MMJ
Volume 27, Issue 4, 2015
Malta Medical Journal
University of Malta
Medical School
http://www.um.edu.mt/umms/mmj
Editorial
Editorial
New gold standard treatment for acute stroke:
endovascular thrombectomy using stentretrievers
Patrick Pullicino, Steve M. Cordina
The last year has seen the most dramatic
advance in the treatment of acute stroke since the United
States National Institutes of Health tissue plasminogen
activator (tPA) study1 showed in 1995 that intravenous
(IV) thrombolysis delivered within three hours of stroke
onset could improve outcome. IV tPA became standard
treatment for acute stroke after that study, but there was
still difficulty in recanalising large vessel occlusions and
up to one half of patients were left with severe deficits
despite IV tPA. In 2008, the European Cooperative
Acute Stroke Study (ECASS) III2 extended the IV tPA
time window from three to four and a half hours from
stroke onset but favourable outcome at 90 days was still
only seen in 52% of patients, as in other studies. In
cardiology, it was demonstrated that endovascular
treatments were superior to IV, but it appeared that this
was going to be one area where stroke differed.
Repeated endovascular studies, the largest of which was
Interventional Management of Stroke (IMS) III trial3
showed no advantage over IV tPA. The only exception
was the borderline results of the Prolyse in Acute
Thromboembolism (PROACT) II4 trial in 1999. One
common recurring theme was the need for early
recanalization for maximal benefit5 and the decreased
recanalization noted with larger clot burden.6
Patrick Pullicino
Professor of Clinical Neuroscience,
Rutherford Building,
University of Kent
Steve M. Cordina, MD
Assistant Professor of Neurology,
Neurosurgery and Radiology Director,
Stroke,
Neurocritical Care and Endovascular
Neurosurgery University of South Alabama
College of Medicine
Malta Medical Journal
Volume 27 Issue 04 2015
All this has dramatically changed. Since October
2014, no less than seven randomized clinical trials have
been reported and shown that endovascular therapy is
highly beneficial for intracranial occlusions compared
with IV tPA up to 8 hours after stroke onset These
ground breaking trials include the Multicenter
Randomized Clinical Trial of Endovascular Treatment
for Acute Ischemic Stroke (MR CLEAN), 7 the
Extending the Time for Thrombolysis in Emergency
Deficits — Intra-Arterial (EXTEND-IA) trial,8 the
Endovascular Treatment for Small Core and Anterior
Circulation Proximal Occlusion with Emphasis on
Minimizing CT to Recanalization Times (ESCAPE)
trial,9 the Solitaire with the Intention for Thrombectomy
as Primary Endovascular Treatment (SWIFT PRIME)
trial,10 the Randomized Trial of Revascularization with
Solitaire FR Device versus Best Medical Therapy in the
Treatment of Acute Stroke Due to an Anterior
Circulation Large Vessel Occlusion Presenting within
Eight Hours of Symptom Onset (REVASCAT),11 the
Assess the Penumbra System in the Treatment of Acute
Stroke (THERAPY) trial,1, and the Trial and Cost
Effectiveness Evaluation of Intra-arterial Thrombectomy
in Acute Ischemic Stroke (THRACE) trial.13
New guidelines have recently been rushed out by
the American Heart Association and American Stroke
Association.14 These state that rapid administration of IV
tPA to appropriate patients remains the mainstay of early
treatment of acute ischemic stroke. The new trials show
that some people will benefit from additional treatment
with a stent retrieval device or aspiration if a clot
continues to obstruct a vessel after tPA is given. There is
now class I, level of evidence A that a stent retriever
should be used in cases in which all of the following
criteria are met: a) Pre-stroke modified Rankin Scale
score of 0-1, b) Occlusion located in the internal carotid
artery or proximal middle cerebral artery (usually
identified on head CT angiography immediately after the
initial bolus dose of iv TPA is administered), c) Patient
at least 18 years of age, d) NIH Stroke Scale score of at
least 6, e) Substantial portion of brain tissue on the side
of the stroke is not permanently damaged, f) Treatment
can be initiated within 6 hours of symptom onset.
The guidelines underline that endovascular therapy
should be performed at an experienced stroke centre
1
Editorial
Editorial
with rapid access to cerebral angiography and qualified
neuro-interventionalist. In addition, they outline a
variety of scenarios in which use of a stent retriever may
be reasonable, meaning benefit is uncertain due to sparse
or no randomized evidence for example in basilar artery
occlusion.
The cost of IV tPA in the United Kingdom is
£1,214 and mechanical thrombectomy is about seven
times more expensive (£8,365) because of the cost of the
stent, materials and surgery.15 However, thrombectomy
doubles the number of patients with major intracranial
artery occlusions who become functionally independent,
with improved quality-adjusted life expectancy. The
probability analysis has shown therefore that
thrombectomy is cost effective.15
Despite the high up-front cost, endovascular acute
treatment is likely to be taken up by all major stroke
centres, as in coronary disease. Malta already has the
capacity to administer tPA to eligible patients. In
addition, over the last year, stroke thrombectomy has
been introduced and is now available for patients that
need this advanced treatment The life-altering effect of
severe disability after intracranial arterial occlusions
behoves that this new dramatic advance in stroke
treatment be put into practice as quickly as possible.
7.
8.
References
1.
2
3.
4.
5.
6.
The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue Plasminogen Activator for
Acute Ischemic Stroke. N Engl J Med 1995; 333:1581-1588.
Werner Hacke, Markku Kaste, Erich Bluhmki, Miroslav
Brozman, Antoni Dávalos, Donata Guidetti, Vincent Larrue,
Kennedy R. Lees, Zakaria Medeghri, Thomas Machnig,
Dietmar Schneider, Rüdiger von Kummer, Nils Wahlgren, and
Danilo Toni for the ECASS Investigator. Thrombolysis with
Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J
Med 2008; 359:1317-1329.
Joseph P. Broderick, Yuko Y. Palesch, Andrew M. Demchuk,
Sharon D. Yeatts, Pooja Khatri, Michael D. Hill, Edward C.
Jauch, Tudor G. Jovin, Bernard Yan, Frank L. Silver, Rüdiger
von Kummer, Carlos A. Molina, Bart M. Demaerschalk,
Ronald Budzik, Wayne M. Clark, Osama O. Zaidat, Tim W.
Malisch, Mayank Goyal, Wouter J. Schonewille, Mikael
Mazighi, Stefan T. Engelter, Craig Anderson, Judith Spilker,
Janice Carrozzella, Karla J. Ryckborst, L. Scott Janis, Renée H.
Martin, Lydia D. Foster, and Thomas A. Tomsick for the
Interventional Management of Stroke (IMS) III Investigators
Endovascular Therapy after Intravenous t-PA versus t-PA
Alone for Stroke. N Engl J Med 2013; 368:893-903.
Anthony Furlan, Randall Higashida, Lawrence Wechsler,
Michael Gent, Howard Rowley, Carlos Kase, Michael Pessin,
Arvind Ahuja, Fred Callahan, Wayne M. Clark, Frank Silver,
Frank Rivera, for the PROACT Investigators Intra-arterial
prourokinase for acute ischemic stroke. The PROACT II study:
a randomized controlled trial. Prolyse in Acute Cerebral
Thromboembolism. JAMA. 1999;282:2003-11.
Labiche LA, Al-Senani F, Wojner AW. Is the benefit of early
recanalization sustained at 3 months? A prospective cohort
study. Stroke. 2003;34:695-8.
Saqqur M, Uchino K, Demchuk AM. Site of Arterial Occlusion
Identified by Transcranial Doppler Predicts the Response to
Intravenous Thrombolysis for Stroke. Stroke. 2007;38:948-54.
Malta Medical Journal
Volume 27 Issue 04 2015
9.
10.
Olvert A. Berkhemer, Puck S.S. Fransen, Debbie Beumer,
Lucie A. van den Berg, Hester F. Lingsma, Albert J. Yoo,
Wouter J. Schonewille, Jan Albert Vos, Paul J. Nederkoorn,
Marieke J.H. Wermer, Marianne A.A. van Walderveen, Julie
Staals, Jeannette Hofmeijer, Jacques A. van Oostayen, Geert J.
Lycklama à Nijeholt, Jelis Boiten, Patrick A. Brouwer, Bart J.
Emmer, Sebastiaan F. de Bruijn, Lukas C. van Dijk, L. Jaap
Kappelle, Rob H. Lo, Ewoud J. van Dijk, Joost de Vries, Paul
L.M. de Kort, Willem Jan J. van Rooij, Jan S.P. van den Berg,
Boudewijn A.A.M. van Hasselt, Leo A.M. Aerden, René J.
Dallinga, Marieke C. Visser, Joseph C.J. Bot, Patrick C.
Vroomen, Omid Eshghi, Tobien H.C.M.L. Schreuder, Roel J.J.
Heijboer, Koos Keizer, Alexander V. Tielbeek, Heleen M. den
Hertog, Dick G. Gerrits, Renske M. van den Berg-Vos, Giorgos
B. Kara,, Ewout W. Steyerberg, H. Zwenneke Flach, Henk A.
Marquering, Marieke E.S. Sprengers, Sjoerd F.M. Jennisken,
Ludo F.M. Beenen, René van den Berg, Peter J. Koudstaal,
Wim H. van Zwam, Yvo B.W.E.M. Roos, Aad van der Lugt,
Robert J. van Oostenbrugge, Charles B.L.M. Majoie, and
Diederik W.J. Dippel for the MR CLEAN Investigators. A
randomized trial of intraarterial treatment for acute ischemic
stroke. N Engl J Med 2015;372:11-20.
Bruce C.V. Campbell, Peter J. Mitchell, Timothy J. Kleinig,
Helen M. Dewey, Leonid Churilov, Nawaf Yassi, Bernard Yan,
Richard J. Dowling, Mark W. Parsons, Thomas J. Oxley,
Teddy Y. Wu, Mark Brooks, Marion A. Simpson, Ferdinand
Miteff, Christopher R. Levi, Martin Kraus., Timothy J.
Harrington, Kenneth C. Faulder, Brendan S. Steinfort, Miriam
Priglinger, Timothy Ang, Rebecca Scroop, P. Alan Barber, Ben
McGuinness, Tissa Wijeratne, Thanh G. Phan, Winston Chong,
Ronil V. Chandra, Christopher F. Bladin, Monica Badve,
Henry Rice, Laetitia de Villiers, Henry Ma, Patricia M.
Desmond, Geoffrey A. Donnan, and Stephen M. Davis, for the
EXTEND-IA Investigators Endovascular therapy for ischemic
stroke with perfusion-imaging selection. N Engl J Med
2015;372:1009-18.
Mayank Goyal, Andrew M. Demchuk, Bijoy K. Menon,
Muneer Eesa, Jeremy L. Rempel, John Thornton, Daniel Roy,
Tudor G. Jovin, Robert A. Willinsky, Biggya L. Sapkota, Dar
Dowlatshahi, Donald F. Frei, Noreen R. Kamal, Walter J.
Montanera, Alexandre Y. Poppe, Karla J. Ryckborst, Frank L.
Silver, Ashfaq Shuaib, Donatella Tampieri, David Williams,
Oh Young Bang, Blaise W. Baxter, Paul A. Burns, Hana Choe,
Ji-Hoe Heo, Christine A. Holmstedt, Brian Jankowitz, Michael
Kelly, Guillermo Linares, Jennifer L. Mandzia, Jai Shankar,
Sung-Il Sohn, Richard H. Swartz, Philip A. Barber, Shelagh B.
Coutts, Eric E. Smith, William F. Morrish, Alain Weill, Suresh
Subramaniam, Alim P. Mitha, John H. Wong, Mark W.
Lowerison, Tolulope T. Sajobi, and Michael D. Hill, for the
ESCAPE Trial Investigators Randomized assessment of rapid
endovascular treatment of ischemic stroke. N Engl J Med
2015;372:1019-30.
Jeffrey L. Saver, Mayank Goyal, Alain Bonafe, Hans-Christoph
Diener, Elad I. Levy, Vitor M. Pereira, Gregory W. Albers,
Christophe Cognard, David J. Cohen, Werner Hacke, Olav
Jansen, Tudor G. Jovin, Heinrich P. Mattle, Raul G. Nogueira,
Adnan H. Siddiqui, Dileep R. Yavagal, Blaise W. Baxter,
Thomas G. Devlin, Demetrius K. Lopes, Vivek K. Reddy,
Richard du Mesnil de Rochemont, Oliver C. Singer, and Reza
Jahan, for the SWIFT PRIME Investigators. Stent-retriever
thrombectomy after intravenous t-PA vs. t-PA alone in stroke.
N Engl J Med 2015;2285-95.
2
Editorial
Editorial
11.
12.
13.
14.
15.
T.G. Jovin, A. Chamorro, E. Cobo, M.A. de Miquel, C.A.
Molina, A. Rovira, L. San Román, J. Serena, S. Abilleira, M.
Ribó, M. Millán, X. Urra, P. Cardona, E. López-Cancio, A.
Tomasello, C. Casta.o, J. Blasco, L. Aja, L. Dorado, H.
Quesada, M. Rubiera, M. Hernández-Pérez, M. Goyal, A.M.
Demchuk, R. von Kummer, M. Gallofré, and A. Dávalos, for
the REVASCAT Trial Investigators. Thrombectomy within 8
hours after symptom onset in ischemic stroke. N Engl J Med
2015;2296-306.
Assess the Penumbra System in the Treatment of Acute Stroke
(THERAPY) (Presented at The European Stroke Organization
Conference, Glasgow 2015.)
Trial and Cost Effectiveness Evaluation of Intra-arterial
Thrombectomy in Acute Ischemic Stroke (THRACE)
(Presented at The European Stroke Organization Conference,
Glasgow 2015.)
William J. Powers, Colin P. Derdeyn, José Biller, Christopher
S. Coffey, Brian L. Hoh, Edward C. Jauch, Karen
C. Johnston, S. Claiborne Johnston, Alexander A.
Khalessi, Chelsea S. Kidwell, James F. Meschia, Bruce
Ovbiagele, and Dileep R. Yavagal, on behalf of theAmerican
Heart Association Stroke Council. AHA/ASA focused update
of the 2013 guidelines for the management of patients with
acute stroke regarding endovascular treatment: a guideline for
health care professionals from the American Heart
Association/American Stroke Association. Stroke 2015; Epub
ahead of print.
Jeban Ganesalingam, Elena Pizzo, Stephen Morris, Tom
Sunderland, Diane Ames, and Kyriakos Lobotesis. Cost-utility
of mechanical thrombectomy using stent retrievers in acute
ischemic stroke. Stroke 2015;46:2591-2598.
Cover Picture:
‘Sighisoara’
Watercolour
By Peter Paul Vassallo
Peter Paul Vassallo graduated Doctor of Medicine and Surgery from the University of Malta in 1992. He proceeed to
the United Kingdom where he passed surgical examinations with the Royal colleges of surgeons in Edinburgh and
Ireland. He underwent military training at the Royal Military Academy in Sandhurst and saw operational duties in
Northern Ireland and Iraq. Upon his return to Malta he was appointed registrar in cardiothoracic surgery but moved on
to be commisioned Surgeon Lieutenant Colonel in the Armed Forses of Malta where he currently practices. Among
his many interests watercolour painting is a recent addition.
Malta Medical Journal
Volume 27 Issue 04 2015
3
OEdArticle
Original
Autologous haemodialysis access in Malta
Luana Caruana, Rosemarie Vella Baldacchino, Mauro Sacco,
Kevin Cassar
Introduction
Chronic kidney disease is a worldwide problem
which is rapidly increasing.1-3 In the United States the
incidence and prevalence of end stage renal disease has
doubled in the last ten years and is expected to continue
rising in the future.4-5 In Malta the high prevalence of
diabetes and the ageing population has similarly resulted
in a significant increase in patients requiring
haemodialysis over the last decade. 6 Despite advances in
dialysis and transplantation, prognosis has not improved
worldwide.7
Creation of an arteriovenous fistula is recognized to
be the optimal vascular access for dialysis. 8 The National
Kidney Foundation – Kidney Disease Outcome
Qualitative Initiative (KDOQI) guidelines state that
when a patient reaches CKD stage 4 or 5, the forearm
and upper limb veins should not be used for
venipuncture, peripheral cannulation, peripheral venous
catheter insertion or central lines. This is important, as it
might render potential veins inadequate for fashioning of
a primary fistula.9
Luana Caruana MD
BST 1 Accident and Emergency
Mater Dei Hospital,
Msida
Rosemarie Vella Baldacchino MD
BST 1 Psychiatry
Mount Carmel Hospital,
Attard
Mauro Sacco MD
BST 1 General Medicine
Mater Dei Hospital,
Msida
Kevin Cassar MD, FRCS*
Consultant Vascular Surgeon
Mater Dei Hospital,
Msida
kevin.b.cassar@gov.mt
*Corresponding Author
Malta Medical Journal
Patients who require dialysis without established
access, have significantly increased risk of mortality and
morbidity compared with those who have a functioning
fistula at first dialysis.10-13 The National Service
Framework in the UK identified that access needs to be
achieved some months in advance of its anticipated need.
The K-DOQI guidelines state that patients, who are at
late stage chronic kidney disease, should have an
arteriovenous fistula fashioned at least six months prior
to needling of the fistula, to obviate the use of other
types of vascular access.14
Patients should have fully functional permanent
access, by the time dialysis is required. Being functional
implies that it not only delivers adequate blood flow but
that it should also be easily needled. For this to be met
the diameter should be around 0.6 cm, depth of 0.6 cm
and a minimum flow volume of approximately 600
ml/min2.
Referral for creation of an autologous fistula should
be made early enough to allow for maturation time as
well as the possibility of access failure and
refashioning .9
The prevalence of diabetes in the Maltese
population is high. This cohort of patients is being
serviced by only one main teaching hospital, Mater Dei
Hospital.
There are currently five consultant
nephrologists (four consultants catering for the adult
population and one paediatric consultant) responsible for
patients with renal pathology. Patients undergo
haemodialysis either at the renal unit at Mater Dei
Hospital or at a small satellite unit at Gozo General
Hospital on the island of Gozo. Patients requiring
dialysis are referred to a vascular surgeon for assessment
and creation of an arteriovenous fistula. These cases are
discussed by the Renal Committee which is made up of
nephrologists, surgeons and renal nurses. Patients
referred for assessment for arteriovenous fistula
fashioning are given priority and are seen on an urgent
basis and given a date for surgery within two to three
weeks of assessment.
