symptom Diary (CFRSD),
which focusses on the eight most frequently cited
and burdensome symptoms. 18 Additionally, the
CFRSD includes eight items related to the impact
on daily life and the emotional impact of the disease.
Appetite was not included in the questionnaire as
it was not considered respiratory in nature, despite
the fact that lack of appetite was cited twice as often
as other items such as fever which was included
in the questionnaire. Interestingly, a recent study
found that lack of appetite was one of the most
common symptoms associated with the onset of
an exacerbation in children and adults with CF
suggesting that regularly assessing appetite as part
of a symptom survey could give valuable insight
into health status.20
In our local setting, we observed that patient
compliance/non-compliance influenced the speed
of disease progression, treatment, and, ultimately,
outcome. It is of particular interest that patients with
the same genotype exhibit different levels of disease
severity suggesting there are other factors at work.
It is likely that a holistic approach that provides
an individualized approach to CF care will be of
particular merit in Oman, where regular monitoring
and tracking of an individual’s symptoms may
contribute to a slowing of symptom progression and
an increase in quality of life.25
The aim of the study was to develop a simple
survey that could be used by a nurse during regular
CF clinic visits. This survey would have two primary
roles, firstly to provide clinicians with a standardized
means of longitudinally assessing and monitoring
the progressive health status of individual children
with CF and secondly, through its regular use and
repetition of the survey, provide an opportunity for
patient engagement and relationship building. It was
also hoped that this individualized and longitudinal
approach to symptom progression would enhance
patient education and facilitate improved adherence
to treatment, thereby improving quality of life for
Omani children with CF.
M ET H O D S
A total of 12 children with CF ranging from the
age of five months to 15 years (mean age: six years)
were assessed using the Cystic Fibrosis Symptom
Progression Survey (CF-SPS) during routine
outpatient visits to the main hospital serving the
North Al Batinah region. Participants who attended
less than six times during the study period were
excluded from the data analysis. Children under
the age of nine were assessed by proxy, usually the
mother, and all children were encouraged to share
their opinions about their symptoms.
19
Cat herin e Norrish, et al.
Part 1: Survey Development
The items considered for inclusion in the CF-SPS
were identified through a detailed literature search
of studies relating to PEx in CF. These included
the various symptom parameters that were used
in defining a PEx 7,16,17,20,26-28 and CF PRO, 21,29,30
as well as factors involved in CF lung disease and
nutrition.4-6,8,31-33 The various existing questionnaires
and scoring systems in CF such as the CFQ-RRSS
and the CFRSD were also reviewed.34
Since this survey was being designed to be used
regularly with patients, only items that could be
reasonably reported by patients (or their proxy) were
considered. A preliminary thematic content analysis
of the items identified in the literature review
revealed 10 items that were frequently associated
with PEx, and therefore symptom progression,
in CF. These included seven respiratory-related
items: cough frequency, condition of child during
coughing, description of child’s coughing episodes,
amount of sputum, colour of sputum, effort of
breathing, and short/shallow/fast breathing and
three generic items: level of activity, usual appetite,
and recent changes in appetite.
Responses to each item were in the form of
either a visual analogue scale or a Likert scale. The
survey score was then transformed linearly to a
100-point scale, with higher scores indicating higher
symptom severity, revealing a significant decline in
health status, and thus an increased likelihood of
a PEx. Where appropriate pictures were added to
maximize face validity and make it user-friendly
particularly for the younger participants. The survey
was translated into Arabic by a native speaker with
a postgraduate level of English, using the iterative
forward-backward translation sequence.35 All of the
data presented here was completed using the Arabic
version of the CF-SPS.
The CF-SPS was administered using a nurseled individualized and informal interview style
approach. This took the form of a two to five minute
discussion with the patient or their proxy. In many
instances the survey items were read aloud to the
parent by the nurse, as some of the parents did not
have educational ability to read through the items
clearly. The temporal focus of the CF-SPS is to
report symptoms within the previous one week.
Analysis of the psychometric properties of the
CF-SPS included face validity (determination
of whether the questions are clearly worded and
Table 1: Glossary of psychometric terms.
Principal
component
analysis
(PCA)
A multivariate statistical technique that,
essentially, reduces a correlation matrix
into a few major pieces. It describes
which variables “go together” and aims
to extract principal components to
condense as much of the total variation
in the data as possible with a minimum
number of components.
Factor loading
In factor analysis this describes
the correlation between one of the
variables and the factor. It selectivity
differentiates individuals with a high
occurrence of the construct from
persons with a low occurrence of that
construct.
KolmogorovSmirnov test
A statistical test that determines
whether the distribution of a variable is
different from the normal distribution.
Homogeneity
(Cronbach’s
alpha)
A measure of the consistency of a test
scale; it examines whether all items of a
scale measure the same construct.
Mahalanobis
distance
A descriptive statistic that is used to
detect outliers in a dataset.
understood by patients). Internal scale consistency
was also assessed using Cronbach’s alpha coefficient
and confirmatory factor analysis, using a principle
component analysis with varimax rotation, to
determine scale component properties.
For the reliability and factorial analysis,
each survey completion was considered as an
independent sample. While it is statistically
desirable for the psychometric analysis involved in
survey development to be based on a large sample
of individuals there are often constraints imposed
by contextual and clinical factors. For example, the
sample used here constitutes all patients with CF who
make use of the local regional hospital. In addition,
tests of variability, such as the KolmonogorovSmirnov test, and tests of collinearity (see
Table 1 for glossary of psychometric terms) was
conducted to ensure that the non-independent
data did not unduly influence the reliability
analysis and interpretation.
Part 2 : Survey Use
The CF-SPS is a patient-focused account of
symptoms. In order to have clinical relevance it
is important to compare it with objective clinical
measures done during the same visit. For this
study, the clinical measures used as dependent
variables were: the patient’s body mass index
(BMI) percentile,36 assessment of chest sounds,
and whether the child was admitted to hospital
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
20
Cat herin e Norrish, et al.
Table 2: Construct and reliability analysis of the ten
items included in the survey.
Symptoms
Cronbach’s
alpha
coefficient
if item deleted
Factor
loadings
Amount of sputum
0.71
0.63
Color of sputum
0.75
0.35
Condition/state of
child during coughing
0.72
0.67
Description of child’s
coughing episodes
0.75
0.41
Cough frequency
0.72
0.69
Effort of breathing
0.71
0.76
Short, shallow, fast
breathing
0.72
0.69
Level of activity
0.74
0.57
Recent changes in
appetite
Usual appetite
0.73
0.51
0.76
0.30
for treatment of PEx (with intravenous (IV)
antibiotics). Chest sounds were assessed by
auscultation using a standardized scoring scale from
0 to 12, based on the presence or absence of lung
sounds in the six lung fields (front and back), with 0
indicating “clear” lungs.
The CF-SPS was completed for every occasion
that a child with CF visited the clinic. Symptoms
among CF sufferers vary according to a wide
range of factors including, disease severity, age,
general health status, and adherence. Therefore,
it is important to use an individualized approach
to patient monitoring. In order to facilitate this,
a baseline was determined for each patient on the
basis of the mean of the patient’s four lowest CFSPS scores during the study. In order to derive a
range for the normal variation in symptom severity,
the five patients with the most stable CF-SPS scores
over a six-month period were selected. The normal
variation range was defined as twice the standard
deviation (SD) of the scores from these five stable
patients. None of these patients experienced a PEx
during this period. This range equated to a 10-point
variation in the CF-SPS score.
An individual’s normal variation during a period
of stable symptom expression was therefore defined
as 10 points above and below their baseline. This will
be referred to as the green zone. Therefore, survey
scores that occurred within the green zone were
considered to be acceptable and not indicative of
new intervention. The area above the green zone will
be referred to as the red zone, within which, scores
were considered significant declines in health status.
A score in the red zone will be referred to as a spike.
Comparison between the CF-SPS and the other
clinical measures used as dependent variables was
made using standardized inferential and relational
statistics (t-test, Chi-square test, and Pearson's
correlation), and performed using the SPSS
statistical package. The project was approved by
the Institutional Review Board of Oman Medical
College and the Ethical Committee of the Ministry of
Health of Oman.
R E S U LT S
A total of 12 pediatric CF patients were included
in the study and a total of 139 CF-SPS were
completed. During the study period (November
2011–September 2013), there were 17 admissions
for PEx. Patient demographics are given in
Table 2. The average age on first visit was six years
(range: five months to 15 years). There were five
males and seven females. The average sweat chloride
level was 98.60 (SD 6.90) and fecal elastase level
110.80 (SD 7.60). The genetic profile of patients
with CF has been reported previously.37
Part 1: Survey Development
The CF-SPS has good internal consistency with
a Cronbach’s alpha coefficient (C-alpha) of 0.76.
In addition, all items are independently worthy of
inclusion in the CF-SPS. The greatest increase in
C-alpha would result from removing the item on
“usual appetite”, but this would lead to a rise of only
0.002 in internal consistency, therefore all 10 items
were maintained.
As with most clinical data most of the items in this
survey are non-parametric and displayed significant
skew. This is to be expected since the desirable
distribution for clinical datasets is usually a skewed
sample in favor of a healthy status. Multivariate,
non-parametric outlier analysis showed that this
data did not include any significant outliers with
Mahalanobis distance showing no items with a
probability less than 0.001 (for the 10 items).
In addition, factor analysis suggests that it
is reasonable to consider the CF-SPS as a single
construct. Principle component factor analysis
indicated that the item loadings for all 10 questions
21
Cat herin e Norrish, et al.
70
60
a
50
50
CF-SPS score (%)
CF-SPS score (%)
60
40
30
20
‘green zone’
10
70
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Consecutive visits
b
CF-SPS score (%)
50
40
30
10
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Consecutive visits
c
CF-SPS score (%)
60
50
40
30
10
30
Green
zone
Red
zone
20
88
2
31
15
10
0
No admission
Admission
‘green zone’
20
20
No
admission Admission
Figure 2: Mean Cystic Fibrosis Symptom
Progression Survey (CF-SPS) scores for hospital
admissions. The colors on the figure represent the
total proportions of the CF-SPS that were in the
green or red zones. The admissions frequency table
is shown to the left.
60
70
40
‘green zone’
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Consecutive visits
Figure 1: Cystic fibrosis health diagrams showing
the Cystic Fibrosis Symptom Progression Survey
(CF-SPS) score of three patients during the study
period. The green (base) zone for each individual
is shown. (a) Patient showed a stable pattern and
favorable health status with no admissions or
suspected acute pulmonary exacerbations (PEx).
(b) The patient was stable but showed a suspected
spike. The patient was not admitted for PEx. In
contrast (c) shows a patient who exhibits an erratic
pattern and unfavorable health status with two
spikes (scores in the red zone) corresponding with
admissions for PEx.
were greater than 0.30 for the first component of the
construct [Table 2].
An analysis of missing cases showed that for
two items there was a significant increase in missing
data. These two items both involved sputum
symptoms. Some participants were not habitually
expectorating sputum, but would rather swallow it.
For this reason several participants did not complete
these two items: color and amount of sputum. This
preference for non-expectoration of sputum has
been previously noted in the literature.38,39 The
internal consistency of a partial CF-SPS with these
two items removed was nearly identical to the full
scale indicator of reliability (C-alpha=0.75). Since
these two items seem to contribute to the same
single factor construct as the other eight items it
was decided that for patients who could not answer
these questions the remaining eight items would be
transformed linearly to a 100-point scale, to allow
for comparison to be made.
Part II: Survey Use
Analysis of CF-SPSs obtained during clinic visits
allowed us for the first time to plot and track the
longitudinal course of pulmonary function, as
shown in Figure 1. Two distinct patterns emerged,
a consistent pattern characteristic of a stable health
status and an erratic pattern representing an unstable
health status. A CF patient with a controlled and
stable health status will have a longitudinal CFSPS profile that falls largely within the green zone,
as seen in Figure 1a. In contrast, Figure 1c showed
a longitudinal CF-SPS profile from an unstable
patient, with an erratic fluctuating pattern, defined
by frequently occurring spikes in the red zone.
These red zone spikes are the result of an increase in
symptom severity and represent periods of worsening
health status. Interestingly, the spikes often coincide
with clinician-diagnosed PEx experienced by the
patient, represented by the arrows in Figure 1c.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
22
Cat herin e Norrish, et al.
100
90
Admission
No admission
80
CF-SPS score (%)
70
60
50
40
30
20
10
0
20
40
60
80
100
BMI percentile
Figure 3: A scatter graph showing the relationship between body mass index (BMI) percentiles and Cystic
Fibrosis Symptom Progression Survey (CF-SPS) scores. Crosses indicate non-admissions with the solid
line displaying the corresponding trend line. Red diamonds indicate an admission, with the trend line for
admissions shown by the broken line.
The CF-SPS that were associated with admission
were significantly higher compared to those not
associated with admission (t(1,132)=6.3, p<0.001)
with mean scores of 52.7 and 34.4, respectively.
Thus a higher CF-SPS score is a useful indicator of
likelihood for hospital admission and PEx.
Chi-square analysis shows that this frequency
data [Figure 2] is significantly different from that
expected from a null hypothesis (Χ2=25.7, p<0.001).
Specifically, red zone spikes are associated with
hospital admission. We observed that 88 green zone
surveys were coupled with no admission and only
two admissions associated with green zone surveys.
Of the 46 red zone spikes 15 were associated with
admission for PEx while, surprisingly, no admissions
occurred in 31 of the visits in which a spike was
identified. Eleven out of the 12 participants
experienced at least one red zone spike in CF-SPS
during the study period.
A similar significant relationship was established
between the CF-SPS score and chest sound scores
when analyzed by Pearson’s correlation (R2=0.45,
p<0.001). In addition, using a t-test to test the
difference in chest sound scores between green zone
and red zone CF-SPS score, showed that there were
significantly worse chest sounds for survey scores in
the red zone (t(1,112)=5.65, p<0.001) with a mean
chest sound score of 4.10 for surveys in the red zone
and 0.90 for surveys in the green zone.
Using Pearson’s correlation we observed a
significant negative correlation between CF-SPS
score and BMI (R2=-0.42, p<0.001). Figure 3
illustrates that a low BMI percentile is associated
with a higher CF-SPS score as highlighted by the
solid trend line. It appears that those patients with
lower BMI percentiles are more susceptible to
respiratory symptoms including PEx. However,
no significant correlation was found between
BMI percentiles and admissions. So while CFSPS is predictive of an admission, a low BMI was
not predictive of admission for PEx. Admissions
compared to non-admissions appear to be associated
with significantly higher CF-SPS scores illustrated
by the higher dashed trend line.
DISCUSSION
The CF-SPS performs well as a psychometrically
valid clinical tool. In addition to patient satisfaction
as a measure of face validity, it also shows good
internal scale consistency and reliability. Thus we
recommend the CF-SPSa (Arabic version) as a valid
tool for the longitudinal monitoring of symptom
progression in CF in Arabic speaking populations.
Our results suggest that the CF-SPS is able to
identify significant declines in health status in
line with routine clinical patient assessment. We
observed that CF-SPS scores were found to be
23
Cat herin e Norrish, et al.
significantly higher in patients who were admitted.
Patients with chest sounds indicative of chest
infection also displayed higher CF-SPS scores.
The majority of CF-SPS scores in the green zone
were associated with no admission, suggesting
that the survey is also able to identify periods of
stability in health.
Systematic and longitudinal use of the CF-SPS
for each patient can provide valuable individual and
cohort information that may not have been identified
previously. These individual health profiles are a
valuable addition to the clinician during clinic visits.
Participants who exhibit an erratic or unfavorable
health pattern in their CF-SPS scores can be
identified as “at risk” and perhaps requiring further
investigation to identify contributing factors such as
non-compliance, lack of knowledge, or nutritional
deficiencies. Conversely, the treatment regime for
a patient who exhibits a consistently low CF-SPS
score with a stable pattern could be considered as
adequate and low risk.
Our study also confirms a strong link, which
is well documented, between nutritional status
and lung health.4,6,31,32 We found that a low BMI
was associated with a higher CF-SPS score. On
average our participants had a BMI well below the
recommended 50th percentile. One important
characteristic of the cohort in this study was the
frequent number of PEx, with seven out of 12
participants admitted at least once for IV antibiotics.
It appears that those with poor nutritional status are
more susceptible to acute respiratory exacerbations.
With further significant declines in BMI common
during periods of PEx (due to increased metabolic
requirements), and the subsequent decline in lung
function. This could, in part, explain the low survival
rate seen in our patients.26,27,33 We propose that the
most favorable picture for a child with CF is a low
CF-SPS score (within an individual’s green zone),
with a higher BMI percentile. In contrast, a child
with a low BMI and CF-SPS scores frequently in the
red zone reveals an unfavorable health status.
We observed that there were 46 CF-SPS scores
that fell within the red zone (spikes) during the
study period. However, 31 of these did not result in
admission for IV antibiotics. There could be many
reasons for this outcome, for example, the green zone
may underestimate the range of healthy states and
therefore small spikes are frequently identified when
the child is doing well and does not need additional
hospital-based treatment. The CF-SPS relies on the
honesty of the participant or proxy and therefore it
may be possible that the information provided was
biased to avoid admission. We have observed several
occasions when an admission for the treatment of a
PEx has been strongly recommended by the clinician
but refused by the patient and/or family. It is worth
noting that in Oman no home care is available so all
IV treatment requires a lengthy hospital stay, which
can be very disruptive for families.
As this study represents the longitudinal findings
for only 12 patients, the extent to which they can be
generalized to other patient groups is limited. While
it may be statistically desirable for there to have been
a larger sample size, clinical factors constrained this
and these 12 patients constituted all of patients with
CF available who make use of the local regional
hospital. We would welcome the use of this survey in
other clinical centers to enhance the generalizability
of these findings.
Cultural, social, educational, and economic
factors undoubtedly play a major role in CF care
in Oman, influencing attitudes towards illness and
treatment compliance, and in turn may affect the
number of admissions, type of treatment children
receive, and ultimately, the outcome. For example,
according to the World Health Organization world
health statistics 2013, literacy in Oman is around
87% among adults aged 15 or over.40 However, the
13% who remain illiterate are thought to be living
in rural/mountainous regions such as in the north
Al Batinah region of Oman, in which this study was
conducted. Socioeconomic status is known to have
a major influence on outcomes in CF, with more
frequent PEx and significantly lower BMI and lung
function being associated with lower incomes.41,42
This may in part explain the poor health status
observed among some of the participants.
The CF-SPS was generally well received by
participants and their families. Many parents
appeared to welcome its inclusion into their regular
scheduled clinical visit as it involved a one-to-one
aspect to their visit, and provided an opportunity
for them to freely share how they considered their
child to be doing. Parents appreciated a listening
ear and the empathetic approach, a core aspect of
the nursing role.43 Used systematically over many
clinic visits, the CF-SPS became a familiar part
of the routine and a platform for discussing other
issues relating to the disease. Fostering better
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
24
Cat herin e Norrish, et al.
communication and understanding through this
patient-centered time has been a positive part of this
study. This is especially important in Middle Eastern
culture, where building trust between caregiver
and patient has to be established before personal
information can be shared freely.44,45 Participants/
parents can feel empowered when they feel listened
to, leading to better collaboration, shared decisionmaking, and potentially improved adherence.22,46
This patient-centered approach to nursing care
is a useful example of a culturally contextualized
approach to professional practice.47
In the Arab world, it has been noted that the
incidence of CF is believed to be higher than the
reported rates as a result of under-diagnosis. 48
To further compound this, the life expectancy
for patients who have been diagnosed with CF in
Oman is far lower than international expectations.12
Together these illustrate a significant problem in
both the diagnosis and the management of CF. In
response to this problem, it is essential that efforts are
made to build beneficial and longitudinal health care
relationships with patients and their families and to
educate both patients and health professionals in
best practice in managing CF within the Omani
context. The CF-SPS is one tool that can help
with this endeavor.
C O N C LU S I O N
We propose that the CF-SPS could benefit
clinicians and other health care professionals
in making decisions regarding treatment and
diagnosis. It is a practical tool especially suitable
for use in regular clinic visits, and limited resource
settings. It provides a standardized way of assessing
and monitoring the changing health status of
children with CF, giving a unique and ongoing
picture of their health status. Additionally, tracking
the relationship between BMI and the CF-SPS
provides an additional dimension bringing together
respiratory and nutritional elements that are so
interlinked in this complex disease. Finally, the CFSPS along with other clinical measures provides
important information that aids the clinician,
highlighting patients most at risk and in need of
closer monitoring and intervention.
Disclosure
The authors declared no conflicts of interest. This research was
funded by a grant from The Oman Research Council (TRC
Grant #ORG OMC HSS 10 008).
r ef er ences
1. Mehta G, Macek M Jr, Mehta A; European Registry
Working Group. Cystic fibrosis across Europe: EuroCareCF
analysis of demographic data from 35 countries. J Cyst
Fibros 2010 Dec;9(Suppl 2):S5-S21.
2. Seliger VI, Rodman D, Van Goor F, Schmelz A, Mueller P.
The predictive potential of the sweat chloride test in cystic
fibrosis patients with the G551D mutation. J Cyst Fibros
2013 Dec;12(6):706-713.
3. Zemanick ET, Harris JK, Conway S, Konstan MW, Marshall
B, Quittner AL, et al. Measuring and improving respiratory
outcomes in cystic fibrosis lung disease: opportunities and
challenges to therapy. J Cyst Fibros 2010 Jan;9(1):1-16.
4. Leonard A, Davis E, Rosenstein BJ, Zeitlin PL, Paranjape
SM, Peeler D, et al. Description of a standardized nutrition
classification plan and its relation to nutritional outcomes
in children with cystic fibrosis. J Pediatr Psychol 2010 JanFeb;35(1):6-13.
5. Konstan MW, Butler SM, Wohl ME, Stoddard M, Matousek
R, Wagener JS, et al; Investigators and Coordinators of
the Epidemiologic Study of Cystic Fibrosis. Growth and
nutritional indexes in early life predict pulmonary function
in cystic fibrosis. J Pediatr 2003 Jun;142(6):624-630.
6. Peterson ML, Jacobs DR Jr, Milla CE. Longitudinal
changes in growth parameters are correlated with changes
in pulmonary function in children with cystic fibrosis.
Pediatrics 2003 Sep;112(3 Pt 1):588-592.
7. Elborn JS, Bell SC. Pulmonary exacerbations in cystic
fibrosis and bronchiectasis. Thorax 2007 Apr;62(4):288290.
8. Matel JL, Milla CE. Nutrition in cystic fibrosis. Semin
Respir Crit Care Med 2009 Oct;30(5):579-586.
9. Dodge JA, Lewis PA, Stanton M, Wilsher J. Cystic fibrosis
mortality and survival in the UK: 1947-2003. Eur Respir J
2007 Mar;29(3):522-526.
10. Döring G, Flume P, Heijerman H, Elborn JS; Consensus
Study Group. Treatment of lung infection in patients with
cystic fibrosis: current and future strategies. J Cyst Fibros
2012 Dec;11(6):461-479.
11. Chakrabarty B, Kabra SK, Gulati S, Toteja GS, Lodha R,
Kabra M, et al. Peripheral neuropathy in cystic fibrosis: a
prevalence study. J Cyst Fibros 2013 Dec;12(6):754-760.
12. Fass U, Al Oraimi M, Thomas R, Dhouwayani S, Al Naqbi
M, Al Balushi N, et al. Survival analysis of cystic fibrosis
(CF) patients in the North Al Bathina region of the
Sultanate of Oman. Journal of Cystic Fibrosis 2010;1(9)
S112:432.
13. Britto MT, Kotagal UR, Hornung RW, Atherton HD,
Tsevat J, Wilmott RW. Impact of recent pulmonary
exacerbations on quality of life in patients with cystic
fibrosis. Chest 2002 Jan;121(1):64-72.
14. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs
JR, Marshall BC. Predictive 5-year survivorship model of
cystic fibrosis. Am J Epidemiol 2001 Feb;153(4):345-352.
15. Goss CH, Burns JL. Exacerbations in cystic fibrosis.
1: Epidemiolog y and pathogenesis. Thorax 2007
Apr;62(4):360-367.
16. Dakin C, Henry RL, Field P, Morton J. Defining an
exacerbation of pulmonary disease in cystic fibrosis. Pediatr
Pulmonol 2001 Jun;31(6):436-442.
17. Bilton D, Canny G, Conway S, Dumcius S, Hjelte L,
Proesmans M, et al. Pulmonary exacerbation: towards
a definition for use in clinical trials. Report from the
EuroCareCF Working Group on outcome parameters in
clinical trials. J Cyst Fibros 2011 Jun;10(Suppl 2):S79-S81.
25
Cat herin e Norrish, et al.
18. Goss CH, Edwards TC, Ramsey BW, Aitken ML, Patrick
DL. Patient-reported respiratory symptoms in cystic
fibrosis. J Cyst Fibros 2009 Jul;8(4):245-252.
19. Abbott J, Hart A, Morton AM, Dey P, Conway SP, Webb
AK. Can health-related quality of life predict survival in
adults with cystic fibrosis? Am J Respir Crit Care Med 2009
Jan;179(1):54-58.
20. Abbott J, Holt A, Morton AM, Hart A, Milne G, Wolfe
SP, et al. Patient indicators of a pulmonary exacerbation:
preliminary reports from school aged children map onto
those of adults. J Cyst Fibros 2012 May;11(3):180-186.
21. Rothman ML, Beltran P, Cappelleri JC, Lipscomb J,
Teschendorf B; Mayo/FDA Patient-Reported Outcomes
Consensus Meeting Group. Patient-reported outcomes:
conceptual issues. Value Health 2007 Nov-Dec;10(Suppl
2):S66-S75.
22. Quittner AL, Alpern AN, Kimberg CI. Integrating patientreported outcomes into research and clinical practice. In
Wilmott et al. Disorders of the Respiratory Tract in
Children. 8th Edition. Oxford, 2012. p.251-60.