The aims of this study were to assess patency rates
of autologous arteriovenous fistulae created at Mater Dei
Hospital, utilization of these fistulae, interventions
required to maintain patency and timing of referral for
fashioning of dialysis access.
Method
A retrospective analysis of prospectively collected
Volume 27 Issue 05 2015
4
OEdArticle
Original
data of patients who underwent primary fashioning of an
autologous arteriovenous fistula, under the care of one
vascular surgeon at Mater Dei Hospital, between
October 2012 and May 2014 was performed.
Data collected included demographics (gender and age),
major risk factors for arterial disease (smoking,
hypertension, hypercholesterolemia, diabetes and
ischemic heart disease), presence of coagulation
disorders, estimated glomerular filtration rate at time of
referral, time period when fistula was fashioned, whether
the patient was already on dialysis prior to surgery and
type of fistula created. This data was collected
prospectively and recorded in a vascular database. Other
data collected included type of autologous AV fistula
created. Details on maturation, patency, usability,
successful cannulation and measurement of fistulae
(diameter, depth, flow volume and peak systolic velocity
(PSV)) was also recorded. Details on any reinterventions
that were required were also recorded.
The case files were reviewed at the Renal Unit,
between August and September 2014 to identify the
maturation, patency, usability, success of cannulation
and any problems encountered before and after
cannulation. Case files of deceased patients were
reviewed, at the Mater Dei Hospital Medical Records, in
September 2014 to identify the cause and the time lapse
from fistula creation to the date of demise.
A proforma was constructed to ensure thorough
comprehensive data gathering. All data was finally
inputted in an excel sheet and coded for easier data
analysis.
Results
Between October 2012 and May 2014, sixty eight
patients underwent primary fashioning of an autologous
arteriovenous fistula. Forty nine (72.1%) were male. The
mean age was 60.9 years with a range from 14 to 90
years. As illustrated in figure 1 eleven patients (16.2%)
passed away during the study period with a median
follow up of 14 weeks and a range from three days to
fifty two weeks. Of these eleven, three (27.3%) passed
away in the early post-operative period (within 30 days)
as a result of myocardial infarctions or pulmonary
embolism.
Sixteen (23.5%) were current or previous smokers,
sixty (88.2%) were known hypertensive on treatment,
thirty seven (54.4%) had hypercholesterolemia and
eighteen (26.5%) were known to suffer from ischemic
heart disease having undergone previous surgery or
percutaneous coronary intervention. Thirty eight
(55.8%) patients were diabetic; of these three (7.89%)
were diet controlled, nineteen (50%) were on oral
hypoglycaemic agents and sixteen (42.1%) on insulin.
Six (8.82%) were on anti-coagulation treatment upon
referral.
Malta Medical Journal
Volume 27 Issue 05 2015
Figure 1: Graph showing outcome versus number of
patients
Passed away
11
Living
57
0
20
40
60
Number of patients
The mean estimated glomerular filtration rate
(eGFR) at referral was 11.9 mls/min/1.73m2 with a
range from 5-35mls/min/1.73m2. The vast majority,
fifty one (75%), were already on dialysis at referral.
Thirty seven (72.5%) were dialysed through a
central venous catheter and fourteen (27.59%) via
peritoneal dialysis. Nine (13.2%) had a fistula
fashioned six months before initiation of dialysis
while eight (11.8%) had a fistula created within six
months of commencing dialysis (Figure 3). Only
25% had a functioning fistula at the time of
initiation of dialysis.
All patients were examined preoperatively and
also underwent duplex scanning of the upper limbs.
Of the arteriovenous fistulae created, forty nine
(72.1%) were brachiocephalic, ten (14.7%) radio
cephalic fistulae, six (8.82%) transposed
brachiobasilic fistulae, two (2.94 %) ulnar cephalic
fistulae and one (1.47%) snuff box fistula, as shown
in figure 2.
Figure 2: Type of AV Fistulae fashioned
5
OEdArticle
Original
Excluding those patients who passed away in the
immediate post-operative period, forty three fistulae
(66.2%) matured by six weeks while twenty two did not
(33.8%). The median follow up was of thirty eight
weeks with a range from three weeks to eighty nine
weeks. Fifty four fistulae (83.1%) were patent and forty
nine (75.4%) were successfully cannulated. To date six
fistulae (9.23%) were not used. Excluding those six
fistulae and those that passed away in the immediate
post-operative period, forty seven fistulae (79.7%) had
successful first time cannulation while twelve (20.3%)
did not.
Twenty nine (44.6%), did not require any
subsequent interventions. Eight fistulae (12.3%) required
interventions before cannulation, twenty (30.7%) after
cannulation and two (3.07%) needed both. As shown in
table 1, before cannulation three required endovascular
interventions, four open surgery and one needed both.
After
cannulation
fourteen
fistulae
required
endovascular interventions, five open surgery and one
needed both.
Figure 3: Status of patients upon referral of fashioning
of AV fistula
Within 6 months of
commencing dialysis
8
6 months before dialysis
9
Already on dialysis
51
0
10
20
30
40
50
60
The autologous fistulae were assessed using duplex
scanning in the early postoperative period to assess for
maturation. The measurements were; mean diameter
5.76 mm, mean depth 6.37 mm, flow volume 1.87 L/min
and peak systolic volume (PSV) 282.85 m / sec.
Table 1: Intenterventions prior and after cannulation (Excluding two patients that needed intervention both before
and after cannulation)
Before Cannulation
Number of patients
Endovascular
Repair
Open
Repair
Needing
Both
Endovascular
Repair
Open
Repair
Needing
Both
3
4
1
14
5
1
Discussion
The
patency
rates
of
autologous
arteriovenous fistulae fashioned at Mater Dei
Hospital (83.1%) are comparable to those reported
in the literature (between 43% and 85% one year
patency).15-17
Locally the majority of patients (75%) were
already on some form of renal replacement therapy
when referred for fistula creation with the majority
being dialysed through a central venous catheter.
The mean eGFR was 11.9 mls/min/1.73m2 at
referral indicating late referral. Early referral for
fashioning of an arteriovenous fistula is
recommended both by K-DOQI guidelines as well
as local National Service Frameworks. Lack of a
usable fistula for dialysis necessitates insertion of
temporary lines which is associated with a
significant increase in morbidity and mortality in
this cohort of high risk patients.
Malta Medical Journal
After Cannulation
Volume 27 Issue 05 2015
In the majority of patients the timing of dialysis
requirement can be predicted, while in a small
proportion this is not possible. Referral as early as
one year prior to predicted requirement for dialysis,
ensures that there is adequate time for fashioning
and maturation of an AV fistula as well as the
possibility of failure and refashioning. This obviates
the need for potentially dangerous insertion of
central venous catheters and their associated
complications, particularly line sepsis, bacteraemia
and mortality in the short-term and the long-term
complications of central vein stenosis and
occlusions.
Early referral also ensures that acute
admissions to hospital secondary to line
complications are reduced and therefore
unnecessary cannulation of arm veins with resultant
loss of dialysis access possibilities is avoided.
Furthermore in those patients who are already on
6
Original Article
OEd
haemodialysis, once the AV fistula is created there
is often pressure for early cannulation before
adequate maturation of the fistula is achieved.
There is clear evidence that early needling leads to a
higher rate of fistula failure.8
Late referral of patients also results in a
significant number of unnecessary interventions by
interventional radiologists such as insertion of
tunnelled lines, which could be avoided. This
implies unnecessary utilisation of scarce resources
from other departments, apart from the patients’
morbidity associated with the additional
interventions.
The proportion of patients in this study with a
functioning AV fistula at time of first dialysis is
very low (25%) and certainly well below current
recommendations. Reasons for this may include
delay in diagnosis due to inadequate primary care
facilities, inappropriate delay in referral to tertiary
hospital, reluctance by patients to be referred,
patient failure to accept dialysis or dialysis access,
service provision pressures to increase peritoneal
dialysis
use,
bureaucratic
delays,
poor
communication between physicians and surgeons,
and other factors. Further studies need to be carried
out to identify the causes of delay in referral in
order to improve the current quality of care.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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Akizawa T, et al. Creation, cannulation and survival of
arteriovenous fistulae: Data from the Dialysis Outcomes and
Practice Patterns Study. Kidney Int. 2003; 63: 323–30.
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[cited 2014 Oct 20]. Available from:
https://www.kidney.org/professionals/guidelines
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Lacson E Jr, Lazarus JM, Himmelfarb J, Ikizler TA Hakim RM.
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Wasse H, Kutner N, Zhang R, Hunag Y. Association of initial
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R, Howd A, Nagy J, Griffiths GD. Natural history of upper limb
arteriovenous fistulae for chronic dialysis. J Vasc Access. 2012;
13(3):332-7.
Eisharawy MA. Prospective evaluation of factors associated
with early failure of arteriovenous fistulae in hemodialysis
patients. Vascular 2006; 14(2):70-4.
Dixon BS, Novak L, Fangman J. Hemodialysis vascular access
survival: upper arm native arteriovenous fistulae. Am J Kidney
Dis. 2002; 39(1):92-101.
References
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3.
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6.
7.
Rhee CM, Kovesdy CP. Epidemiology: spotlight on CKD
deaths - increasing mortality worldwide, Nat Rev Nephrl 2015;
11(4):199-200.
Hossain MP, Dodder EC, Rigby JE, El Nahas M. CKD and
poverty: a growing global challenge. Am J Kidney Dis 2009;
53(1):166-74.
Mills KT, Xu Y, Zhang W, Bundy JD, Chen CS, Kelly TN,
Chen J, He J. A systematic analysis of worldwide populationbased data on the global burden of chronic kidney disease in
2010. Kidney Int 2015; koi: 10.1038/ki.2015.230.
Centers for Disease Control and Prevention. Chronic Kidney
Disease Surveillance System, Atlanta, Atlanta, GA: Centers for
Disease Control and Prevention, US Dept of Health and Human
Services [Internet]; 2011 [cited 2014 Oct 22]. Available from:
http://www.cdc.gov/ckd.
US Renal Data System. USRDS 2013 Annual Data Report:
Atlas of chronic Kidney Disease and End-stage renal Disease in
the United States. Bethesda, MD: National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney
Disease[Internet];2013[cited 2014 Oct 25]. Available from:
http://www.usrds.org/atlas.aspx.
Guariguata L, Nolan T, Beagley J, Linnenkamp U, Jacqmain O
editors. International Diabetes Federation Diabetes Atlas
[Internet]; 2014 [cited 2014 Oct 20]. Available from:
http://www.idf.org.
Schoolwerth AC, Engelgau MM, Hostetter TH. A public health
action plan is needed for chronic kidney disease. Adv Chronic
Kidney Dis 2005; 12:418-23.
Malta Medical Journal
Volume 27 Issue 05 2015
7
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Original
Evaluation Of FRAX® score use in Maltese
osteoporosis management guidelines
Mark R. Brincat, Raymond P. Galea, Eleanor Borg
Abstract
Objectives: Recent years have brought a shift
towards evidence-based fracture risk engines. Fracture
Risk Assessment Tool (FRAX®) is one such diagnostic
tool used to evaluate the ten-year probability
of osteoporotic fracture risk. The aim of this study was
to evaluate the Maltese FRAX® score-based osteoporosis
management guidelines and identify the suitability of
using such a risk factor engine-based protocol.
Study design: Data from 702 patients presenting
for bone mineral density (BMD) estimation in 20102011 were collected. In this period, local guidelines
were devised but not yet put into practice so all referred
patients underwent BMD estimation. These patients
were below 65 years of age and above the minimum age
for FRAX® use: 40 years. Data included Age, Weight,
Height, BMI and the presence of any risk factor
components of the FRAX® score tool. BMD was
assessed using Norland/Hologic densitometers. FRAX®
scores (excluding BMD) for each patient were calculated
using the online tool www.shef.ac.uk/FRAX as accessed
in 2014. The resulting major osteoporotic fracture risk
was compared to age-specific assessment thresholds as
set by Kanis et al. (2013). Thus the appropriateness (or
otherwise) of densitometry measurements as dictated by
local guidelines was determined.
Main outcome measures: The main outcome
measures in this study were the femoral neck and
vertebral body BMD. The sensitivity, specificity,
positive predictive value (PPV) and negative predictive
value (NPV) of using the FRAX®-based guidelines in
under 65 year olds were calculated.
Mark R. Brincat MD*
Basic Specialist Trainee in Obstetrics and Gynaecology
Mater Dei Hospital
Raymond P. Galea MD, FRCOG, Acc.Spec.O&G(Leuv),
Ph.D.
Consultant Obstetrician and Gynaecologist
Mater Dei Hospital
Eleanor Borg MD
Foundation Doctor
Mater Dei Hospital
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 05 2015
Results: Local guidelines for managing <65
year olds were found to have a PPV of 11.26% and a
NPV of 94.38 %
Conclusion: FRAX®-guided local guidelines are
well suited at excluding non-osteoporotic patients (False
omission rate of 5.62 %). Positive likelihood ratio for the
protocol was found to be 1.27. This means that 1 in
every 8.8 patients that would have been referred for
BMD estimation were actually osteoporotic.
Keywords
Malta; Osteoporosis; Guidelines; Bone mineral
density
Introduction
Due to increased longevity modern societies in
developed countries face the exponential challenge of
ageing populations. Consequently certain chronic
medical conditions are becoming more frequent thus
increasing the morbidity and mortality of the patients
concerned. These chronic conditions are also consuming
a bigger component of our health budgets.1
One of the problems associated with the aging
process is a decrease in bone mass resulting in
osteoporosis.2 Osteoporosis has been defined as a multifactorial skeletal condition which is characterised by low
bone mass and a deterioration of bone tissue leading to a
deterioration of its macro and micro-architecture.3 This
results in increased bone fragility and consequently
increased risk of fractures. It is termed to be a “silent
disease”, however, osteoporosis has potential serious
implications on the functional status of the individuals
concerned as well as the national health economy. 4
The diagnosis of osteoporosis is dependent on the
presence of either a fragility fracture or else on the bone
density measurement. These fragility fractures can occur
at any anatomical site although certain sites have been
considered to be more characteristic than others.
Vertebral fractures are the most common and even so, a
significant proportion are clinically undiagnosed. 5 Hip
fractures are associated with significant morbidity and
mortality. About 50% of patients who lived
independently before sustaining a hip fracture are unable
regain their independent lifestyle.6
The World Health Organization (WHO) developed
Bone Mineral Density (BMD) criteria for the diagnosis
of osteoporosis from epidemiologic data that describe
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the normal distribution of BMD in a young healthy
reference population.7-8 Osteoporosis is diagnosed when
the BMD at the spine, hip, or wrist is 2.5 or more
standard deviations (SD) below the reference mean. Low
bone density or mass (sometimes referred to as
osteopenia) is diagnosed when BMD is between 1.0–2.5
SD below the reference mean.
The number of standard deviation units above or
below the young healthy mean is called the T-score.
Another score used in the interpretation of BMD results
is the Z-score which signifies the number of standard
deviation units above or below the mean for the
individual’s own age group. Unfortunately BMD is only
assessing one aspect of this condition and it does not
cater for other factors such as bone quality and
architecture which may play a significant role in fracture
prediction.9
The epidemiology, pathophysiology and treatment
of osteoporosis have greatly improved in the past decade
and a change has been noted, from subjective casespecific strategies to risk engines that integrate all the
risk factors, country-specific fracture rates and healtheconomic
scenarios
to offer
country-specific
intervention thresholds.
Various tools have been proposed so as to assess
the patient’s fracture risk by incorporating clinical risk
factors with BMD. The World Health Organisation has
developed one such tool which is based on individual
patient models and incorporates the risks associated with
clinical risk factors as well as BMD at the femoral neck.
This tool is known as Fracture Risk Assessment Tool
(FRAX®) and was developed at the World Health
Organization Collaborating Centre for Metabolic Bone
Diseases, in the University of Sheffield, UK. 10
The algorithms used in FRAX® provide the 10-year
probability of patients sustaining a fracture. The results
are given as the 10-year probability of a fracture at the
hip as well as at other sites such as spine, forearm, or
shoulder (major osteoporotic fractures). The 10-year
fracture probability is calculated from age, body mass
index and dichotomized risk factors comprising prior
fragility fracture (a fracture caused by injury that would
be insufficient to fracture a normal bone), current
tobacco smoking, use of long-term oral glucocorticoids,
rheumatoid arthritis, other causes of secondary
osteoporosis and alcohol consumption.
The FRAX tool has been adopted at the Bone
Density unit in Mater Dei Hospital in Malta. According
to Maltese National Osteoporosis Management
Guidelines women over 65 years of age with a FRAX®
score (including BMD) above the intervention threshold
are referred to the appropriate specialist for treatment. If
FRAX® score (including BMD) lies below the
intervention threshold, then the patient is re-assessed
after two years. (Figure 1) Women under the age of 65
years who have a 10-year fracture probability as
Malta Medical Journal
Volume 27 Issue 05 2015
obtained using FRAX® (excluding BMD) above the
assessment threshold limits described below (Table 1)
are referred for BMD assessment. If FRAX® (excluding
BMD) 10-year fracture risk lies below the threshold the
patient is reassured and reassesed after two years.
(Figure 2) All patients with a history of previous
fragility fracture are investigated and treated. The aim
of this study was to assess the reliability of these
guidelines and identify any particular positive or
negative aspects of using such a risk factor engine-based
protocol.
Table 1: Age-specific major osteoporotic fracture risk
assessment thresholds as used in FRAX-score guided
local guidelines
10-year Fracture
Age
probability (%)
40 – 44
2.3
45 - 49
2.4
50 – 54
2.9
54 - 59
3.6
60 - 64
4.9
Methods
Data for 702 patients that presented for official
radiographic investigation of bone mineral density
(BMD) estimation in 2010-2011 were collected. The
data were collected during a period when local
guidelines on management of osteoporosis were devised
but not yet put into practice. Consequently, all referred
patients underwent BMD estimation. It included age,
indication for the test, weight, height and current
medication. The presence of any of the risk factor
components in the FRAX® score tool was also noted:
previous fragility fracture, family history of hip fracture,
tobacco use, alcohol consumption, glucocorticoid use,
secondary causes of osteoporosis and confirmed
rheumatoid arhritis. BMD (Lumbar and Femoral Tscore) was assessed using Norland or Hologic
densitometers and was noted on patients’ data sheets.
BMI was calculated following data entry.
FRAX® scores (without including BMD) for each
patient were calculated using the online tool
www.shef.ac.uk/FRAX® as accessed between JulyOctober 2014. The resulting major osteoporotic fracture
risk was compared to age-specific risk thresholds as set
by Kanis et al. (2013). Thus the appropriateness (or
otherwise) of densitometry measurements as dictated by
local guidelines was determined.
9
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Figure 1: Maltese Osteoporosis Management guidelines concerning over 65 year olds
Age ≥ 65
Previous fragility fracture
Determine FRAX score using BMD
Investigate and treat
FRAX score < intervention
threshold
Repeat FRAX (incl BMD)
assessment in 2 years
FRAX score >
intervention threshold
Investigation and treatment
Figure 2: Maltese Osteoporosis Management guidelines concerning 40-64 year olds
Age < 65
Previous fragility fracture
Investigate and treat
FRAX without BMD testing
FRAX score < assessment
threshold
FRAX score > assessment
threshold
Reassure pt. & reassess
after 2 years
Determine FRAX score
using BMD
FRAX + BMD <
intervention threshold
FRAX + BMD >
intervention threshold
FRAX + BMD in 2 years
Malta Medical Journal
Volume 27 Issue 05 2015
Investigation and
treatment
10
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Results
Patient Data
Table 2: Mean BMI, probability of major osteoporotic risk and hip fracture risk in the studied population
AGE GROUP
40-44
45-49
50-54
55-59
60-64
POPULATION
SIZE (N)
5
40
184
226
247
MEAN 10 YEAR PROBABILITY OF
MAJOR OSTEOPOROTIC
FRACTURE (FRAX)
2.28
2.82
3.29
4.62
6.78
MEAN BMI
26.4
27.7
28.1
27.9
28.6
MEAN 10 YEAR
PROBABILITY OF HIP
FRACTURE (FRAX)
0.2
0.255
0.38
0.74
1.45
Table of Sensitivity and Specificity
Table 3: Sensitivity and specificity of using the local osteoporosis management guidelines according to age group
AGE GROUP
TRUE POSITIVE
FALSE POSITIVE
TRUE NEGATIVE
FALSE NEGATIVE
SENSITIVITY
40-44
0
1
4
0
0%
45-49
1
27
11
1
50%
50-54
4
83
92
5
44.44%
OVERALL
49
386
252
15
76.56%
95% CI:64.3-86.2%
80%
28.95% 52.57% 38.92% 30.41%
39.21%
SPECIFICITY
95% CI:35.7-43.41%
FRAX®(without BMD) based guideline use for managing under 65 year olds was found to have a positive predictive
value of 11.26% (CI 8.45% to 14.62%) and a negative predictive value of 94.38% (CI 90.90% to 96.82%)
Sensitivity, specificity, positive predictive
value and negative predictive value of using the
FRAX® engine in under 65 year olds were
calculated using true positive/negative and false
positive/negative rates of each age group as
described in local Maltese guidelines. The age
groups under investigation were: 40-44, 45-49, 5054, 55-59 and 60-64 year olds.
Discussion
From the data obtained it can be observed that
FRAX®-guided local guidelines are well suited at
excluding patients who are not osteoporotic. This can be
seen from the high negative predictive value of 94.32%
(with a false ommission rate of only 5.68%). If FRAXguided local guidelines were strictly adhered to during
this period, 252 bone density measurements (35.9% of
all estimations) could have been avoided.
The likelihood ratios are used as part of evidencebased medicine to assess the value of carrying out a
diagnostic test, in this case using the FRAX® score. The
positive likelihood ratio for the protocol was found to be
1.27. This means that 1 in every 8.8 patients that would
have been referred for BMD estimation would have
actually been osteoporotic.
The protocol has a mean sensitivity of 76.56%
Malta Medical Journal
Volume 27 Issue 05 2015
55-59
18
124
79
5
78.26%
60-64
26
151
66
4
86.67%
across age groups, with the highest sensitivity being in
the older age groups. This means that in these patients
there is a higher probability that osteoporotics are
correctly identified. The sensitivity of the local protocol
investigated in this study is comparable to that obtained
by Henry and colleagues in 2011. 11 This study
prospectively evaluated the use of FRAX® in the United
Kingdom (Sensitivity of 64.2%, Specificity of 62.9%)
and in the United States (Sensitivity of 66.7%,
Specificity of 59.7%). In a population of
postmenopausal Thai women, Yingyuenyong and
colleagues found FRAX® to have a sensitivity of 83.6%
and a specificity of 72.1%.12 The specificity of the
protocol in the Maltese population (39.21%) is lower
than that quoted in these studies. These observations
may be due to dissimilarities in the assessment
thresholds used, wherein increasing the sensitivity of a
protocol (by lowering assessment thresholds) comes at
the expense of decreasing the protocol’s specificity. In
this regard, a study by Bansal et al (2015) found
lowering the assessment threshold from >9.3% major
osteoporotic fracture risk (as recommended by the US
preventative Services Task Force) to 5.5% resulted in a
higher sensitivity (From 37 to 80%) and a lower
specificity (From 74 to 27%).13
In agreement with other studies, linear regression
analysis of Hip and Vertebral T-scores found them to be
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in a significant negative relationship with age and in a
positive relationship with BMI. This could be suggestive
of a protective effect of obesity on bone density. In
obese postmenopausal women, increased estrogen
synthesis by fat tissue has been suggested as one of the
potential mechanisms for the protective effect of fat
mass on bone. 14
A follow up assessment of the Maltese National
Osteoporosis Management guidelines is planned in the
coming years to assess the impact they will have on
local practice and cost-effectiveness of bone mineral
density estimation and to evaluate how these can be
improved. A ten year follow up of the patients involved
in this study is also planned in order to assess actual
fracture incidence.
13.
14.
Bansal S, Pecina JL, Merry SP, Kennel KA, Maxson J, Quigg S
et al. US Preventative Services Task Force FRAX threshold has
a low sensitivity to detect osteoporosis in women ages 50-64
years. Osteoporos Int. 2015 Apr;26(4)
Migliaccio S, Greco E, Fornari R, Donini L, Lenzi A. Is obesity
in women protective against osteoporosis? Diabetes Metab
Syndr Obes. 2011;4.
Conclusion
FRAX®-guided local guidelines are well suited at
excluding non-osteoporotic patients, with a false
omission rate of 5.62%. The sensitivity of the local
protocol increases with increasing age, and its proper use
in the Maltese community care could reduce load at the
Bone Density units at Mater Dei Hospital.
References
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2.
3.
4.
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6.
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8.
9.
10.
11.
12.
Harvey N, Dennison E, Cooper C. Osteoporosis: impact on
health and economics. Nat Rev Rheumatol. 2010 Feb 6;2.
Edwards M, Dennison E, Aihie Sayer A, Fielding R, Cooper C.
Osteoporosis and sarcopenia in older age; Bone. 2015 Apr;14.
Brandi M. Microarchitecture, the key to bone quality.
Rheumatology. 2009;48.
Compston J. Osteoporosis: social and economic impact. Radiol
Clin North Am. 2010 May;48(3).
Nuti R, Caffarrelli C, Guglielmi G, Gennari L, Gonnelli S.
Undiagnosed vertebral fractures influence quality of life in
postmenopausal women with reduced ultrasound parameters.
Clin Orthop Relat Res. 2014 July;472(7).
Brunner L, Oates L. Hip Fractures in Adults. Am Fam
Physician. 2003 Feb;67(3).
World Health Organization. Assessment of fracture risk and its
application to screening for postmenopausal osteoporosis.
WHO Technical Report Series. Geneva; 1994. Report No.: 843.
Kanis J, Melton L, Christiansen C, Johnston C, Khaltaev N.
The diagnosis of osteoporosis. Journal of Bone and Mineral
Research. 1994;9.
Paschalis EP. Infrared Assessment of Bone Quality: A Review.
Clin Orthop Relat Res. 2011 Jan.
Kanis J. FRAX™ and the assessment of fracture probability in
men and women from the UK. Osteoporos Int. 2008;19(385).
Henry MJ, Pasco JA, Merriman EN, Zhang Yu, Sanders KM,
Kotowicz MA et al. Fracture Risk Score and Absolute Risk of
Fracture Radiology 2011 May;259(2).
Yingyuenyong S. Validation of FRAX® WHO Fracture Risk
Assessment Tool with and without the Alara Metriscan
Phalangeal Densitometer as a Screening Tool to Identify
Osteoporosis in Thai Postmenopausal Women. Thai Journal of
Obstetrics and Gynaecology 2012 Jul;20(111-120).
Malta Medical Journal
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Article
Women’s satisfaction of the Maltese breast
screening programme:
a cross-sectional survey
Danika Marmara`, Judi Curtis, Vincent Marmara`
Abstract
Introduction: Breast cancer is the most common
form of cancer among women, 1 with 425,000 new cases
diagnosed in Europe each year.2 The latter posed a
detrimental health problem for years in Malta and
consequently, a National Breast Screening Programme
was established in 2009. Previous studies regarding
client satisfaction with mammography screening
services have shown a large variability between different
centres. High levels of client satisfaction within
Screening Programmes encourage attendees to
recommend breast screening to others,3 while unsatisfied
clients are less likely to comply with follow-up
appointments.3-4
Aim: To evaluate women’s satisfaction of the
Maltese Breast Screening Programme (MBSP) in its
prevalent call.
Methods: A cross-sectional survey was conducted
by telephone to collect data retrospectively from a
purposively defined, random sample of 380 women who
had accepted to be screened until the time of study. The
sample included women born between 1950 and 1954,
comprising those who received a normal result and those
recalled for further tests. Thematic analysis was applied
to women’s qualitative responses.
Danika Marmarà B.Sc.(Hons), M.Sc.(Lond.), LRSM*
Office of the Director General (Healthcare Services)
Ministry of Energy and Health (Health), Malta
School of Health Sciences,
University of Stirling, Scotland (UK)
attard.danika@gmail.com
Judi Curtis MSc TDCR
School of Radiography,
Faculty of Health and Social Care Sciences,
Kingston University and St. George’s,
University of London, UK
Vincent Marmarà B.Sc.(Hons), M.Sc.(Sheff.)
Department of Mathematics,
University of Stirling, Scotland (UK)
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 05 2015
Results: The emergent five themes included
accessibility, efficiency, perception, supportive care and
acceptability. Women’s experiences of their screening
appointment, care perception and overall programme
were described in a very positive way (‘good service –
31.3%’, ‘excellent service – 68.7%’) with the majority
of clients willing to re-attend and recommend the
programme to others. For satisfaction related to
screening appointments, 95.5% were very satisfied,
99.2% were very satisfied with the standard of care and
68.7% were very satisfied with the whole programme.
However, a minority of participants (29.74%) faced
difficulties in accessing the unit, resulting in less
programme
satisfaction.
Those
who
found
mammography ‘severely uncomfortable’ also found it
‘severely painful’ (67.6%), which had a less excellent
result on client satisfaction. Women related this
negatively to radiographers’ confidence, care and
communication. More than half of participants
experienced anxiety prior to mammography (56.3%) and
higher anxiety (92.3%) when recalled.
Conclusions: Our results concur with earlier
studies showing high satisfaction among women in other
breast screening programmes.
Keywords
Patient Satisfaction,
Acceptance, Efficiency.
Pain,
Anxiety,
Patient
Introduction
Breast cancer is the most common reason for
cancer-related deaths in Maltese women and accounts
for 21% of all female cancers excluding non-melanoma
skin cancers (NMSC).5 In the last decade, around 280
women were diagnosed with breast cancer every year in
Malta.5
Since the introduction of the Maltese Breast
Screening Programme in October 2009, local women
born between 1950-1959 (aged 50-60) have been invited
to undergo mammography in the first screening round.
Presently, the programme has completed its initial cycle
and has expanded its cohort to screen women until 65
years of age in its second cycle.
A large body of evidence demonstrates that the
physical, psychological and social aspects associated
13
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Article
with and resulting from the screening process increase or
decrease client satisfaction andre-attendance.6-7 Some
studies have shown that the latter affect satisfaction
irrespective of patient characteristics, 8-9 while others
recognise that social status, age and demographic factors
are related to women’s satisfaction of screening
programmes.10-11 Therefore, programme acceptability
and efficiency is dependent on women’s participation
and re-attendance rates.12-15 Furthermore, since women's
experience during their initial screen can influence their
participation in subsequent screening, there is an urgent
need to improvewomen’s overall satisfaction with initial
screening experiences.16
This study aimed, for the first time, to investigate
client satisfaction of the Maltese Breast Screening
Programme by evaluating women’s perceptions and
identifying factors that affect client experiences.
Methods
A cross-sectional survey was conducted over a
three-month period with a purposively defined, random
sample of 380 women born between 1950 and 1954.
Since the programme was in its first round at the time of
data collection, a telephone interview survey method
was employed to collect data retrospectively.
Ethical approval for this study was obtained from
the Health Ethics Committee (Reference No.:
HEC06/11). Approval was also obtained from the
authors of an established satisfaction questionnaire17 and
was modified to local needs and translated into
Maltese.The tool incorporated fixed dichotomy response
questions and the Likert Scale as in similar studies.3,17-18
Semi-structured questions were used to seek clients’
perceptions and in-depth responses through open-ended
questions.
A simple random sample was computer generated
from the local screening register and selected from a
purposively identified population (9,125 women had
accepted to be screened at the time of study).This
sample comprised those who received a normal result
and those recalled for further tests, following which,
they still received an ‘all clear’ result (False Positives).
Women were notified in advance by telephone to
participate in this study. Upon providing their consent,
the screening coordinators organised pre-arranged
appointment times with the researcher to conduct this
study.
Statistical analyses were carried out with SPSS
software (Version 17.0) and Excel databases. Both
descriptive and inferential statistics were analysed
through the chi-square test (χ2). For those questions with
a Likert-scale, the chi-square test was also used and
complemented by displaying cross tabulations. All
analyses were conducted through a 95% confidence
level and a confidence interval of 4.92%. A p value
≤0.05 was taken to represent a statistically significant
result. Thematic analysis was applied to women’s
responses and categorised into main themes.
Results
The main factors that increase or decrease clients’
satisfaction were grouped into five categories (Table 1).
Table 1: Factors of the study
Factors
Main Themes
Access to care
Accessibility
Perception of the:
Environment
Organisation
Psychological, emotional and
physical factors
Efficiency
Perception
Support strategies
Supportive Care
Re-attendance
Acceptability
Malta Medical Journal
Volume 27 Issue 05 2015
Meaning
- Physical needs
-
Expectations of the service
Convenience
Choice
Risk perception
Impact on ‘self’
Impact on family
Survival
The procedure
Staff behaviour
Radiographer’s role
Interpersonal competence
Personal needs
Touch
Influence of screening experience
Participation in subsequent screening
Departmental practice
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Table 2: The main factors in relation to satisfaction with screening appointment, care perception and the whole
programme
*χ2 tested at the 0.001 level of significance
Five emergent themes were established during the
course of data analysis (Table 1), namely accessibility,
efficiency, perception, supportive care and acceptability.
These themes were analysed with the three dependent
variables (overall satisfaction of appointment, overall
programme and care perception).
For these three dependent variables related to
client’s satisfaction, all respondents claimed that the
Malta Medical Journal
Volume 27 Issue 05 2015
service was either “good” (31.3%) or “excellent”
(68.7%). For satisfaction related to screening
appointments, 95.5% were very satisfied, 99.2% were
very satisfied with care standards and 68.7% were very
satisfied with the whole programme. These dependent
variables were compared to several main factors of this
study (Table 2).
In general, clients were extremely pleased with the
15
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Article
pleasant and clean environment as well as the staff. The
majority of clients felt that the examination was not
lengthy and that they had enough privacy.
A client minority (29.74%) faced difficulties in
accessing the unit due to a ‘busy road’, ‘no bus access’,
‘non-central location’ and ‘limited parking’, resulting in
less programme satisfaction. Those who were not
satisfied with the directions tended to be less satisfied
with their appointment and overall programme. From
those who did not find immediate parking, 89.7% were
very satisfied with their appointment, which is 5.6% less
than those who found immediate parking (p=0.227).
From those who read the information leaflet
prior to their test, 74.8% of clients rated the overall
satisfaction as excellent, while 61.3% of those who were
uninformed rated the programme as excellent (13.5%
less).
The majority of the clients rated the mammogram
as ‘slightly uncomfortable’. Those that found the
mammogram ‘severely uncomfortable’ rated the
standard of care and overall programme satisfaction less
excellent than those who found the mammogram more
comfortable. Those who found the mammogram
‘severely uncomfortable’ are doubtful of repeat
attendance and 2.7% would not re-attend. Almost the
same results are mirrored when comparing re-attendance
versus pain (p<0.001).
The absolute majority found the test ‘not at all
painful’. Those who found the test ‘severely painful’
rated the standard of care less excellent (93.8% versus
99.5%). A large proportion of those who stated that the
mammogram was ‘severely uncomfortable’ stated that
the examination was ‘severely painful’ (67.6%), while
those eliciting that the mammogram was ‘not at all
uncomfortable’ stated that the examination was ‘not
painful’ (81.8%).
Overall, clients experienced a wide range of
emotions prior mammography (Figure 1). A high
percentage of women experienced anxiety, with 75.23%
of clients stating that their main anxiety was due to ‘fear
of the result’ and ‘its impact on the self and their
family’. Results show that those aged 59-61 were more
anxious (63.1%) than women aged 56-58 (50.2%)
(p=0.038).
Figure 1: Clients’ perception of the examination prior to mammography
The radiographer’s communication was rated very
positively by clients (‘Strongly Agree’) with 97.9%
claiming they felt ‘at ease’ and that radiographers
provided ‘excellent care’ (98.4%). However, if the
radiographer was male, 68.9% of women would not
undergo mammography. Those with primary and
secondary educational level (71.6% and 70.4%
Malta Medical Journal
Volume 27 Issue 05 2015
respectively) strongly refuse to undergo mammography
if the radiographer was male, while the refusal rate of
participants with tertiary education is 52.3%, which is
around 19% less (p=0.038).
Less than one-fifth of the clients (17.1%) were
recalled for further tests. Out of these, 18.5% underwent
a biopsy. A large majority (75%) of biopsied clients
16
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were ‘very satisfied’ with their appointment and 83.3%
‘very satisfied’ with the care received, while all recalled
clients who did not undergo a biopsy were ‘very
satisfied’ with their appointment and standard of care.
For both comparisons, high statistical significant
difference was found (Table 3).