23. Oermann CM, Retsch-Bogart GZ, Quittner AL, Gibson
RL, McCoy KS, Montgomery AB, et al. An 18-month study
of the safety and efficacy of repeated courses of inhaled
aztreonam lysine in cystic fibrosis. Pediatr Pulmonol 2010
Nov;45(11):1121-1134.
24. Jarad NA, Sequeiros IM. A novel respiratory symptom
scoring system for CF pulmonary exacerbations. QJM 2012
Feb;105(2):137-143.
25. Sawyer SM, Aroni RA. Sticky issue of adherence. J Paediatr
Child Health 2003;39(1):2-5.
26. Ferkol T, Rosenfeld M, Milla CE. Cystic fibrosis pulmonary
exacerbations. J Pediatr 2006 Feb;148(2):259-264.
27. Rabin HR, Butler SM, Wohl ME, Geller DE, Colin
AA, Schidlow DV, et al; Epidemiologic Study of Cystic
Fibrosis. Pulmonary exacerbations in cystic fibrosis. Pediatr
Pulmonol 2004 May;37(5):400-406.
28. Rosenfeld M, Emerson J, Williams-Warren J, Pepe
M, Smith A, Montgomery AB, et al. Defining a
pulmonary exacerbation in cystic fibrosis. J Pediatr 2001
Sep;139(3):359-365.
29. Turner RR, Quittner AL, Parasuraman BM, Kallich JD,
Cleeland CS; Mayo/FDA Patient-Reported Outcomes
Consensus Meeting Group. Patient-reported outcomes:
instrument development and selection issues. Value Health
2007 Nov-Dec;10(Suppl 2):S86-S93.
30. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara
J, Montgomery AB. Determination of the minimal
clinically important difference scores for the Cystic Fibrosis
Questionnaire-Revised respiratory symptom scale in two
populations of patients with cystic fibrosis and chronic
Pseudomonas aeruginosa airway infection. Chest 2009
Jun;135(6):1610-1618.
31. Steinkamp G, Wiedemann B. Relationship between
nutritional status and lung function in cystic fibrosis:
cross sectional and longitudinal analyses from the German
CF quality assurance (CFQA) project. Thorax 2002
Jul;57(7):596-601.
32. Borowitz D, Baker RD, Stallings V. Consensus report on
nutrition for pediatric patients with cystic fibrosis. J Pediatr
Gastroenterol Nutr 2002 Sep;35(3):246-259.
33. Naon H, Hack S, Shelton MT, Gotthoffer RC, Gozal D.
Resting energy expenditure. Evolution during antibiotic
treatment for pulmonary exacerbation in cystic fibrosis.
Chest 1993 Jun;103(6):1819-1825.
34. Henry B, Aussage P, Grosskopf C, Goehrs JM. Development
of the Cystic Fibrosis Questionnaire (CFQ) for assessing
quality of life in pediatric and adult patients. Qual Life Res
2003 Feb;12(1):63-76.
35. Beaton DE, Bombardier C, Guillemin F, Ferraz MB.
Guidelines for the process of cross-cultural adaptation
of self-report measures. Spine (Phila Pa 1976) 2000
Dec;25(24):3186-3191.
36. World Health Organization. Child growth standards.
Geneva, 2006. Available at http://www.who.int/
childgrowth/en/. Accessed June 24, 2013.
37. Fass UW, Al-Salmani M, Bendahhou S, Shivalingam G,
Norrish C, Hebal K, et al. Defining a mutational panel and
predicting the prevalence of cystic fibrosis in oman. Sultan
Qaboos Univ Med J 2014 Aug;14(3):e323-e329.
38. de Jongste JC, Shields MD. Cough. 2: Chronic cough in
children. Thorax 2003 Nov;58(11):998-1003.
39. Tierney S, Riley D, Jones AM, Webb AK, Horne M.
Differing perspectives of sputum and its expectoration:
a qualitative study involving patients with cystic fibrosis
and physiotherapists. Physiother Theory Pract 2011
May;27(4):278-286.
40. World Health Organization. World health statistics 2013.
Geneva, 2013.
41. Schechter MS, Shelton BJ, Margolis PA, Fitzsimmons SC.
The association of socioeconomic status with outcomes in
cystic fibrosis patients in the United States. Am J Respir
Crit Care Med 2001 May;163(6):1331-1337.
42. Quittner AL, Schechter MS, Rasouliyan L, Haselkorn T,
Pasta DJ, Wagener JS. Impact of socioeconomic status,
race, and ethnicity on quality of life in patients with cystic
fibrosis in the United States. Chest 2010 Mar;137(3):642650.
43. McCullough C, Price J. Caring for a child with cystic
fibrosis: the children’s nurse’s role. Br J Nurs 2011
Feb;20(3):164-167.
44. Lipson JG, Meleis AI. Issues in health care of Middle
Eastern patients. West J Med 1983 Dec;139(6):854-861.
45. Al-Wahaibi A, Almahrezi A. An application of educational
theories and principles of teaching and learning
communication skills for general practitioners in oman.
Oman Med J 2009 Apr;24(2):119-127.
46. Jimmy B, Jose J. Patient medication adherence: measures
in daily practice. Oman Med J 2011 May;26(3):155-159.
47. Norrish MI. Learning about Challenges to Medical
Professionalism in Oman: A Culturally Contextualized
Approach? Oman Med J 2012;27(2):182.
48. Al-Kindy H, Ouhtit A, Al-Salmi Q, Al-Bimani M, AlNabhani M, Gupta I. Novel Mutation in the CFTR Gene
of Cystic Fibrosis Patients in Oman. Journal of Molecular
Biomarker and Diagnosis 2014;5(168):2-5.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
original article
Oman Medical Journal [2015], Vol. 30, No. 1: 26–30
Adolescents and Adults with Congenital Heart
Diseases in Oman
Asim Al-Balushi1*, Hamood Al-Kindi2, Hamood Al-Shuaili3, Suresh Kumar1 and
Salim Al-Maskari1
Department of Pediatric Cardiology, Royal Hospital, Muscat, Oman
Department of Cardiothoracic Surgery, Sultan Qaboos University Hospital, Muscat, Oman
3
Department of Pediatric, Royal Hospital, Muscat, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 6 November 2014
Accepted: 10 February 2015
Online:
DOI 10.5001/omj.2015.05
Keywords:
Congenital Heart Disease;
Oman; Adult; Adolescent.
A B S T R AC T
Objectives: The aim of our study was to examine the spectrum, demographics, and
mortality rate among adolescents and adults with congenital heart diseases (CHD) in
Oman. Methods: Data was collected retrospectively from the Royal Hospital, Muscat,
electronic health records for all patients with a diagnosis of CHD aged 13 years and
above. Data was analyzed according to the type of CHD and in-hospital mortality was
assessed using Kaplan-Meier survival analysis. Results: A total of 600 patients with CHD
were identified, among them 145 (24%) were aged 18 years or below. The median age
was 24 years. The majority of patients had a simple form of CHD. Atrial and ventricular
septal defects together constituted 62.8% of congenital heart diseases. Most patients
were clustered in Muscat (32%) and the Batinah regions (31.1%) of Oman. Patients with
tetralogy of Fallot and Fontan had shorter survival time than recorded in the published
literature. Conclusion: Mostly simple forms of CHD in younger patients was observed.
The survival rate was significantly shortened in more complex lesions compared to
simple lesions. A national data registry for CHD is needed to address the morbidities
and mortality associated with the disease.
C
ongenital heart disease (CHD) is the
most common form of congenital
anomalies1 with a reported incidence in
Oman of 7.1 per 1000 births.2 Much of
the literature on adults with congenital heart disease
(ACHD) emerged from North America and Europe.
As congenital heart surgery has been performed for
more than half a century, the profile of the ACHD
is largely that of operated CHD. Due to advances in
the field of pediatric cardiology, cardiac surgery, and
critical care, most children born with CHD survive
to adulthood with the adult population with CHD
exceeding the number in the pediatric population. The
estimated population of ACHD in the United States
is more than one million and 1.2 million in Europe.3,4
This growing population of ACHD has special medical
and surgical needs due to the nature and complexity of
the lesions. One of the first challenges in adults is the
transition from pediatric to adult care, which should
be optimized and well-structured to avoid interruption
of care.5 In addition, as surgical treatment is seldom
curative, this population has long-term complications
including arrhythmias, infective endocarditis, stroke,
*Corresponding author:  dr_albalushi@hotmail.com
pulmonary hypertension, and heart failure, which
may require transplantation. 6,7 Although most
emerging data about ACHD was published from
North America and Europe,8-10 there was a substantial
increase in the number of publications related to
ACHD from other parts of the world in the last few
years.11-14 Several guidelines have also been published
for the management of ACHD.15,16
To date, there is no published data on the
spectrum of CHD in adolescents and adults in
Oman. We sought to examine this for patients in
Oman with CHD above the age of 13 years. In
addition, we performed survival analysis for some
forms of CHD among the study population.
M ET H O D S
In this retrospective cohort study data was collected
from hospital records at the Royal Hospital, Muscat,
which is the referral center for all CHD in Oman.
All patients at or above 13 years of age who were
registered in the hospital electronic health records
and that had CHD were included in the study, which
27
Asim A l-Balushi, et al.
took place between January 2006 and January 2013.
We included patients aged 13 years and above as this
is the age of transition from pediatric care to adult
care in Oman. The definition of CHD was based
on international classification of diseases version
10.17 Patients with Marfan syndrome, hypertrophic
cardiomyopathy, isolated dextrocardia with no
CHD, and isolated congenital heart block with
no structural abnormalities were not included in
the study. If two lesions were present the more
hemodynamically significant lesion was considered
for primary diagnosis. The primary diagnosis was
verified using echocardiography results to exclude
the possibility of miscoding. The following variables
were obtained in addition to the primary diagnosis:
age, sex, address, date of last follow-up, and inhospital mortality during study period. The study
was approved by the research and ethics committees
at the Royal Hospital, Muscat, Oman.
Statistical analysis was performed using SPSS,
version 16 (Chicago, Illinois, USA) and GraphPad
Prism version 5.00 (San Diego, California, USA).
Categorical variables were presented as percentage
and numbers, and continuous variables as mean with
standard deviation (SD) or median with interquartile
range (IQR). All-cause mortality during the study
period was examined with the date of birth as starting
time and the date of last follow up as the end-point
for the analysis, using the Kaplan-Meier curve with
log rank test to assess the significance. A p-value of
<0.050 was considered significant.
R E S U LT S
A total of 600 patients were included in the study.
Patients baseline characteristics are shown in Table
1. The mean follow up time was 4.5 years (range
2–7 years). Over half (54%) of patients were female
(n=326). There were 145 (24%) patients aged 18
years or below and 455 (76%) patients aged over 18
years. The lesions specific median age for the study
population is also given in Table 1. Forty patients with
ventricular septal defect (32%) and 31 with atrial septal
defect (12%) had unrepaired lesion at the last follow
up. The distribution of all CHDs per geographical area
is shown in Figure 1. The majority of patients were in
capital area Muscat (32%) followed by North Batinah
(17%), South Batinah (14%), and the Dakhliya region
(14%). The other regions contributed to less than 6%
each to the total population.
The spectrum of CHD per diagnosis is shown in
Figure 2. The majority of patients had atrial septal
defects (41.8%) followed by ventricular septal defects
(21%). The following defects were more common
in females than males: atrial septal defects, patent
ductus arteriosus, pulmonary valve stenosis, Fontan
circulation, tetralogy of Fallot, and atrioventricular
septal defect. In addition, male patients had more
transposition of great arteries, Ebstein’s anomaly,
coarctation of aorta, and bicuspid aortic valve, and
slightly more ventricular septal defects than females.
All cause in-hospital mortality for selected
CHD is shown in Figure 3. The mortality was
lowest in non-cyanotic defects with patients
Table 1: Patient baseline characteristics.
Diagnosis
Frequency (n)
Age in years median
(IQR)*
Gender
male/female (%)
Atrial septal defect
251
32 (23–32)
38.2/61.8
Ventricular septal defect
126
21(17–21)
25.9/24.3
Patent ductus arteriosus
8
25 (18–25)
25.0/75.0
Pulmonary valve stenosis
17
28(18–28)
17.6/82.4
D-transposition of great arteries
30
21(19–21)
66.7/33.3
L-transposition of great arteries
12
24(18–24)
58.3/41.7
Fontan circulation
36
20(17–20)
47.2/52.8
Coarctation of aorta
13
21(16–21)
69.2/30.8
Ebstein anomaly
18
27(21–27)
76.2/23.8
Tetralogy of Fallot
61
21(17–21)
45.9/54.1
Bicuspid aortic valve
21
26(19–26)
71.4/28.6
Atrioventricular septal defect
7
23(20–23)
14.3/85.7
600
24(19–24)
45.7/54.3
Overall
*IQR: interquartile range.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
28
Asim A l-Balushi, et al.
Musandam Burami
North
Sharqya
Dakhliya
Dhahera
South
Batinah
Wusta
North
Batinah
Dhofar
ASD
VSD
PDA
PS
Fontan
CoA
Ebstein
TOF
South
Sharqya
Muscat
1% 0.8%
10.2%
14.3%
DTGA
CTGA
Bicuspid AV septal
aortic valve defect
3.5% 1.2%
3%
31.8%
2.2%
14.3%
6%
2%
5%
4.5%
41.8%
2.8%
1.3%
0.7%
16.8%
4.8%
5.2%
5.7%
Figure 1: Geographical distribution of adolescents
and adults with congenital heart diseases according
to different regions in Oman.
diagnosed with atrial septal defects having the
lowest mortality. The survival time among
patients with ventricular septal defect was reduced
Survival function
1.0
21%
ASD: atrial septal defect; VSD, ventricular septal defect; PDA: patent ductus
arteriorsus; PS: pulmonary stenosis: DTGA: dextro-transposition of great arteries;
CTGA: corrected transposition of great arteries; CoA: coarctation of aorta;
TOF: tetralogy of Fallot; AV: atrioventricular.
Figure 2: Spectrum of congenital heart diseases in
adolescents and adults in Oman.
compared to patients with atrial septal defects.
Patients with tetralog y of Fallot and Fontan
had the highest mortality with median survival
time of 51 years and 31 years, respectively. This
difference was statistically significant with log
rank test p-value of <0.050.
0.8
Overall survival
DISCUSSION
0.6
Atrial septal defect
Ventricular septal defect
Tetralogy of Fallot
Fontan
0.4
0.2
0
10
20
30
40 50 60
Time (Years)
70
80
90 100
Figure 3: Kaplan-Meier curve for selected groups
of congenital heart diseases.
This is the first study in Oman that has described
the spectrum and demographics of adolescents and
adults with CHD. The available data shows that this
is a young population with the majority of surviving
patients having simple forms of CHD. The current
overall median age for this cohort is 24 years, which
is lower than what has been reported in Europe9,10
where the median age is 27 years, and 29 years in
North America.16-18 We found more females with
CHD in our cohort than males. This is consistent
with the literature. The spectrum of CHD in this
population emerging from our data is similar to
29
Asim A l-Balushi, et al.
other published studies that have shown that simple
defects are more common in this population than
cyanotic and complex defects. A previous study
from Oman looking at the incidence of CHD
showed no difference in the incidence of different
types of CHD when compared to western countries,
albeit with higher incidence of atrioventricular
septal defects.2
Early mortality from CHD have been well
described.18,19 It has been shown that mortality
in CHD is related to either surgical mortality,
or catheter related interventions in younger
populations. 19,20 Thus, early mortality and loss
to follow-up among patients with more complex
forms of CHD is a potential explanation for the
predominance of simple forms of CHD in this
study rather than due to lower birth incidence. To
date, there is no published data from Oman on the
mortality and morbidity after pediatric congenital
heart surgery.
Another major finding from our study is
the variability of geographical distribution of
adolescents and adults with CHD in Oman; the
majority of patients were in the capital area Muscat
and nearby Batinah region and fewer patients living
in far northern Musandam region and far south
Dhofar region. Therefore, there were less registered
patients in the electronic health care system from
areas far from the hospital. This finding raises the
issue of accessibility to health care for patients with
CHD, as patients living close to the tertiary care
center will tend to follow-up more than patients
living far away from the center. It has been shown
that the location of a CHD clinic contributed to the
loss of follow-up5 with patients living close to clinic
being more likely to be followed up.
An important potential explanation for
this geographical variability is the presence of
consanguinity in Oman. It has been shown that
consanguinity, in particular, the marriage of first
cousins may increase risk of CHD.20-22 However, the
rate of consanguinity in Oman has not been shown
to be different between different regions,22,23 thus
we believe that consanguinity may not contribute
to the regional variability that we have seen
in this study.
The mortality of adolescent and adults with
CHD in the study is consistent with what has
been reported previously with the mortality being
higher in cyanotic and Fontan patients and the
lowest mortality rate in patient with atrial and
ventricular septal defects. 9,10 However, patients
with cyanotic defects and Fontan in this cohort
are younger compared to published literature.23-25
The reduced survival in patients with tetralogy of
Fallot and Fontan is expected knowing that patients
with repaired tetralogy of Fallot and Fontan
circulation are more prone to complications like
arrhythmias, pulmonary hypertension and heart
failure. Furthermore, we found that patients with
ventricular septal defect had shorter survival time
compared to patients with atrial septal defect, and
this could be due to the fact that patients with
unrepaired ventricular septal defects are at high
risk of infective endocarditis10 and pulmonary
hypertension if left untreated.26,27
As our data represent a single center experience,
some patients may have presented to other
regional hospitals with complications and died
or lost to follow-up there. Interruption of followup, arrhythmias, sudden death, and infective
endocarditis have been well described in this
population.25,28,29 This is true for all forms of CHD
including the simple forms.26-28
A major limitation of this study is the inclusion
of adolescent age group to the study population;
however, the pediatric age cut off in Oman is 13
years and thus these patients will be taken care
in the adult health care system. The retrospective
nature of this study renders it subject to recall bias.
Efforts were made to minimize this by reviewing
echocardiography results and making sure there is
no miscoding in the diagnosis.
C O N C LU S I O N
This was the first study which looked at the
spectrum of CHD outside the pediatric age group in
Oman. The population emerging from this study is
young compared to other developed countries with
predominance of simple forms of CHD and shorter
survival for those with complex forms. Further
research is needed in the early outcome of pediatric
heart surgery as this may impact the overall survival.
In addition, research into the associated morbidities
and the transition of care from pediatric to adult is
needed. This can be done only by having a national
registry for patients with CHD, which would help
in optimizing a cost effective health care plan for
this growing population.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
30
Asim A l-Balushi, et al.
Disclosure
The authors declared no conflicts of interest. No funding was
received for this work.
Acknowledgements
We would like to thank the medical record department at
the Royal Hospital for their assistance in data retrieval and
organization.
r ef er ence s
1. van der Bom T, Zomer AC, Zwinderman AH, Meijboom
FJ, Bouma BJ, Mulder BJ. The changing epidemiology of
congenital heart disease. Nat Rev Cardiol 2011 Jan;8(1):5060.
2. Subramanyan R, Joy J, Venugopalan P, Sapru A, al Khusaiby
SM. Incidence and spectrum of congenital heart disease in
Oman. Ann Trop Paediatr 2000 Dec;20(4):337-341.
3. Zomer AC, Vaartjes I, Grobbee DE, Mulder BJ. Adult
congenital heart disease: new challenges. Int J Cardiol 2013
Feb;163(2):105-107.
4. Greutmann M, Tobler D. Changing epidemiology and
mortality in adult congenital heart disease: looking into
the future. Future cardiology. 2012;8(2):171-177.
5. Gurvitz M, Valente AM, Broberg C, Cook S, Stout K, Kay J,
et al; Alliance for Adult Research in Congenital Cardiology
(AARCC) and Adult Congenital Heart Association.
Prevalence and predictors of gaps in care among adult
congenital heart disease patients: HEART-ACHD (The
Health, Education, and Access Research Trial). J Am Coll
Cardiol 2013 May;61(21):2180-2184.
6. Kovacs AH, Verstappen A. The whole adult congenital
heart disease patient. Prog Cardiovasc Dis 2011 JanFeb;53(4):247-253.
7. Mondésert B, Abadir S, Khairy P; MondŽsert B.
Arrhythmias in adult congenital heart disease: the year in
review. Curr Opin Cardiol 2013 May;28(3):354-359.
8. Mylotte D, Pilote L, Ionescu-Ittu R, Abrahamowicz M,
Khairy P, Therrien J, et al. Specialized adult congenital heart
disease care: the impact of policy on mortality. Circulation
2014 May;129(18):1804-1812.
9. Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis
MA, Thilén U, et al. The spectrum of adult congenital heart
disease in Europe: morbidity and mortality in a 5 year followup period. The Euro Heart Survey on adult congenital heart
disease. Eur Heart J 2005 Nov;26(21):2325-2333.
10. Qureshi SA, Hildick-Smith D, de Giovanni J, Clift
P, Stuart G, Henderson R, et al; British Congenital
Cardiac Association; British Cardiovascular Intervention
Society; British Cardiovascular Society. Adult congenital
heart disease interventions: recommendations from a
joint working group of the British Congenital Cardiac
Association, British Cardiovascular Intervention Society,
and the British Cardiovascular Society. Cardiol Young 2013
Feb;23(1):68-74.
11. Kempny A, Fernández-Jiménez R, Tutarel O, Dimopoulos
K, Uebing A, Shiina Y, et al. Meeting the challenge: the
evolving global landscape of adult congenital heart disease.
Int J Cardiol 2013 Oct;168(6):5182-5189.
12. Shiina Y, Toyoda T, Kawasoe Y, Tateno S, Shirai T, Wakisaka
Y, et al. Prevalence of adult patients with congenital heart
disease in Japan. Int J Cardiol 2011 Jan;146(1):13-16.
13. Hannoush H, Tamim H, Younes H, Arnaout S,
Gharzeddine W, Dakik H, et al. Patterns of congenital
heart disease in unoperated adults: a 20-year experience in a
developing country. Clin Cardiol 2004 Apr;27(4):236-240.
14. Gnanappa GK, Ganigara M, Prabhu A, Varma SK, Murmu
U, Varghese R, et al. Outcome of complex adult congenital
heart surgery in the developing world. Congenit Heart Dis
2011 Jan-Feb;6(1):2-8.
15. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly
HM, Dearani JA, et al. ACC/AHA 2008 guidelines for
the management of adults with congenital heart disease: a
report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines
(Writing Committee to Develop Guidelines on the
Management of Adults With Congenital Heart Disease).
Developed in Collaboration With the American Society
of Echocardiography, Heart Rhythm Society, International
Society for Adult Congenital Heart Disease, Society for
Cardiovascular Angiography and Interventions, and
Society of Thoracic Surgeons. J Am Coll Cardiol 2008
Dec;52(23):e143-e263.
16. Marelli A, Beauchesne L, Mital S, Therrien J, Silversides
CK. Canadian Cardiovascular Society 2009 Consensus
Conference on the management of adults with congenital
heart disease: introduction. Can J Cardiol 2010
Mar;26(3):e65-e69.
17. Houyel L, Khoshnood B, Anderson RH, Lelong N,
Thieulin AC, Goffinet F, et al; EPICARD Study group.
Population-based evaluation of a suggested anatomic and
clinical classification of congenital heart defects based on
the International Paediatric and Congenital Cardiac Code.
Orphanet J Rare Dis 2011;6:64.
18. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote
L. Congenital heart disease in the general population:
changing prevalence and age distribution. Circulation 2007
Jan;115(2):163-172.
19. Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M,
Pilote L, Marelli AJ. Changing mortality in congenital
heart disease. J Am Coll Cardiol 2010 Sep;56(14):11491157.
20. Larsen SH, Emmertsen K, Johnsen SP, Pedersen J,
Hjortholm K, Hjortdal VE. Survival and morbidity
following congenital heart surgery in a population-based
cohort of children–up to 12 years of follow-up. Congenit
Heart Dis 2011 Jul-Aug;6(4):322-329.
21. Becker S, Al Halees Z. First-cousin matings and congenital
heart disease in Saudi Arabia. Community Genet 1999;2(23):69-73.
22. Shieh JT, Bittles AH, Hudgins L. Consanguinity and the
risk of congenital heart disease. Am J Med Genet A 2012
May;158A(5):1236-1241.
23. Islam MM. The practice of consanguineous marriage in
Oman: prevalence, trends and determinants. J Biosoc Sci
2012 Sep;44(5):571-594.
24. Greutmann M, Tobler D, Kovacs AH, Greutmann-Yantiri
M, Haile SR, Held L, et al. Increasing Mortality Burden
among Adults with Complex Congenital Heart Disease.
Congenit Heart Dis 2014 Jul.
25. Atz AM, Zak V, Mahony L, Uzark K, Shrader P, Gallagher
D, et al; Pediatric Heart Network Investigators. Survival
data and predictors of functional outcome an average
of 15 years after the fontan procedure: the pediatric
heart network fontan cohort. Congenit Heart Dis 2015
Jan;10(1):E30-E42.
26. Lin YS, Liu PH, Wu LS, Chen YM, Chang CJ, Chu PH.
Major adverse cardiovascular events in adult congenital
heart disease: a population-based follow-up study from
Taiwan. BMC Cardiovasc Disord 2014;14:38.
27. Walsh EP, Cecchin F. Arrhythmias in adult patients with
congenital heart disease. Circulation 2007 Jan;115(4):534545.
28. Perry JC. Sudden cardiac death and malignant arrhythmias:
the scope of the problem in adult congenital heart patients.
Pediatr Cardiol 2012 Mar;33(3):484-490.
29. Koyak Z, Harris L, de Groot JR, Silversides CK, Oechslin
EN, Bouma BJ, et al. Sudden cardiac death in adult congenital
heart disease. Circulation 2012 Oct;126(16):1944-1954.
original article
Oman Medical Journal [2015], Vol. 30, No. 1: 31–35
Frequency of Obstructive Sleep Apnea Syndrome
Among Patients with Epilepsy Attending a Tertiary
Neurology Clinic
Mohammed Al-Abri1*, Abdullah Al-Asmi2, Aisha Al-Shukairi1, Arwa Al-Qanoobi1,
Nandhagopal Rmachandiran2, Povothoor Jacob2 and Arunodaya Gujjar2
Department of Clinical Physiology, Sultan Qaboos University Hospital, Muscat, Oman
Department of Medicine , Sultan Qaboos University Hospital, Muscat, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 25 June 2014
Accepted: 4 February 2015
Online:
DOI 10.5001/omj.2015.06
Keywords:
Epilepsy; Sleep Apnea;
Obstructive; Snoring.
A B S T R AC T
Objectives: Epilepsy is a common neurological disorder with a median lifetime prevalence
of 14 per 1000 subjects. Sleep disorders could influence epileptic seizure. The most common
sleep disorder is obstructive sleep apnea syndrome (OSAS) which occurs in 2% of adult
women and 4% of adult men in the general population. The aim of this study is to estimate
the frequency of OSAS among patients with epilepsy and to study the seizure characteristics
among those patients with co-morbid OSAS. Methods: Patients with a confirmed
diagnosis of epilepsy who attended the Sultan Qaboos University Hospital neurology clinic
were recruited for the study between June 2011 and April 2012. Patients were screened for
OSAS by direct interview using the validated Arabic version of the Berlin questionnaire.
Patients identified as high-risk underwent polysomnography. Results: A total of 100
patients with epilepsy (55 men and 45 women) were screened for OSAS. Generalized
and focal seizure was found in 67% of male and 27% of female patients. Six percent of the
participants had epilepsy of undetermined type. Only 9% of the sample was found to have
high risk of OSAS based on the Berlin questionnaire. No significant correlation was found
between risk of OSAS, type of epilepsy, and anti-epileptic drugs. Conclusion: The risk of
OSAS was marginally greater in patients with epilepsy compared to the general population
with the overall prevalence of 9%.
E
pilepsy is a common neurological disorder
with a median lifetime prevalence of 14
per 1000 subjects in developing countries.1
The discrete electroclinical event, termed
epileptic seizure, could be influenced by changes in
the physiological sleep pattern. In certain epileptic
syndromes, for example nocturnal frontal lobe
epilepsy, seizures are typically encountered during
sleep. In general, sleep disorders are also highly
prevalent in the general population. However,
only in recent years considerable attention has
been focused on the comorbid sleep disorders in
patients with epilepsy.2,3
Among the sleep disorders, obstructive sleep
apnea syndrome (OSAS) is a common problem
occurring in 2% of adult women and 4% of adult
men in the general population.4 OSAS disrupts
sleep and can cause significant sleep deprivation
and fragmentation, causing impaired sleep
continuity, increased daytime sleepiness and
impaired cognitive functions.5 Such alterations in
*Corresponding author:  malabri@squ.edu.om
sleep pattern could have considerable influence
on seizure activity in patients with epilepsy. The
frequency of comorbid OSAS among patients
with epilepsy and the relationship between the
severity of epilepsy and the degree of obstruction
in OSAS are still not well studied. We conducted
this study to estimate the hospital-based frequency
of OSAS among patients with epilepsy and to study
the seizure characteristics among those patients
with comorbid OSAS.
M ET H O D
We recruited patients with a confirmed diagnosis
of epilepsy attending the neurology clinic of the
Sultan Qaboos University Hospital, Muscat, Oman,
between June 2011 and April 2012. We included
adult patients above the age of 18 years. The
diagnosis of epileptic seizure was based on clinical
characteristics with or without electrographic ictal
abnormalities. Those with purely psychogenic
32
Moh a mmed A l-A bri, et al.
Table 1: Clinical characteristics of cohort of
patients with epilepsy.
Screening of epileptic
patients (n=100)
High risk of OSAS
n=9
Low risk of OSAS
n=91
Polysmnography
n=1
Final data collection
and analysis
Characteristics
Figure 1: Flow chart of the patients included in the
cross-sectional retrospective study.
seizures, uncertain diagnosis (for instance patients
with a differential diagnosis of seizure vs. syncope),
symptomatic or provoked seizures (seizure occurring
as a symptom or manifestation of a known cerebral
insult) and those who were diagnosed with epilepsy
but lost to follow-up before the study period
were excluded. The study was approved by the
institutional ethics committee.
In this cross-sectional retrospective study,
patients with epilepsy were screened for OSAS
by direct interview using the validated Arabic
version of the Berlin questionnaire.6,7 Those who
scored high on the questionnaire underwent
diagnostic polysomnography. The flow of patients is
shown in Figure 1.
Each patient completed clinical evaluation
including appropriate medical history and
clinical examination, and the Epworth sleepiness
scale. They also underwent a full diagnostic
polysomnography (Grass, Astromed, USA). The
polysomnography was conducted and scored
Number of
patients
Gender
Male
Female
Age range(14-58 years)
<20
20-40
>40
Mean
Median
Body mass index (n=59)*
Range
Comorbid medical conditions (Median)
55
45
24
61
15
28
27
27 ±7
16–47
25.2
Hypertension
8
Diabetes
4
Type of Epilepsy
Generalized
Focal
Unclassified
Seizure frequency
Almost everyday
1–2 times per week
1–2 times per month
Never or almost never
Disease duration (years)*
67
27
6
9
6
19
65
13 ±9
* Mean ±SD
according to American Academy of Sleep Medicine
(AASM) guidelines 8 and has been described
fully in our previous studies.9,10
Descriptive statistics in the form of percentage,
mean with standard deviation (SD), and
range were used.
Table 2: Anti-epileptic drug use and risk of obstructive sleep apnea syndrome (OSAS).
OSAS characteristics
Risk
Low
High
Total
Daytime sleepiness
Negative
Positive
Total
Apnea
Nearly everyday
3–4 times a week
1–2 times a week
1–2 times per month
Never
Total
Number of antiepileptic drugs n (%)
Poly therapy
Total
Monotherapy
Dual therapy
50 (92.6)
4 (7.4)
54 (100)
28 (87.5)
4 (12.5)
32 (100)
11 (91.7)
1 (8.3)
12 (100)
89 (90.8)
9 (9.2)
98 (100)
52 (96.3)
2 (3.7)
54 (100)
28 (87.5)
4 (12.5)
32 (100)
10 (83.3)
2 (16.7)
12 (100)
90 (91.8)
8 (8.2)
98 (100)
0 (0)
2 (3.7)
2 (3.7)
7 (13)
43 (79.6)
54 (100)
1 (3.1)
0 (0)
0 (0)
5 (15.6)
26 (81.3)
32 (100)
0 (0)
2 (16.7)
1 (8.3)
1 (8.3)
8 (66.7)
12 (100)
1 (1)
4 (4.1)
3 (3.1)
13 (13.3)
77 (78.6)
98 (100)
33
Moh a mmed A l-A bri, et al.
Table 3: Subjects response to Berlin questionnaire.
Item
Percentage
(%)
Do you snore?
a. Yes
41
b. No
59
c. Don’t know
0
a. Slightly louder
than breathing
25
b. As loud as talking
11
c. Louder than
talking
4
d. Very loud – can be
heard in adjacent
rooms
1
Your snoring is:
How often do you snore?
a. Nearly everyday
8
b. 3–4 times a week
3
c. 1–2 times a week
23
d. 1–2 times a month
7
e. Never or nearly
never
0
Has your snoring ever bothered other people?
a. Yes
9
b. No
27
c. Don’t know
5
Has anyone noticed that you quit breathing
during your sleep?
a. Nearly everyday
b. 3–4 times a week
1
4
c. 1–2 times a week
3
d. 1–2 times a month
e. Never or nearly
never
13
79
R E S U LT S
One hundred patients with epilepsy (55 male and
45 female) were screened for OSAS. The clinical
characteristics of these subjects are shown in Table 1.
Generalized seizure was found in 67% of patients
(n=36 male, n=31 female), 27% had focal seizure
(n=17 male, n=10 female) and 6% of the patients
had epilepsy of an undetermined type. The majority
of our patients had low frequency of seizures. Sixty
five percent of patients had almost no seizure attacks
for a minimum of six months at the time of screening,
19% had one to two attacks per month, 6% had
one to two seizures per week, and 9% had seizures
almost every day.
The average epilepsy duration in our sample was
13 years (SD±9 years). The majority (62.2%) of
patients had been diagnosed with epilepsy for more
than 10 years, 27% for less than five years, and 10%
between five and10 years [Table 1].
The analysis of Berlin Questionnaire determined
that 41 of the 100 patients were snorers (26 male and
15 female). Over half of snorers (n=25) reported
snoring slightly louder than breathing. Only one
patient had a very loud snoring, which could be
heard from the adjacent room. Twenty-three patients
reported snoring one to two times a week and eight
patients reported snoring every day. The rest of Berlin
questionnaire results can be found in Tables 2 and 3.
Hypertension was reported in eight patients. There
was no significant association between generalized
and focal epileptic patients and daytime sleepiness
(p=0.700). However, positive daytime sleepiness was
reported by only nine patients (9%). After analyzing
patient’s responses to the Berlin questionnaire, 9%
of the patients (n=9) were determined to be at high
risk of developing OSAS. Only six patients with
high risk OSAS had their BMI calculated (mean
±SD=34.20±7.21) and 53 patients with low risk
OSAS (mean ±SD=26.06±5.86). A high BMI was
significantly associated with the risk of OSAS (p=
0.003). No significant association was found with
age (p=0.400) [Table 4]. The number of men and
women in the high-risk group was nearly equal
(four men and five women). Six patients with high
risk of OSAS had generalized epilepsy. Four of the
epileptic patients with high risk of OSAS received
Table 4: Obstructive sleep apnea syndrome (OSAS) risk factor in the study population.
Characterstics
Low risk of OSAS
High risk of OSAS
p-value
n
Mean±SD
n
Mean±SD
Age
91
27.8±9.8
9
20.89±10.093
0.367
Weight
Body Mass Index
91
53
67.29±16.63
26.06±5.86
9
6
94.48±31.28
34.20+7.21
0.032**
0.003**
** Significant p-value <0.050
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
34
Moh a mmed A l-A bri, et al.
monotherapy, four received dual therapy, and only
one received polytherapy [Table 2]. Twenty-six
patients received sodium valproate and there was
no significant association with snoring, breathing
pauses and daytime sleepiness (p>0.100).
DISCUSSION
This cross-sectional study aimed to find out the
frequency of OSAS among patients with epilepsy
using simple methodology, the Berlin questionnaire.
The Berlin questionnaire is a valid tool to screen for
OSAS6 in a source-limited setting and has been
validated for Arabic speaking population. 7 We
included only adult patients (>18 years old) and
that may have contributed to the limited number
of patients below the age of 20 (24%). Furthermore,
more than 50% of our patients had epilepsy for
more than 10 years and the other 25% had it for less
than five years. This could be related to the fact that
most of the patients were 20–40 years old and had
developed seizures in early childhood.
The study showed that the risk of OSAS
was marginally greater in patients with epilepsy
compared to general population4 with an overall
prevalence of 9%. BMI revealed that 32% of patients
were obese or overweight. BMI was calculated for
only 59 patients due to incomplete data. However,
another study reported obesity and overweight
in 50% of patients with epilepsy.11 One possible
explanation for patients with epilepsy being
overweight is the type of anti-epileptic drugs (AED)
the patient is taking, especially sodium valproate.11
However, we did not have enough evidence to
confirm this explanation in our study. Snoring
was reported in 41% of the epileptics, which was
not not very different from general population.12
Daytime sleepiness was reported in only nine
patients with no significant association with either
type or severity of epilepsy nor with the number of
AEDs. Other studies tried to evaluate the rate and
features of OSAS in adult epilepsy patients. Manni
et al, 13 found that the major risk factors for OSAS
in epilepsy patients were the same as those typically
found in the general population. Of the epilepsyrelated factors, older age at onset of seizures appeared
to be significantly related to comorbidity. He also
found increasing evidence that OSAS coexists in
epilepsy in 10% of unselected adult epilepsy patients
and 20% of children with epilepsy, and up to 30%
of drug-resistant epilepsy patients.14 However, in
our study, we found no significant correlation of the
presence of OSAS with the number or type of AEDs
or duration of treatment.
The major limitations in this study were the
small sample size and methodology. A larger
sample size may give a better understanding of the
real association between epilepsy and OSAS. Even
though the Berlin questionnaire is a validated tool to
assess high risk,7 the sensitivity of this method may
not be as accurate as performing polysmnography.
The inherent problem with the questionnaire is the
results prone to subjective estimation and underreporting of some parameters. Nevertheless, eight
patients who had a high risk of OSAS refused or
did not come to do the test and only one of them
did polysmnography, which was not enough for
statistical analysis. Other issues in the study included
the unavailability of data related to height and
weight in some of the patients’ records, therefore, we
were unable to calculate the BMI for large number
of patients (n=41).
C O N C LU S I O N
The study revealed that the frequency of OSAS
among epilepsy patients is 9%. However, because
of the limitations, a prospective study to screen
bigger population of patients with epilepsy using
portable sleep study, including airflow sensors,
chest movement, body position, and finger oxygen
saturation would be more reliable to estimate the
real prevalence of sleep-related breathing disorder.
This method is widely used in sleep medicine
epidemiological and clinical studies.15
Disclosure
The authors declared no conflict of interest. No funding was
received for this work.
r ef er ences
1. Newton CR, Garcia HH. Epilepsy in poor regions of the
world. Lancet 2012 Sep;380(9848):1193-1201. PubMed
doi:10.1016/S0140-6736(12)61381-6.
2. Derry CP, Duncan S. Sleep and epilepsy. Epilepsy Behav
2013 Mar;26(3):394-404. PubMed doi:10.1016/j.
yebeh.2012.10.033.
3. Ehrenberg B. Importance of sleep restoration in co-morbid
disease: effect of anticonvulsants. Neurology 2000;54(5)
(Suppl 1):S33-S37.
4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S.
The occurrence of sleep-disordered breathing among middleaged adults. N Engl J Med 1993 Apr;328(17):1230-1235.
35
Moh a mmed A l-A bri, et al.
5. Engleman HM, Kingshott RN, Martin SE, Douglas NJ.
Cognitive function in the sleep apnea/hypopnea syndrome
(SAHS). Sleep 2000 Jun;23(23)(Suppl 4):S102-S108.
6. Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan
S, Islam S, et al. Validation of the Berlin questionnaire
and American Society of Anesthesiologists checklist as
screening tools for obstructive sleep apnea in surgical
patients. Anesthesiology 2008 May;108(5):822-830.
7. Saleh AB, Ahmad MA, Awadalla NJ. Development
of Arabic version of Berlin questionnaire to identify
obstructive sleep apnea at risk patients. Ann Thorac Med
2011 Oct;6(4):212-216.
8. Iber C, Ancoli-Israel S, Chesson A, Quan S. The AASM
Manual for the Scoring of Sleep and Associated Events:
Rules, Terminolog y and Technical Specifications.
Westchester. American Academy of Sleep Medicine.
2007;IL:45-47.
9. Al-Abri M, Al-Hashmi K, Jaju D, Al-Rawas O, Al-Riyami
B, Hassan M. Gender difference in relationship of apnoea/
hypopnoea index with body mass index and age in the
omani population. Sultan Qaboos Univ Med J 2011
Aug;11(3):363-368.
10. Al-Abri M, Al-Hamhami A, Al-Nabhani H, Al-Zakwani I.
Validation of the Arabic version of the Epworth sleepiness
scale in Oman. Oman Med J 2013 Nov;28(6):454-456.
11. Morrell MJ, Isojärvi J, Taylor AE, Dam M, Ayala R, Gomez
G, et al. Higher androgens and weight gain with valproate
compared with lamotrigine for epilepsy. Epilepsy Res 2003
May;54(2-3):189-199.
12. Ohayon MM, Guilleminault C, Priest RG, Caulet M.
Snoring and breathing pauses during sleep: telephone
interview survey of a United Kingdom population sample.
BMJ 1997 Mar;314(7084):860-863.
13. Manni R, Terzaghi M, Arbasino C, Sartori I, Galimberti
CA, Tartara A. Obstructive sleep apnea in a clinical series
of adult epilepsy patients: frequency and features of the
comorbidity. Epilepsia 2003 Jun;44(6):836-840.
14. Manni R, Terzaghi M. Comorbidity between epilepsy and
sleep disorders. Epilepsy Res 2010 Aug;90(3):171-177.
15. Punjabi NM, Aurora RN, Patil SP. Home sleep testing for
obstructive sleep apnea: one night is enough! Chest 2013
Feb;143(2):291-294.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
original article
Oman Medical Journal [2015], Vol. 30, No. 1: 36–41
The Relationship between Body Mass Index
and Periodontitis in Arab Patients with Type 2
Diabetes Mellitus
Manal Awad1*, Betul Rahman1, Haidar Hasan2 and Houssam Ali3
College of Dental Medicine, University of Sharjah, Sharjah, United Arab Emirates
College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
3
Rashid Center for Diabetes and Research, Ajman, United Arab Emirates
1
2
A RT I C L E I N F O
Article history:
Received: 20 January 2014
Accepted: 22 February 2015
Online:
DOI 10.5001/omj.2015.07
Keywords:
Type 2 Diabetes Mellitus;
Obesity; Periodontal
Diseases; Cross-Sectional
Studies.
A B S T R AC T
Objective: Our study sought to evaluate the association between periodontitis and body
mass index (BMI) among patients with type 2 diabetes mellitus. Methods: In this crosssectional case control study analysis of 186 diabetic patients, 112 patients had a body
mass index >30kg/m2 and 74 control patients had BMI <30kg/m2. All participants
underwent oral examinations including a full mouth recording of clinical attachment
level (CAL). Information regarding HbA1c levels and high-sensitivity C-reactive protein
(hs-CRP) were also gathered. Results: Over half (61%) of patients had a BMI >30. Of
these 52% had CAL less than 2mm. Multivariate logistic regression analysis showed
that there was no association between BMI and CAL. In addition, hs-CRP levels were
significantly and positively associated with CAL (OR:1.06, 95% CI: 1.01, 1.12; p=0.007). Conclusion: Among patients with type 2 diabetes mellitus, there was no association
between periodontitis and BMI. More studies are needed to further explore this
relationship taking into consideration additional lifestyle factors.
T
he prevalence of obesity continues
to increase worldwide. Obesity is
now regarded as a significant health
problem and a major contributor to the
development of several chronic diseases including
type 2 diabetes mellitus (T2DM).1-5 In the United
Arab Emirates (UAE) approximately 25% of
the population was reported to be diabetic.3 In
addition, the age-standardized rates for prevalence
of diagnosed and undiagnosed T2DM among 30–
64 years olds were 29.0% and 24.2%, respectively.4
Thus, the prevalence of T2DM in the UAE is one
of the highest worldwide.3,4 The most consistent
explanation for this high rate of T2DM was obesity,
which appears to be on the rise in the UAE.5 Obesity
leads to immunoinflammatory modifications and
the condition has also been linked to periodontitis.6-8
Periodontal disease is an infection of the structures
around the teeth, which include the gums,
periodontal ligament, and alveolar bone.9-11 Clinical
signs and symptoms of periodontal disease include
redness, swelling, and formation of periodontal
pockets between the gingiva and tooth roots. The
presence of these pockets promotes the overgrowth
*Corresponding author:  awad@sharjah.ac.ae
of anaerobic bacteria and subsequent ulceration
of the epithelium and destruction of collagen,
periodontal ligament, and the bone that forms the
attachment between the jaw and tooth root.9,10
Gingivitis is the first category of periodontal
disease in which the inflammation is limited to
the gingiva,9 and is usually determined by gingival
bleeding. In some cases the inflammation can extend
to the periodontium resulting in destruction of the
dental attachment apparatus and the occurrence of
periodontitis. Clinical attachment level (CAL) and
pocket depth (PD) are the clinical measures used to
diagnose periodontitis.10
An analysis of the Third National Health and
Nutrition Examination Survey (NHANES III)
showed that body mass index (BMI) was significantly
associated with periodontal disease. This led to
the suggestion that abnormal fat metabolism may
be an important factor in the pathogenesis of
periodontal disease.9
The presence of periodontitis in a diabetic
patient is considered to be a health hazard, as this
chronic infection could worsen the patient’s diabetic
status.10,11 Alteration in host immunity, including
37
M anal Awad, et al.
increase secretion of adipokines has been proposed
as the biological association between obesity,
diabetes, and periodontitis.10
Some studies reported a positive association
between being overweight/obese and periodontal
disease, 12,13 while others have either reported
moderate or no association between severity of
periodontitis and BMI.14,15
Therefore, the aim of this study was to assess the
relationship between BMI and periodontal disease,
measured by CAL, in an Arab diabetic population.
Additionally, the association between CAL and
diabetic status was also evaluated.
M ET H O D S
All 186 participants in this study were recruited
from the Rashid Center for Diabetes and Research
in Ajman, UAE. The case group (n=113) was
composed of a random sample of patients with
T2DM and a BMI greater than 30kg/m2. The control
group (n=73) included patients of similar age with
T2DM and a BMI less than 30kg/m2. This sample
size was adequate to observe a 25% difference in
the proportion of patients with periodontal disease
between the cases and the controls.16 The inclusion
criteria was that patients must have a confirmed
diagnosis of T2DM and must have at least eight
teeth present in their oral cavity. The study was
approved by the University of Sharjah Research
Ethics Committee and participants signed consent
forms prior to enrollment in the study.
Participants underwent a full-mouth clinical
periodontal examination at six sites per tooth (third
molars were excluded) carried out by two calibrated
dentists using a manual periodontal probe with
Williams markings and a tip diameter of 0.45mm.
The oral examinations were carried out at the Rashid
Diabetes & Research Center using portable dental
chairs and appropriate lighting. The periodontal
parameters included the following assessments:
(i) pocket depth: the distance of the free gingival
margin to the base of the probable pocket, recorded
to the nearest millimeter and (ii) gingival recession,
the location of the free gingival margin in relation
to the cementoenamel junction (positive if
located apical to the cementoenamel junction and
negative if located coronal to the cementoenamel
junction). The algebraic sum of pocket depth and
gingival margin were used to compute the CAL.
Measurements were made in millimeters and were
rounded off to the nearest millimeter.17,18
Periodontitis was operationalized using methods
that are currently used in literature studying the
association between periodontitis and other
diseases. All measurements were calculated using
conventional clinical measurements obtained
during the full-mouth periodontal examination.
Mean CAL was also calculated.19
Blood samples were obtained from all of
the participants. The samples (10ml) were
collected in the morning between 10am–12pm
by venous puncture and analyzed for glycated
hemoglobin (HbA 1c ) and high sensitivity
C-reactive protein (hs-CRP).
Fasting glucose level was measured by enzymatic
reference method with hexokinase and hs-CRP was
measured by immunoturbidimetry. All samples were
processed by the same laboratory, using principles
of good laboratory practice. Glycemic control was
assessed by HbA1c for which values greater than
6.5% were considered as good control and less than
6.5% as unsatisfactory control.
Participant’s weight and height were measured,
with subjects wearing light clothing and no shoes,
by an experienced nurse. Weight and height were
measured using a portable digital scale and a portable
stadiometer. BMI was calculated as the ratio of
weight (kilograms) to the square of height (meters).
According to the WHO guidelines, obesity for
men and women was defined as a BMI of 30kg/m2
or more.20
Assuming that obesity causes greater periodontal
disease, and hence tooth loss, the remaining teeth
could appear healthier. Accordingly, the number of
remaining teeth is a potential confounder and was
controlled for in the analysis.
Data were also collected on participants’ age, sex,
and smoking status.
The statistical package SPSS (version 20) was
used for data processing and analysis. Participants’
characteristics were described using frequency
distribution for categorical variables and mean and
standard deviation for continuous variables. Clinical
attachment levels (mm) were calculated for each
individual and then averaged across participants in
each group. Differences in CAL (>2mm vs. <2mm)
according to BMI were assessed using the Chi-square
test. Multiple logistic regression analysis was used
to assess the association of BMI and CAL adjusted
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
38
M anal Awad, et al.
Table 1: Participants’ characteristics and clinical
characteristics according to body mass index (BMI).
Variables
Total
BMI
<30kg/
m2
BMI
>30kg/
m2
185
73
113a
Female (%)
61(33)
33(45)
28(25)
Male(%)
124(67)
40(55)
85(75)
186
74
112
55.4, 9.6
55.2, 9.9
185
73
112
School
145(78)
18(25)
90(80)
University
40(22)
18(25)
22(20)
Smoking (n)
185
73
112a
Sex (n)
Age (n)
mean, SD
Education (n)
54.3, 10.8
b
a
No
19(10)
10(14)
9(08)
Yes
166(90)
63 (86)
103(92)
185
73
112b
Number of teeth (n)
mean, SD
20.8, 6.7
20.6, 7.4
21.2, 6.4
CAL (n)**
185
73
112a
<2 n (%)
84 (45)
30 (41)
54 (47)
>2 n (%)
101 (55)
43 (59)
58 (52)
185
73
112
(7.43,
11.2)
(4.7, 1.5)
(9.2, 12.3)
185
73
112a
hs-CRP (n)**
mean, SD
HBA1c n(%)**
b*
<6.5
50 (27)
24 (33)
26 (24)
>6.5
135 (73)
49 (67)
86 (76)
Table 2: Multivariate logistic regression analysis
for the association between body mass index and
clinical attachment level (CAL) when adjusted for
participants’ characteristics.