Table 3: Biopsied clients versus non-biopsied clients
*χ2tested at the 0.001 level of significance
The vast majority (91.7%) of those who underwent
a biopsy were anxious prior to attendance, while 92.5%
of those who did not have a biopsy were also anxious
prior to attendance (p=0.843). There were 16.7% more
‘very satisfied’ non-biopsied clients than biopsied clients
when asked about the radiographer’s communication.
Discussion
Overall Satisfaction
Previous studies indicate that experiences of pain,
discomfort and distress, among others, are associated
with dissatisfaction and undermine women’s decisions
to undergo repeat screening.3,19 Moreover, a woman’s
satisfaction with her mammography experience may also
affect whether relatives or friends undergo
mammography or attend a particular mammography
unit.20
For the first time, our study reports on women’s
satisfaction of the Maltese Breast Screening Programme
in its prevalent call. Overall, women described a positive
experience of their screening appointment, care
provision and the overall programme. These results
concur with similar studies showing a high satisfaction
Malta Medical Journal
Volume 27 Issue 05 2015
level of women participating in other national breast
screening programmes.3,6,15,17
Accessibility
Unit accessibility (directions, travel and parking)
was one of the factors in this study that predicted
women’s satisfaction. Accessibility or ‘access to care’,
often defined as “the actual use of personal health
services and everything that facilitates or impedes that
use,”21 is closely related to concepts of ‘quality of care’
and ‘satisfaction with care’.22 Limited access to care has
been shown to impede the use of preventive health
services23 and is significantly associated with attendance
and re-attendance.24 Our national survey found that car
drivers were less satisfied than non-car drivers since the
former group encountered greater obstacles in
accessibility. Although no statistical significance was
found, those who experienced difficulties in accessing
the unit tend to be less satisfied with the programme
overall. As a result, women tend to opt for services that
provide free and accessible parking facilities, which
enhance satisfaction.25
17
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Efficiency
Many women stated that they were pleased with
the efficiency of the service. Furthermore, all clients
were satisfied with the unit’s environment since they
“felt at home” and “everything is well kept” (Breast
Screening client). These were a few of a series of
positive results regarding the satisfaction with the
programme overall. This is consistent with other
research findings where pleasant surroundings have
shown to enhance satisfaction, which in turn, helps to
minimize women’s anxiety.25-27
Women’s positive experiences with privacy level,
short waiting times and staff efficiency were found to be
important in determining clients’ overall satisfaction and
are also consistent with findings in other surveys. 3,6,17,25
This pleasant environment helped women to face the test
with a more positive approach, resulting in a more
optimistic perception of the examination.
Perception
Perception of the mammography examination:
Pain and Discomfort
The general public’s perception of mammography
has sometimes been reported as one of pain. 3,19 Both of
two studies found lower prevalence of pain than
discomfort,28,29 supporting the idea that discomfort is
considered less severe than pain.30 This study found a
strong association between discomfort and pain since
those
who
found
mammography
‘severely
uncomfortable’ also found it ‘severely painful’ and vice
versa, which had a less than excellent score on women’s
satisfaction. While 73.1% of women in this study
reported some discomfort, only 22% reported the
examination as ‘severely uncomfortable’, whereas from
those who reported some form of pain (43.9%), only
11.8% reported the examination as ‘severely painful’.
These percentages coincide with other authors’ findings
which ranged significantly from 1.3% to 92.3% for pain
or discomfort31,32 and specifically between 41% and 76%
for discomfort.8, 33-34 The above may be due to various
reasons, such as age-related anatomic breast differences
between younger and older women. 6 Nonetheless, this
study found no difference between the groups.
The impact of discomfort on client satisfaction was
not often examined in other studies, as most studies
focused on either discomfort or satisfaction. 6 In this
study, findings show that those who found the
mammogram ‘severely uncomfortable’ are more likely
not to re-attend when compared with those who did not
find the test ‘severely uncomfortable’. This level of
discomfort was one of the factors why not all clients
rated the programme as ‘excellent’. Such findings are
supported in several studies where bad experiences
decrease satisfaction and deter re-attendance, resulting in
a reluctancy to recommend the examination.3,12,24,35
Thus, this provides further insight to women’s
Malta Medical Journal
Volume 27 Issue 05 2015
perception of their overall satisfaction in order to
improve mammography experiences and service
provision.
European guidelines for quality assurance in
breast cancer screening and diagnosis recommend that
population-based breast screening programmes with
mammography
are
implemented
throughout
Europe. Several European countries nevertheless still
have opportunistic breast screening36 as is the case in
Malta. This study found that prior opportunistic
screening experience was not influential on pain level in
contrast to other studies. This shows that differences in
departmental practices did not have an effect on pain in
this study.
The Psychological and Emotional Challenge:
Fear and Anxiety
Fears and anxieties often arise before, during or
after screening and during the provision of results,37-39
and this often has an impact on reducing women’s
satisfaction. Studies have shown that women with a
family history of breast cancer and previous breast
cancer experiences expressed less service satisfaction. 6
This may be due to more anxiety than women at average
risk. However, it has also been reported that women who
undergo first time mammography have higher anxiety
levels.40 In our study, no difference was found between
the above groups and those with no previous
mammography experience. These findings contrast with
other research findings, as local women seem to focus
on their experience within the unit rather than on
external factors, potentially contributing towards high
service satisfaction. Moreover, when we compared
anxiety with age distribution, results show that women,
aged 59-61 were more anxious than those aged 56-58.
This concurs with similar studies denoting that age
increases risk perception.10,19
Anxiety levels during recall assessment
There is a wide variability of recall rates between
countries,41,42 ranging from less than 1% to about 15%
for screening mammography.43,44 European guidelines
recommend a target recall rate of 5% (acceptable rate of
˂7%) for first screen and a target recall rate of 3%
(acceptable rate 5%) for subsequent screens. 45 In our
study, 17.1% were recalled for further tests, which is
higher than that recommended by European
Guidelines.45
Research has shown that women recalled for
assessment had a higher incidence (30%) of measurable
anxiety than non-recalled women. 19,39 The explanation
for this is that women often react as though they have
already been diagnosed with cancer since their belief of
being healthy has been challenged. Consequently, being
recalled may take away one’s sense of security and
control among multiple wellbeing domains, reflecting
findings reiterated by Coumans and Lee46 and Corney. 47
18
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Moreover, recalled clients and those with considerable
or extreme anxiety about the results are the ones who
express the highest level of dissatisfaction and are
reluctant to undergo repeat screening.20 In our study,
women’s second visit at the unit (due to being recalled)
affected women’s anxiety. In fact, there were 36% more
anxious clients during the second visit.
Moreover, research has shown that women
undergoing breast biopsies may have escalated feelings
of anxiety and psychological distress due to implications
for family, sexuality and mortality. 39 Such findings are
supported in this study. Women who underwent a biopsy
were less satisfied than non-biopsied women, mainly
due to the increased anxiety about the biopsy procedure.
In fact, 8.8% of biopsied clients were more ‘very
anxious’ than non-biopsied clients during recall.
Furthermore, biopsied women were ‘less satisfied’ than
non-biopsied clients regarding the quality of
communication during assessment. Information provided
to women, and more specifically, the way results are
reported to a patient, has been associated with
dissatisfaction in other studies. 20 Hence, our results
substantiate the constant need for effective
communication and psychological support throughout
the screening process.
Supportive Care
Standard of Care Perception and Quality of Care
High levels of satisfaction with the staff have been
expressed in various studies 3,6,25 and are consistent with
our findings. This consistent response may be the result
of careful staff selection and training, as well as their
motivation to maintain the screening programme a
successful one.
The Radiographer
Our findings are supported in other studies 3,19
where the radiographers’ supportive care led women to
have positive screening experiences. Clients who
experienced more pain and discomfort related this
negatively to the radiographer’s confidence, care
provision and communication. This is consistent with
other findings48 where lack of communication during
mammography increased pain.
In this study, the majority of clients claimed that
they were given pertinent procedural information with
effective
communication
maintained
during
mammography, leading to higher satisfaction levels than
uninformed clients. Furthermore, the ‘female’
radiographer was an important factor to screening
adherence due to intimacy in interaction, consistent with
other studies.19,49 In fact, almost everyone felt at ease
and that “the ‘contact’ with the radiographer made all
the difference” (Breast Screening client). Results show
that if the radiographer was male, 68.9% of all women
would not have undergone the test. Being assured of a
Malta Medical Journal
Volume 27 Issue 05 2015
female radiographer was therefore an impacting factor in
this research, leading to a positive screening experience
and consequently high satisfaction.
Pre-procedural Information
This study found that pre-procedural information
has positively influenced women’s perception of the
programme. This is consistent in other studies where an
understanding of what to expect during screening and
assessment resulted in positive diagnostic experiences.50
This study further claims that those who read the leaflet
rated the overall programme satisfaction as more
positive than those who did not. This shows that preprocedural information may have positively influenced
women’s perception of the whole setup/organisation.
However, the expectation of pain might not only be
related to pre-procedural information, but also due to
information received from friends or relatives in first
time attendees.51
Although pre-procedural information is provided to
women attending the programme, women may need to
be better informed on the consequences of screening and
the possibility that a biopsy procedure may progress to
extensive surgery, depending on the subsequent
pathological findings. Women's understanding of the
potential benefits, harms and shortcomings of breast
screening, including overdiagnosis and overtreatment,
has shown to be imperfect in this study, which is also
concordant to findings in other studies, 52 thus requiring
better informed consent to guide screening decisionmaking.
Acceptability
This study’s results show a high level of
acceptability by clients since almost everyone is willing
to re-attend (99.2%) and recommend the programme.
This is consistent with other findings12,17,24 promoting
acceptability as one of the basis for the programme’s
success.15 Moreover, satisfied clients will more likely
provide positive comments to relatives and friends.
Therefore, service acceptability may have an impact on
initial participation rates as suggested by other
programmes.3,24
Limitations and Recommendations of the study
The retrospective data included a set timeframe
ranging from one month to one-and-a-half years; hence
participants responded to the survey after receiving a
normal screening result. This might have led women to
be more positive about the programme, thus superseding
the service’s negative aspects. Therefore, this study
recommends conducting another research into two parts:
a study regarding women’s satisfaction immediately
after mammography and another study following their
screening result to compare satisfaction levels between
the first and second study. Variables that could not be
19
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Article
accounted for included radiographers’ training and their
individual experience. More importantly, this study did
not incorporate those who received a breast cancer
diagnosis due to limitations in time and personnel. The
satisfaction level may have varied for this group.
Nonetheless, the pain experience is a consequence of a
combination of different pain factors (the radiographer,
breast tenderness, breast thickness, among others). The
latter were not investigated, since this study focused on
women’s overall satisfaction of the breast screening
programme. Therefore, this is an area for further
investigation.
Conclusions and Implications for the service
Among the measures to increase satisfaction of women
in organized screening:
There is solid evidence that women who face
difficulties to access the screening unit are less
satisfied with the screening programme. Strategies
to reduce logistical barriers are required, including
external signage to enhance accessibility to the
centre.
An internal non-clinical, welcoming ambience is
more effective in creating an atmosphere conducive
towards increased satisfaction, proving that the
modernization of health facilities greatly
contributes towards customer satisfaction and care.
There is solid evidence that the female radiographer
was an impacting factor towards high satisfaction
and a positive screening experience. Due to the
intimacy of the procedure, this factor leads women
to feel at ease during screening.
Strategies to minimize pain and discomfort are
required if high levels of satisfaction and attendance
are to be maintained.
Pre-procedural information has shown to be
effective to minimize anxiety and is essential for
Maltese women invited for screening to make
informed choices.
Continuous service evaluation by means of
satisfaction surveys is necessary to ensure that high
standards of care are provided and to enable service
improvements to meet women’s needs.
Since the participation rate at the time of study was
found to be 55.9%, urgent research to investigate
local reasons for non-attendance is vital in order to
increase the screening compliance rate in Malta as
recommended by European screening guidelines.
Acknowledgements
The authors wish to acknowledge the assistance
of the Quality Assurance Reference Centre at the North
East, Yorkshire and The Humber, UK and the Faculty of
Health and Social Care Sciences, Kingston University
and St. George’s, University of London, UK. STEPS –
Malta Medical Journal
Volume 27 Issue 05 2015
the Strategic Educational Pathways Scholarship Scheme
(ESF 1.25) funded this research. The Scholarship was
part-financed by the European Union Operational
Programme II – Cohesion Policy 2007-2013,
Empowering People for More Jobs and a Better Quality
of Life, European Social Fund.
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21
OrigEd
Original
Article
Breast Cancer Patients Diagnosed by National
Breast Screening Programme
Sarah Ellul, Kay Vanhear, Ramona Camilleri,
Gordon Caruana-Dingli,
Abstract
Breast cancer is the most common cancer in Malta.
A National Breast Screening Programme (NBSP) was
introduced in 2009 for women in the 50 to 60 year old
age group.
The first 112 patients diagnosed by the NBSP were
compared to a matched control group of symptomatic
patients randomly selected from the Breast Clinic, who
had presented to the clinic with a breast lump. The files
of all these patients were reviewed retrospectively.
In the screening group there were 94 patients with
invasive cancer and 18 patients with ductal carcinoma in
situ (DCIS) while in the control group there were 114
patients with invasive cancer and 3 with DCIS.
In the screening group, 81 (86.2%) patients with
invasive cancer underwent wide local excision (WLE)
and 13 (13.8%) underwent mastectomy. In the control
group 88 (77.2%) patients with invasive cancer
underwent WLE and 26 (22.8%) had a mastectomy.
Out of all the patients in the screened group with
DCIS, 12 (66.7%) underwent WLE and 6 (33.3%)
underwent mastectomy. In the control group only 3
patients had DCIS and these were all treated by WLE.
Sarah Ellul MD (Melit.)
Breast Clinic,
Mater Dei Hospital
Kay Vanhear MD (Melit.)*
Breast Clinic,
Mater Dei Hospital
kay.vanhear@gov.mt
Ramona Camilleri MD (Melit.), BSc (Melit.)
Breast Clinic,
Mater Dei Hospital
Gordon Caruana-Dingli MD(Melit.) LRCPEdin
LRCSEdin LRCP&SGlasg FRCSEdin FRCS
RCP&SGlasg
Head, Breast Clinic,
Mater Dei Hospital;
University of Malta
Medical School
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 05 2015
The average Nottingham Prognostic Index (NPI) of
the screening population with invasive cancer is (3.28
(95% CI)) and is lower than the NPI of the control group
is (3.74 (95% CI)).
This study shows that in the screening group there
is a higher percentage of patients with DCIS when
compared to the control group. Furthermore, the
screened group patients with DCIS were more likely to
undergo mastectomy than those with invasive cancer.
Keywords
NBSP, Breast Cancer, NPI, Mastectomy, DCIS
Introduction
The concept of breast screening is to detect the
disease at an earlier stage with the intention of
increasing the life expectancy of the cohort of screened
women.
The decision for a country to introduce breast
screening is usually political (UK, EU, Malta) and the
available evidence is based on Scandinavian trials
carried out in the 1970s. The evidence for the benefit for
breast screening has been recently analysed concluding
that although breast screening will save some women
from dying from breast cancer, it over diagnoses the
disease and will submit many women to unnecessary
surgery and other treatment.1
The benefits of breast screening have been
questioned. 2-3 Some claim that overall mortality in
patients screened for breast cancer may be worse than
those that are not screened. This is because of damage to
the coronary arteries secondary to unnecessary
radiotherapy.4
There have been dramatic advances in surgery and
adjuvant treatment for breast cancer in the fourty years
since the Scandinavian trials were carried out. The
effectiveness of modern treatment may mean that there
is little benefit from detecting a breast cancer at an
earlier stage. Breast screening has also led to an increase
in patients diagnosed with ductal carcinoma in situ
(DCIS). The clinical course of this condition has not
been elucidated and as a result, a high proportion still
undergo mastectomy. Studies in populations who have
undergone breast screening fail to demonstrate the
expected decrease in women presenting with late
22
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Article
cancers.3
The National Breast Screening Programme (NBSP)
was introduced in Malta in October 2009. 5 A dedicated
unit was established at Lascaris, Valletta, and a database
was established to screen patients between the ages of 50
and 60 every three years. Opportunistic screening is also
carried out in the private sector and this is very popular
due to a strong media campaign by the two breast nongovernmental organisations (NGOs)6 and also the private
hospitals and clinics.7
At this stage it is not possible to compare mortality
in the screened group with the unscreened population
because of the small numbers and the short follow up
period. This paper will study surrogates, even though it
is accepted that they are imprecise indicators of the
overall benefit of breast screening a population. We have
studied mastectomy rates, number of patients with
DCIS, size of tumour and Nottingham Prognostic Index
(NPI).
Breast cancer in Malta
The crude incidence and crude mortality from
breast cancer in Malta in the years 1995-2011 is plotted
in graph 1. This shows that there has been a dramatic
rise in incidence but the number of deaths has remained
stable.
When the figures are adjusted to European Age
Standardised Rates (EASR) the increase in incidence is
less marked and this implies that crude figures have
increased partly because of an aging population. The
decrease in mortality is substantial, as shown in graph 2.
The third graph charts the age specific crude
incidence of breast cancer in Malta. This has remained
stable in the below 50 year age group. There was a
marked increase in the 50-60 year age group and it has
risen dramatically in the above 60 year age group. The
fourth graph shows that the crude mortality rates
remained constant in the three age groups studied.
Figure 1: Crude incidence and mortality of breast cancer in Malta 1995-2011
360
345
340
307
320
320
300
280
260 260
267
247
240
208 207 211 205
200 199
220
200
180
173
218 222
181
160
140
100
95
103
73
70
80
95
88
87
73
64
69
61
71
77
74
2007
120
2006
Crude number for all ages
260
79
66
60
40
20
2011
2010
2009
2008
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
0
Year
Incidence
Malta Medical Journal
Volume 27 Issue 05 2015
Mortality
23
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Article
127.27
94.35
118.23
103.3 105.18
93.48
118.64
96.97
27.99
22.85
34.44 25.82
2011
29.6
2010
28.13
2009
24.21
2008
28.5
2007
27.64
2006
30.61
2005
46.08
2004
40.59 34.43
89.35
2003
1997
32.73
89.71
2002
42.38
98.21
2001
100.16
1999
47.7
100.26
92.76
1998
89.86
107.1
2000
103.2
1996
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
1995
EASR
Figure 2: European age standardised rates of incidence and mortality of breast cancer in Malta
Year
Incidence
Mortality
Figure 3: Age-Group Specific Crude Incidence Trends for Female Breast Cancer
220
192
200
170
180
150
107
115
121
102
113
96
91
117
103
97
77
75
49
61
64
58
51
41
44
60
41
20
39
38
49
43
75
63
59
51
2004
46
60
66
67
2003
42
45
53
2002
32
56
2001
40
55
2000
74
60
1998
80
53
50
2011
120
2010
140
40
153
160
140
1997
Crude Number
160
100
196
44
2009
2008
2007
2006
2005
1999
1996
1995
0
Year
Age Specific incidence <50
Malta Medical Journal
Volume 27 Issue 05 2015
Age specific incidence >59
Age specific incidence 50-59
24
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Article
Graph 4: Age group specific crude mortality for female breast cancer
80
68
67
66
56
60
36
31
25
13
2000
4
9
7
5
8
8
2006
11
2005
13
16
13
2003
5
1997
1995
0
12
1996
10
29
27
26
24
20
17
2002
10
24
23
20
18
1999
20
2001
25
2004
30
9
3
10
3
2010
42
41
2007
40
47
46
45
41
45
1998
Crude Number
50
63
53
51
2009
69
2008
70
70
Year
Age Specific Mortality <50
Age Specific Mortality <59
In Malta there has been a decrease in mean tumour
size of invasive breast cancers from 28.2mm in 2000 to
22.9mm in 2010 (p value =0.007).8 The same study also
showed a decrease in axillary node metastases at
presentation and an increase in breast conservation
surgery. This change is attributed to the establishment of
the breast clinic in 2000 and various programmes to
increase breast awareness and not solely to the
introduction of the NBSP.
Method
Two cohorts of patients were compared in this
study. The screening group were all the patients who
were found to have in situ and invasive carcinoma from
the start of the NBSP (October 2009) until the date of
this study (October 2012). There were 112 patients in
this group.
The control group were patients who were
diagnosed as having in situ or invasive breast cancer
outside the NBSP during the same time period. The files
of all such patients who were operated for in situ or
invasive breast cancer in this same period were screened
for age and those in the same age group as the screening
group were selected. Of these, 117 were randomly
chosen to form the control group.
The patient files were retrieved from the Medical
Records Office at Mater Dei Hospital and the following
data was compiled: patient’s age, type of cancer (DCIS
or Invasive), type of surgery (mastectomy or wide local
Malta Medical Journal
Volume 27 Issue 05 2015
Age Specific Mortality >59
excision (WLE)), and histological details for tumour
size, grade and NPI.
The data was analysed as shown in Table 1 showing
screening group data and control group data.
Statistical Analysis
The data collected was analysed using Statistical
Package for the Social Sciences (SPSS).
The following variables using Pearson Chi-Square
test were analysed: the numbers of mastectomies and
WLE done in the screened group and control group, as
well as, the type of surgery performed (mastectomy and
WLE) and tumour status (DCIS and Invasive
carcinoma).
In order to evaluate the tumour status with the type
of surgery performed in screened group and control
group independently, the Pearson Chi-Square and
Fisher’s Exact test were used respectively.
The p value of 0.05 was used as the cut-off for
statistical significance.
The t-test was used in order to evaluate if age was a
significant variable between the screened and the control
group.
The univariate analysis of variance (UniANOVA)
was used to analyse the mean NPI between the screened
group and the control group, corrected for age. The p
value of 0.05 was used as the cut-off for statistical
significance.
25
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Article
Table 1: Screening Group and Control Group Data
Screening Group
Control Group
Screening Group
Control Group
DCIS
(non-invasive)
Invasive
(lobular/ductal/infiltrative)
WLE
Mastectomy
12
6
81
13
WLE
3
88
Mastectomy
0
26
WLE
Mastectomy
DCIS
(non-invasive)
12
6
Invasive
(lobular/ductal/infiltrative)
81
13
WLE
3
88
Mastectomy
0
26
Results
Our unit aims at breast conservation treatment and
opt for mastectomy if large tumours, small breasts or
multifocal and multicentric disease is involved. 9
The number of mastectomies in the control group
was 26/107 (24%) which is higher than the number in
the screening group which was 19/112 (17%), but these
did not reach statistical significance according to the
Pearson Chi- Sqaured Test (p 0.317).
There were less cases of DCIS in the control group
(n=3, 2.6%) than in the screening group (n=18, 16.1%)
using Fisher Exact Test (p<0.001).
The Nottingham Prognostic Index (NPI) uses the
size, grade and lymph node status of a tumour to predict
the prognosis.10 The mean NPI in the control group (3.74
(95% CI)) was higher than that of the screening group
which had a mean NPI (3.279 (95% CI)) adjusted for
age (60.9).
The average tumour size for the control group was
20.24mm which was higher than that of the screening
group which was 18.11mm.
Discussion
This study shows that in the screened group there
was a higher percentage of patients with DCIS when
compared to the control group. The difference in size of
tumour in both groups did not reach statistical
significance however the NPI was significantly lower in
the screened group than in the control group.
In the screened group, patients with DCIS were
likely to undergo mastectomy (33.3%) than those with
invasive cancer (13.8%).
Ductal carcinoma in situ (DCIS) is an intraepithelial
neoplastic proliferation of epithelial cells that is
separated from the breast stroma by an intact layer of
basement membrane and myoepithelial cells. 11 DCIS is
Malta Medical Journal
Volume 27 Issue 05 2015
usually detected by screen mammography. Up to 40% of
these lesions progress to invasive disease if untreated but
it is not yet possible to accurately predict which DCIS
will progress to invasive breast cancer. 12
The challenge is to treat DCIS effectively to
decrease the risk of recurrence with the best possible
cosmetic outcome. Mammography often underestimates
the size of the lesion and MRI allows more accurate
planning of surgery. Also large lesions often have foci of
unsuspected invasive cancer. Mastectomy, possibly with
immediate reconstruction, offers the highest possibility
of clearance of DCIS but the cosmetic appearance can be
severely compromised. Breast conservation surgery
requires a balance between the margin of excision and
oncological risk and cosmetic outcome but it is not
suitable for large lesions or multicentric disease.
Studies in other institutions have shown that
screened patients may be overtreated and this is also
suggested by the results of this study.4, 13-14 The lower
NPI in the screened group implies a better prognosis in
screened patients. However this has to be interpreted
with caution because of lead time bias and possible
complications from overtreatment.
The authors suggest repeating this study when a
larger number of patients are screened.
1.
2.
3.
References
Marmot G, Altman DG, Cameron DA, Dewar JA, Thompson
SG, Wilcox M. Independent UK Panel on Breast Cancer
Screening. The benefits and harms of breast cancer screening:
an independent review. Br J Cancer 2013;108(11):2205-2240
Baum M. Harms from breast cancer screening outweigh
benefits if death caused by treatment is included. BMJ
2013;346:f385.
Gøtzsche PC, Nielsen M. Screening for breast cancer with
mammography. Cochrane Database Syst Rev
2011;1;CD001877.
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Gilbert Welch H. Overdiagnosis and mammography screening.
BMJ 2009: 339:b1425
Malta Breast Screening: Available at
http://maltabreastscreening.info/. (Accessed on 20th May
2014).
Europa Donna Malta: Available at
http://www.europadonnamalta.org.mt/index.php?p=about.
(Accessed on 20th July 2014).
Action for Breast Cancer Foundation: Available at
http://www.actionforbreastcancer.com/about-abcf/. (Accessed
on 20th July 2014).
Caruana M, Dingli Caruana G. Breast cancer in Malta – a
comparative study between the year 2000 and 2010. MMJ
2013;25:27-30
Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R,
Luini A, et al. Twenty-Year Follow-up of a Randomized Study
Comparing Breast- Conserving Surgery with Radical
Mastectomy for Early Breast Cancer. N Eng J Med 2002;
347:1277-1232.
Improved survival for screen-detected breast cancer: Available
at
http://www.ncin.org.uk/publications/data_briefings/improved_s
urvival_for_screen_detected_breast_cancer. (Accessed on 20th
June 2015).
Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchio C,
Reis-Filho J.S. Breast cancer precursors revisited: molecular
features and progression pathways. Histopathology
2010; 57: 171–192
Cowell CF, Weigelt B, Sakr RA, Ng CKY, Hicks J, King TA,
et al. Progression from ductal carcinoma in situ to invasive
breast cancer: Revisited. Mol Oncol 2013; 7(5):859-869
Jørgensen KJ, Keen J, Gøtzsche PC. Is mammographic
screening justifiable considering its substantial overdiagnosis
rate and minor effect on mortality? Radiology 2011;260;621627
Vainio H, Bianchini F, IARC: Handbooks of Cancer
Prevention-Breast Cancer Screening Volume 7. France; Oxford
University Press, 2002
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Volume 27 Issue 05 2015
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Article
Pathogenesis of endocrine thyroid cancer
Nicola Mallia, Josanne Vassallo
Abstract
This review aims to discuss the different genetic
alterations that may come about and thus give rise to
thyroid cancer. The importance of understanding the
pathogenesis of this disease is in the use of these genetic
alterations as prognostic markers and as targets in
treatment. Principal alterations to these central
pathways, namely the MAPK pathway and PI3K/AKT
pathway, are mutations, increase in gene number,
methylations and translocations. The effects of the
environment on the progression of thyroid cancer, such
as the effects of the microenvironment and exposure to
endocrine disruptors, will also be discussed.
Keywords
Thyroid cancer, pathogenesis, signalling pathways
Nicola Mallia
Department of Medicine
Josanne Vassallo MD FRCP*
Department of Medicine
Medical School
University of Malta
Josanne.vassallo@um.edu.mt
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 05 2015
Introduction
While the prevalence of most cancers has remained
the same or decreased, the incidence of thyroid cancer
has increased.1 Therefore there is a great need for us to
understand the mechanism of this disease since this may
help us understand and determine the factors that are
causing this increase in incidence. More importantly we
hope that by understanding the pathogenesis of thyroid
cancer we will be one step closer in finding a cure or at
least a better treatment for this disease. The majority of
thyroid cancers are derived from follicular cells, namely
papillary carcinomas (PTC), follicular carcinomas (FTC),
anaplastic carcinomas (ATC) and poorly differentiated
thyroid cancers (PDTC). The remaining of thyroid
cancers arise form parafollicular cells (also known as C
cells) and are known as medullary thyroid cancers
(MTC).2
Mutations
A mutation is a permanent change in the DNA
sequence of a gene, this may be somatic or germline. A
somatic mutation is one that occurs in somatic tissue i.e.
any of the cells body except germ cell and so cannot be
passed on to future generations. Germline muations
occur in germ cells and so can be passed on to future
generations. Two of the most common genetic mutations
in thyroid cancer are those of BRAF and RAS, both of
which are somatic mutations. BRAF is a gene coding for
a proto-oncogene, the mutant form being BRAF-V600E.
This form of mutation tends to be common and is
commonly associated with papillary thyroid cancer.
BRAF mutations have been shown to be related with
poor clinicopathological outcomes and have a high risk
of recurrence. It is also associated with metastasis of the
lymph nodes, advanced stages of cancer and
extrathyroidal extensions. BRAF-V600E leads to the
continuous activation of the serine/threonine kinase, also
known as the MAP kinase pathway (MAPK). BRAF
mutations are associated with an aggressive form of
PTC, this is not seen in other mutations such as that of
RAS (both of which are involved in the constitutive
activation of MAPK pathway). This may come about as
a result of the increased production of tumour promoting
molecules such as vascular endothelial growth factor
(VEGF), matrix metalloprotein, proinhibitin, Ki-67 and
c-MET. BRAF-V600E is also associated with the
methylation of the promoters of several tumour
suppressor genes and therefore the decreased expression
of the tumour suppressor genes. Both of these events
make PTC particularly aggressive.3
28
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RAS mutation is another very common mutation in
thyroid cancer, following BRAF, but tends to be less
aggressive.2 RAS proteins are GTPase proto-oncogenes,
that are important in the regulation of the MAPK and
PI3K/AKT pathways.4 The RAS mutation is associated
with the transformation of follicular thyroid adenoma,
which is a premalignant lesion, in thyroid cancer. 2 PTCs
with the RAS mutation tend to be encapsulated and have
a lower rate of lymph node metastasis. 4
Methylation
Methylation is the addition of a methyl group to
DNA. Hypomethylated genes are found to be over
expressed in the presence of the BRAFV600E mutation.
The hypo- or hyper-methylation of genes arises from
signals that come about from the MAPK pathway driven
by a mutation.5 The hypermethylation of promoters
seems to be commonly associated with thyroid cancers
and is the most common mechanism for the inactivation
of genes. In fact methylation is also seen in the promoter
of the PTEN gene, and is commonly seen in sporadic
tumours. Normally PTEN acts as a tumour suppressor
gene by down-regulating the PI3K/AKT pathway. The
driving force of thyroid cancer from low grade to high
grade is associated with the deviation of the PI3K/AKT
pathway from its normal course. Thus a normally
functioning PTEN gene prevents apoptosis. PTEN
methylation results in the amplification and mutation of
PIK3CA and is also associated with RAS mutations. This
is commonly seen in FTC.6
Translocations
In translocation a segment from one chromosome
breaks off and reattaches to a nonhomolgous
chromosome or to a new site on the same chromosome.
Chromosomal rearrangements involved in PTC are those
of the proto-oncogenes RET and Neurotropic tyrosine
kinase (NTRK1). DNA is susceptible to strand breaks
when exposed to ionising radiation, something that is
commonly seen in PTC. In fact there is a relationship
between radiations, RET/PTC rearrangements leading to
PTC formation.7 Chromosomal rearrangements come
about not only because the gene loci involved have been
damaged by radiation but also because they come in
close vicinity during interphase of a thyroid cell.
RET and NTRK1 rearrangements come about
because of paracentric inversions. These events happen
on chromosome 10 in the case of RET and on
chromosome 1 in the case of NTRK1.8 Both of these
proto-oncogenes code for tyrosine kinase receptors that
are found on cell membranes. RET acts as a receptor for
the growth factor of glial cell line-derived neurotrophic
factor (GDNF) family, it permits the survival of many
neurones and prevents apoptosis. NTRK1 binds nerve
growth factor and is also important for the maintenance
of neurons. RET and NTRK1 are both normally
Malta Medical Journal
Volume 27 Issue 05 2015
expressed in follicular C cells. eventually activate other
cellular pathways including RAS/MAPK and PI3K.
Chromosomal recombination retains the promoter and
this results in the constitutive expression of the
oncogene. The break point occurs between the coding
sequence for the extracellular and transmembrane
domain and that of the tyrosine kinase domain.
Spontaneous dimerization comes about because of an
intact protein-protein interaction domain. This results in
ligand-independent autophosphorylation and therefore
activation of downstream signalling cascades via cellular
pathways. PTC can develop due to the chromosomal
rearrangement of RET, unaided by other genetic
alterations.7 The relationship of radiation in thyroid
cancer was studied closely in post-Chernobyl patients. It
was very clear that children exposed to radiation were
more likely to develop functional PTC, and were found
to have RET/PTC rearrangements, amongst other
genetic alterations such as mutations leading to BRAFV600E.4
Increases in gene number
In thyroid cancers we also have an increase in
genomic number, particularly those of the RTK genes
and also of genes that code for members of the PI3KAKT pathway. These were even more evident in ATC,
with the gain of the PDGFRα, PDGFRß, EGFR and
VEGFR1 genes. The copy gain of RTK genes may act as
potential therapeutic targets. The increase of the RTK
gene more commonly interacts with AKT, that is, it
promotes tumourigenesis and invasiveness though the
PI3K/AKt pathway in ACT.
Commonly increases in gene number are not seen
as an isolated genetic alteration, but rather are seen to
exist with mutations, as seen in ATC. This may aid in
the irregular signalling of pathways. Genetic mutations
are commonly associated with increases of the RTK
genes. An exception to this is seen in FTC were PI3KCa
increases in number, rather than RTK. 9
IQGAP1 (Ras GTPase-activating-like protein 1) is
a scaffold protein. The increase expression of its
corresponding gene plays a vital role in the spread of
thyroid cancer. It may also be used as a marker and
therapeutic target. The IQGAP1 polypeptide is very
similar to the RAS- related GTP-ase proteins. In most
cancer cells it might also be able to alter the RAS ->
RAF -> MEK -> MAP kinase pathway.10
MAPK signalling pathway
An extracellular mitogen binds to a membrane
bound receptor, this activates SOS which promotes the
removal of GDP from RAS in exchange for GTP. This
in turn activates RAF (MAP3K), which activates
MAPK2, which then activates MAPK, which then
activates transcription factors. Ras activates RAF which
then phosphorylates and activates
MEK, thus
29
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Article
phosphorylating and activating MAPK. 11
Mutant RTKs are a common genetic event in most
forms of hereditary MTC. RET is a proto-oncogene, its
activation leads to the constitutive activation of the
MAPK pathway and this stimulates tumourigenesis. This
hereditary mutant RET gene is commonly seen in
patients with multiple endocrine neoplasia type 2A or
2B or familial MTC.12 Constitutively active mutant RAF
proteins that are typically seen in tumour cells, induce
quiescent cultured cells to divide uncontrollably (even in
the absence of hormones). On the other hand a
constitutively active RAS protein cannot stimulate a
defective RAF protein to proliferate.13 The most
common mutations found in DTC are those of the BRAF
gene. Most of the time a valine takes the place of a
glutamine acid. The BRAF V600E mutation is
associated with lymph node metastasis, extra thyroidal
extension and advanced stage of the disease. 12 The most
common genetic alteration that occurs in sporadic adult
papillary carcinomas is the BRAF point mutation. On the
other hand patients who had been previously exposed to
radiation, both accidentally and for therapeutic reasons,
presented with a high frequency of RET/PTC
rearrangements, with no or little occurrence of BRAF
point mutations.1
Figure 1: Diagram showing the events of the MAPK pathway. From Molecular Cell Biology. 7th edition. 2012
PI3K-AKT Pathway
PTEN is one of the most commonly lost tumour
suppressor genes, during tumour development mutations
and deletions occur that inactivate its enzyme activity to
increase cell proliferation and reduce cell death. PTEN is
a natural inhibitor to the PI3K/AKT pathway. PTEN
inhibits the conversion of PIP3 to PIP2. PIP2 limits
AKTs’ ability to bind to the membrane and therefore
decrease activity. The increase in PIP3 results in an
accumulation of AKT that is activated by PDK1. AKT
activates mTOR by inhibiting TSC2, through
phosphorylation. mTOR regulates protein translocation
through phosphorylation of S6K1 and eIF4E binding
Malta Medical Journal
Volume 27 Issue 05 2015
proteins, this activates protein translation and cell
survival. 15
Increases in gene number of the PIK3Ca gene occur
particularly in ATC and FTC, this leads to the over
expression and activity of the PIK3Ca protein and thus
phosphorylation of Akt. This is also associated with the
conversion of precancerous epithelial lesions to cancer,
distant metastasis and decreased patient survival. 10 Thus
RTK (receptor tyrosine kinase) uses the PI3K pathway
to promote tumourigenesis and invasiveness of ATC and
FTC. Then again this may be used to our advantage to
target this genetic event as a potential therapeutic
target.16 RAS is also involved in the PI3K pathway due
30
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Article
to RAS-binding site of p110 catalytic subunits such as
that of PI3KCa. RAS mutations are associated with the
phosphorylation of Akt. PTEN methylation is associated
with genetic alterations in the PI3K-Akt pathway, such
as hypermethylation of the PTEN gene which reduces
the inhibitory effect of PTEN. PTEN methylation is in
fact linked with aggressive cancer. 17
Figure 2: Diagram showing the PI3K pathway. It depicts the different components of the PI3K-AKT and MAPK
pathway that are typically affected in cancer. From Weigelt, B. & Downward, J. 2012. Genomic Determinants of PI3K
Pathway Inhibitor Response in Cancer. Front Oncol.2012;2:109
Malta Medical Journal
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Article
The Role of BRAF-V600E in the microenvironment
Patients with PTC who also have the BRAF-V600E
mutation tend to exhibit a more aggressive clinical
behaviour. This might be due to the effect of this
mutation on the microenvironment thus effecting
proliferation, motility, viability and adhesion. This
mutation may also play a part in the conversion of PTC
into ATC. Tumorignenesis is affected by the
microenvironment of the tumour i.e. non-malignant
cells. Genes that are abnormally expressed in cancer
may code for receptors and proteins that have an effect
on stromal cells such as endothelial cells, macrophages
and smooth muscle cells, and on components of the
extracellular matrix (ECM). Genes expressed by cells
that harbour the BRAF-V600E mutation are for example
those of the metallo-proteases (MMPs). MMPs are
involved in the breakdown of the ECM and may
therefore promote the tumour metastasis. The BRAFV600E mutation has also been shown to have an effect
on thrombospondin-1 (TSP-1). In non-malignant cells,
wild-type p53 inhibits angiogenesis by promoting the
expression of TSP-1. Reduced expression of TSP-1 is
associated with mutated RAS. The role of integrins is to
attach the cell to the ECM. Some integrins may act as
tumour suppressors and so there is a decreased
expression as the cancer progresses, whereas other
integrins promote tumour progression such as α2β1.