Variables
Odds
Ratio
95%
confidence
interval
p-value
Sex
Female
1
Male
0.39
0.19, 0.77
0.007
Age
1.04
0.97, 1.04
0.820
0.50, 2.47
0.800
Education
School
University
1
1.11
Smoking
No
Yes
Number of teeth
1
0.50
0.17, 1.50
0.680
1.20
0.93, 1.04
0.600
HbA1c*
<6.5
1
>6.5
0.66
0.31, 1.29
0.470
hs-CRP*
1.06
1.01, 1.12
0.007
0.59, 2.43
0.520
CAL
<2mm
1
>2mm
1.20
*hs-CRP: high sensitivity C reactive protien; HBA1c: glycated hemoglobin
a: based on chi-square test; b: based on independent T-test
*Significant p-value <0.050
**CAL: clinical attachment level; hs-CRP: high sensitivity C reactive protien;
HBA1c: glycated hemoglobin
for the independent variables in this study; diabetic
status, HbA1c (%), hs-CRP (mg/L), number of teeth
present, smoking status (0: no, 1: yes), age, sex, and
level of education (school education complete/
incomplete and university education complete/
incomplete). In addition, multivariate logistic
regression was also used to assess the relationship
between CAL and diabetic status adjusted for the
independent variables in the study.
Table 3: Multivariate logistic regression analysis for
the association between clinical attachment levels
and HbA1c, adjusted for participants variables.
Variables
95%
Confidence
Interval
p-value
0.36
0.17, 0.78
0.010
1.06
1.03, 1.11
0.001
0.29, 1.60
0.690
1.07
0.30, 3.78
0.910
0.90
0.85, 0.96
0.001
Odds
Ratio
Sex
Female
Male
Age
1
Education
School
University
1
0.69
Smoking
R E S U LT S
Table 1 displays the demographic characteristics
of the study participants, BMI, hs-CRP, HbA1c
levels, and smoking status. Most patients (78%)
were school level education, non-smokers (90%),
and obese (60%).
Chi-square test revealed that the association
between clinical attachment loss and BMI was
No
Yes
Number of teeth
1
HbA1c*
<6.5
1
>6.5
hs-CRP*
0.66
1.06
0.61, 2.86
1.01, 1.11
0.470
0.047
*hs-CRP: high sensitivity C reactive protien; HBA1c: glycated hemoglobin
39
M anal Awad, et al.
not statistically significant (p>0.050). This lack of
association was also observed in the multivariate
logistic regression analysis [Table 2]. However,
in this model a significant positive association
was observed between hs-CRP levels and BMI
(OR=1.06, 95% confidence interval (CI): 1.01,
1.12; p=0.007). In addition, Table 3 shows that
increase in age was associated with increase in odds
of having CAL >2mm (OR:1.07, 95% CI: 1.03,
1.12; p<0.001). More teeth was also associated with
less likelihood of having CAL greater than 2mm
(OR: 0.90, 95% CI: 0.84, 0.96; p<0.050).
DISCUSSION
The findings of the present study show that there
is no relationship between BMI and CAL among
diabetic patients. This lack of association persisted
after adjustment for possible confounding variables.
Our results are in contrast to those previously
reported,13,18 where high BMI was significantly
associated with an increased risk of periodontitis,
but they are in agreement to those reported by
other researchers who found no association or
negative relationship between BMI and periodontal
disease.21,22 For example, Saito et al,18 reported that
obese individuals had a three-fold increase in risk of
periodontitis compared to non-obese individuals.
Genco et al,12 suggested that an inflammatory
pathway could explain the relationship between
obesity and periodontitis and that tumor necrosis
factor-α (TNFα) and soluble tumor necrosis
factor α receptors could be elevated in obese
people. Conversely, de Castilhos et al,21 reported
that among a group of 720 individuals, aged 24
years old, no association was observed between
obesity, (measured by waist circumference) and
periodontitis, (measured by periodontal pockets).
The authors explained that the lack of association
could be due to the younger age of their participants
in which obesity may not be related to periodontitis.
They also added that they only used periodontal
pocket depth to assess the presence of periodontitis,
which may have underestimated the presence of the
disease due to possible attachment levels loss without
the presence of pockets. Although the results of our
studies are in agreement with findings reported by
de Castilhos et al,21 this explanation does not apply
to our study results because older patients were
included and CAL were used to assess periodontitis.
Interestingly, Al Zahrani et al,14 reported that high
waist circumference was positively associated with
periodontal disease in 18–34 year olds, but not
in older patients.
Suvan and colleagues,23 at the time of their
systematic review, concluded that the association
between body composition and periodontitis is
inconclusive and more prospective studies are
needed to establish the temporal relationship
between body composition and periodontal disease.
Moreover, the use of several criteria for the definition
of periodontal disease by different researchers could
contribute to the current lack of consensus regarding
the above mentioned association.
Consistent with previous reports, 24 in this
study hs-CRP was significantly and independently
associated with BMI. In addition, the results from
this study and other reports findings that also
showed a relationship between C-reactive protein
and periodontal disease14,24,25 suggesting that this
relationship could be of public health relevance.
For example, if one of the objectives of a weight
reduction program is to reduce a proinflammatory
state then evaluation of the patient’s periodontal
status is important to effectively reduce hs-CRP
levels. Results of several randomized clinical trials
corroborate the current view that periodontal
treatment is effective in reducing hs-CRP levels;26
this underlines the importance of good oral health
in maintaining systemic health. 25 Accordingly,
health promotion programs that are designed to
assist obese patients to lose weight and reduce
the risks of cardiovascular disease should include
oral health promotion.
In this study a high percentage of participants
(73%) had uncontrolled diabetes (HbA1c >6.5),
these findings are similar to previous reports in
the UAE, in which the percentage of patients
with poorly controlled diabetes ranged from
68% to 73%.27 However, the glycemic status of
the patients (controlled vs. uncontrolled) in this
study was not related to the patients’ periodontal
condition. These results are in agreement with
other research findings that have also found no
significant relationship between HbA1c levels and
periodontal disease measured by CAL.28 On the
contrary, other researchers have demonstrated that
glycemic control worsens with the increase in the
severity of periodontal disease.29,30 For example, Lim
et al,29 results depict a positive association between
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
40
M anal Awad, et al.
HbA1c levels and the percentage of sites with PD
>5mm. The reason suggested by the authors for
poorer periodontal health among patients with
poor glycaemic control was that the hyperglycaemic
state results in accumulation of advanced glycated
end products. These products in turn lead to
several inflammatory reactions leading to the
release of inflammatory mediators like interleukins
1 and 6, TNF-α and hs-CRP, thereby enhancing
the periodontal breakdown process. 29 Santos el
al,28 suggested that a possible explanation for the
inconsistency of findings between the association
of patients’ glycemic control and periodontal
condition was the severity of periodontitis in the
samples of patients selected in different studies.
They argued that, compared to previous studies,
their study included a large number of subjects
with a relatively high mean CAL (>5mm) and
periodontal PD, suggesting that a threshold above
which periodontitis severity and HbA1c level are
not associated. Our study findings do not support
this hypothesis because the percentage of subjects
with a CAL above 5mm was only 8% (data not
shown), yet our findings are in agreement with
those of the authors.
The limitations of our study include the crosssectional design, although the age of cases and
controls were similar there was no gender balance
between the obese and control group. We did
not assess participants’ oral hygiene habits and
other life style factors31 and therefore, the effect
of variables such as frequency of brushing may
have been informative.
C O N C LU S I O N
Our findings indicate that among Arab patients
with T2DM, there was no association between BMI
and periodontitis assessed by CAL. The positive
and significant association between BMI, CAL
and hs-CRP is in agreement with previous findings
and could have clinical implications when patients
attempt weight loss. Longitudinal studies and clinical
trials are needed to establish the causal association
between diabetes, obesity, and periodontitis taking
into consideration additional lifestyle factors to
establish the impact of periodontal treatment on
weight loss efforts.
Disclosure
The authors declared no conflict of interest. This study was
supported by Sheikh Hamdan Bin Rashid Al Maktoum Award
for Medical Sciences (Grant # MRC 09/10).
Acknowledgements
The authors wish to thank Drs Heba Madi, Asma Alemam,
and Najla El Bluwi for the collection of data. We also wish to
thank Dr Salah Abu Sinana, Director of Rashid Diabetes and
Research Center, Ajman.
r ef er ences
1. Kopelman PG. Obesity as a medical problem. Nature 2000
Apr;404(6778):635-643.
2. Ajlouni K, Khader YS, Batieha A, Ajlouni H, El-Khateeb
M. An increase prevalence of diabetes and its complications.
J of Diab Complicat 2008;22:317-324.
3. Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes
mellitus: a review of current trends. Oman Med J 2012
Jul;27(4):269-273.
4. Alrawahi AH, Rizvi SG, Al-Riyami D, Al-Anqoodi Z.
Prevalence and risk factors of diabetic nephropathy in
omani type 2 diabetics in Al-dakhiliyah region. Oman Med
J 2012 May;27(3):212-216.
5. Al-Riyami A. Type 2 Diabetes in Oman: Can we learn from
the Lancet editorial. Oman Med J 2010 Jul;25(3):153-154.
6. Malik M, Bakir A, Saab BA, King H. Glucose intolerance
and associated factors in the multi-ethnic population of the
United Arab Emirates: results of a national survey. Diabetes
Res Clin Pract 2005 Aug;69(2):188-195.
7. Saadi H, Carruthers SG, Nagelkerke N, Al-Maskari F,
Afandi B, Reed R, et al. Prevalence of diabetes mellitus
and its complications in a population-based sample in Al
Ain, United Arab Emirates. Diabetes Res Clin Pract 2007
Dec;78(3):369-377.
8. Carter A, Saadi HF, Reed RL, Dunn EV. Obesity, lifestyle
and reproductive health in a representative sample of
women citizens of Al Ain, United Arab Emirates. J HPN
2004;22:75-83.
9. Wood N, Johnson RB, Streckfus CF; Third National
Health and Nutrition Examination Survey (NHANES III).
Comparison of body composition and periodontal disease
using nutritional assessment techniques: Third National
Health and Nutrition Examination Survey (NHANES III).
J Clin Periodontol 2003 Apr;30(4):321-327.
10. Taylor GW, Borgnakke WS. Periodontal disease:
associations with diabetes, glycemic control and
complications. Oral Dis 2008 Apr;14(3):191-203.
11. Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2
diabetes mellitus and periodontal disease. J Am Dent Assoc
1990 Oct;121(4):532-536.
12. Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A
proposed model linking inflammation to obesity, diabetes,
and periodontal infections. J Periodontol 2005 Nov;76(11)
(Suppl):2075-2084.
13. Dalla Vecchia CF, Susin C, Rösing CK, Oppermann
RV, Albandar JM. Overweight and obesity as risk
indicators for periodontitis in adults. J Periodontol 2005
Oct;76(10):1721-1728.
14. Al-Zahrani MS, Bissada NF, Borawskit EA. Obesity and
periodontal disease in young, middle-aged, and older
adults. J Periodontol 2003 May;74(5):610-615.
15. Nishida N, Tanaka M, Hayashi N, Nagata H, Takeshita T,
Nakayama K, et al. Determination of smoking and obesity
as periodontitis risks using the classification and regression
tree method. J Periodontol 2005 Jun;76(6):923-928.
16. Ryan ME, Carnu O, Kamer A. The influence of diabetes
on the periodontal tissues. J Am Dent Assoc 2003
Oct;134(Spec No):34S-40S.
41
M anal Awad, et al.
17. Grossi SG, Genco RJ. Periodontal disease and diabetes
mellitus: a two-way relationship. Ann Periodontol 1998
Jul;3(1):51-61.
18. Saito T, Shimazaki Y, Sakamoto M. Obesity and
periodontitis. N Engl J Med 1998 Aug;339(7):482-483.
19. 0. Sheiham A. Steele JG, Marcenes W, Finch S, Walls AW.
The relationship between oral health and body mass index
among older people: A national survey of older people in
Great Britain. Br Dent J 2008; l192:703-706.
20. WHO Obesity and overweight factsheet. From www.
who.int/mediacentre/factsheets/fs311/en/. Accessed 9
February 2015.
21. <unknown>221. de Castilhos ED, Horta BL, Gigante
DP, Demarco FF, Peres KG, Peres MA. Association
between obesity and periodontal disease in young adults:
a population-based birth cohort. J Clin Periodontol 2012
Aug;39(8):717-724.
22. Kongstad J, Hvidtfeldt UA, Grønbaek M, Stoltze K,
Holmstrup P. The relationship between body mass index
and periodontitis in the Copenhagen City Heart Study. J
Periodontol 2009 Aug;80(8):1246-1253.
23. Suvan J, D’Aiuto F, Moles DR, Petrie A, Donos N.
Association between overweight/obesity and periodontitis
in adults. A systematic review. Obes Rev 2011
May;12(5):e381-e404.
24. Gomes-Filho IS, Freitas Coelho JM, da Cruz SS, Passos JS,
Teixeira de Freitas CO, Aragão Farias NS, et al. Chronic
periodontitis and C-reactive protein levels. J Periodontol
2011 Jul;82(7):969-978.
25. Slade GD, Ghezzi EM, Heiss G, Beck JD, Riche E,
Offenbacher S. Relationship between periodontal disease
and C-reactive protein among adults in the Atherosclerosis
Risk in Communities study. Arch Intern Med 2003
May;163(10):1172-1179.
26. Freitas CO, Gomes-Filho IS, Naves RC, Nogueira Filho
GdaR, Cruz SS, Santos CA, et al. Influence of periodontal
therapy on C-reactive protein level: a systematic review and
meta-analysis. J Appl Oral Sci 2012 Feb;20(1):1-8.
27. Al-Maskari F, El-Sadig M, Al-Kaabi JM, Afandi B,
Nagelkerke N, Yeatts KB. Knowledge, attitude and practices
of diabetic patients in the United Arab Emirates. PLoS One
2013;8(1):e52857.
28. Santos VR, Lima JA, Miranda TS, Feres M, Zimmermann
GS, Nogueira-Filho GdaR, et al. Relationship between
glycemic subsets and generalized chronic periodontitis in
type 2 diabetic Brazilian subjects. Arch Oral Biol 2012
Mar;57(3):293-299.
29. Lim LP, Tay FB, Sum CF, Thai AC. Relationship between
markers of metabolic control and inflammation on severity
of periodontal disease in patients with diabetes mellitus. J
Clin Periodontol 2007 Feb;34(2):118-123.
30. Takeda M, Ojima M, Yoshioka H, Inaba H, Kogo M,
Shizukuishi S, et al. Relationship of serum advanced
glycation end products with deterioration of periodontitis
in type 2 diabetes patients. J Periodontol 2006 Jan;77(1):1520.
31. Al-Lawati JA, Barakat MN, Al-Maskari M, Elsayed MK,
Al-Lawati AM, Mohammed AJ. HbA1c Levels among
Primary Healthcare Patients with Type 2 Diabetes Mellitus
in Oman. Oman Med J 2012 Nov;27(6):465-470.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
original article
Oman Medical Journal [2014], Vol. 29, No. 6: 42–47
Impact of Acne on Quality of Life of Students at
Sultan Qaboos University
Asma Al-Shidhani1*, Samia Al-Rashdi2, Hamdan Al-Habsi3 and Syed Rizvi4
Family Medicine, North Mawaleh Health Center, Oman
Family Medicine, Buldan Al-Awamir Health Center, Oman
3
Family Medicine, Sultan Qaboos University Hospital, Al-Khoud, Oman
4
Statistics, Sultan Qaboos University, Al-Khoud, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 14 July 2014
Accepted: 19 December 2014
Online:
DOI 10.5001/omj.2015.08
Keywords:
Acne Vulgaris; Quality Of
Life; University students;
Impact.
A B S T R AC T
Objectives: The purpose of this study was to assess the impact of acne on the quality of life
of students at Sultan Qaboos University (SQU). Its secondary objective was to assess the
influence of gender and severity of symptoms on the quality of life. Methods: A crosssectional study was conducted on 100 students (40 males and 60 females) diagnosed with
acne who attended the Student Clinic during a period of three months from September
to December 2009. The Acne Quality Of Life index (Acne-QoL) questionnaire was used
to assess the patient’s quality of life in four different domains: self-perception, social,
emotional, and acne symptoms. Results: Acne affected all areas of the patients quality of
life with the emotional domain found to be the most affected. Overall, female patients
reported more adverse QoL effects. The mean score for self-perception for female students
was 2.5 and 2.8 for males (p=0.300). The role-social domain approached a significant
difference between genders (p=0.078). There was a statistically significant correlation
between severity of acne symptoms and the other three domains. The correlation was
highest between acne symptoms score and self-perception score. Conclusion: This study
showed that acne affects the quality of life of affected SQU students treated by primary
care physicians at the Student Clinic. Therefore, physicians should take into account the
effect of acne on the persons’ quality of life when individualizing treatment.
A
cne vulgaris is a chronic multifactorial
inflammatory skin disorder in which
there is an alteration in the pattern of
keratinization within the pilosebaceous
follicles. This results in comedone formation, an
increase in sebum production, proliferation of
the bacterium Propionibacterium acnes, and the
production of perifollicular inflammation.1
Acne has long been associated with ill
psychological effects and was well described in 1948
by Sulzberger and Zaidens: “There is probably no
single disease which causes more psychic trauma, more
maladjustment between parents and children, more
general insecurity and feeling of inferiority and greater
sums of psychic suffering than does acne vulgaris.”2
Although patients with acne are not affected
in terms of general health status, morbidity, or life
span, even mild acne can have major effects on the
patients’ quality of life. However, these effects are
not fully appreciated by the treating physician and
even dismissed as merely a cosmetic nuisance.3
*Corresponding author:  asma.shidhani@gmail.com
Several studies worldwide have reported that acne
has major effects on patients’ quality of life (QoL).4-12
Some studies have tackled the psychological effects
of acne such as anxiety, depression, emotions, selfidentity, self-esteem, and suicidal tendency.7,13
Others have addressed the impact of acne on QoL
in comparison to other skin diseases and general
medical conditions.6,12 Few studies have claimed
that there is no significant association between the
grades of acne severity and its impact on patients’
QoL.13,14 There have been a few published papers
from the Arab Gulf states to explore this effect.11
Furthermore, there are no publications from Oman
that have addressed this issue. Thus, the aim of this
study was to assess the effects of acne on the patient’s
QoL. Its secondary objective was to assess the
influence of gender and symptom severity on QoL.
M ET H O D S
This descriptive cross-sectional study was conducted
43
Asm a A l- Shidh an i, et al.
Table 1: Domain structure of the Acne Quality Of Life questionnaire. All questions were framed to be
disease specific (‘... because of your facial acne’).
Self-perception
Role-social
Role-emotional
Acne Symptoms
Feeling unattractive
Concern about meeting new
people
Upset about having
facial acne
Bumps on your face
Feeling embarrassed
Concern about going out in
public
Annoyed about time spent
cleaning and treating face
Bumps full of pus on face
Feeling self-conscious
Socializing a problem
Concern about not looking
your best
Scabbing from facial acne
Dissatisfied with appearance
Interacting with the opposite
sex a problem
Concern about acne
medication not working fast
enough
Concern about scarring from
facial acne
Bothered by need to have
medication and cover-up
available
Oily facial skin
Self-confidence
(negatively affected)
in the Student Clinic at Sultan Qaboos University
(SQU). The study examined the response of male
and female students at SQU who were diagnosed
with acne and attended the Student Clinic during a
three-month period (1 September to 31 December
2009). The diagnosis of acne was confirmed by the
family physicians working in the clinic. The study
group included all acne patients aged between
17–27 years. Students who could not understand
the questionnaire in English were excluded, as
permission to translate the questionnaire into
Arabic was not obtained. Doctors on duty at the
clinic approached eligible students, and those who
agreed to participate were asked to self-fill the Acne
Quality Of Life index (Acne-QoL) questionnaire.15
The index is an internationally used tool, which has
been validated in many places around the world,
including Saudi Arabia.11,14 The study sample size
was calculated for the population of SQU students
with a confidence level of 95% to be 95.
The Acne-QOL questionnaire contains 19
questions organized into four domains, which
address the impact of facial acne on health-related
quality of life as shown in Table 1. The advantage of
the Acne-QOL questionnaire is that all questions
were disease specific (“. . . because of your facial
acne”) which meant that the QoL effect was unlikely
to be due to other factors.
Scoring of the Acne-QoL questionnaire was
performed as follows: 1) Each response was coded.
2) Missing values were identified and any missing
value was replaced with the mean of the given subscore (score for questions under each domain).
3) An overall domain score was calculated by
summing the coded responses to each question in
the domain.
Responses were numbered starting from 0
in ascending order (0=extremely, 1=very much,
2=quite a bit, 3= a good bit, 4=somewhat, 5=a little
bit, 6=not at all). This coding scheme was adopted
so that higher scores for each domain reflected
increased health related QoL, that is less negative
self-perception, social, emotional, and symptomatic
effects associated with acne. However, if there were
less than three questions answered in a given domain
then the subscore was not calculated.
Analysis of data was performed using SPSS (version
17) and the sub-scores for each QoL domain were
calculated. Error bars were used to compare the impact
of acne on the different domains. In addition, the effect
of gender on the sub-scores of different scores was
assessed. Furthermore, the correlation between acne
symptom score (severity of acne) and the other three
domains was assessed using Pearson correlation (R).
R E S U LT S
A total of 100 acne patients participated in the
study. Of those, 40 were males and 60 were females.
There were few missing values (<1) in each domain
for every subject, and these values were substituted
by the mean of the subscore as explained in the
methods. Therefore, there were no missing values in
the overall statistical analysis of the results.
Figure 1 shows the average scores of cases in
the four different Acne-QoL domains. The most
negatively affected domain was role-emotional
(mean score 1.7), followed by self-perception (mean
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
44
Asm a A l- Shidh an i, et al.
Scale; (0-6): Extremely 0 .... 6: Not at all
Female
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Male
4.5
95% CI Average score
95% CI Average score
4.0
3.5
3.0
2.5
2.0
1.5
Roleemotional
SelfAcne
perception symptoms
Acne-QoL Domains
1.0
Rolesocial
Roleemotional
Selfperception
Acne
symptoms
Rolesocial
Acne-QoL Domains
Figure 1: Average scores for the four Acne Quality
of Life domains (Acne-QoL).
Figure 2: The relationship between gender and average
scores in the four Acne Quality of Life (QoL) domains.
ROLE-SOCIAL
Correlation=0.479
6
Average score
5
4
3
2
1
0
0
1
2
3
4
Acne symptoms (average score)
5
ROLE-EMOTIONAL
6
Correlation=0.599
6
Average score
5
4
3
2
1
0
0
1
2
3
4
Acne symptoms (average score)
5
SELF-PERCEPTION
6
Correlation=0.743
6
Average score
5
4
3
2
1
0
0
1
2
3
4
Acne symptoms (average score)
5
6
Figure 3: Impact of acne symptoms on the role-social, role-emotional and self-perception of quality of life
score.
45
Asm a A l- Shidh an i, et al.
score 2.6), and the least affected domain was rolesocial (mean score 3.4).
Figure 2 shows the relationship between
gender and the sub-scores for each of the four
QoL domains. Though not statistically significant,
female participants reported more adverse effects.
The mean score for the self-perception domain was
2.5 for female students, and 2.8 for male students
(p=0.300). The role-social domain approached
a significant difference between the genders, the
mean score was 3.6 for males and 3.0 for females
(p=0.078). For the role-emotional domain the mean
score was 1.8 for male and 2.5 for female students.
Figure 3 shows the correlation between acne
symptom sub-score and the other three AcneQoL domains. There was a statistically significant
correlation between severity of acne symptoms and
the other three domains (p<0.001 for all domains).
The correlation was highest between acne symptoms
score and self-perception score (R=0.74). Pearson’s
correlation was 0.59 for the role-emotional domain,
and 0.47 for the role-social domain.
DISCUSSION
We sought to assess the impact of acne on the QoL
of students at SQU as well as assess the influence
of gender, and severity of symptoms. Our results
agreed with previously published studies3-12 and
emphasized that acne, often regarded as a simple
disease, has a great impact on patients’ QoL. This
information can be valuable for physicians and other
health care professionals to better understand the
psychosocial impact of this condition on patients’
lives. QoL was measured by four important domains:
self-perception, role-social, role-emotional, and acne
symptoms. A study conducted by Cresce et al,13
concluded that the health-related QoL impact of
acne was similar to asthma, epilepsy, diabetes, back
pain, arthritis, and coronary heart disease.
Our study found that the effect of acne on
the emotional aspect of QoL was worst when
compared to the other three domains. This was
because emotions are usually influenced by the
physical appearance of the individual. Lasek and
Chren2 reported similar findings, they used Skindex,
(a validated tool to measure of the effects of skin
diseases on patients’ QoL16) to determine the effect
of acne on the QoL of 60 patients who were on
follow-up with dermatology specialists. They found
that the emotional aspect was the most negatively
affected in patients’ lives.2 Tasoula et al17 reported a
significant impact of acne on patients’ emotions in
terms of self-embarrassment, self-esteem, feelings of
unworthiness, and disturbance due to acne symptoms
such as pain and itching, and discomfort from
treatment. The second most affected domain was
self-perception, which measured the patients’ selfimage. This finding can be explained since the acne
affects mainly the face (and facial acne was assessed
here), which plays a major role in the appearance of
the person. This effect was evident in both genders;
but female students were more negatively affected
than males, as expected. The same results were seen
in other studies.9,15,18-20 However, some studies have
reported that acne was more severe and frequent in
boys than in girls.9,18,20 In general, female students
scored more negative results in all four domains
than male students, although the difference was
not significant. This difference is not surprising,
as females are usually more concerned about their
physical appearance. Similar findings were reported
by Al Robaee et al,11 and others,14-25 who found that
female patients were more concerned about their
appearance and negatively affected by the presence
of acne vulgaris.
In addition, this study examined the correlation
between the acne symptom domain (which
represents the severity of acne) and the other
three domains of the Acne-QoL index. We found
a significant correlation between acne symptoms
and all of the other domains. This was an expected
finding, as any increase in acne severity would lead
to an increase in the negative effects on the patients’
feelings, self-perception, and socialization as the
lesions became more prominent and if scarring
occurred. Few studies reported a significant
relationship between the severity of acne and its
effect on the patient’s QoL,6,21 most did not report
any significant association.3,5,6,12,14 The reason for this
difference is not clear, but most of these studies were
carried out in a secondary care setting where most
patients present with more severe forms of acne
whereas this study was carried out in a primary care
setting where all grades of acne are present. A second
explanation could be the age of the patients, as most
of the studies assessed secondary school students
(a younger age group) who might have a less severe
form of acne. This explanation is supported by the
results of Tasoula et al,17 which showed that middle
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
46
Asm a A l- Shidh an i, et al.
and late adolescents suffered a greater negative
impact on their QoL because of acne. Therefore,
family medicine and primary care physicians should
take into account the effect of acne on patients’ QoL
(irrespective of the severity of their acne) rather than
just focus on individualizing treatment.
The strengths of the study include that it was
conducted on university students who are in early
adulthood during which time acne vulgaris is
most prevalent and when the effects of any health
problem on the QoL would have greater effects on
the patient’s future. Furthermore, the study used a
self-administered questionnaire making it less likely
for the candidates’ responses to be affected by the
clinician’s opinion.
There were some study limitations. The study
participants were university students who are a
small subgroup of the general population and were
more homogenous in terms of age (the age group of
our study was 17–25 years) and their educational
level was almost equal, so the study sample may
not represent the general Omani population. In
addition, the demographics of the participants were
not assessed in the study. However, this might not
have significant effects as the scale used was disease
specific (all the questions contained the statement
“because of your facial acne”). Another limitation
was that the questionnaire was in English and a
significant number of students were excluded as they
could not understand the questionnaire.
C O N C LU S I O N
This study showed that facial acne affects the quality
of life of the affected students. Therefore, physicians
and other health care professionals should address
the psychosocial aspect while managing patients
with acne. Since acne is a very common problem in
the community, further studies using a larger sample
size representing the general population are needed
to address the extent of the problem among the
acne sufferers. In order to increase participation, an
Arabic version of the scale needs to be developed.
Disclosure
The authors declared no conflict of interests. No funding was
received for this work.
r ef er ences
1. Hanna S, Sharma J, Klotz J. Acne vulgaris: more than skin
deep. Dermatol Online J 2003 Aug;9(3):8.
2. Lasek RJ, Chren MM. Acne vulgaris and the quality of
life of adult dermatology patients. Arch Dermatol 1998
Apr;134(4):454-458.
3. Pawin H, Chivot M, Beylot C, Faure M, Poli F, Revuz J,
et al. Living with acne. A study of adolescents’ personal
experiences. Dermatology 2007;215(4):308-314.
4. Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan
TJ, Finlay AY. The quality of life in acne: a comparison with
general medical conditions using generic questionnaires. Br
J Dermatol 1999 Apr;140(4):672-676.
5. Aktan S, Ozmen E, Sanli B. Anxiety, depression, and
nature of acne vulgaris in adolescents. Int J Dermatol 2000
May;39(5):354-357.
6. Klassen AF, Newton JN, Mallon E. Measuring quality of
life in people referred for specialist care of acne: comparing
generic and disease-specific measures. J Am Acad Dermatol
2000 Aug;43(2 Pt 1):229-233.
7. Jones-Caballero M, Chren MM, Soler B, Pedrosa E, Peñas
PF. Quality of life in mild to moderate acne: relationship
to clinical severity and factors influencing change
with treatment. J Eur Acad Dermatol Venereol 2007
Feb;21(2):219-226.
8. Gupta MA, Johnson AM, Gupta AK. The development
of an Acne Quality of Life scale: reliability, validity, and
relation to subjective acne severity in mild to moderate acne
vulgaris. Acta Derm Venereol 1998 Nov;78(6):451-456.
9. Pearl A, Arroll B, Lello J, Birchall NM. The impact of acne:
a study of adolescents’ attitudes, perception and knowledge.
N Z Med J 1998 Jul;111(1070):269-271.
10. Gupta MA, Gupta AK. Depression and suicidal ideation
in dermatology patients with acne, alopecia areata,
atopic dermatitis and psoriasis. Br J Dermatol 1998
Nov;139(5):846-850.
11. Al Robaee AA. Prevalence, knowledge, beliefs and
psychosocial impact of acne in University students in
Central Saudi Arabia. Saudi Med J 2005 Dec;26(12):19581961.
12. Ilgen E, Derya A. There is no correlation between acne
severity and AQOLS/DLQI scores. J Dermatol 2005
Sep;32(9):705-710.
13. Cresce ND, Davis SA, Huang WW, Feldman SR. The
quality of life impact of acne and rosacea compared to
other major medical conditions. J Drugs Dermatol 2014
Jun;13(6):692-697.
14. Zaraa I, Belghith I, Ben Alaya N, Trojjet S, Mokni M, Ben
Osman A. Severity of acne and its impact on quality of life.
Skinmed 2013 May-Jun;11(3):148-153.
15. Acne-Specific Quality of Life Questionnaire (Acne-QoL):
Manual and Interpretation Guide. Whitehouse Station, NJ:
Merck and Co., Inc; 1997.
16. Chren MM. The Skindex Instruments to Measure the
Effects of Skin Disease on Quality of Life. Dermatol Clin.
Apr 2012;30(2):231–236.
17. Tasoula E, Gregoriou S, Chalikias J, Lazarou D, Danopoulou
I, Katsambas A, et al. The impact of acne vulgaris on quality
of life and psychic health in young adolescents in Greece.
Results of a population survey. An Bras Dermatol 2012
Nov-Dec;87(6):862-869.
18. Rapp DA, Brenes GA, Feldman SR, Fleischer AB Jr,
Graham GF, Dailey M, et al. Anger and acne: implications
for quality of life, patient satisfaction and clinical care. Br J
Dermatol 2004 Jul;151(1):183-189.
19. Tahir CM, Ansari R. Beliefs, perceptions and expectations
among acne patients. J Pak Assoc Dermatol 2012;22:98104.
20. Smithard A, Glazebrook C, Williams HC. Acne prevalence,
knowledge about acne and psychological morbidity in mid-
47
Asm a A l- Shidh an i, et al.
adolescence: a community-based study. Br J Dermatol 2001
Aug;145(2):274-279.
21. Shahzad N, Nasir J, Ikram U, Asmaa-ul-Haque, Qadir A,
Sohail MA. Frequency and psychosocial impact of acne on
university and college students. J Coll Physicians Surg Pak
2011 Jul;21(7):442-443.
22. Abdel-Hafez K, Mahran AM, Hofny ER, Mohammed KA,
Darweesh AM, Aal AA. The impact of acne vulgaris on the
quality of life and psychologic status in patients from upper
Egypt. Int J Dermatol 2009 Mar;48(3):280-285.
23. Dunn LK, O’Neill JL, Feldman SR. Acne in adolescents:
quality of life, self-esteem, mood, and psychological
disorders. Dermatol Online J 2011;17(1):1.
24. Uslu G, Sendur N, Uslu M, Savk E, Karaman G, Eskin M.
Acne: prevalence, perceptions and effects on psychological
health among adolescents in Aydin, Turkey. J Eur Acad
Dermatol Venereol 2008 Apr;22(4):462-469.
25. Hanisah A, Omar K, Shah SA. Prevalence of acne and its
impact on the quality of life in school-aged adolescents in
Malaysia. J Prim Health Care 2009 Mar;1(1):20-25.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
original article
Oman Medical Journal [2015], Vol. 30, No. 1: 48–54
Quality of Diabetes Care at Outpatient Clinic,
Sultan Qaboos University Hospital
Sawsan Al-Sinani1*, Ali Al-Mamari2, Nicolas Woodhouse2, Omaiyma Al-Shafie2,
Fatima Amar2, Mohammed Al-Shafaee3, Mohammed Hassan4 and Riad Bayoumi1
Department of Biochemistry, Sultan Qaboos University, Muscat, Oman
Department of Medicine, Sultan Qaboos University, Muscat, Oman
3
Department of Family & Community Medicine, Sultan Qaboos University, Muscat, Oman
4
Department of Physiology, Sultan Qaboos University, Muscat, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 7 November 2014
Accepted: 5 January 2015
Online:
DOI 10.5001/omj.2015.09
Keywords:
Oman; Type 2 Diabetes
Mellitus; Outpatient Clinics,
Hospital.
A B S T R AC T
Objective: To assess the clinical care of type 2 diabetes mellitus (T2D) patients at Sultan
Qaboos University Hospital (SQUH), a countrywide tertiary referral center in Muscat,
Oman. Methods: We performed a retrospective, observational, cross-sectional study
using a total of 673 Omani T2D patients from the Diabetes and Family Medicine
Clinics at SQUH. We collected patient data from June 2010 to February 2012 from
the Hospital Information System (HIS). Patients had to be Omani, aged more than 18
years old, and have T2D with active follow-up and at least three visits within one year
to be included in the study. Ninety-three percent of the patients (n=622) were on oral
hypoglycemic drugs and/or insulin, and 70% were on statins. Patients’ anthropometric
data, biochemical investigations, blood pressure, and duration of diabetes were recorded
from the HIS. Results: Using the recommended standards and guidelines of medical
care in diabetes (American Diabetes Association and the American National Cholesterol
Education Program III NCDP NIII standards), we observed that 22% of the patients
achieved a HbA1C goal of <7%, 47% achieved blood pressure goal of <140/80mm Hg,
48% achieved serum low density lipoprotein cholesterol goal of <2.6mmol/L, 67%
achieved serum triglycerides goal of <1.7 mmol/L, 59% of males and 43% of females
achieved high density lipoprotein cholesterol goals (males>1.0; females >1.3mmol/L).
Almost 60% of the patients had urinary microalbumin/creatinine ratio within the normal
range. Conclusions: The clinical outcomes of the care that T2D patients get at SQUH
were lower than those reported in Europe and North America. However, it is similar to
those reported in other countries in the Arabian Gulf.
T
ype 2 diabetes mellitus (T2D) results
in the progression of hyperglycemia
with time, and can cause multiple organ
damage. Long-term complications of
hyperglycemia include heart disease, stroke, diabetic
retinopathy, kidney failure, and poor circulation
of limbs leading to amputations. Accordingly,
glycemic control and associated conditions need to
be assessed and monitored frequently. Glycosylated
hemoglobin (HbA1C) provides the main method
by which clinicians can relate individual’s glycemic
control to risk of complication development.1,2
Many people with diabetes have an elevated blood
pressure. High blood pressure is associated with a
spectrum of adverse outcomes, including eye damage,
kidney damage, cardiovascular disease (CVD), and
premature mortality. Treatment to reduce elevated
*Corresponding author:  sawsan.alsinani@gmail.com
blood pressure reduces these adverse outcomes.1,2
CVD is the major cause of morbidity and
mortality in people with T2D. Assessment and
management of CVD risk factors in T2D is
a core part of diabetic care. Dyslipidemia is a
well-recognized and modifiable risk factor that
should be identified early to institute aggressive
cardiovascular preventive management.3 Evaluation
is achieved by the measurements of serum lipid
levels, especially low-density lipoprotein (LDL),
cholesterol, and triglycerides. The most common
form of diabetic dyslipidemia consists of moderate
elevation in triglyceride levels, low high-density
lipoprotein (HDL) cholesterol, and high level
of LDL cholesterol. However, LDL cholesterol
levels in patients with T2D are generally similar to
those found in the general population.3 In the UK
49
Sawsan A l- Sinan i, et al.
Prospective Diabetes Study (UKPDS) triglyceride
levels did not predict coronary heart disease (CHD)
events. High LDL cholesterol was the strongest
independent predictor of CHD followed by low
HDL cholesterol levels.4 This supports current
guidelines in which lowering LDL cholesterol is the
primary lipid target.
All patients with diabetes, even those with
normal lipid profiles, will likely benefit from statin
use. There is strong evidence that statins reduce the
risk of CVD or death events irrespective of age and
gender, across a wide range of cholesterol levels.5-7
In addition, for people with established CVD, the
benefit of long-term aspirin use for reducing the risk
of myocardial infarction (MI), stroke, and vascular
death is well established.8,9
Diabetes is now the leading cause of chronic kidney
disease (CKD) in many developed countries. The
prevalence of CKD in people with T2D varies between
25–50%.1 The two main manifestations of CKD
in people with T2D are a reduction in glomerular
filtration rate, or the presence of albuminuria/
proteinuria.1 Treatment in the early stages of CKD
reduces progression of kidney damage. Therefore,
patients with T2D should be screened regularly (at
diagnosis and then annually) to detect early indications
of kidney damage and receive treatment.
In Oman, most epidemiological studies on T2D
were done in primary health care centers where new,
controlled, and less advanced cases of T2D patients
were seen.10-12 This study assessed the quality of
diabetes care at Sultan Qaboos University Hospital
(SQUH), a countrywide tertiary referral center in
Oman, through the evaluation of HbA1C, blood
pressure, serum lipids and urine albumin/creatinine
ratio in a sample of Omani T2D patients. The
assessment was done using the American Diabetes
Association (ADA) standards of medical care in
diabetes and guidelines from the American National
Cholesterol Education Program III NCDP NIII
Adult Treatment Panel (ATP).
M ET H O D S
SQUH is one of the two main referral hospitals
in Oman, catering for a catchment area including
more than 2,000,000 people. In 2010, 3,003 people
of different ages and nationalities with diabetes
were registered at SQUH. About half of those were
Omanis (n=1687). Of those, 673 adults with T2D
were included in the study.
We performed a retrospective, observational,
cross-sectional study using Omani T2D patients
that were seen at the diabetes (n= 523) and family
medicine (n= 150) clinics at SQUH. We collected
patient data from June 2010 to February 2012 from
the Hospital Information System (HIS). A history
of T2D among patients was determined using
diagnosis and medical history stored in the electronic
records of the HIS. Patients had to be Omani, aged
more than 18 years old, and have T2D with active
follow-up and at least three visits within one year to
either clinic to be included in the study. Exclusion
criteria included: patients with type 1 diabetes,
positive antibodies testing for islet cell antibodies
and glutamic acid decarboxylase antibodies, or
patients diagnosed with cancer. Participants were
informed about the project and written consent
obtained. The study was approved by the Ethics and
Research Committee of the College of Medicine,
Sultan Qaboos University, Muscat, Oman.
Anthropometric variables collected included:
age, gender, height, and weight [Table 1]. Obesity
status was defined according to the international
classification of an adult’s weight, their body mass
index (normal BMI: 18.5–24.99kg/m2, overweight:
25.00–29.99kg/m 2 and obese ≥30.00kg/m 2).
The biochemical investigations retrieved were:
HbA1C level, serum lipids (total cholesterol, LDL
cholesterol, HDL cholesterol, and triglycerides)
and urine microalbumin/creatinine ratio (ACR)
[Table 1]. Blood pressure and duration of diabetes
were also noted.
In this study for assessment purposes, the ADA
standards for medical care in diabetes (2013) were
used.2,13 Glycemic control was defined by the HbA1C
goal of <7%. HbA1C control was divided into three
categories: optimal (<7%), fair (7.0–8.9%), and
poor control3 (9%). Blood pressure goal was defined
as systolic <140mmHg and diastolic <80mmHg.13
The guidelines of American National Cholesterol
Education Program (NCEP) Adult Treatment Panel
(ATP) III (2001/2004) was used for serum lipids
goals.14,15 Total cholesterol (desirable <5.17mmol/L);
LDL cholesterol (optimal <2.59mmol/L);
triglycerides (desirable <1.69mmol/L); and HDL
cholesterol (high >1.55mmol/L). In addition,
urinary ACR values were divided into four categories:
normal values (≤2.5mg/mmol (men), ≤3.5mg/
mmol (women)); microalbuminuria (2.6–29mg/
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
50
Sawsan A l- Sinan i, et al.
Table 1: Characteristics of Omani patients
(n=673) with type 2 diabetes seen at Sultan Qaboos
University Hospital, Muscat, Oman.
20
10
0
%)
31 (±6)
Dia
0m
sto
mH
lic
g)
B
LDL
P (<
cho
80m
lest
HD
mH
ero
Lc
g)
l (<
hol
est
2.6
ero
m
HD
m
l (M
ol/
Lc
l)
ale
hol
s: >
est
ero
1
.
0m
l (F
mo
em
l/l)
ale
s
:
>1
AC
R(
.
3
Trig
mm
ma
lyce
les
ol/
ride
l)
≤2
.5,
s (1
fem
.7m
ale
mo
s≤
l/l)
3.5
mg
/m
mo
l)
Duration of diabetes (years), (n=562)
≤5
174 (31)
>5–10
155 (28)
>10–15
90 (16)
>15–20
102 (18)
>20
41 (7)
30
(<1
4
1 (0.2)
57 (11)
189 (35)
294 (54)
40
(<7
BMI (n=541)
<18.5 (underweight)
18.5–24.99 (normal weight)
25.00–29.99 (overweight)
≥ 30.00 (obese)
54 (±10)
50
1C
21 (3)
202 (30)
357 (53)
90 (13)
60
BP
Age (years), (n=670)
≤35
>35–50
>50–65
>65
70
tolic
310 (46)
359 (54)
80
11 (±8)
BMI: Body mass index, SD: Standard deviation
Sys
Gender (n=669)
Male
Female
Mean (±SD)
Patients with type 2 diabetes (%)
n (%)
90
HbA
Variable
100
Diabetes care outcome indicator
BP: Blood pressure; LDL: Low density lipoprotein; HDL: High density lipoprotein;
ACR: Urine microalbumin/creatinine ratio; HbA1C: Glycosylated hemoglobin
mmol (men), 3.6–29mg/mmol (women)); clinical
proteinuria (30–60mg/mmol); overt nephropathy/
heavy proteinuria (≥70 mg/mmol).1,2
Data analyses were performed using SPSS
version 20.0. Anthropometric data was expressed
as mean ±SD and percentage. Age was divided
into four intervals (≤35, 36–50, 51–65, and >65
years), and the percentage of patients in each age
group was calculated. Duration of diabetes was also
divided into five intervals (≤5, 6–10, 11–15, 16–20,
and >20 years). The percentage of patients in each
interval was calculated. In addition, the percentage
of patients who reached the recommended goals for
HbA1C, blood pressure, serum lipids, and urine ACR
was calculated and used as indicator outcomes to
assess the care given to patients with T2D.
R E S U LT S
A total of 673 Omani patients with T2D were
included in our study. The mean ±SD age of patients
was 54 ±10 years, ranging from 30 to 84 years. Over
half of patients were in the 51–65 years age group.
Forty six percent were males and 54% females.
The mean duration of diabetes was 11 ±8 years,
ranging from less than 1 year to 40 years. Almost
three-quarters (69%) had diabetes for more than
Figure 1: Proportion of patients with type 2
diabetes mellitus patients reaching the American
Diabetes Association standards of medical care
in diabetes at Sultan Qaboos University Hospital,
Muscat, Oman.
five years [Table 1].
Almost all patients (n=622, 93%) were on
treatment, either oral hypoglycemic drugs and/or
insulin. Thirty-nine patients (6%) had no record
of the type of drugs used, and 10 patients (1%) did
not use any drugs. During the observation period
insulin was prescribed to 278 patients (41%). Only
27 patients (4%) documented refusing insulin
treatment. Aspirin was prescribed to 423 patients
(63%) while statins (simvastatin and rosuvastatin)
were prescribed to 470 patients (70%).
Twenty-two percent of patients had HbA1C less
than 7%, and 47% had blood pressure less than
<140/80mmHg. For serum lipids, 48% and 67%
of patients achieved the LDL cholesterol goal of
less than 2.6mmol/L, and triglyceride goal of less
than1.7mmol/L, respectively. While 59% of males
and 43% of females achieved the HDL cholesterol
goals (males >1.0mmol/L, females >1.3mmol/L).
For urinary ACR, 60% of patients were within
51
Sawsan A l- Sinan i, et al.
Table 2: Characteristics of clinical variables of Omani patients with type 2 diabetes (n=673) seen at Sultan
Qaboos University Hospital, Muscat, Oman.
Variables
n (%)
Mean ±SD
HbA1C (%), (n=673)
Optimal < 7% (<53mmol/mol)
Fair ≥7 to < 9 % (≥53 to 75mmol/mol)
Poor ≥ 9 % (≥75mmol/mol)
150 (22)
245 (36)
277 (41)
Hypertension optimal control, (n=673)
<140/80mmHg
319 (47)
Systolic blood pressure, (n=673)
≤120mmHg
>120–139mmHg
140–159mmHg
≥160 mmHg
110 (16)
255 (38)
200 (30)
108 (16)
140 ±20
Diastolic blood pressure, (n=673)
<80mmHg
80–89mmHg
90–99mmHg
>100mmHg
412 (61)
187 (28)
63 (9)
10 (2)
77 ±11
Lipid targets
Total cholesterol (n= 657)
Desirable: <5.17mmol/L (<200mg/dL)
Borderline high: 5.17–6.18mmol/L (200–239mg/dL)
High: ≥6.2mmol/L (≥240mg/dL)
8.7 ±2.1 %
(72 mmol/mol)
474 (72.1)
130 (19.8)
53 (8.1)
4.7 ±1.1
LDL cholesterol (n=644)
Optimal: <2.59mmol/L (<100mg/dL)
Near optimal/above optimal: 2.59–3.33 mmol/L (100–129mg/dL)
Borderline high: 3.36–4.1 mmol/L (130–159 mg/dL)
High: 4.14–4.89 (160–189mg/dL)
Very high: >4.91mmol/L (≥190mg/dL)
307 (47.7)
193 (30)
91 (14.1)
34 (5.3)
19 (2.9)
2.7 ±0.96
Triglyceride (n=655)
Desirable: <1.69mmol/L (<150mg/dL)
Borderline high: 1.69–2.25mmol/L (150–199mg/dL)
High: 2.26–5.63 mmol/L (200–499mg/dL)
Very high: >5.65mmol/L (≥500mg/dL)
440 (67.2)
114 (17.4)
97 (14.8)
4 (0.61)
1.6 ±0.95
HDL cholesterol (n=656)
Low: <1mmol/L (<40mg/dL)
Intermediate: 1–1.55mmol/L (40–60mg/L)
High (Protective against heart disease):
>1.55mmol/L (≥60mg/dL)
Urinary microalbumin/creatinine ratio (n= 655)
Normal: ≤2.5mg/mmol (males), ≤3.5mg/mmol (females)
Microalbuminuria: 2.6–29mg/mmol (males), 3.6–29mg/mmol
(females)
Clinical proteinuria: 30–60mg/mmol
Overt nephropathy: ≥70mg/mmol
200 (30.5)
363 (55.3)
93 (14.2)
1.2 ±0.47
391 (60)
173 (26)
30 (5)
61 (9)
SD: Standard deviation; LDL: Low density lipoprotein; HDL: High density lipoprotein; HBA1c: Glycosylated hemoglobin
normal range [Table 2 and Figure 1].
On the other hand, 41% of the patients had
poor HbA1C control (≥9%). Forty-six percent had
systolic blood pressure ≥140mmHg and 39% had
diastolic blood pressure ≥80mmHg. Twenty six
percent of patients had microalbuminuria, while
14% of patients had either clinical proteinuria or
overt nephropathy.
DISCUSSION
This study describes and assesses the clinical care
given to a sample of Omani patients with advanced
and uncontrolled cases of T2D attending SQUH,
a tertiary hospital. Using the ADA standards of
medical care in diabetes,2,13 22% of the patients
achieved HbA1C goal, 47% achieved the blood
pressure goal, 48% achieved serum LDL cholesterol
goal, 67% achieved serum triglycerides goal, and 59%
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
52
Sawsan A l- Sinan i, et al.
of males and 43% of females achieved serum HDL
cholesterol goal. In addition, almost 60% of the
patients had urinary ACR within the normal range.
The patients included in this study were middle aged
and elderly with a mean age of 54 ±10 years, and 69%
had diabetes for more than five years. Additionally,
35% were overweight and 54% were obese.
Omani patients get free medical care including
free medication at government hospitals. Most
patients with T2D are seen, on average, four times
annually at primary health care centers. Advanced
and uncontrolled cases of patients with T2D are
referred to SQUH, expecting optimum control
of those patients. In this study, the proportion of
patients who reached HbA1C goal was lower than
those obtained from a previous study conducted at
SQUH.16 Other Omani studies, done at primary
health care centers, also reported a higher number
of patients (24–30%) with glycemic control.10,12
The clinical outcomes from care that patients
with T2D received at SQUH did not match those
from Europe, 17,18 North America, 19 Canada, 20
and Australia. 21 Compared to reports from
similar tertiary centers in Europe,17 Canada,20 and
Australia,21 clinical outcomes in Omani patients
were lower. For example, 42% of the patients in
Portugal, USA, and Canada were at HbA1C goal
(<7.0%)17,19 compared to 22% in Oman.
Although we rated the quality of T2D
management among Omani patients as inadequate,
the outcomes are similar, and in some cases better
than those reported from other tertiary diabetes
centers in the Arab region.22,23 For example, only
21–28% of the patients in the region met the HbA1C
level goal. However, a recent study in a tertiary
hospital in the United Arab Emirates24 showed an
improvement in diabetes care outcomes, from 2008
to 2010, comparable to developed countries.
Hypertension is a disease that is associated with
diabetes, and is known to contribute to diabetic
microvascular and macrovascular complications. In
this study, 47% of patients with T2D had their blood
pressure at goal. Previous studies among Omani
patients, at primary health care centers reported similar
results.10-12 Our blood pressure control results are
similar to tertiary centers in Saudi Arabia, the United
Arab Emirates, and Lebanon.22-24 Other studies
reported it at 11–36%.25,26 However, different criteria
for blood pressure control among diabetics was used
in different studies, which makes evaluation difficult.