ECM components may also interact together to promote
cell proliferation, invasiveness and migration. For
example, there seems to be a link between integrins and
the N-terminal of TSP-1. Fibronectin is over expressed
in BRAF-V600E positive cells. It promotes cancer
invasiveness through its interaction with integrins. This
is due to the constitutive signalling of BRAFV600E/ERK
kinase.
Targeting
non-malignant
components i.e. ECM molecules may provide a novel
perspective to treating patients with such cancers. 18
Medullary Thyroid Cancer
Medullary thyroid cancer is not as common and
accounts for only 3-4% of thyroid cancers. Of these 75%
are of the sporadic form while the other 25% account for
hereditary cancers. Medullary thyroid cancer occurs in
most cases of people who have the MEN 2a syndrome.
This is associated with germline mutations in the RET
(rearranged during transfection) proto-oncogene, in
about 80% of patients this occurs in codon 634 on
chromosome 10. Apart from medullary thyroid cancer,
MEN 2a is also associated with phaeochromocytomas
and parathyoird adenomas.19
The primary oncogenic event is thought to be a
mutation in the receptor tyrosine kinase. In fact therapies
target this receptor leading to the development of
tyrosine kinase inhibitors (TKI). A receptor tyrosine
kinase that is coded for by the RET gene, binds to a
family of ligands know as glial cell line-derived
Malta Medical Journal
Volume 27 Issue 05 2015
neurtrophic factor (GDNF). This in turn leads to the
activation of two important pathways that are important
in cell differentiation and cell growth, namely the
RAS/mitogen-activated protein kinase (MAPK) and the
phosphatidylinositol 3’ kinase (PI3K)/Akt.
Another receptor that may be involved in MTC is
also a tyrosine kinase receptor and is known as the
epidermal growth factor receptor (EGFR). The binding
of a ligand to this receptor leads to its dimerization and
autophosphorylation, which then activates downstream
signal pathways. This is involved in only a few MTCs,
and was shown to be overexpressed, but not due to gene
amplification but as result of polysomes. Therefore drug
therapies may target EGFRs and such inhibitors do in
fact inhibit the growth of MTC’s.
On the other hand vascular endothelial growth
factor receptors (VEGFR) are involved in angiogenesis.
There are three main VEGFRs: VEGFR-1, VEGFR-2
and VEGFR-3. VEGFR-2 is thought to be involved in
tumour metastasis and growth. Tyrosine kinase
inhibitors that block VEGFRs have been developed,
however their effect is only short lived. Another receptor
that may be overexpressed in MTC is the fibroblast
growth factor receptor 4 (FGFR4). This receptor is
usually involved in cell growth and proliferation and so
inhibiting it would halt cell proliferation and therefore
tumour growth. The tumour suppressor genes (TSG)
retinoblastoma; pRB protein and p53 protein (TP53) are
also involved in MTC’s. Their interaction with RET
results in tumour growth. Mutations and therefore
inactivation of both these genes are required in order to
prevent apoptosis. Loss of another TSG may result in
MTC, PTEN. This may lead to the constitutive
activation of the PI3K/Akt pathway. 20
Conclusion
The accumulation of genetic alterations of cellular
pathways leads to their aberrant signaling. This is what
then leads to the development and progression of cancer.
These genetic alterations may function as markers and
so have a vital role in diagnostics. On the other hand,
knowledge of the cellular pathways is useful for
therapeutic purposes. Knowledge of the effect of
environmental factors may be useful for the prevention
of cancer. For example we know that the formation of
the RET/PTC oncogene is related to exposure of ionizing
radiation. The link between endocrine disruptors and the
development of cancer in children may further
emphasize the importance of prenatal care.
References
1.
Howlader N, Noone A, Krapcho M, Garshell J, Neyman N,
Altekruse S, et al. SEER Cancer Statistics Review, 1975-2012.
2015; Available at: http://seer.cancer.gov/csr/1975_2012/.
Accessed July, 10, 2015.
32
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2.
3.
4.
5.
6.
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8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Xing M. Molecular pathogenesis and mechanisms of thyroid
cancer. Nature Reviews Cancer 2013;13(3):184-199.
Xing M. Prognostic utility of< i> BRAF</i> mutation in
papillary thyroid cancer. Mol Cell Endocrinol 2010;321(1):8693.
Kim JG. Molecular Pathogenesis and Targeted Therapies in
Well-Differentiated Thyroid Cancer. Endocrinology and
Metabolism 2014;29.
Hou P, Liu D, Xing M. Genome-wide alterations in gene
methylation by the BRAF V600E mutation in papillary thyroid
cancer cells. Endocr Relat Cancer 2011 Nov 14;18(6):687-697.
Hou P, Ji M, Xing M. Association of PTEN gene methylation
with genetic alterations in the phosphatidylinositol
3‐kinase/AKT signaling pathway in thyroid tumors. Cancer
2008;113(9):2440-2447.
Reddi HV, Algeciras-Schimnich A, McIver B, Eberhardt NL,
Grebe SK. Chromosomal rearrangements and the pathogenesis
of differentiated thyroid cancer. Oncology Reviews
2007;1(2):81-90.
Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde
C, Voza F, Knauf JA, et al. Identification of kinase fusion
oncogenes in post-Chernobyl radiation-induced thyroid
cancers. J Clin Invest 2013 Nov 1;123(11):4935-4944.
Liu Z, Liu D, Bojdani E, El-Naggar AK, Vasko V, Xing M.
IQGAP1 plays an important role in the invasiveness of thyroid
cancer. Clin Cancer Res 2010 Dec 15;16(24):6009-6018.
Xing M. Genetic alterations in the phosphatidylinositol-3
kinase/Akt pathway in thyroid cancer. Thyroid 2010;20(7):697706
Dhillon A, Hagan S, Rath O, Kolch W. MAP kinase signalling
pathways in cancer. Oncogene 2007;26(22):3279-3290.
Liebner DA, Shah MH. Thyroid cancer: pathogenesis and
targeted therapy. Therapeutic advances in endocrinology and
metabolism 2011;2(5):173-195.
Lodish H, Berk A, Zipursky S, Matsudaira P, Baltimore D,
Darnell J. MAP Kinase Pathways. Molecular Cell Biology. 7th
ed. New York: W. H. Freemasn; 2012.
Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova
MN, et al. Oncogenic AKAP9-BRAF fusion is a novel
mechanism of MAPK pathway activation in thyroid cancer. J
Clin Invest 2005 Jan;115(1):94-101.
Song MS, Salmena L, Pandolfi PP. The functions and
regulation of the PTEN tumour suppressor. Nature reviews
Molecular cell biology 2012;13(5):283-296.
Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al.
Highly prevalent genetic alterations in receptor tyrosine kinases
and phosphatidylinositol 3-kinase/akt and mitogen-activated
protein kinase pathways in anaplastic and follicular thyroid
cancers. Journal of Clinical Endocrinology & Metabolism
2008;93(8):3106-3116.
Reddi HV, Algeciras-Schimnich A, McIver B, Eberhardt NL,
Grebe SK. Chromosomal rearrangements and the pathogenesis
of differentiated thyroid cancer. Oncology Reviews
2007;1(2):81-90.
Nucera C, Lawler J, Parangi S. BRAF(V600E) and
microenvironment in thyroid cancer: a functional link to drive
cancer progression. Cancer Res 2011 Apr 1;71(7):2417-2422.
Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak
K, et al. The North American Neuroendocrine Tumor Society
consensus guideline for the diagnosis and management of
neuroendocrine tumors: pheochromocytoma, paraganglioma,
and medullary thyroid cancer. Pancreas 2010 Aug;39(6):775783.
Giunti S, Antonelli A, Amorosi A, Santarpia L. Cellular
signaling pathway alterations and potential targeted therapies
for medullary thyroid carcinoma. International journal of
endocrinology 2013;2013.
Malta Medical Journal
Volume 27 Issue 05 2015
33
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Article
A review of the One Health concept: increasing
awareness and collaboration between the
Maltese medical and veterinary professionals
Mauro Buttigieg
Abstract
The One World, One Health concept was initiated
in 2004 by the Wildlife Conservation Society with the
aim of establishing an interdisciplinary and crosssectoral approach to preventing epidemic or epizootic
diseases and to maintain ecosystem integrity. This
concept has gained importance nowadays due to the
increase in emerging and re-emerging diseases most of
which are zoonotic in nature. Collaboration between the
Maltese medical and veterinary professions is necessary
to diagnose and control these diseases. A number of
points are made questioning the current state of
collaboration between these professions, with the aim of
increasing the trust and communication between the said
professions thus ensuring the best possible defence
against diseases which can be a threat to both the human
and animal population on the Maltese islands.
Keywords
Emerging diseases;
Veterinary; Medical.
Zoonoses;
Collaboration;
Dr. Mauro Buttigieg DMV (Perugia), MSc (Lond.), Phd
(Padua)
Veterinary Surgeon and Visiting Lecturer
Institute of Earth Systems,
Division of Rural Sciences & Food Systems,
University of Malta,
Msida
mauro.buttigieg@um.edu.mt
Malta Medical Journal
Volume 27 Issue 05 2015
Introduction
The “One World, One Health concept” was
formulated by the Wildlife Conservation Society in 2004
and establishes an interdisciplinary and cross-sectoral
approach to preventing epidemic or epizootic disease
and for maintaining ecosystem integrity. Twelve
principles known as the Manhattan principles were
defined at the time, outlining the holistic approach
towards these diseases.1 A summary of these principles
is given in Table 1. Building on this concept, in 2008 the
FAO (United Nations Food and Agricultural
Organisation), OIE (World Organisation for Animal
Health), WHO (World Health Organisation), UNICEF
(United Nations Children’s Fund), the World Bank and
UNSIC (United Nations System Influenza Coordinator),
produced a document entitled ‘Contributing to One
World, One Health: a Strategic Framework for Reducing
Risks of Infectious Diseases at the Animal-HumanEcosystems Interface ‘further strengthening the
importance of this concept.2
Although One Health is a concept that has now
been around for a decade, it has become more important
in recent years and the initiative has been rapidly gaining
ground. This is especially so in view of new risks to both
animals and humans such as the increasing trade of
commodities of animal origin within and between
different countries which allows pathogens to spread
quickly. Climate change also plays a part since insect
vectors are being found in areas which were previously
free from such vectors, due to different reasons such as
raising ambient temperatures, changes in microclimate
etc. These changes have led to the emergence and reemergence of a number of diseases such as highly
pathogenic Avian Influenza, West Nile fever, Ebola and
sever acute respiratory syndrome (SARS).
It is estimated that about 60% of emerging infectious
diseases are zoonotic in nature and around 72% of these
originate in wildlife ( (SARS) and Ebola virus). 3 These
emerging infectious diseases can pose challenges in their
identification and control and demand closer
collaboration between medical and veterinary
researchers.4
34
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Table 1: Summary of the Manhattan Principles1
1. Recognise the link between human, domestic animal and wildlife health in the spreading of
certain disease and the importance of biodiversity in maintaining healthy environments.
2. Recognise that changes in land and water use may lead to shifts in disease emergence and
spread.
3. Wildlife health should be considered as an important component of global disease
prevention, surveillance and control.
4. Recognise that public health programmes can contribute to conservation efforts.
5. Devise systems to facilitate the prevention, surveillance, monitoring, control and mitigation
of emerging and resurging diseases keeping in mind the complex interactions among
species.
6. Seek ways to integrate biodiversity conservation perspectives and human needs when
developing solutions to infectious disease threats.
7. Reduce the demand for and better regulate the international live wildlife and bush meat
trade to protect wildlife populations and to lessen the risks of disease movement and the
development of novel pathogen-host relationships.
8. Restrict the mass culling of free-ranging wildlife species for disease control to situations
where there is a multidisciplinary, international scientific consensus that it poses a
significant threat.
9. Increase investment in the global human and animal health infrastructure in view of the
serious nature of emerging and resurging disease threats to people, domestic animals and
wildlife.
10. Form collaborative relationships among governments, local people, and the private and
public sectors to meet the challenges of global health and biodiversity conservation.
11. Provide adequate resources and support for global wildlife health surveillance networks that
exchange disease information as part of early warning systems for the emergence and
resurgence of disease threats.
12. Raise awareness and increase education so that we can better understand the relationships
between health and ecosystem integrity to succeed in improving prospects for a healthier
planet.
The importance of the One Health Concept
One of the challenges faced by humanity nowadays
is the risk of spreading of infectious diseases that emerge
due to the interactions between animals, humans and the
ecosystems in which they live. This risk is on the
increase due to a number of reasons mainly the
exponential growth in human and livestock populations,
rapid urbanisation, rapidly changing farming systems,
closer integration between livestock and wildlife, forest
encroachment, changes in ecosystems and the
globalisation of trade in animal and animal products. 2 It
has also been reported that some infectious diseases such
as those caused by Nipah virus and Hendra virus arise
due to destruction of habitat and changes in land use. 5
Apart from the loss of human lives and livestock,
major epidemics also lead to a huge economic loss.
Nabarro and Wannous, 2014 reported that the six major
epidemics of zoonotic disease namely Nipah virus in
Malaysia; West Nile fever in the United States; SARS in
numerous countries; highly pathogenic Avian Influenza
(H5N1) in various countries; bovine spongiform
encephalopathy in the United Kingdom, United States
and Canada and Rift Valley fever in Tanzania, Kenya
and Somalia, which were reported globally from 1997 to
Malta Medical Journal
Volume 27 Issue 05 2015
2009, led to economic losses of around US$80 billion
excluding indirect costs.6
Although some animal diseases are not
transmissible to humans, these can still cause public
health issues especially in less developed countries since
they may lead to a diminishing supply of proteins of
animal origin such as meat, milk and eggs. It is
estimated that by 2050 the world’s population will
increase by 34% reaching 9.1 billion. The great majority
of this increase will occur in developing countries.
Moreover, 70% of the world’s population will be urban
compared to 49% of today. In order to feed this
increasing population, food production must increase by
70%. The annual meat production will need to rise by
more than 200 million tonnes to reach 470 million
tonnes.7 Loss of livestock either attributed directly to
infectious diseases or due to culling programmes will
invariably lead to hardship in these circumstances.
Recent crises such as those of highly pathogenic
avian influenza (HPAI) caused by the virus A (H5N1),
the influenza pandemic caused by the virus A (H1N1)
and outbreaks of Ebola in West Africa have
demonstrated that communication on pandemic
readiness is one of the weaker points in the whole chain
35
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of events which needs to be addressed.8 Even though the
Maltese Islands are relatively isolated, globalisation,
trade movements and climatic changes may create new
risk factors both from an animal health and public health
aspect. Although local wildlife may be limited on the
Maltese Islands and as a result present a limited risk of
harbouring and spreading disease, importation of
livestock, pets and wildlife especially if brought into the
country illegally may pose a risk. Animals brought into
the country illegally will bypass the necessary veterinary
checks envisaged by local legislation. As a result, if they
happen to be carriers of a dangerous zoonotic disease,
they may pose a risk to their owner and to other animals
and human beings with which they come into contact.
Although the One Health concept is mainly about
public health as we know it today, it touches upon a
number of different and varied fields such as veterinary
public health, food safety, the environment, biodiversity,
climate change and also the socio-economic aspects of
prevention and cure of infectious zoonotic diseases. For
example, the decline in open spaces which is present in
our densely populated country together with reduced
interaction with nature can be a contributing factor to
mental health problems as described by Maller et al,
2006.9 This is another important aspect when
considering the broad definition of the One Health
concept. Furthermore, the majority of emerging diseases
in humans are zoonotic, mostly having wildlife as their
origin and effecting livestock living in close contact with
human beings.3 Preventing and controlling these
diseases is considered as an international public good
requiring commitment at national and international
levels.10
The increased awareness of diseases moving from
animals to humans may lead us towards trying to
eliminate the contact with animals because of fear of
diseases. However, due to a number of reasons, this is
not possible in practice and instead we should aim
towards a better understanding of how the environment
can be shared safely.11
The World Medical Association (WMA) in its
resolution on the collaboration between Human and
Veterinary Medicine adopted in October 2008,
recommends the collaboration between human and
veterinary medicine and supports the concept of joint
educational efforts between human and veterinary
medical schools. It also encourages the national medical
and veterinary associations within countries to enhance
collaboration in areas such as medical education and
research, clinical care and public health. 12
The main recommendations from the Global Conference
on One Health held in Spain in May 2015 by the World
Veterinary Association (WVA) and the WMA included
the need to increase cross-disciplinary collaboration
between the veterinary and medical professionals in
order to improve both human and animal well-being.