A specific dyslipidemia phenotype is particularly
common in patients with diabetes.27-30 In our
study, 48% were at the goal for LDL cholesterol.
In previous studies at primary care centers in
Oman, only 15–24% of the patients achieved
LDL cholesterol goal.10,12 Our study showed better
management of lipids among patients attending
SQUH. Approximately, two-thirds of the patients
with diabetes attending SQUH were on aspirin and
statins treatment to reduce the risk of CVD events
or death. However, lipid management outcomes in
patients attending SQUH were lower than those
from tertiary centers in the Arabian Gulf.22,24
Microalbuminuria may be used as an early
indicator of diabetic nephropathy. In this study, 26%
of patients had microalbuminuria. A previous study
among Omani patients at SQUH showed similar
findings.31 However, Al-Lawatiya et al,12 reported a
higher figure (37%) in patients attending primary
health care centers. Prashanth et al,32 estimated the
prevalence of microalbuminuria in patients with
T2D among three Arabian Gulf countries (Bahrain,
the UAE, and Oman) at 28–35%. However, high
rates of microalbuminuria were reported among
patients attending different levels of health care
in Saudi Arabia (41%) and India (36%). 33,34
Epidemiological studies reported the prevalence of
microalbuminuria, approximately 10 years after the
diagnosis of T2D, between 25–40%.35-38
Despite the impression from this study that
Omani patients with T2D are not well controlled
at SQUH, bearing in mind the patient’s older age,
long duration of diabetes, advanced cases, and the
late presentation of the disease SQUH receives,
the clinical outcome attained for care given to
patients with T2D could be considered acceptable.
In addition, many barriers impact on achievement
of the recommended care such as the reluctance of
Omani patients to accept insulin therapy, which
delays the proper treatment in complicated cases.
Another is low compliance with treatment plans.
A third problem is the traditional dietary habits
(traditional Omani food is high in carbohydrates,
fats, and sugars) combined with the increasing
prevalence of sedentary lifestyles and reduced
physical activity. Therefore, improving the outcome
of the clinical care given to Omani T2D patients,
such as those found in this study, is a challenge
for health care providers who need to address
multifactorial issues in their management plans.
53
Sawsan A l- Sinan i, et al.
C O N C LU S I O N
The goals of clinical outcome attained for care given
to patients with T2D at SQUH were lower than
those reported in Europe, North America, Canada,
and Australia. However, it is similar, and sometimes
better, than those reported in the Arab region. There
is scope for better control and a higher number of
patients reaching recommended targets, but many
barriers in the Omani community impact on the
recommended care, particularly educational and
lifestyle factors.
Diabetes is a complex disease; treatment requires
multiple processes involving both provider and
patient. In our community, that should also include
patient education, the importance of lifestyle
modification, altering the traditional dietary habits,
increasing physical activity and training of primary
care physicians.
Disclosure
The authors declared no conflict of interests. This project was
supported by the Research Council (TRC), Muscat, Oman
(grant number RC/MED/BIOC/10/01).
Acknowledgements
We thank Nassra Al Maani and Ranjitha K. Sukumaran for their
contribution in data collection. We also thank George Khaukha
and Taruna Dutt for their support. We are grateful to the staff of
the Diabetes and FAMCO clinics at SQUH for their help and
support. We are indebted to all subjects who participated in this
study. We are grateful to the Deanship of postgraduate studies
at Sultan Qaboos University, Muscat, Oman for the PhD grant
to Sawsan Al-Sinani.
r ef er enc e s
1. IDF. Global Guideline for Type 2 Diabetes. International
Diabetes Federation; 2012 [cited 2012]; Available
from http://www.idf.org/global-guideline-type-2diabetes-2012.
2. ADA. Standards of medical care in diabetes 2013. Diabetes
Care 2013;36(1):S11-S66.
3. Solano M, Goldberg R. Lipid management in type 2
diabetes. Clin Diabetes 2006;24(1):27-32 .
4. Turner RC, Millns H, Neil HA, Stratton IM, Manley
SE, Matthews DR, et al. Risk factors for coronary artery
disease in non-insulin dependent diabetes mellitus: United
Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ
1998 Mar;316(7134):823-828.
5. Brugts J, Yetgin T, Hoeks S, Gotto A, Shepherd J,
Westendorp R, et al. The benefits of statins in people
without established cardiovascular disease but with
cardiovascular risk factors: meta-analysis of randomised
controlled trials. BMJ 2009;338:b2376.
6. Taylor F, Ward K, Moore T, Burke M, Davey Smith
G, Casas J, et al. Statins for the primary prevention of
cardiovascular disease. Cochrane database of systematic
reviews. 2011;(1):CD004816.
7. Amarenco P, Labreuche J. Lipid management in the
prevention of stroke: review and updated meta-analysis
of statins for stroke prevention. Lancet Neurol 2009
May;8(5):453-463.
8. Baigent C, Sudlow C, Collins R, Peto R; Antithrombotic
Trialists’ Collaboration. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention
of death, myocardial infarction, and stroke in high risk
patients. BMJ 2002 Jan;324(7329):71-86.
9. Baigent C, Blackwell L, Collins R, Emberson J, Godwin
J, Peto R, et al; Antithrombotic Trialists’ (ATT)
Collaboration. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis
of individual participant data from randomised trials.
Lancet 2009 May;373(9678):1849-1860.
10. Al-Mandhari A, Al-Zakwani I, El-Shafie O, Al-Shafaee M,
Woodhouse N. Quality of Diabetes Care: A cross-sectional
observational study in Oman. Sultan Qaboos Univ Med J
2009 Apr;9(1):32-36.
11. El-Shafie K, Rizvi S. Control of Hypertension among Type
II Diabetics. Oman Med J 2010 Jan;25(1):32-36.
12. Al-Lawati JA, N Barakat M, Al-Zakwani I, Elsayed MK,
Al-Maskari M, M Al-Lawati N, et al. Control of risk factors
for cardiovascular disease among adults with previously
diagnosed type 2 diabetes mellitus: a descriptive study from
a middle eastern arab population. Open Cardiovasc Med J
2012;6(1):133-140.
13. ADA. Executive summary: Standards of medical care in
diabetes--2013. Diabetes Care 2013;36(1):S4-S10.
14. Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. Executive Summary of
The Third Report of The National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High Blood Cholesterol In Adults (Adult
Treatment Panel III). JAMA 2001 May;285(19):24862497.
15. CDC. State Heart Disease and Stroke Prevention Programs
Address High Blood Cholesterol. 2007 [cited 2014
December]; Available from: http://www.cdc.gov/dhdsp/
data_statistics/fact_sheets/fs_state_cholesterol.htm.
16. Al-Maskari MY, Al-Shookri AO, Al-Adawi SH, Lin KG.
Assessment of quality of life in patients with type 2 diabetes
mellitus in Oman. Saudi Med J 2011 Dec;32(12):12851290.
17. Panarotto D, Teles AR, Schumacher MV. Factors associated
to glycaemic control in patients with type 2 diabetes. Rev
Assoc Med Bras 2008 Jul-Aug;54(4):314-321.
18. Khunti K, Gadsby R, Millett C, Majeed A, Davies M.
Quality of diabetes care in the UK: comparison of
published quality-of-care reports with results of the Quality
and Outcomes Framework for Diabetes. Diabet Med 2007
Dec;24(12):1436-1441.
19. Saaddine JB, Cadwell B, Gregg EW, Engelgau MM, Vinicor
F, Imperatore G, et al. Improvements in diabetes processes
of care and intermediate outcomes: United States, 19882002. Ann Intern Med 2006 Apr;144(7):465-474.
20. Malcolm JC, Maranger J, Taljaard M, Shah B, Tailor C,
Liddy C, et al. Into the abyss: diabetes process of care
indicators and outcomes of defaulters from a Canadian
tertiary care multidisciplinary diabetes clinic. BMC Health
Serv Res 2013;13(1):303.
21. Bryant W, Greenfield JR, Chisholm DJ, Campbell LV.
Diabetes guidelines: easier to preach than to practise? Med
J Aust 2006 Sep;185(6):305-309.
22. Kharal M, Al-Hajjaj A, Al-Ammri M, Al-Mardawi G,
Tamim HM, Salih SB, et al. Meeting the American Diabetic
Association standards of diabetic care. Saudi J Kidney Dis
Transpl 2010 Jul;21(4):678-685.
23. Akel M, Hamadeh G. Quality of diabetes care in a university
health center in Lebanon. Int J Qual Health Care 1999
Dec;11(6):517-521.
24.Alhyas L, Cai Y, Majeed A. Type 2 diabetes care for patients
in a tertiary care setting in UAE: a retrospective cohort
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
54
Sawsan A l- Sinan i, et al.
study. JRSM Short Rep 2012 Oct;3(10):67.
25. Pérez-Cuevas R, Doubova SV, Suarez-Ortega M, Law M, Pande
AH, Escobedo J, et al. Evaluating quality of care for patients with
type 2 diabetes using electronic health record information in
Mexico. BMC Med Inform Decis Mak 2012;12:50.
26. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for
vascular disease among adults with previously diagnosed diabetes.
JAMA 2004 Jan;291(3):335-342.
27. Taskinen MR. Diabetic dyslipidaemia: from basic research to
clinical practice. Diabetologia 2003 Jun;46(6):733-749.
28. Krauss RM, Siri PW. Dyslipidemia in type 2 diabetes. Med Clin
North Am 2004 Jul;88(4):897-909, x.
29. Del Pilar Solano M, Goldberg RB. Management of diabetic
dyslipidemia. Endocrinol Metab Clin North Am 2005
Mar;34(1):1-25, v.
30. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat
Clin Pract Endocrinol Metab 2009 Mar;5(3):150-159.
31. Al-Futaisi A, Al-Zakwani I, Almahrezi A, Al-Hajri R, AlHashmi L, Al-Muniri A, et al. Prevalence and predictors of
microalbuminuria in patients with type 2 diabetes mellitus: a
cross-sectional observational study in Oman. Diabetes Res Clin
Pract 2006 May;72(2):212-215.
32.Prashanth P, Sulaiman KJ, Kadaha G, Bazarjani N, Bakir S, El
Jabri K, et al; DEMAND Gulf Study Investigators. Prevalence
and risk factors for albuminuria among type 2 diabetes mellitus
patients: a Middle-East perspective. Diabetes Res Clin Pract 2010
Jun;88(3):e24-e27.
33. Al-Khader AA. Impact of diabetes in renal diseases in Saudi
Arabia. Nephrol Dial Transplant 2001 Nov;16(11):2132-2135.
34. Varghese A, Deepa R, Rema M, Mohan V. Prevalence of
microalbuminuria in type 2 diabetes mellitus at a diabetes centre
in southern India. Postgrad Med J 2001 Jun;77(908):399-402.
35. Newman D, Mattock M, Dawnay A, Kerry S, McGuire A,
Yaqoob M, et al. Systematic review on urine albumin testing for
early detection of diabetic complications. Health Technol Assess.
2005;9(30):iii-vi, xiii-163.
36. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M,
et al; ADVANCE Collaborative Group. Intensive blood glucose
control and vascular outcomes in patients with type 2 diabetes. N
Engl J Med 2008 Jun;358(24):2560-2572.
37. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman
RR; UKPDS GROUP. Development and progression of
nephropathy in type 2 diabetes: the United Kingdom Prospective
Diabetes Study (UKPDS 64). Kidney Int 2003 Jan;63(1):225232.
38. Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker
LG; DEMAND investigators. Prevalence and risk factors for
microalbuminuria in a referred cohort of type II diabetic patients:
a global perspective. Kidney Int 2006 Jun;69(11):2057-2063.
case report
Oman Medical Journal [2015], Vol. 30, No. 1: 55–58
Acute Myocardial Infarction after Switching from
Warfarin to Dabigatran
Wael Abuzeid, Hatim Al-Lawati and Neil Fam*
Division of Cardiology, University of Toronto, Toronto, Canada
A RT I C L E I N F O
Article history:
Received: 20 March 2013
Accepted: 21 May 2014
Online:
DOI 10.5001/omj.2015.10
Keywords:
Dabigatran; Direct thrombin
inhibitor; Myocardial
Infarction; Warfarin.
A B S T R AC T
Dabigatran etexilate is a recently approved direct thrombin inhibitor (DTI), which is
superior to warfarin in the prevention of stroke and systemic embolism in patients with
atrial fibrillation (AF). However, dabigatran use is associated with an increased risk of
myocardial infarction (MI) compared to warfarin. The mechanisms for this association
effect remain speculative. We present a case of an acute MI and cardiac arrest in a patient
with chronic AF who had been recently switched from warfarin to dabigatran. Urgent
coronary angiography, at St. Michael’s hospital (Toronto, Canada), revealed evidence
of thromboembolism to the distal posterior descending artery. The patient was treated
medically and switched back from dabigatran to warfarin. He did well and was discharged
after an uneventful stay in the coronary care unit.
D
abigatran etexilate, an oral direct
thrombin inhibitor (DTI), is rapidly
hydrolyzed by serum and hepatic
esterases to its active form. Irrespective
of the dose, the drug is only 6.5% bioavailable and
has a plasma elimination half-life of 12 to 14 hours.1
Its predictable pharmacokinetic profile allows for
a fixed dose regimen without the need for routine
coagulation monitoring. In 2008, dabigatran was
approved in Europe and Canada for use in patients
with venous thromboprophylaxis following knee
and hip replacement surgery. 2 More recently,
the drug was approved by the Food and Drug
Administration (FDA) and Health Canada for use
in thromboprophylaxis in patients with non-valvular
atrial fibrillation (AF).3-5
Dabigatran has several clinical advantages
over warfarin. These include fixed dosing without
the need for routine laboratory monitoring, and
significantly less drug interactions without the
narrow therapeutic window of warfarin. In addition,
warfarin has known food interactions that could
affect the efficacy of the drug.6 However, the lack
of an antidote to dabigatran in the event of major
bleeding poses a serious limitation.
Furthermore, the original study comparing
dabigatran to warfarin demonstrated a small,
but statistically significant, excess of myocardial
infarctions (MI) in patients treated with dabigatran.
The rate of MI was 0.5% per year with warfarin and
was higher with dabigatran: 0.7% per year in the
*Corresponding author:  famn@smh.ca
110mg group (relative risk, 1.4; 95% confidence
interval (CI), 0.98 to 1.9; p=0.070) and 0.7% per
year in the 150mg group (relative risk, 1.4, 95% CI,
1.0 to 1.9; p=0.048).7
Several mechanisms to explain this increased risk
include the known benefit of warfarin in reducing
MI compared to other anticoagulants, 8 and a
possible platelet activating effect of dabigatran in
patients not on aspirin.9 There is a paucity of reports
describing post-marketing adverse events and cases
of dabigatran failure. Here, we report a case of an
acute MI complicated by cardiac arrest in a patient
with chronic AF who was switched from warfarin
to dabigatran.
C A S E R E P O RT
A 67-year-old male was transferred to our institution
for an urgent coronary angiogram after he woke
from sleep with severe retrosternal chest pain and
diaphoresis. In the ambulance, while en-route to
the hospital, he was successfully resuscitated after
an episode of ventricular fibrillation (VF). The
patient had a medical history of permanent nonvalvular AF for which he was appropriately rate
controlled and anticoagulated with warfarin (since
1999), and had no previous thromboembolic events.
Three weeks prior to the current presentation,
he was switched from warfarin to dabigatran for
convenience. Dabigatran was started one day after
discontinuation of warfarin. His cardiac risk factors
56
Wael A buzeid, et al.
Figure 1: Coronary angiogram (left anterior
oblique view) showing (red arrow) an abruptly
occluded distal posterior descending artery (PDA)
with the angiographic appearance of an embolus.
Figure 2: Coronary angiogram (right anterior
oblique view) showing only minor irregularities in
the remaining coronary arteries.
included treated hyperlipidemia, hypertension
and a family history of premature coronary artery
disease (CAD). The patient had undergone previous
investigations for atypical chest pain and exertional
dyspnea. A coronary angiogram performed one year
prior revealed only minor luminal irregularities. In
addition, an exercise treadmill test performed a few
months prior to the present event was clinically and
electrically negative. His medications at the time
included, in addition to dabigatran 150mg twice
daily, bisoprolol, rampiril, atorvastatin, furosemide,
and vitamin supplements. He was not on aspirin.
Physical examination revealed a man of stated
age in no apparent distress. He was in AF with a
controlled ventricular rate of 58 beats per minute.
Cardiovascular examination was unremarkable.
His initial blood tests, including renal function,
were normal. Initial troponin I (Tn-I) and total
creatine kinase (CK) levels, which was obtained 80
minutes after onset of symptoms, were undetectable
but peaked the following day at 37.45μg/L and
598U/L, respectively.
His initial electrocardiogram showed transient
ST-segment elevation in the inferior leads. This
evolved into inferior T-wave inversion, with
resolution of ST-segment elevation and chest
pain. The patient received aspirin, clopidogrel,
and intravenous unfractionated heparin. Coronary
angiography occurred 18 hours from onset of
chest pain. The culprit lesion was an abruptly
occluded distal posterior descending artery (PDA)
with the angiographic appearance of an embolus
[Figure 1]. The other coronary arteries had
minor luminal irregularities [Figure 2]. Left
ventriculography demonstrated distal inferior wall
akinesis with overall preserved left ventricular (LV)
systolic function. Medical therapy was pursued.
A Definity® contrast-enhanced transthoracic
echocardiogram was obtained the next day and
showed no evidence of LV thrombus. The LV
ejection fraction was mildly reduced at 46% with
an akinetic inferoapical segment. There was no
evidence of an intracardiac shunt.
The rest of hospital course was unremarkable
and dabigatran was discontinued. He was switched
to warfarin. Intravenous heparin was concurrently
used until his international normalized ratio (INR)
was in the therapeutic range. His other medications
continued without change. Given that his VF arrest
occurred in the setting of an acute MI, he did not
require an implantable defibrillator.
DISCUSSION
The present case describes a probable cardioembolic
inferior MI, presumably originating in the left
atrium or its appendage. A comprehensive literature
search revealed a paucity of reports on adverse
57
Wael A buzeid, et al.
effects related to dabigatran. Most emphasis has
been on the hemorrhagic complications associated
with dabigatran use. One case report describes
massive and fatal rectal bleeding a few hours after
digital rectal evacuation of a fecaloma in an 84-yearold female with moderate renal dysfunction.10
Dabigatran also rarely causes false elevations of the
INR, which has the potential to adversely affect
patient care.11
The Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-LY) trial showed
that dabigatran, at a dose of 150mg twice daily,
compared to dose-adjusted warfarin was associated
with lower rates of stroke and systemic embolism but
similar rates of major bleeding.7 The trial also noted
an increase in the rate of MI in patients receiving
dabigatran. This was also reported by a recently
published meta-analysis of 12 randomized control
trials showing dabigatran to be associated with a
significant increased risk of MI.7,12 The mechanisms
underlying this observation remain speculative,
and previous studies have suggested a protective
effect of warfarin against ischemic cardiac events.8,13
However, a similar signal of increased cardiac
events and MI was also observed with another DTI,
ximelagatran.14
Several theories could explain why our patient
suffered an MI shortly after being switched from
warfarin to dabigatran. DTIs target the final step
in the coagulation cascade, thereby inhibiting the
conversion of fibrinogen to fibrin and subsequent
thrombus formation. Since thrombin also activates
platelets, DTIs are suggested to have an antiplatelet
effect.15 However, dabigatran has been reported to
increase urinary thromboxane excretion in patients
not receiving aspirin, suggesting a paradoxical
platelet activating effect. 9 In contrast, warfarin
inhibits the synthesis of multiple coagulation
factors, possibly translating into greater efficacy as a
treatment for preventing MI.
It has been suggested that inhibition of more
proximal stages of the coagulation cascade might be
more effective in inhibiting atherothrombosis.16 This
is supported by the results of a large randomized trial
of the factor Xa inhibitor rivaroxaban in patients
with acute coronary syndrome, which demonstrated
a reduction in MI compared to placebo.17
Although not directly applicable to our case,
drug-drug interaction should always be considered.
There are reports of decreased bioavailability of
dabigatran by 50–60% when certain medications
such as pantoprazole were administered, signaling
decreased absorption with lower gastric pH.18 This
may also play a role in dabigatran failure.
It is possible our patient suffered a MI due to a
decrease in platelet inhibition after being switched
from warfarin to dabigatran. This could potentially
be mitigated by concurrent aspirin use in a select
patient population. One study reported that aspirin
100µM showed 85.3% and 87.8% inhibition against
adenosine 5'-diphosphate (ADP) and adrenalineinduced platelet aggregation, respectively.19
However, our patient also had several risk
factors for ischemic heart disease and we cannot
rule out definitively other sources of embolism. It
is possible that the increased risk of MI in patients
on dabigatran is an associative effect rather than a
causative one.
C O N C LU S I O N
Dabigatran is now commonly used for
thromboprophylaxis in patients with AF for its
advantages over warfarin. The risk of bleeding in the
elderly and in patients with impaired renal function
has been described previously. To our knowledge,
our case is the first report of an acute myocardial
infarction in a patient with chronic AF in the
context of switching from warfarin to dabigatran.
This finding is consistent with the signal of increased
MI rates observed in the RE-LY study as explained
above. The excess of MIs with dabigatran may be an
associative rather than causative effect. A dabigatran
induced platelet-activating effect may be mitigated
by concomitant aspirin use. Further studies to
elucidate the mechanism of increased MI risk with
dabigatran and identify the subset of patients who
should be preferentially treated with warfarin are
needed.
Disclosure
The authors declared no conflict of interest.
r ef er ences
1. Stangier J, Clemens A. Pharmacology, pharmacokinetics,
and pharmacodynamics of dabigatran etexilate, an oral
direct thrombin inhibitor. Clin Appl Thromb Hemost
2009 Sep-Oct;15(Suppl 1):9S-16S.
2. EMEA. Pradaxa EPAR. Product information; 2010
March 18. Available at www.ema.europa.edu/docs/en_
GB/document_library/EPAR_Product_Information/
human/000829/WC500041059.pdf. Accessed 18
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
58
Wael A buzeid, et al.
November 2011.
3. Health Canada. Pradaxa product monograph; 2010
November 3. Webprod. Available at hs_sc.gc.ca/dpd-bdpp/
info.do?lang=eng&code=. Accessed 18 Nov 2011.
4. FDA. Pradaxa Label. Package Insert; 2010 Oct 19. Available
at http://www.accessdata.fda.gov/drugsatfda_docs/
label/2010/022512s0001bl.pdf. Accessed 18 November
2011.
5. FDA; Cardiovascular and Renal Drugs Advisory
Committee. Food and Drug Administration ;
2010 September 20. www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeetingMaterails/
Drugs/ardiovascularandRenalDrugsAdvisoryCommittee/
UCM226011.pdf. Accessed 18 November 2011.
6. Bushra R, Aslam N, Khan AY. Food-drug interactions.
Oman Med J 2011 Mar;26(2):77-83.
7. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J,
Oldgren J, Parekh A, et al; RE-LY Steering Committee and
Investigators. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med 2009 Sep;361(12):11391151.
8. Lip GY, Lane DA. Does warfarin for stroke
thromboprophylaxis protect against MI in atrial fibrillation
patients? Am J Med 2010 Sep;123(9):785-789.
9. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA,
Nagarakanti R, Parcham-Azad K, et al. Dabigatran with or
without concomitant aspirin compared with warfarin alone
in patients with nonvalvular atrial fibrillation (PETRO
Study). Am J Cardiol 2007 Nov;100(9):1419-1426.
10. Legrand M, Mateo J, Aribaud A, Ginisty S, Eftekhari P, Huy
PT, et al. The use of dabigatran in elderly patients. Arch
Intern Med 2011 Jul;171(14):1285-1286.
11. DeRemer CE, Gujral JS, Thornton JW, Sorrentino RA.
Dabigatran falsely elevates point of care international
normalized ratio results. Am J Med 2011 Sep;124(9):e5-e6.
12. Douxfils J, Buckinx F, Mullier F, Minet V, Rabenda
V, Reginster JY, et al. Dabigatran etexilate and risk of
myocardial infarction, other cardiovascular events, major
bleeding, and all-cause mortality: a systematic review and
meta-analysis of randomized controlled trials. J Am Heart
Assoc 2014 Jun;3(3):e000515.
13. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H.
Warfarin, aspirin, or both after myocardial infarction. N
Engl J Med 2002 Sep;347(13):969-974.
14. Diener HC; Executive Steering Committee of the
SPORTIFF III and V Investigators. Stroke prevention
using the oral direct thrombin inhibitor ximelagatran in
patients with non-valvular atrial fibrillation. Pooled analysis
from the SPORTIF III and V studies. Cerebrovasc Dis
2006;21(4):279-293.
15. Brass LF. Thrombin and platelet activation. Chest 2003
Sep;124(3)(Suppl):18S-25S.
16. Lippi G, Franchini M, Targher G. Arterial thrombus
formation in cardiovascular disease. Nat Rev Cardiol 2011
Sep;8(9):502-512.
17. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter
R, Misselwitz F, et al; ATLAS ACS-TIMI 46 study group.
Rivaroxaban versus placebo in patients with acute coronary
syndromes (ATLAS ACS-TIMI 46): a randomised, doubleblind, phase II trial. Lancet 2009 Jul;374(9683):29-38.
18. Committee for Medicinal Product for Human assessment
report, Pradaxa. European Medicines Agency 2011;1-79.