Malta Medical Journal
Volume 27 Issue 05 2015
This collaboration should arise at all levels i.e. students
of the veterinary and medical sciences, their respective
associations and also at intergovernmental organisation
levels.13 Greater communication between these
professions at all levels is required to build mutual trust
and lead to better preparedness in cases of threats of
emerging zoonotic diseases.
A few examples of existing One Health
collaborations (being national, transnational or global
partnerships) include those controlling rabies in Bali,
Indonesia; controlling Q fever outbreaks in the
Netherlands; the Human Animal Infections and Risk
Surveillance (HAIRS) group in the United Kingdom;
control of foodborne Salmonella in the European Union,
and the tripartite collaboration formed in 2010 between
the FAO, OIE and WHO listing as their main priorities
the control of Rabies, zoonotic influenza and
antimicrobial resistance. 14 The Centre for Disease
Control and Prevention of the United States of America
(CDC) uses a One Health approach by working with
physicians, ecologists, and veterinarians to monitor and
control public health threats and learning how diseases
spread among the human population, animals and also
the environment.15
Conclusions
In light of the above considerations a number of
questions arise regarding the current state of
collaboration between the medical and veterinary
professions in Malta:
Is there adequate and efficient communication
between the veterinary and medical departments
with regards to food borne and zoonotic diseases?
Are veterinary surgeons and medical general
practitioners adequately informed of any new or
emerging zoonotic disease which may be present on
our islands? A case in point is the outbreak of Qfever on farms detected in 2013 as described by
Bonnici, 2015 in an unpublished thesis entitled
“The presence of Q-fever in ruminants and small
ruminants on the island of Malta and Gozo”. This is
a good example of why collaboration between the
veterinary and medical professions is important
even locally.
Are veterinary and medical students receiving
enough training in detecting zoonotic diseases?
This is especially important due to the fact that it is
now easier for example, for pets and livestock to
travel in the European Union and the veterinarian
might be the first person to identify or suspect a
zoonotic disease such as rabies or brucellosis.
Fortunately Malta has been free from Rabies since
1911 and the last major outbreak of Brucellosis was
in 1996.16 We must therefore ensure that all checks
are in place to maintain freedom from these
diseases.
36
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Is there sharing of information between the
veterinary surgeon treating an animal suffering
from a zoonotic disease and the medical practitioner
of the owner of the animal, since they may also be
at risk?
Likewise, do medical practitioners share
information with veterinarians when they suspect
that a zoonotic disease may have been transmitted
from the owner’s pet?
Are there systems in place whereby notification of
zoonotic diseases can be shared by both the
veterinary and medical profession easily and
rapidly?
Should working groups from the Maltese veterinary
and medical professions, via their respective
associations, be organised to tackle the points
mentioned above?
It is not only the medical and veterinary profession
who should be involved in the One Health concept.
Morner, Fishcher and Bengis, 2014, report that several
non-governmental organisations (NGOs) which are
involved with the study and care of wildlife can also
collaborate in the One Health concept through disease
monitoring and assisting in field studies, since in many
cases their members have very good knowledge of the
local environment. They are also involved in educating
their members and the public in general. 17 Local
examples of such NGOs include BirdLife Malta and
Nature Trust Malta. Communication between
veterinarians working in the veterinary public health
sector and medical professionals dealing with public
health is very important. Effective communication at this
level is the first step towards increasing the collaboration
between the two professions thus limiting the risk of
introduction and spread of epidemic or epizootic
diseases on the Maltese islands.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
References
1.
2.
3.
4.
5.
Wildlife Conservation Society. One World - One Health
[updated 2004; cited July
2015]. Available from:
http://www.wcs.org/conservation-challenges/wildlifehealth/wildlife-humans-and-livestock/one-world-onehealth.aspx.
FAO, OIE, WHO, UNSIC, UNICEF, The World Bank.
Contributing to One World, One Health: A Strategic
Framework for Reducing Risks of Infectious diseases at the
Animal-Human-Ecosystem Interface 2008.
Jones K, Patel N, Levy M, Storeygard A, Balk D, Gittleman J,
Daszak P. Global Trends in Emerging Infectious Diseases.
Nature 2008;451(21):990-994.
Taylor L, Latham S, Woolhouse M. Risk factors for human
disease emergence. Philosophical Transactions - Royal Society.
Biological Sciences 2001; 356(1411):983-989.
McConnell I. One health in the context of medical and
veterinary education. Scientific and Technical Review
2014;33(2):651-657.
Malta Medical Journal
Volume 27 Issue 05 2015
17.
Nabarro D, Wannous C. The potential contribution of livestock
to food and nutrition security: the application of the One Health
approach in livestock policy and practice. Scientific and
Technical Review 2014;33(2):475-485.
FAO. How to feed the world in 2050 [updated 2009; cited July
2015]. Available from:
http://www.fao.org/fileadmin/templates/wsfs/docs/expert_paper/
How_to_Feed_the_World_in_2050.pdf.
European Union External Action. Health [updated 2015; cited
July 2015] available from: http://www.eeas.europa.eu/health/.
Maller C, Townsend M, Pryor A, Brown P, St. Leger L.
Healthy nature health people: 'contact with nature' as an
upstream health promotion intervention for populations. Health
Promotion International 2006;21(1):45-54.
Nuttall I, Miyagishima K, Roth C, de La Rocque S. The United
Nations and One Heatlh: the International Health Regulations
(2005) and global heatlh security. Scientific and Technical
Review 2014;33(2):659-668.
Decker D, Leong K, Evensen D. Perceptions of wildlifeassociated disease risk: a challenge or opportunity for "One
Health" in national parks? Proc. 2009 George Wright Society
Conference Michigan 2009;101-106.
World Medical Association (WMA). World Medical
Association Resolution on Collaboration between Human and
Veterinary medicine [updated 2008; cited July 2015]. Available
from:
http://www.wma.net/en/30publications/10policies/v2/index.htm
l.
World Veterinary Association/World Medical Association.
WVA/WMA Global Conference on One Health, Drivers
towards One Health, Strenghtening collaboration between
Physicians and Veterinarians. Madrid [updated 2015; cited
August
2015].
Available
from:
http://www.worldvet.org/uploads/news/docs/gcoh_report_may
_2015.pdf.
Vandersmissen A, Welburn S. Current initiatives in One
Health: consolidating the One Heatlh Global Network.
Scientific and Technical Review 2014;33(2):421-432.
Centers for Disease Control and Prevention. Centers for
Disease Control and Prevention, One Health [updated 2013;
cited
July
2015].
Available
from:
http://www.cdc.gov/onehealth/index.html.
World Organisation for Animal Health. World Animal Health
Information Database (WAHID) Interface. [updated 2014; cited
August
2015].
Available
from:
http://www.oie.int/wahis_2/public/wahid.php/Countryinformati
on/Animalsituation.
Morner T, Fischer J, Bengis R. The value of increasing the role
of private individuals and organisations in One Health.
Scientific and Technical Review 2014;33(3):605-613.
37
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Article
Hypopituitarism following Traumatic Brain
Injury
Carol Attard, Sandro Vella
Abstract
Traumatic brain injury (TBI) is a worldwide public
health problem and an important cause of
hypopituitarism.
The incidence of hypopituitarism
following moderate to severe TBI varies in different
studies and may occur as multiple or isolated hormonal
deficiencies, with gonadotrophin and growth hormone
insufficiencies predominating, particularly in the acute
setting. Adrenocorticotropic hormone deficiency is also
common during the recovery phase. Pituitary function
assessment in the acute phase post TBI is subject to
multiple caveats and pitfalls due to hormonal alterations
which occur as normal physiological responses to
critical illness and the effects of drugs that are used in
the intensive care unit. Nonetheless, assessment of the
hypothalamo-pituitary-adrenal axis is of paramount
importance during this period.
Predictors of
hypopituitarism during the acute phase of TBI remain
unclear - further research is warranted.
Keywords
Traumatic
brain
injury,
hypopituitarism,
pathophysiology, incidence, assessment.
Carol Attard MD, MRCP (UK)*
Diabetes and Endocrine Centre,
Mater Dei Hospital,
Msida, Malta.
Department of Medicine,
University of Malta
Medical School,
Msida, Malta
carol-diane.attard@gov.mt
Sandro Vella MSc (Roehampton), MD (Dundee), MRCP
(UK)
Diabetes and Endocrine Centre,
Mater Dei Hospital,
Msida, Malta.
Department of Medicine,
University of Malta
Medical School,
Msida, Malta
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 04 2015
Introduction
Traumatic brain injury (TBI) is a major public
health problem worldwide as it is the principal cause of
death and disability among young adults, resulting in
physical, emotional, social, cognitive and behavioural
impairments, leading to poor quality of life. 1-3 The most
common causes of TBI include motor vehicle accidents,
violence, sport injuries, falls and child abuse. Children
younger than 4-5 years of age, young adults (aged 15-24
years) and the elderly (older than 65 years of age) are the
age groups most at risk.2-3
Hypopituitarism is becoming an increasingly
recognized complication following TBI, ranging from
total to isolated deficiencies.2 It can occur in the acute,
post-acute recovery or chronic phase (after 1 year).
Prevalence of hypopituitarism varies widely between
studies, possibly due to differences in inclusion criteria,
dynamic tests employed, timing of testing post TBI and
choice (if any) of confirmatory tests following
identification of abnormal results. 1 A pooled prevalence
of 27.5% was reported in a systematic review evaluating
pituitary function 3 months to 7 years post-TBI. Patients
suffering from severe TBI had a higher incident rate of
hypopituitarism compared with those sustaining mild or
moderate injury.4
Hypopituitarism post TBI is a
dynamic process1,4, in which adrenocorticotropic
hormone (ACTH) deficiency can represent a lifethreatening pathology, particularly during the acute
phase.
Methods
We performed a Medline/Trip database search to
identify relevant studies or systematic reviews on this
topic. Search terms used were the various combinations
of
'traumatic
brain
injury/'head
injury'/'brain
injury'/'trauma'/'injury’,,'pituitary'/'hypopituitarism'/'pitui
tary dysfunction', ‘pathophysiology’ and ‘assessment’.
The search was conducted in December 2014. Case
reports, case series and non-original research
publications were not included. Articles were included
regardless of the date of publication.
Pathophysiology
Primary injury may lead to hypothalamo-pituitary
dysfunction by direct mechanical damage to the pituitary
gland, pituitary stalk and hypothalamus (table 1). The
pituitary gland is particularly vulnerable to mechanical
38
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Review
Article
injury/swelling as it lies within the confined space
between the sella turcica and diaphragma sella, and is
joined to the hypothalamus by a stalk.5 The
hypothalamo-pituitary axis may also suffer from
secondary injury through multiple mechanisms (table 1).
Of note, if the stalk is damaged at the point of
attachment to the hypothalamus leaving the rest of the
stalk and its vessels intact, anterior pituitary infarction
does not occur.3
Table 1: Mechanisms of hypothalamo-pituitary injury.2-3, 5, 7, 26
Type of injury
Mechanism
Primary injury
- Fractures through sella turcica/skull base
- Rotational/shearing injuries (including rupture of pituitary stalk)
- oedema
Secondary injury
- skull fracture
- haemorrhage
- oedema/brain swelling
- raised intracranial pressure
- hypotension
- anaemia
- hypoxia
- inflammatory
- vasospasm
- thrombosis
-reperfusion injury
-denervation (supraoptic and paraventricular nuclei, pituitary stalk or axon terminals in
the neurohypophysis, leading to diabetes insipidus)
- inflammatory mediators (e.g. nitric oxide, cytokines, free radicals, N-methyl-Daspartate)
-autoimmunity (anti-pituitary antibodies)
Following an ischaemic insult, re-perfusion causes
excitotoxicity and oxidative stress which, along with the
surrounding inflammation, leads to neuronal cell death
through necrosis or apoptosis. 6
Acute hormonal
deficiencies, particularly growth hormone (GH)
(involved with vascular tone and brain repair processes)
and insulin-like growth factor-1 (IGF-1) (important for
myelination and prevention of oligodendrocyte
apoptosis) may adversely affect repair after TBI.
Recurrent mild TBI e.g. contact sports, effects of
sedative/anaesthetic agents (such as etomidate and
propofol) and the stress of critical illness (transiently
suppressing the hypothalamo-pituitary axis) are other
mechanisms
leading
to
hypothalamo-pituitary
dysfunction.5
Dysfunction/infarction of the posterior pituitary is
less common than that of the anterior pituitary. This is
because vascularisation of the posterior pituitary derives
from the short/inferior hypophyseal vessels (arising
below the diaphragma sella), while the anterior
pituitary’s blood supply, namely the long hypophyseal
vessels (arising from the subarachnoid space and
Malta Medical Journal
Volume 27 Issue 04 2015
traversing the diaphragma sella) and portal capillaries in
the pituitary stalk, are far more susceptible. Moreover,
somatotrophs and gonadotrophs, located in the lateral
regions of the anterior pituitary (vascularised by the long
hypophyseal vessels), are much more susceptible to
damage than the medially located corticotrophs and
thyrotrophs (vascularised by short hypophyseal
vessels).2,5
The syndrome of inappropriate anti-diuretic
hormone secretion (SIADH) may develop secondary to
cytokine (especially interleukin-6) induced stimulation
of vasopressin release.7 Diabetes insipidus (DI) occurs
if the posterior pituitary gland becomes denervated
secondary to injury to the paraventricular and supraoptic
hypothalamic nuclei, pituitary stalk or axon terminals in
the neurohypophysis. Additionally, reversible DI may
complicate transient inflammatory oedema surrounding
the hypothalamus and the neurohypophysis. 3
Incidence of Hypopituitarism in the acute and
recovery phase of moderate to severe TBI
In the acute phase of moderate to severe TBI, Agha
39
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Article
A et al reported that 80% of patients suffered from
gonadotrophin deficiency, 18% had GH deficiency, 16%
glucocorticoid deficiency, 2% thyroid stimulating
hormone (TSH) deficiency8-9, while cranial DI occurred
in 26%.9 DI occurred in 22 out of 102 consecutive
patients presenting with TBI.10 In a study by Tanriverdi
et al, 56.5% of individuals had at least one axis affected
in the acute phase. 36.9% had isolated hormonal
dysfunction, 19.6% suffered from combined hormonal
deficiencies, while none had panhypopituitarism. These
authors reported no significant difference in anterior
pituitary hormone levels between individuals with mild,
moderate and severe TBI in the acute phase, with the
exception of total testosterone, which was much lower
among those suffering from severe injury. The most
common deficiencies were gonadotrophin deficiency
(41.6%) followed by GH deficiency (20.4%). 11
The reported incidence of hypopituitarism in the
recovery phase post moderate to severe TBI varies in
different studies, as summarised in table 2. In a study by
Bondanelli et al, 30.5% had at least one pituitary axis
affected and 1.4% suffered from panhypopituitarism. 12
There was no association between
incidence of
hypopituitarism and severity of TBI in some studies 6,1213
, while an association was noted in others. 10, 14 GH and
gonadotrophin deficiencies predominated in some
studies 6,12, while ACTH and gonadotrophin deficiencies
predominated in others 8,13-14, as outlined in table 2.
The incidence of hypopituitarism in the
chronic/recovery phase post TBI was reported as 35.3%
following severe TBI and 10.9% following moderate
TBI in a systematic review.4 New onset deficiencies
were seen within the first six months (particularly
ACTH deficiency), but not subsequently. In most
instances, there was a tendency towards amelioration in
pituitary function with time4,8, with the majority of
patients
showing
complete
recovery
of
hyperprolactinaemia and the gonadotrophin axis.
Patients with more severe GH and cortisol deficiency
during the acute phase were more likely to remain
deficient in these two hormones during recovery. 8
In a prospective study by Kaulfers et al, moderate
to severe TBI in children was associated with pituitary
dysfunction in 15% of affected individuals at 1-5 weeks,
25% at 2-3 months, 75% at 6 months and 29% at 12
months. Pituitary function generally recovered within a
year of TBI. Pituitary hormonal impairment persisting
thereafter was isolated, with precocious puberty being
the most common (14%), followed by central
15
hypothyroidism (9%) and GH deficiency (5%).
Assessment of pituitary function in the acute phase
post-TBI
Several caveats and pitfalls must be considered when
assessing pituitary function in the acute phase post TBI.
Malta Medical Journal
Volume 27 Issue 04 2015
Anaesthetic drugs (such as etomidate, pentobarbital and
propofol) can induce adrenal insufficiency. Vasopressors
(such
as
dopamine
agonists)
can
cause
hypoprolactinaemia.5 Anticonvulsants, sedatives (such as
midazolam) and narcotic analgesics (such as morphine and
fentanyl) can also affect corticosteroid metabolism or
suppress the hypothalamic-pituitary-adrenal axis.16-17
Hepatic enzyme inducing anticonvulsants, such as
carbamazepine or oxcarbazepine, can decrease circulating
thyroid hormone in 25-50% of patients (TSH remaining
stable) as well as increase the production of sex hormone
binding globulin (SHBG) and/or increase breakdown of
gonadal hormones, leading to low levels of free gonadal
steroids.18
An increase in the stress hormones (GH, ACTH,
cortisol, vasopressin and prolactin) may occur postTBI.18 In polytrauma patients, GH may be normal to
low due to reduced secretory pulse amplitude. 19
However, peripheral GH resistance can occur in critical
illness, leading to high GH and low IGF-1.7 Moreover,
acute illness causes changes in hormone binding
proteins. Alterations in serum albumin and a lowering
of cortisol binding globulin (CBG) concentration occur
in the first week, causing higher circulating levels of free
cortisol albeit a low total cortisol which will not reflect
free and bioavailable cortisol.4,18 High cytokine levels
increase corticosteroid metabolism (lowering free
cortisol levels), decrease corticosteroid receptors and
cause peripheral resistance to glucocorticoids, leading to
‘relative adrenal insufficiency’.19 On the other hand,
metabolism of circulating hormones may be reduced by
damage or decrease in blood flow of organs/tissues
responsible for their metabolism, often leading to higher
circulating levels. Diurnal rhythms are often disturbed. 20
Central hypogonadism and hypothyroidism will
occur in most patients, which may be indistinguishable
from post traumatic central hypothyroidism and
hypogonadism. 18 A drop in tri-iodothyronine (T3) (low
T3 syndrome) is observed due to decreased peripheral
conversion of thyoxine (T4) to T3. T4 and TSH may
remain normal or fall acutely especially following severe
injuries.7, 21
As a result, whether free or total hormone measurements
are taken, interpretation of such measurements is
unreliable in the acute phase of TBI. Moreover, a
standard Synacthen test does not exclude cortisol
deficiency, as the adrenal glands have not yet atrophied
in the acute phase and will respond to exogenous ACTH,
rendering this test dangerously misleading. An insulin
tolerance test (ITT) is relatively contraindicated and
dangerous in this setting due to a risk of inducing
seizures.18, 20
40
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Table 2: Incidence of hypopituitarism in the recovery phase of patients who had suffered from moderate to severe TBI in
different studies.