19. Viswanatha GL, Mohamed R, Rajesh S, Sandeep RS,
Mohammed A, Anturlikar SD, et al. Anti-platelet and
Anti-thrombotic Effects of a Poly-ingredient formulation:
In vitro and in vivo experimental evidences. Oman Med J
2012;27(6).
case report
Oman Medical Journal [2015], Vol. 30, No. 1: 59–62
Hughes-Stovin Syndrome and Massive Hemoptysis:
A Management Challenge
Khalfan Al-Zeedy*, B. Jayakrishnan, Dawar Rizavi and Juma Alkaabi
Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
A RT I C L E I N F O
Article history:
Received: 8 July 2013
Accepted: 01 March 2014
Online:
DOI 10.5001/omj.2015.11
Keywords:
Behcet’s Disease; Hemoptysis;
Hughes-Stovin syndrome;
Immunosuppressants.
A B S T R AC T
Hughes-Stovin syndrome is a very rare clinical entity characterized by pulmonary
artery aneurysms and deep vein thrombosis (DVT). Here we report the case of a
53-year-old man, admitted to Sultan Qaboos University Hospital, Muscat, Oman, with
bilateral pulmonary artery aneurysms and lower-limb DVT who developed massive
hemoptysis. He was managed successfully with high-dose steroids in combination with
cyclophosphamide.
H
ughes-Stovin syndrome (HSS) is a
very rare clinical entity characterized
by pulmonary artery aneurysms and
deep vein thrombosis (DVT).1 The
exact etiology of this syndrome is not clear and it
is often considered a variant of Behçet’s disease.
Although the symptoms can be non-specific,
HSS can sometimes present with life-threatening
hemoptysis.2 We report a patient with bilateral
pulmonary artery aneurysms and lower-limb DVT
who developed massive hemoptysis shortly after
admission.
C A S E R E P O RT
A 53-year-old Omani male was referred to Sultan
Qaboos University Hospital from a private clinic in
Muscat for a malignancy work-up. He presented with
a four-month history of coughing, fever, shortness of
breath, repeated episodes of mild hemoptysis, and
significant weight loss. A chest radiograph showed
bilateral hilar shadows [Figure 1].
Clinical examination was unremarkable except
for a heart rate of 115 beats/minute and a swelling in
the right leg. The initial working diagnosis included
malignancy, mediastinal lymphadenopathy, or
pulmonary artery aneurysms. The following day the
patient developed massive hemoptysis, and became
tachycardic and tachypnoeic. His blood pressure
dropped to 97/50 mmHg and saturation went down
to 86% on room air. He was subsequently referred
*Corresponding author:  khalfanalzidi@hotmail.com
to the intensive care unit for closer observation and
possible intubation. The cardiothoracic team and
interventional radiologists were alerted in preparation
for possible interventions. His hemoglobin dropped
from 11.2g/dL to 9.4g/dL. A multi-detector helical
computed tomography (CT) angiogram of the
chest showed bilateral multiple pulmonary artery
aneurysms with characteristic intraluminal thrombi
[Figure 2]. A Doppler ultrasound of the lower limbs
showed evidence of DVT in the right leg involving
the femoral, popliteal, and small veins. Investigations
showed normal white cell and platelet counts,
a high erythrocyte sedimentation rate (94mm/
hour), high C-reactive protein levels (114mg/L),
weakly positive antinuclear antibodies (ANA),
and normal rheumatoid factor and antineutrophil
cytoplasmic antibody (ANCA) titres. D-dimer was
high (5.9mg/L) and the renal, liver and thyroid
profiles were all within normal range. Screening
for hepatitis and human immunodeficiency virus
(HIV) was negative. There was no history of genital
or oral ulcers, uveitis, rashes, or other skin lesions.
As there were no other features suggesting Behçet’s
disease, a diagnosis of Hughes-Stovin syndrome was
considered.
The patient was treated with pulsed methyl
prednisolone (500mg daily for three days) and
intravenous cyclophosphamide (750mg ). He
continued to have mild hemoptysis for one day
before it settled. His blood pressure remained
within the low range and he required high flow
60
Kh alfan A l-Z eed y, et al.
Figure 1: Chest radiograph showing bilateral hilar
enlargement.
oxygen for a couple of days, initially at 10L/
minute through a non-rebreather mask. A bedside
echocardiogram did not show any evidence of
intracardiac thrombi or pulmonary hypertension.
The patient had massive hemoptysis, features of
thrombus in the pulmonary artery, and DVT. This
raised the question of prescribing anticoagulants.
However, anticoagulants were not given due to the
known risk of a fatal hemorrhage occurring from the
pulmonary artery aneurysms. The patient was then
prescribed oral prednisolone at 50mg daily for one
week, followed by 40mg daily for two weeks, which
was later tapered to a maintenance dose. Monthly
cyclophosphamide injections were continued for a
year. A chest radiograph after three months showed
almost complete resolution of the hilar shadows
[Figure 3]. At two-year follow-up, the patient was on
a daily dose of prednisolone 5mg and mycophenolate
5mg, he did not redevelop hemoptysis and had
remained relatively asymptomatic.
DISCUSSION
Figure 2: Computed tomography chest scan
showing the right pulmonary artery aneurysm
measuring about 3cm in diameter. Evidence of the
characteristic intraluminal thrombi lining the wall
is visible.
Figure 3: Chest radiograph taken three months
after presentation showing marked resolution of the
hilar shadows.
HSS is a very rare clinical condition which was first
described by two British physicians, Hughes and
Stovin, in 1959.3 It usually affects young men aged
between 12–40 years. The characteristics of HSS
are the formation of DVT and pulmonary artery
aneurysms. The initial presentation is usually nonspecific and patients may present with coughing,
shortness of breath, fever, or chest pain. Hemoptysis
can either arise later or be observed at the initial
presentation.4 The aneurysms usually involve the
pulmonary and/or the bronchial arteries, although
the systemic circulation can be affected too.5 They
can present with vascular thromboembolism,
arterial aneurysms, arterial and venous occlusions,
non-specific vasculitis and even thrombophlebitis.
The most serious complication of HSS is the
possibility of developing a massive and potentially
fatal hemorrhage.
The exact etiology of HSS remains unclear.
While infection and sepsis were considered
possible causes of this syndrome, the absence of any
positive cultures and the lack of patient response to
antibiotics does not support this hypothesis.6,7 The
current consensus is that HSS results from vasculitis,
similar to the vasculitis seen in Behçet’s disease.8,9
In fact, some consider HSS an "incomplete" form
of Behçet’s disease since the same combination of
61
Kh alfan A l-Z eed y, et al.
multiple pulmonary aneurysms and peripheral
vein thrombosis have been described in Behçet’s
disease.9,10 However, the typical features of Behçet’s
disease such as orogential ulcers, skin lesions, iritis,
or arthritis are missing in most HSS cases.
The exact pathogenesis of pulmonary artery
aneurysms is not well established, although they have
been attributed to a weakness of the vessel wall due to
inflammation.3,7,11 Hughes and Stovin suggested that
the aneurysms develop due the degenerative changes
in the walls of the bronchial arteries, with subsequent
changes in the vasa vasorum of the pulmonary artery.
This theory was supported by findings of dilated and
distorted bronchial arteries and convoluted small
branches in digital subtraction angiograms.5,12 The
pulmonary artery thrombosis develops in situ due
to the inflammation of the arterial wall and not as
thromboembolism developing from peripheral vein
thrombosis.10,13 In fact, pulmonary embolism is rare
in patients with Behçet’s disease and DVT. This is
possibly due to the fact that the thrombi in these
patients adhere to the walls of the veins.10,13
No standardized guidelines exist for the
treatment of HSS and immunosuppressant drugs
remain the predominant first-line therapy. 11,14
This usually involves a combination of steroids
and cytotoxic agents, the most commonly used
being cyclophosphamide. Anticoagulants and
thrombolytic agents are generally contraindicated
in patients with HSS due to the increased risk of
fatal hemorrhage from pulmonary aneurysms.7,15
Therefore, the physician is often confronted with
a challenge regarding optimal patient management
particularly when an embolic state is noted in
patients with a pro-thrombotic tendency.8 Some
of these patients may even have hemoptysis upon
initial presentation. Hemoptysis can occur due
to the rupture of an aneurysm, acute vasculitis, or
due to rupture of the angiodysplastic bronchial
arteries. Anticoagulants have been used judiciously
in patients with intracardiac thrombi or embolisms
in the main pulmonary artery and in those with
hemodynamic instability.16 Some physicians have
used anticoagulants in cases of unilateral single
pulmonary aneurysms that were surgically resected,
or after adequate immunosuppressive treatment.2,15
However, the need for anticoagulation is not
always clear as the risk of pulmonary embolism
is very low and these patients may still develop
thrombosis despite adequate anticoagulation.7,17
Anticoagulation should be considered with extreme
caution and only in clinical situations where the
benefits clearly outweigh the risks. More studies are
required to reach a consensus on this issue.
Surgical resection of the affected lung can be
considered if the aneurysms are at a high risk of
rupturing and/or are localized to one segment or
one lung.2,5 However, surgical interventions usually
carry a higher risk and the pulmonary aneurysms
often tend to be both bilateral and multiple.
Embolization can also be considered in patients in
danger of rupturing or in cases of fatal hemoptysis.5,15
In our patient, the massive hemoptysis was managed
successfully with a combination of steroids and
cyclophosphamide. This case highlights the
effectiveness of immunosuppressant treatment in
the management of massive hemoptysis in a patient
with HSS.
C O N C LU S I O N
HSS is a very rare clinical disorder characterized
by pulmonary artery aneurysms and DVT,
which resembles Behçet’s disease in many ways.
Management of patients with HSS who develop
massive hemoptysis is often tricky and requires
supportive care along with immunosuppressive
treatment. In our case the patient was managed
successfully using a combination of steroids and
cyclophosphamide.
Disclosure
The authors declared no conflict of interest.
r ef er ences
1. Kopp WL, Green RA. Pulmonary artery aneurysms
with recurrent thrombophlebitis. The "Hughes-Stovin
syndrome". Ann Intern Med 1962 Jan;56:105-114.
2. Al-Jahdali H. Massive hemoptysis and deep venous
thrombosis presenting in a woman with Hughes-Stovin
syndrome: a case report. J Med Case Rep 2010;4:109.
3. Hughes JP, Stovin PG. Segmental pulmonary artery
aneurysms with peripheral venous thrombosis. Br J Dis
Chest 1959 Jan;53(1):19-27.
4. Choh NA, Jehangir M, Mir KM, Kuchay S, Wani NA.
Hughes-Stovin syndrome: A rare cause of hemoptysis. Lung
India 2011 Oct;28(4):285-286.
5. Herb S, Hetzel M, Hetzel J, Friedrich J, Weber J. An
unusual case of Hughes-Stovin syndrome. Eur Respir J 1998
May;11(5):1191-1193.
6. Charlton RW, Du Plessis LA. Multiple pulmonary artery
aneurysms. Thorax 1961 Dec;16:364-371.
7. Khalid U, Saleem T. Hughes-Stovin syndrome. Orphanet
J Rare Dis 2011;6:15.
8. Durieux P, Bletry O, Huchon G, Wechsler B, Chretien
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
62
Kh alfan A l-Z eed y, et al.
J, Godeau P. Multiple pulmonary arterial aneurysms in
Behcet’s disease and Hughes-Stovin syndrome. Am J Med
1981 Oct;71(4):736-741.
9. Grenier P, Bletry O, Cornud F, Godeau P, Nahum H.
Pulmonary involvement in Behcet disease. AJR Am J
Roentgenol 1981 Sep;137(3):565-569.
10. Emad Y, Ragab Y, Shawki Ael-H, Gheita T, El-Marakbi A,
Salama MH. Hughes-Stovin syndrome: is it incomplete
Behçet's? Report of two cases and review of the literature.
Clin Rheumatol 2007 Nov;26(11):1993-1996.
11. Bowman S, Honey M. Pulmonary arterial occlusions and
aneurysms: a forme fruste of Behçet's or Hughes-Stovin
syndrome. Br Heart J 1990 Jan;63(1):66-68.
12. Mahlo HR, Elsner K, Rieber A, Brambs HJ. New approach
in the diagnosis of and therapy for Hughes-Stovin
syndrome. AJR Am J Roentgenol 1996 Sep;167(3):817818.
13. Ketchum ES, Zamanian RT, Fleischmann D. CT
angiography of pulmonary artery aneurysms in
Hughes-Stovin syndrome. AJR Am J Roentgenol 2005
Aug;185(2):330-332.
14. Lee J, Noh JW, Hwang JW, Kim H, Ahn JK, Koh EM, et
al. Successful cyclophosphamide therapy with complete
resolution of pulmonary artery aneurysm in Hughes-Stovin
syndrome patient. Clin Rheumatol 2008 Nov;27(11):14551458.
15. Erkan F, Gül A, Tasali E. Pulmonary manifestations of
Behçet's disease. Thorax 2001 Jul;56(7):572-578.
16. Tsai CL, Lu TC, Tsai KC, Chen WJ. Hemoptysis caused
by Hughes-Stovin syndrome. Am J Emerg Med 2005
Mar;23(2):209-211.
17. Erkan D, Yazici Y, Sanders A, Trost D, Yazici H. Is HughesStovin syndrome Behçet's disease? Clin Exp Rheumatol
2004 Jul-Aug;22(4 Suppl 34):S64-S68.
case report
Oman Medical Journal [2015], Vol. 30, No. 1: 63–65
Post-aural Nodular Fasciitis
Mohammed Al-Rahbi1*, Hunaina Al-Kindi2 and Salma Al-Sheibani1
Department of Otorhinolaryngology, Al-Nahdha Hospital, Muscat, Oman
Department of Histopathology, Khoula Hospital, Muscat, Oman
1
2
A RT I C L E I N F O
Article history:
Received: 27 February 2013
Accepted: 23 January 2014
Online:
DOI 10.5001/omj.2015.12
Keywords:
Fasciitis; Nodular;
Adenoma; Pleomorphic.
A B S T R AC T
Nodular fasciitis is a rare benign lesion. Here we report a case of post-auricular nodular
fasciitis, which was misdiagnosed by fine-needle aspiration cytology (FNAC) as
pleomorphic adenoma. Physical examination of an 18-year-old male revealed a right post
aural firm immobile mass. Radiology suggested the presence of a hypo-dense to iso-dense
subcutaneous mass. The swelling was excised and sent for histopathological examination
which suggested the diagnosis of nodular fasciitis. FNAC reported pleomorphic adenoma
of unusual location should raise the suspicion of nodular fasciitis.
N
odular fasciitis is a benign rapidly
growing lesion that usually occurs
in the subcutaneous tissue of upper
extremities, such as the trunk, head,
and neck of young adults. We present what we
believe is the first case of post-auricular nodular
fasciitis in Oman.
CASE REPORT
An 18-year-old male presented to our clinic with
right post-auricular swelling that had lasted six
months. The swelling was painless and slowly
increasing in size. It was first noticed after shaving
over the area. The patient had a history of occasional
bleeding from the right ear.
On examination, there was a right, non-tender,
firm, post-auricular mass of about 3cm by 6cm
[Figure 1a]. The swelling was immobile and attached
to the skin; however, there were no skin changes or
signs of inflammation. Examination of the right
external auditory canal revealed a bulge on the
posterior wall with small area of laceration and
crusting [Figure 1b]. Examination of the tympanic
membrane, the rest of ENT, and head and neck were
unremarkable.
A computed tomography (CT) scan of the
temporal bone showed a right post-auricular
hypodense to isodense subcutaneous mass with
homogeneous enhancement with IV contrast
[Figure 1c]. There were no bony erosions.
*Corresponding author: moh39112@gmail.com
Fine needle aspiration cytolog y (FNAC)
showed small cohesive clusters of cells with round
to oval nuclei and moderate cytoplasm. Strands
of fibromyxoid material was seen [Figure 2]. The
overall picture suggested a diagnosis of pleomorphic
adenoma.
The mass was excised through a post-auricular
incision, it was firm in consistency, approximately
4cm by 3cm in size, attached to the underlying postauricular muscles (the periosteum and the conchal
cartilage), and eroding through the posterior
wall of the external auditory canal [Figure 3].
Histopathological examination showed a 5cm by
2.5cm by 2cm irregular mass with a gray and brown
cut surface with papillary like projections.
Microscopy showed a lesion composed of plump
spindle-shaped cells lacking nuclear hyperchromasia,
or pleomorphism. There were numerous mitoses seen
but no atypical forms. The background was loose
myxoid, feathery or tissue culture like. There were
extravasated red blood cells, chronic inflammatory
cells and scattered multinucleated giant cells
[Figure 4a-d]. Immunohistochemical staining showed
that spindle cells were positive for smooth muscle
actin (SMA) and vimentin. Scattered CD68 positive
cells were seen. Tests for cytokeratin, desmin and S100
were negative. The histopathological picture was in
keeping with a diagnosis of nodular fasciitis.
The patient was on regular follow up after
the surgery for two years and there were no signs
of recurrence.
64
Moh a mmed A l-R ahbi, et al.
Figure 1: (a) Right postauricular mass. (b) Bulge and ulceration over posterior wall of the right external
auditory canal. (c) Computed tomography scan of the temporal bone, axial cut, showing right postauricular
hypodense to isodense mass.
Figure 2: Fine needle aspiration: Small cohesive
clusters of cells with round to oval nucleus and
moderate cytoplasm. Magnification=200×.
Figure 3: The right postauricular mass specimen
with piece of conchal cartilage, it was approximately
4cm by 3 cm in size.
Figure 4: (a) Plump spindle-shaped cells in a loose myxoid feathery or tissue culture background. Magnification=
100×. (b) Extravasated red blood cells. Magnification=200×. (c) Cells showed frequent mitosis (arrow).
Magnification=400×. (d) Scattered multinucleated giant cells. Magnification=200×.
65
Moh a mmed A l-R ahbi, et al.
DISCUSSION
Nodular fasciitis is a benign lesion first
described by Konwaler in 1955 when he called
it pseudosarcomatous fasciitis. It is a reactive
fibroblastic proliferation that commonly occurs in
young adults, and presents as a rapidly enlarging
mass over a number of weeks.1 It is a self-limiting
disease and regresses in months. The longest known
duration is 26 months.2 Nodular fasciitis is mainly
seen in the upper extremities (48%) and trunk
(20%).3 They also arise from subcutaneous tissue,
muscles, and fascia,2,3 and from other areas of the
body. Between 13% and 20% were found in the
head and neck region.3,4 The lesion can be mistaken
for sarcoma because of its rapid growth and high
cellularity upon histopathological examination.
The etiology of this condition is unknown.
However, about 10% to 15% of cases had history
of trauma.1 In the present case there was a history
suggestive of minor trauma by shaving over the area
of the swelling.
Nodular fasciitis present in three types:
subcutaneous, intramuscular, and intermuscular
(fascial).3 Thompson et al,5 reported that nodular
fasciitis involving the external ear is more dermally
situated with a tendency of superficial ulceration
and bleeding, a picture similar to our present case.
Weinreb et al,4 reported that in the head and neck
region, the lesion had a tendency to be smaller in size,
have increased skeletal muscle involvement (30%),
and diffuse, strong actin expression compared to
fasciitis elsewhere in the body.
The patient’s CT scan showed homogenous
enhancement. Shin et al,6 reported that nodular
fasciitis lesions showed strong enhancement on CT
and magnetic resonance imaging (MRI). Kim et al,7
concluded that nodular fasciitis should be included
in the differential diagnosis in any head and neck
mass with a superficial location and moderate to
marked enhancement on CT and MRI, especially in
patients with a recent history of trauma and rapidly
growing mass. In our case, the CT scan findings were
consistent with these reported features.
Our case was misdiagnosed as pleomorphic
adenoma by FNAC. This has been reported
previously indicating a pitfall in the diagnosis
of pleomorphic adenoma using FNAC. 2,8-10 The
common morphological features shared by both
pleomorphic adenoma and nodular fasciitis are
spindle and plasmacytoid cells with central-toeccentric nuclei, clumps of intercellular stromal
material, and myxoid background. Mitotic figures
are frequent in most cases of nodular fasciitis but
sparse in cases of pleomorphic adenoma.8
The treatment of choice is surgical excision. However,
the local recurrence rate is high due to incomplete
surgical excision.3,6,7 The local recurrent rate is 9.3% in
the auricular region and 1%–2% in other areas.3
C O N C LU S I O N
Nodular fasciitis is a rare benign lesion that shares
some morphological features with pleomorphic
adenoma on histological examination. However,
the former is distinguished by the presence of
frequent mitotic figures. It should be considered in
the differential diagnosis of any mass, reported as
pleomorphic adenoma on FNAC, on an unusual
location for a salivary gland neoplasm.
Disclosure
The authors declared no conflict of interest.
r ef er ences
1. Kumar V, Corton R, Robbins SL. Basic pathology. 6th ed.
Philadelphia, Pennsylvania: Saunders; 1997.
2. Kaur H, Mardi K, Sharma J. Nodular fasciitis of the hand
– a potential diagnostic pitfall in fine needle aspiration
cytology. Journal of Cytology 2007;24(4): 197-198.
3. Huang CD, Lin YH, Lee FP. Postauricular nodular fasciitis.
Otolaryngol Head Neck Surg 2007 Jul;137(1):164-165.
4. Weinreb I, Shaw AJ, Perez-Ordoñez B, Goldblum JR,
Rubin BP. Nodular fasciitis of the head and neck region: a
clinicopathologic description in a series of 30 cases. J Cutan
Pathol 2009 Nov;36(11):1168-1173.
5. Thompson LD, Fanburg-Smith JC, Wenig BM. Nodular
fasciitis of the external ear region: a clinicopathologic study
of 50 cases. Ann Diagn Pathol 2001 Aug;5(4):191-198.
6. Shin JH, Lee HK, Cho K-J, Han MH, Na DG, Choi CG,
et al. Nodular fasciitis of the head and neck: Radiographic
findings. Clinical Imaging 2003;27(1):31-37.
7. Kim ST, Kim HJ, Park SW, Baek CH, Byun HS, Kim
YM. Nodular fasciitis in the head and neck: CT and MR
imaging findings. AJNR Am J Neuroradiol 2005 NovDec;26(10):2617-2623.
8. Jain D, Khurana N, Jain S. Nodular fasciitis of the external
ear masquerading as pleomorphic adenoma: A potential
diagnostic pitfall in fine needle aspiration cytology.
Cytojournal 2008;5:14.
9. Mallina S, Rosalind S, Philip R, Harvinder S, Gurdeep S,
Sabaria MN. Nodular fasciitis: a diagnostic dilemma. Med
J Malaysia 2007 Dec;62(5):420-421.
10. Saad RS, Takei H, Lipscomb J, Ruiz B. Nodular fasciitis
of parotid region: a pitfall in the diagnosis of pleomorphic
adenomas on fine-needle aspiration cytology. Diagn
Cytopathol 2005 Sep;33(3):191-194.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
case report
Oman Medical Journal [2015], Vol. 30, No. 1: 66–68
Extrahepatic Biliary Cystadenoma: A Rare Cause
of Biliary Obstruction
Adli Metussin1, Pemasari Telisinghe2, Kenneth Kok3 and Vui Chong1
Department of Medicine, Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan, Brunei
Department of Pathology, Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan, Brunei
3
Department of Surgery, Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan, Brunei
1
2
A RT I C L E I N F O
Article history:
Received: 23 September 2014
Accepted: 30 November 2014
Online:
DOI 10.5001/omj.2015.13
Keywords:
Jaundice; Obstructive; Biliary tract
neoplasm; Choledocholithiasis;
Biliary tract disease.
A B S T R AC T
Biliary cystadenoma is a rare tumor of the biliary tree and a rare cause of obstructive
jaundice. Most are intrahepatic, and pure extrahepatic biliary cystadenoma is
less common. Cases are more common in women. Unless suspected, diagnosis of
extrahepatic biliary cystadenoma is often delayed. Here, we report the case of a young
woman with extrahepatic biliary cystadenoma who presented at Raja Isteri Pengiran
Anak Saleha Hospital with obstructive jaundice initially thought to be due to a large
biliary stone based on the endoscopic cholangiogram image. She was successfully
managed with resection of the cystadenoma.
B
iliary obstruction is common in clinical
practice and in most instances is due
to biliary stones disease.1 In the older
population, malignancies also need to be
considered. However, it is important that clinicians
are aware of the rare causes of biliary obstructions.
We report the case of a young woman who presented
with obstructive jaundice and was initially treated
for a biliary stone that turned out to be biliary
cystadenoma, a rare biliary tumor.
C A S E R E P O RT
A 24-year-old woman presented with chronic
epigastric and right upper quadrant pain radiating
to the back, and jaundice. Her medical history
was unremarkable. She had not been taking any
medications (including oral contraceptive pills)
regularly. Apart from jaundice, physical examination
was unremarkable. Laboratory investigations showed
cholestatic liver profile with normal white blood cell
count and inflammatory marker levels. Ultrasound
scan (USS) of the abdomen revealed a dilated
common bile duct. Her background history revealed
that she was admitted two months prior with similar
abdominal pain, but evaluations at that time (liver
profiles, upper gastrointestinal endoscopy and USS
of the abdomen) had been normal. Her symptoms
settled and she was discharged with anti-spasmodic
treatment, and reviewed in our patient clinic.
*Corresponding author:  chongvuih@yahoo.co.uk
The patient underwent an endoscopic retrograde
cholangiography (ERC) which showed a large
filling defect [Figure 1] in the common bile duct,
consistent with a large biliary stone. After endoscopic
sphincterotomy, attempted stone extraction using biliary
mechanical lithotripter and balloon failed. The basket
failed to capture the stone and the extraction balloon
catheter seemed to slip passed the stone whenever it was
pulled down. A stent (Cotton-Leung 10Fr 10cm) was
placed without any difficulty. Following the procedure,
the patient was well without any symptoms.
A planned ERC three months later was again
unsuccessful and similar difficulties were encountered.
A computed tomography (CT) scan showed the
filling defect to be cystic in nature. There were no other
abnormalities such as hepatic cysts away or within
the vicinity of the biliary cystic lesion to suggest any
communication or connection seen on the imaging.
There were no other cystic lesions seen in other organs
including the pancreas. The patient proceeded to
surgery. A biliary polyp (3.5cm by 1.8cm) attached
to the bifurcation of the bile duct was identified.
Resection and Roux-en-Y hepaticojejunostomy was
performed without any complication. On dissection,
the polyp [Figure 2] was biloculated with cysts
measuring 1.5cm and 0.5cm, respectively. Histology
revealed the cysts to be lined with cuboidal to
low columnar cells, a subepithelial mesenchymal
layer of plump spindle shaped cells (ovarian-like
stroma), uniform nuclei, and an outer wall formed
67
A dli Met ussin, et al.
Figure 1: Cholangiogram showing a large oval shaped
filling defect in the proximal common bile duct.
Figure 2: Resected specimen showing cystic
structures with areas of hemorrhages.
Figure 3: (a) Hematoxylin (purple) and eosin (pink/red) stain showing cyst lined with a single layer cuboidal
cell consistent of a biliary cystadenoma, 40x magnification. (b) Positive staining for vemintin (brown) showing
subepithelial mesenchymal layer of plump spindle shaped cells (ovarian-like stroma), 40x magnification.
of hyalinized fibrous connective tissue [Figure 3a].
Stain for vimentin was positive [Figure 3b]. There
was no evidence of malignant transformation. The
final diagnosis was biliary obstruction secondary
to a biliary cystadenoma. The patient remained
well without any symptoms almost three years after
resection and there was no evidence of recurrence on
follow-up imaging. The patient was also advised to
avoid using oral contraceptive pills.
DISCUSSION
Biliary adenoma or biliary cystadenoma is a rare cystic
neoplasm and a rare cause of biliary obstruction.2-6 It
accounts for less than 5% of nonparasitic hepatic cystic
lesions. It was first described in 1943 and, to date, less
than 200 cases have been reported.2 It is a slowly growing
benign tumor that has malignant potential, especially
those with mesenchymal ovarian stroma.7,8 It is more
common in middle aged women (85–95%), with a
gender ratio of 4:1. Our patient was much younger than
those reported in the literature.
Biliary cystadenoma is thought to originate from
embryonic tissue precursors of biliary epithelium,6
and more commonly affects the intrahepatic portion
(90%), and less commonly the extrahepatic duct, as in
our case.4 Macroscopically, it appears as a polypoidal
lesion attached to the biliary tree and is cystic, either
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
68
A dli Met ussin, et al.
unilocular or multilocular, when sectioned with
mucinous or serous fluid. Microscopically, the cyst is
lined with a single layer of cuboidal cells with basally
orientated nuclei. There may be papillary and polypous
excrescences, and mucin filled vacuoles. In our case, the
epithelium was surrounded by a mesenchymal layer of
plump spindle-shaped cells consistent with ovarian-like
stroma. This variant is often referred to as cystadenoma
with mesenchymal stroma in order to differentiate it
from the cystadenoma without the mesenchymal layer.
This variant has malignant potential and is associated
with poorer prognosis to the other variant in cases of
malignant transformation.7,8 Cystadenomas are known
to increase in size during pregnancy and following oral
contraceptive use suggesting hormonal dependency,
and therefore is more common in women.9
Commonly reported symptoms include vague
abdominal pain (up to 90%) and nonspecific mass
symptoms (>30%).4,10 Dyspepsia, anorexia, vomiting,
and weight loss are less common.11 These symptoms
are nonspecific and resemble other cause of obstructive
jaundice. Given the nonspecific nature of the symptoms,
patients often have symptoms that have been present for
a long time.
The diagnosis of biliary cystadenoma require
a high level of suspicion. Generally, the diagnosis
of extrahepatic biliary cystadenoma is not made
preoperatively. Characteristic features on magnetic
resonance imaging have been reported that allowed
preoperative diagnosis of cystadenoma with ovarian
stroma.12 Presence of intramural nodule or irregular
wall is suggestive of malignant transformation. In a
setting where biliary stones are common, finding by
USS and ERC imaging often resemble stones and in
the present case, our patient was managed as such. CT
imaging in our patient revealed the lesion to be cystic in
nature, and this prompted a decision to refer the patient
for surgery. In the intrahepatic variant, involvements of
the extrahepatic biliary tree are through compression by
the cyst, or rarely prolapse of part of the cyst, into the
biliary system causing obstruction. Complete resection
is advised as there is risk of malignant transformation.7,13
Furthermore, recurrence is possible and is often related
to incomplete resection of the lesion even in the absence
of malignant transformation. In our case, only the cystic
adenoma was resected and our surgeon did not consider
any extensive resection, such as a sleeve resection, as there
was no lesion outside of the biliary tree seen on imaging
and during surgery. Our patient remained under
surveillance and to date, after more than three years,
there has been no evidence of recurrence of the lesion.
She was also advised to avoid using any contraceptive
pill since it remains unknown whether these increase
the risk of recurrence of the cystadenoma.
C O N C LU S I O N
This report documents a rare case of intraluminal biliary
cystadenoma that presented with obstructive jaundice,
and that resembled a biliary stone. The diagnosis was
not made until the patient went for surgery. Clinicians,
especially those involved with endoscopy, should be
aware of this entity as there is malignant potential.
Disclosure
The authors declared no conflict of interest.
r ef er ences
1. Beckingham IJ, Ryder SD. ABC of diseases of liver, pancreas,
and biliary system. Investigation of liver and biliary disease.
BMJ 2001 Jan;322(7277):33-36.
2. Ahanatha Pillai S, Velayutham V, Perumal S, Ulagendra Perumal
S, Lakshmanan A, Ramaswami S, Ramasamy R, Sathyanesan J,
Palaniappan R, Rajagopal S. Biliary cystadenomas: a case for
complete resection. HPB Surg. 2012;2012:501705.
3. Soochan D, Keough V, Wanless I, Molinari M. Intra and extrahepatic cystadenoma of the biliary duct. Review of literature
and radiological and pathological characteristics of a very rare
case. BMJ Case Rep 2012;2012:2012.
4. Hernandez Bartolome MA, Fuerte Ruiz S, Manzanedo
Romero I, Ramos Lojo B, Rodriguez Prieto I, Gimenez Alvira
L, et al. Biliary cystadenoma. World J Gastroenterol 2009
Jul;15(28):3573-3575.
5. Rayapudi K, Schmitt T, Olyaee M. Filling Defect on ERCP:
Biliary Cystadenoma, a Rare Tumor. Case Rep Gastroenterol
2013 Jan;7(1):7-13.
6. Gonzalez M, Majno P, Terraz S, Morel P, Rubbia-Brandt
L, Mentha G. Biliary cystadenoma revealed by obstructive
jaundice. Dig Liver Dis 2009 Jul;41(7):e11-e13.
7. Wheeler DA, Edmondson HA. Cystadenoma with
mesenchymal stroma (CMS) in the liver and bile ducts. A
clinicopathologic study of 17 cases, 4 with malignant change.
Cancer 1985 Sep;56(6):1434-1445.
8. Hennessey DB, Traynor O. Extrahepatic biliary cystadenoma
with mesenchymal stroma: a true biliary cystadenoma? A case
report. J Gastrointestin Liver Dis 2011 Jun;20(2):209-211.
9. Del Poggio P, Buonocore M. Cystic tumors of the liver: a practical
approach. World J Gastroenterol 2008 Jun;14(23):3616-3620.
10. Wang C, Miao R, Liu H, Du X, Liu L, Lu X, et al. Intrahepatic
biliary cystadenoma and cystadenocarcinoma: an experience of
30 cases. Dig Liver Dis 2012 May;44(5):426-431.
11. Florman SS, Slakey DP. Giant biliary cystadenoma: case report
and literature review. Am Surg 2001 Aug;67(8):727-732.
12. Nakagawa M, Matsuda M, Masaji H, Goro W. Successful
preoperative diagnosis of biliary cystadenoma with
mesenchymal stroma and its characteristic imaging features:
report of two cases. Turk J Gastroenterol 2011 Dec;22(6):631635.
13. Thomas KT, Welch D, Trueblood A, Sulur P, Wise P, Gorden
DL, et al. Effective treatment of biliary cystadenoma. Ann Surg
2005 May;241(5):769-773, discussion 773-775.
online case report
Oman Medical Journal [2015], DOI 10.5001/omj.2015.16
Congenital Symmetrical Lower Lip Pits:
Van der Woude Syndrome
Abdulrasheed Ibrahim1* and Sunday Ajike2
Department Of Surgery, Ahmadu Bello University, Zaria, Nigeria
Department Of Maxillofacial Surgery, Ahmadu Bello University, Zaria, Nigeria
1
2
A RT I C L E I N F O
Article history:
Received: 23 March 2014
Accepted: 23 October 2014
Keywords:
Van der Woude syndrome;
Cleft lip; Cleft Palate; General
Surgery.
A B S T R AC T
Van der Woude syndrome (VWS) is a rare craniofacial anomaly with autosomal dominant
inheritance and remarkable heterogeneity in expression. It manifests as lower lip pits
with or without a cleft lip and/or cleft palate. The critical importance of lip pits is that
their occurrence may be associated with a phenotypic severity of the cleft lip and cleft
palate. The clinical manifestation of lower lip pits covers a wide spectrum. These include
slight depressions on the vermilion border of the lip, and fistulas that penetrate into
subjacent salivary glands and drain small amounts of saliva. Lip pits are usually circular
or oval shaped, but have also been described as transverse, slit-like, or sulci. They may vary
from an asymptomatic slight depression on the vermilion border of the lower lip to deep
fistulas. The relatively high incidence in females has been attributed to the established
fact that they are more likely to seek surgical intervention for cosmetic considerations.
Cosmetic considerations are thus the most common indication for surgical intervention;
however, some patients with asymptomatic lesions or mild symptoms may neither require
nor request surgery. The goals of treatment are two-fold; removal of sinuses and providing
cosmetic relieve for the disfigurement. The identification of familial lip pits is crucial for
genetic counseling. Physical examination of relatives and interviews with older relatives
are considered essential to identify affected family members. Information regarding the
pattern of inheritance and the consequence of these phenotypes must be emphasized.
Here we report an interesting case of VWS seen at the Ahmadu Bello University Teaching
Hospital, Zaria, Nigeria, to highlight its peculiar clinical presentation and management.
*Corresponding author:  shidoibrahim@yahoo.com
The full article can be found online at www.omjournal.org.
clinical quiz
Oman Medical Journal [2015], Vol. 30, No. 1: 70–71
Localized Acral Hypertrophy
Saifullah Khalid1*, Mohd. Faizan2, Imran Ahmad3, Sabarish Narayanasamy1, Ansarul
Haque3 and Ibne Ahmad1
Department of Radiodiagnosis, Jawaharlal Nehru Medical College and Hospital, AMU, Aligarh, India
Department of Orthopaedic Surgery, Jawaharlal Nehru Medical College and Hospital, AMU, Aligarh, India
3
Department of Plastic Surgery, Jawaharlal Nehru Medical College and Hospital, AMU, Aligarh, India
1
2
A RT I C L E I N F O
Article history:
Received: 10 June 2013
Accepted: 28 January 2014
Online:
DOI 10.5001/omj.2015.14
A
35-year-old male presented with
complaints of a progressive increase in
the size of his right thumb. There was
a significant increase in subcutaneous
tissue, which was most prominent on the palmar
aspect. He was experiencing difficulty in his dayto-day work due to restricted movement. There was
no history of trauma, infection, or a family history
suggestive of neurofibromatosis or any similar
disease. He had undergone surgery two years prior
for similar complaints in the index finger. Plain
radiograph of the hand [Figure 1] was advised
following this magnetic resonance imaging (MRI)
of the right hand was preformed to confirm the
diagnosis and assess the disease status [Figure 2].
A plain X-ray of the hand of another patient
with similar complaints in the middle finger showed
increased lengths of metacarpals and phalanges of
the middle finger with prominent soft tissue and is
shown in Figure 3.
Figure 1: (a) Clinical photograph showing localised enlargement of thumb with postoperative changes
in index finger. (b) X-ray imaging of the hand shows hypertrophy of soft tissue and bone with mushroom
shaped terminal phalanx. Secondary degenerative changes are seen early in the involved digit.
*Corresponding author:  saif2k2@gmail.com
71
S A I F U L L A H K H A L I D, ET A L .
Figure 2: Magnetic resonance imaging of the fingers. (a) T1-weighted imaging shows proliferation of the
fibro-fatty tissue of the thumb. (b and d) Proton Density fat saturated image confirms the fatty nature. (c)
T2-weighted imaging shows osteophyte formation with fibro-fatty proliferation. (a-d)The associated bony
changes are seen. (e) Mushrooming of the terminal phalanx is also seen.
Questions
1. What is the diagnosis?
2. Name the commonly associated nerve pathology
with this condition?
Anwers to the quiz, and the full article, can be
found online at www.omjournal.org.
Figure 3: X-ray imaging of the hand of another
patient shows hypertrophy of soft tissue and bone of
middle finger with advanced degenerative changes
in the involved digits.
O M A N M E D J, V O L 3 0 , N O 1, JA N UA RY 2015
letter to the editor
Oman Medical Journal [2015], Vol. 30, No. 1: 72
Allergic Rhinitis in Oman and Malaysia: The
Similarities and Differences
Irfan Mohamad* and Ramiza Ramli
Department of Otorhinolaryngology, Universiti Sains Malaysia Health Campus, Kelantan, Malaysia
A RT I C L E I N F O
Article history:
Received: 11 February 2015
Accepted: 15 February 2015
Online:
DOI 10.5001/omj.2015.15
Dear Editor,
I
read with great interest the paper on allergic
rhinitis entitled “Allergic rhinitis and
associated comorbidities: Prevalence in Oman
with knowledge gaps in literature” published
in the November issue of the Oman Medical Journal.1
It is a great finding of such a common disease whereby
48% of the patients with non-infective rhinitis were
diagnosed as allergic rhinitis, which constituted 7%
prevalence of the adult population presenting with
nasal symptoms to the center.1 However, these fairly
high figures are often overlooked. In fact, the burden
of the disease is increasing, with the increase of the
prevalence globally.
It is interesting to note that even though Oman
and Malaysia are far apart, and the population,
environment, demographics, and climate of the
two countries are invariably different, there are
many similarities among the studied allergic rhinitis
patients from both countries.
A similar study looking at allergic rhinitis among
the Malaysian population was conducted by Asha’ari
et al, in 2010, over the same period of time (oneyear in a tertiary center).2 Despite a different climate
pattern, only ten out of 61 patients in Al-Abri’s study
were categorized as seasonal type, and all of them
were sensitive to Russian thistle.1 Malaysia is a nonseasonal country thus the majority, if not all, patients
were of the perennial group.3
In the Omani population, 80% were found to be
sensitive to house dust mites (HDM).1 This figure
was the same as the Malaysian population whereby
72 out of 90 patients were positive to the similar
allergen on skin prick test. This constituted exactly
80% of the sample population. In addition to the
HDM, reaction to allergens containing domestic
cat’s fur (37.8%), egg yolk (17.8%), and egg white
(17.8%) were also statistically significant (p<0.050)
among Malaysians. Reactions to peanut and wheat
flour were also high (positive in more than 20%
of the patients); however, this was not statistically
significant.2 Many patients demonstrated sensitivity
to more than a single allergen in both the Omani
and Malaysian population. 1,2 These findings
are also consistent with one study conducted
in Malaysian children, whereby 98 out of 143
patients had a positive 3mm wheal upon testing
with HDM allergen, and 54.6% were positive to
multiple allergens.4
Both of these studies have shown that allergic
rhinitis has universal similarities. As common
features have been revealed between studies we
now need to take steps to try to manage the allergic
rhinitis more effectively and efficiently.
r ef er ences
1. Al-Abri R, Bharghava D, Kurien M, Chaly V, Al-Badaai Y,
Bharghava K. Allergic rhinitis and associated comorbidities:
prevalence in oman with knowledge gaps in literature.
Oman Med J 2014 Nov;29(6):414-418.
2. Asha’ari ZA, Yusof S, Ismail R, Che Hussin CM. Clinical
features of allergic rhinitis and skin prick test analysis based
on the ARIA classification: a preliminary study in Malaysia.
Ann Acad Med Singapore 2010 Aug;39(8):619-624.
3. Elango S. Recent trends in the diagnosis and management
of allergic rhinitis. Med J Malaysia 2005 Dec;60(5):672676, quiz 677.
4. Gendeh BS, Mujahid SH, Murad S, Rizal M. Atopic
sensitization of children with rhinitis in Malaysia. Med J
Malaysia 2004 Oct;59(4):522-529.
author guide
All articles submitted must comply
with the guidelines found online at
http://www.omjournal.org. Articles
that do not adhere to these instructions
may be rejected immediately without
review. Instructions on how to
submit, including a checklist and
what to include in the covering letter,
can also be found online. At the time
of submission, complete contact
information for the corresponding
author is required. After the manuscript
is submitted, the corresponding author
will receive an acknowledgment
confirming receipt. Oman Medical
Journal publishes free of charge.
or igin a l a rt i cl es
The maximum length for an Original Article
is 4000 word of text (not including abstract,
tables, figures, and references) with no more
than a total of six tables and/or figures and
50 references. Abstracts should be structured
and include subheadings summarizing the
objective, methods, results, and conclusions of
the article. The sections of an Original Article
should be arranged as follows: Abstract,
Introduction, Methods, Results, Discussion,
Conclusion, Disclosure, Acknowledgments,
and References. Each manuscript should
clearly state an objective or hypothesis; the
design and methods; the main outcome
measures; the main results of the study; a
comment section placing the results in context
with the published literature and addressing
study limitations; and the conclusions. The
data included must be original and should be
as timely and current as possible.
edi tor ia l s
An Editorial should address an issue that
is topical and of interest to the readership.
Editorials should promote critical thinking
and should express the opinion of the author,
which should be based on an interpretation
of facts that are supported by references.
Editorials are welcomed by the journal and
are generally solicited by the Editor-inChief; however, authors wishing to submit
an unsolicited editorial are invited to contact
the Editor-in-Chief prior to submission to
screen the proposed topic for relevance.
Editorials should be a maximum length
of 1200 words and up to 15 references.
Editorials contain no figures or tables.
br ief com m un i cat i on s
These manuscripts are short reports of original
studies or evaluations or unique, first-time
reports of clinical case series. A structured
abstract is required. The maximum length
for a Brief Communication is 1000 words of
O
man medical journal is published in print and online six times a
year providing an international forum for the publication of a wide range
of articles related to human health and clinical practice. Acceptance of
manuscripts is based on originality, importance to the field of discussion,
the quality of the work, and clarity of its presentation. All articles undergo the peer
review process and are overseen by a member of the editorial board and editorial office.
All articles are expected to be concise, well organized and clearly written, adhering to
the specific guidelines of the journal. These are given briefly below and more detailed
guidelines can be found online at http://www.omjournal.org. For any questions that
are not answered on the website please email at omj@omsb.org. Manuscripts should
be submitted online via Editorial Manager: http://www.editorialmanager.com/omj/.
Authors submit a manuscript with the understanding that it has not been published
elsewhere in any other language or format and is not under consideration elsewhere
for print or electronic publication. Along with the manuscript, authors must submit
an Authorship form, clearly stating their responsibilities, contribution, financial
sources, and any conflicts of interest.
Oman Medical Journal publishes Editorials, Original Articles, Reviews, Brief
Communications, Case Reports, Clinical Quizzes, Clinical Notes, and Letters to the
Editor. Topics of interest include all subjects that relate to the practice of medicine
and the betterment of public health worldwide.
text (not including abstract, tables, figures,
and references) with no more than a total of
two tables and/or figures and 25 references.
The sections of a Brief Communication
should be arranged as follows: Abstract,
Introduction, Methods, Results, Discussion,
Conclusion, Disclosure, Acknowledgments,
and References.
re v i ew a rt i cles
These manuscripts should be a systematic,
critical assessments of the literature and
data sources pertaining to clinical topics,
emphasizing factors such as cause, diagnosis,
prognosis, therapy, or prevention. All
articles or data sources should be searched
and critically evaluated, and the search and
selection process should be described in the
manuscript. The specific type of study or
analysis, population, intervention, exposure,
and tests or outcomes should be described for
each article or data source. The data sources
should be as current as possible, ideally with
the search having been conducted within
several months of manuscript submission.
The maximum length of a Review Article is
4000 words of text (not including abstract,
tables, figures, and references), with no more
than a total of four tables and/or figures and
no more than 50–75 references.
ca s e r ep orts
These should report obser vations
of diseases, clinical findings, and/or
treatment. The sections of a Case Report
should be arranged as follows: Abstract,
Introduction, Case Report, Discussion,
Conclusion, Acknowledgements, and
References. An unstructured abstract
between 200 and 400 words is required.
The maximum length of a Case Report is
1000 words of text (not including abstract,
figures, and references), with no more than
a total of three figures and no more than
20 references.
cli ni ca l quizzes
These should be short quizzes made up
of a real-life clinical case, providing some
background and enough information to
answer questions relating to the diagnosis
and pathophysiolog y/management of
the condition. The text should include
Acknowledgements and References. The
maximum length for a quiz is 750 words of
text (not including figures and references),
with no more than three images and no more
than five references.
cli ni ca l not es
These are narratives describing an important
issue in clinical medicine, public health,
health policy, or medical research in a
scholarly, thorough, well-referenced,
systematic, or evidence-based manner. The
maximum length of a Clinical Note is 1000
words of text, with no more than one table/
figure and 10 references.
let t er s to t h e edi tor
Letters discussing a recent Oman Medical
Journal article should be submitted within
12 weeks of the article’s publication in print.
Letters received after this time will rarely be
considered. Letters should not exceed 400
words of text and five references, one of
which should be to the recent Oman Medical
Journal article. Letters may have no more
than three authors. Letters being considered
for publication ordinarily will be sent to
the authors of the Oman Medical Journal
article, who will be given the opportunity
to reply. We also welcome letters on current
topics in healthcare and will be published if
appropriate and of interest to the readership.
In these cases letters may be peer reviewed.
let t er i n rep ly
Replies by authors should not exceed 500
words of text and six references. They should
have no more than three authors.
Oman Medical Journal
OV E R V I E W
• aims and scope
Oman Medical Journal is an Open Access International Journal,
which intends to engage and inform doctors, researchers
and other health professionals by publishing a wide range of
peer-reviewed articles. Our background is solidly grounded
in publishing a high degree of articles covering all aspects of
medicine.
• information for subscribers
in Context, Academic Journals Database, CAB Abstracts, CABI
Publishing, Chemical Abstracts, Cornell University Library,
EBSCO Publishing Electronic Database, Embase, Electronic
Journals Library (EZB), Expanded Academic ASAP, Genamics
JournalSeek, Gale and Open J-Gate, GFMER, Health Reference
Center, ICMJE, Newjour, SCIRUS, SCImago Journal &
Country Rank, Scopus, Summon by Serial Solution, The John
Rylands Library, UlrichsWeb Directory.
Access to this journal is available free online at:
http://www.omjournal.org/index.aspx
Oman Medical Journal is published six times a year by Oman
Medical Specialty Board. It is distributed free to all medical
doctors and allied health professionals in various institutions
locally and internationally.
Manuscripts should be submitted via the OMJ online
manuscript submission system at http://www.omjournal.org
• copyright and photocopying
• ethical considerations
©2015 All rights reserved to Oman Medical Journal. All articles
published represent the opinions of the authors and do not
reflect the official policy of the journal. No part of the journal
may be reproduced or transmitted for commercial use in any
form or by any means, electronic or mechanical, including
photocopying, recording, or via any storage or retrieval system,
without written permission from the journal.
This open access journal is distributed under the terms of
Oman Medical Specialty Board, permitting non-commercial
use, distribution and reproduction in any medium, provided the
original work is properly cited. Published manuscripts become
the permanent property of Oman Medical Specialty Board and
may not be published elsewhere.
In all experiments and studies on humans or animals, authors
must state whether formal approval from an Institutional
Review Board or Ethics Committee was obtained in the
Methods section of the manuscript. In the absence of such
committee, the Declaration of Helsinki guidelines must be
followed and be clearly stated. All studies on human subjects
must include a statement that the subjects gave informed
consent. Patient anonymity should be preserved. Photographs
need to be cropped to prevent human subjects being recognized.
Experiments involving animals must be demonstrated to be
ethically acceptable and should conform to national guidelines
for animal usage in research.
• abstracting and indexing services
Each author must contribute a significant segment and should
take responsibility for the content and authenticity of the work
as a whole. Authors must complete an Authorship form clearly
stating their responsibilities, contribution and financial sources.
Authors must supply an email address as all correspondence will
be by email.
The journal is listed in PubMed and PubMed Central, and
indexed in Index Medicus for the Eastern Mediterranean Region,
Google Scholar, CrossRef, Index Copernicus, CINAHL,
DOAJ, Global Health, Academic OneFile, Academic Science
• authorship criteria
• copies and inquiries •
Please contact
Oman Medical Journal
Oman Medical Specialty Board
Way #9993, Block 3, Al-Khoudh, Seeb
Muscat, Sultanate of Oman
 (+968) 2418 1050/1082/1186

omj@omsb.org
 http://www.omjournal.org/
Back issues are available at http://www.omjournal.org/ArchivePage.aspx
Oman Medical Journal
INDEXING AND DATABASE
IMEMR
Google
Scholar
GALE
CENGAGE
Open J-Gate
Journal Seek
Academic
Journals
Database
CrossRef
ICMJE
ULRICHS
Web
DOAJ
PubMed
Central
SCOPUS
CABI
Publising
INDEX
COPERNICUS
EBSCO Host
CINAHL
Access to this journal is available free online at: http://www.omjournal.org
oman medical journal
Oman Medical Journal, Oman Medical Specialty Board (OMSB), Way #9993, Block 3, Al-Khoudh, Seeb, Muscat, Sultanate of Oman
 (+968) 2418 1050/1082/1186  omj@omsb.org
 www.omjournal.org