Study
Time to
testing
Hypopituitarism
affecting at least
one anterior
pituitary
hormone
Isolated
anterior
pituitary
deficiencies
Multiple
anterior
pituitary
deficiencies
Pituitary hormonal deficiencies
GH
FSH/
LH
ACTH
TSH
PrL
DI
Dimopoulou
et al 14
Early
recovery
phase after
weaning
from
mechanical
ventilator
53%
35%
18% ( two
axes
affected)
9%
(partially
impaired
on GHRH
testing)
24%
24%
(post
CRH
testing)
15%
U/A
U/A
Agha et al 8
Agha et al 8
Agha et al 13
U/A
U/A
28.4%
U/A
U/A
22.5%
U/A
U/A
5.9%
13%
10%
10.7%
23%
13%
11.8%
19%
19%
12.7%
2%
2%
1%
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
U/A
6.9%
Popovic et al
6 months
12 months
6-36
months
(median 17
months)
6-36
months
(median 17
months)
1 year
34%
24%
10%
9%
7%
4%
7%
4.5%
Bondanelli et
al 12
6 months
to 1 year
26.4%
19.4%
5.5%
15%severe
deficiency
15%insufficient
14%
14%
4%
4%
U/A
1.4%*
Agha et al 10
6
FSH- Follicle stimulating hormone; LH- Luteinizing hormone; ACTH- adrenocorticotropic hormone; TSH- Thyroid stimulating hormone; PrLProlactin; CRH- Corticotropin releasing hormone; GHRH- Growth hormone releasing hormone; U/A-unavailable *isolated
Since the endocrine response in the acute phase
post TBI is markedly dynamic, taking regular hormonal
measurements is acceptable in a bid to detect evolving
endocrine pathology. However, this approach is likely
to increase the risk of false positive results, rates of
which are influenced by the accuracy of the specific
assay employed for diagnostic purposes. 20 Given that
adrenal insufficiency is life threatening and dynamic
testing is impractical in critically ill patients, daily early
morning cortisol should be measured for the first seven
days following brain injury.3,19 One-off measurements
are unreliable as acute hypopituitarism may be transient,
occur unpredictably in the first seven to ten days after
TBI and may be self-resolving.19 In the absence of any
glucocorticoid supplementation, a morning cortisol of
less than 200nmol/L, is highly indicative of
glucocorticoid insufficiency and the patient should be
given intravenous hydrocortisone. If the early morning
cortisol level lies between 200 and 500nmol/L, and the
patient shows features of adrenal insufficiency a trial of
Malta Medical Journal
Volume 27 Issue 04 2015
glucocorticoid replacement should be initiated. 3-4,8
Other reviews recommend treatment when the morning
cortisol level is below 300nmol/L.1,19 Gonadal, thyroid
and GH assessment in the acute phase is not essential, as
replacing these hormones during critical illness has not
been shown to improve outcomes; moreover any
changes are likely to be adaptive responses to critical
illness.3,19 Cranial DI can be diagnosed using Seckl and
Dunger criteria.22 Similarly, SIADH is diagnosed using
established clinical guidelines.23
Assessment
of
pituitary
function
in
the
recovery/chronic phase
Assessment should commence by taking a complete
history and examination to assess for hypopituitarism
and hyperprolactinaemia. Table 3 demonstrates the
various signs and symptoms associated with
hypopituitarism.
Hyperprolactinaemia may cause
galactorrhoea and symptoms of gonadotrophin
deficiency. A serum sodium and a blood glucose will
41
dRe
Review
Article
help to exclude hyponatraemia and hypoglycaemia
respectively,
as
seen in ACTH deficiency
(hyponatraemia may also be seen in TSH deficiency).
Hypernatraemia or a serum sodium towards the upper
end of normal may be found in DI. Pituitary function
tests should include basal serum 7-9am cortisol (if low,
a serum ACTH should be requested), T4, T3 and TSH
levels, luteinizing hormone, follicle stimulating
hormone, oestradiol and SHBG, prolactin, IGF-1 and
paired urine and plasma osmolalities. A basal cortisol of
less than 100nmol/L indicates adrenal insufficiency,
while more than 400nmol/L indicates adequate function
of the hypothamo-pituitary-adrenal axis. If the basal
cortisol lies between 100 and 400 nmol/L and/or GH
deficiency is suspected, an ITT or glucagon stimulation
test is recommended. GH releasing hormone and the
arginine/GH releasing peptide provocative test constitute
two alternative dynamic tests of GH reserve. Magnetic
resonance imaging should be carried out (unless
organised earlier) if the above tests indicate the
possibility of hypothalamic-pituitary dysfunction.24-25
Table 3: Signs and symptoms associated with the various hormonal deficiencies present in hypopituitarism.2, 21, 27
Hormone deficiency
History
Examination
ACTH
Lethargy, weakness, myalgia,
nausea, anorexia, weight loss
decreased libido, dyspareunia,
amenorrhoea/oligomenorrhoea
Weight gain, cold intolerance,
constipation, fatigue, low mood
Impaired concentration, memory
and cognitive function, low mood,
reduced exercise tolerance
Polyuria and polydipsia especially
nocturnal
Pallor, hypotension
Gonadotrophins
TSH
GH
Vasopressin
Conclusion
The investigation and management of pituitary
dysfunction in the acute phase post TBI remains
challenging, particularly given the paucity of good
quality research data. Well designed studies are needed
to identify possible predictors of permanent
hypopituitarism /pituitary dysfunction, while guiding the
most appropriate timing and dosing of hormonal
replacement in an intensive care/acute setting.
6.
7.
8.
9.
References:
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3.
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5.
Glynn N, Agha A. Which patient requires neuroendocrine
assessment following traumatic brain injury, when and how?
Clin Endocrinol (Oxf). 2013;78(1):17-20.
Richmond E, Rogol AD. Traumatic brain injury: endocrine
consequences in children and adults. Endocrine. 2014;45(1):38.
Behan LA, Phillips J, Thompson CJ, Agha A. Neuroendocrine
disorders after traumatic brain injury. J Neurol Neurosurg
Psychiatry. 2008;79(7):753-9.
Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK,
Agha A. Hypothalamopituitary dysfunction following
traumatic brain injury and aneurysmal subarachnoid
hemorrhage: a systematic review. Jama. 2007;298(12):1429-38.
Dusick JR, Wang C, Cohan P, Swerdloff R, Kelly DF.
Pathophysiology of hypopituitarism in the setting of brain
injury. Pituitary. 2012;15(1):2-9.
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10.
11.
12.
13.
Fine wrinkles, breast atrophy,
paucity of body hair
Dry skin, slow relaxing reflexes,
bradycardia
Central adiposity, reduced lean
mass
Popovic V, Pekic S, Pavlovic D, Maric N, Jasovic-Gasic M,
Djurovic B, et al. Hypopituitarism as a consequence of
traumatic brain injury (TBI) and its possible relation with
cognitive disabilities and mental distress. J Endocrinol Invest.
2004;27(11):1048-54.
Bondanelli M, Ambrosio MR, Zatelli MC, De Marinis L, degli
Uberti EC. Hypopituitarism after traumatic brain injury. Eur J
Endocrinol. 2005;152(5):679-91.
Agha A, Phillips J, O'Kelly P, Tormey W, Thompson CJ. The
natural history of post-traumatic hypopituitarism: implications
for assessment and treatment. Am J Med. 2005;118(12):1416.
Agha A, Rogers B, Mylotte D, Taleb F, Tormey W, Phillips J,
et al. Neuroendocrine dysfunction in the acute phase of
traumatic brain injury. Clin Endocrinol (Oxf). 2004;60(5):58491.
Agha A, Thornton E, O'Kelly P, Tormey W, Phillips J,
Thompson CJ. Posterior pituitary dysfunction after traumatic
brain injury. J Clin Endocrinol Metab. 2004;89(12):5987-92.
Tanriverdi F, Senyurek H, Unluhizarci K, Selcuklu A,
Casanueva FF, Kelestimur F. High risk of hypopituitarism after
traumatic brain injury: a prospective investigation of anterior
pituitary function in the acute phase and 12 months after
trauma. J Clin Endocrinol Metab. 2006;91(6):2105-11.
Bondanelli M, Ambrosio MR, Cavazzini L, Bertocchi A,
Zatelli MC, Carli A, et al. Anterior pituitary function may
predict functional and cognitive outcome in patients with
traumatic brain injury undergoing rehabilitation. J
Neurotrauma. 2007;24(11):1687-97.
Agha A, Rogers B, Sherlock M, O'Kelly P, Tormey W, Phillips
J, et al. Anterior pituitary dysfunction in survivors of traumatic
brain injury. J Clin Endocrinol Metab. 2004;89(10):4929-36.
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Dimopoulou I, Tsagarakis S, Theodorakopoulou M, Douka E,
Zervou M, Kouyialis AT, et al. Endocrine abnormalities in
critical care patients with moderate-to-severe head trauma:
incidence, pattern and predisposing factors. Intensive Care
Med. 2004;30(6):1051-7.
Kaulfers AM, Backeljauw PF, Reifschneider K, Blum S,
Michaud L, Weiss M, et al. Endocrine dysfunction following
traumatic brain injury in children. J Pediatr. 2010;157(6):894-9.
Putignano P, Kaltsas GA, Satta MA, Grossman AB. The effects
of anti-convulsant drugs on adrenal function. Horm Metab Res.
1998;30(6-7):389-97.
Asfeldt VH, Buhl J. Inhibitory effect of diphenylhydantoin on
the feedback control of corticotrophin release. Acta Endocrinol
(Copenh). 1969;61(3):551-60.
Klose M, Feldt-Rasmussen U. Does the type and severity of
brain injury predict hypothalamo-pituitary dysfunction? Does
post-traumatic hypopituitarism predict worse outcome?
Pituitary. 2008;11(3):255-61.
Hannon MJ, Sherlock M, Thompson CJ. Pituitary dysfunction
following traumatic brain injury or subarachnoid haemorrhage in "Endocrine Management in the Intensive Care Unit". Best
Pract Res Clin Endocrinol Metab. 2011;25(5):783-98.
Hassan-Smith Z, Cooper MS. Overview of the endocrine
response to critical illness: how to measure it and when to treat.
Best Pract Res Clin Endocrinol Metab. 2011;25(5):705-17.
Schneider M, Schneider HJ, Stalla GK. Anterior pituitary
hormone abnormalities following traumatic brain injury. J
Neurotrauma. 2005;22(9):937-46.
Seckl J, Dunger D. Postoperative diabetes insipidus. Bmj.
1989;298(6665):2-3.
Wass J, Owen K, Turner H (eds.) Oxford Handbook of
Endocrinology and Diabetes - Oxford Medicine: third edition.
Oxford UK; Oxford University Press; 2014.
Drake WM, Trainer PJ. Appendix: Pituitary Function testing.
In: Harris PE, Bouloux P-MG (eds.) Endocrinology in Clinical
Practice, Second Edition. Boca Raton FL: CRC Press Taylor &
Francis Group; 2014. p561-571.
Ghigo E, Masel B, Aimaretti G, Leon-Carrion J, Casanueva FF,
Dominguez-Morales MR, et al. Consensus guidelines on
screening for hypopituitarism following traumatic brain injury.
Brain Inj. 2005;19(9):711-24.
Zaben M, El Ghoul W, Belli A. Post-traumatic head injury
pituitary dysfunction. Disabil Rehabil. 2013;35(6):522-5.
Monson JP, Chung T-T. Hypopituitarism | Endotext May 9,
2012. Available from:
http://www.endotext.org/chapter/hypopituitarism2/?singlepage=true#toc-clinical-manifestation-ofhypopituitarism.
Malta Medical Journal
Volume 27 Issue 04 2015
43
CasEd
Case
Report
Sudden bilateral loss of vision in a 19-year-old
man
Suzanne Pirotta, Gabriella Sciriha, David Cauchi, James Vassallo,
Thomas Fenech
Abstract
Introduction:
Posterior
Reversible
Leukoencephalopathy Syndrome (PRES) is caused by
ischaemia commonly affecting the posterior cerebral
vasculature. It presents with sudden decreased vision,
headaches, nausea, vomiting, seizures, and altered
mental status.
Case presentation: A 19-year-old male presented to
the ophthalmic emergency complaining of sudden
bilateral loss of vision, which was down to light
perception He reported headaches, nausea, and
drowsiness since the previous day. He was a known case
of hypertension secondary to IgA nephropathy.
Magnetic resonance imaging (MRI) with STIR and
FLAIR sequences showed foci of hyperintensity within
the occipital lobes bilaterally. This confirmed the
suspected diagnosis of PRES.
Suzanne Pirotta
Department of Ophthalmology,
Mater Dei Hospital
Msida
Gabriella Sciriha
Department of Ophthalmology,
Mater Dei Hospital
Msida
David Cauchi
Department of Ophthalmology,
Mater Dei Hospital
Msida
James Vassallo*
Department of Ophthalmology,
Mater Dei Hospital
Msida
jamesvassallo2000@yahoo.com
Thomas Fenech
Department of Ophthalmology,
Mater Dei Hospital
Msida
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 05 2015
Discussion: Aetiological factors of PRES include
sudden increase in blood pressure, eclampsia, porphyria,
renal disease, and Cushing syndrome. These lead to
blood-brain barrier injury either by hyper- or hypoperfusion, endothelial dysfunction, changes in blood
vessel morphology, hypocapnea, or immune system
activation. Histopathological changes in PRES include
activated astrocytes, scattered macrophages and
lymphocytes, often in the absence of inflammation or
neuronal damage.
Conclusion: PRES is usually a reversible neuroophthalmological
condition,
however
prompt
recognition and appropriate management is important to
prevent permanent brain injury or even death.
Keywords
Posterior
Reversible
Leukoencephalopathy
Syndrome, PRES, seizures, occipital lobe, hypertension.
Introduction
Posterior reversible encephalopathy syndrome was
first described by Hinchey et al 1 in 1996. It is caused by
ischaemia, usually due to a sudden increase in blood
pressure commonly affecting the posterior cerebral
vasculature. It presents with headaches, nausea,
vomiting, decreased vision, seizures, and altered mental
status. Other causes of PRES include eclampsia,
porphyria, renal disease, Cushing syndrome and
adrenocortical disease, as well as immunosuppressive or
cytotoxic drugs.1-2
To explain the pathophysiology of hypertensive
PRES two theories have been proposed: 1) Severe
hypertension leading to failed auto-regulation with
subsequent hyperperfusion and endothelial injury
causing vasogenic oedema; 2) vasoconstriction and
hypoperfusion leading to brain ischaemia and
consequent vasogenic oedema. Non-hypertensive PRES
may be due to an immune response to endogenous or
exogenous stimuli.3
PRES is usually a reversible condition, however
prompt recognition and appropriate management is
important to prevent permanent brain injury or even
death.
In this paper we present a case of a young
gentleman with IgA nephropathy who presented with
44
CasEd
Case
Report
sudden, severe, bilateral loss of vision due to PRES.
Case Presentation
In January 2012 a 19-year-old Caucasian male
presented to the ophthalmic emergency with sudden
bilateral loss of vision down to light perception
associated with headaches, nausea, and drowsiness since
the previous day. He had been diagnosed with
hypertension secondary to IgA nephropathy at the age of
16 years and was on perindopril 8mg nocte. An
ophthalmological assessment did not reveal any
abnormality, with normal pupillary reflexes to light and
no fundal pathology. On examination he was agitated
but had no focal neurological signs and a GCS of 15.
His blood pressure was 230/140mmHg, pulse rate was
95bpm, and body temperature was 37˚C. He was
referred to the main A&E department for urgent
medical/neurological review and further management.
Neurological examination showed normal power in all
four limbs, normal sensation, no neck stiffness, and
down-going plantar reflexes. His GCS began to
deteriorate and he suffered two episodes of witnessed
seizures in the casualty department. Complete blood
count, liver function tests, erythrocyte sedimentation
rate, C-reactive protein and coagulation screen were all
normal. His serum creatinine was 328µmol/l and serum
potassium 6. A CT scan of the brain revealed
hypodensities in both occipital lobes (Figure 1).
Figure 1: PRES - Initial axial CT showing occipital
hypodensity
MRI with STIR and FLAIR sequences showed foci
of hyperintensity within the occipital lobes bilaterally
(Figure 2). The rest of the brain was normal.
The patient was admitted to the intensive therapy
unit and was started on intravenous labetolol and
phenytoin. In order to control his hypertension he was
gradually started on calcium channel blockers,
angiotensin receptor blockers, and alpha-agonists. An
echocardiogram showed concentric left ventricular
Malta Medical Journal
Volume 27 Issue 05 2015
hypertrophy and no regional wall motion abnormality.
He also required haemodialysis on several occasions to
control his renal failure. Repeat MRI one month later
showed complete resolution of the vasogenic brain
oedema (Figure 3). This confirmed the suspected
diagnosis of PRES. The patient spent 37 days in the
intensive therapy unit and was fit for discharge two
months after admission.
Figure 2: PRES - Axial view MRI FLAIR showing
occipital hyperintensity
Figure 3: PRES - Axial view MRI FLAIR after 1 month
showing resolution of previous changes
Discussion
The differential diagnoses that have to be
considered when a patient presents with confusion,
headaches, nausea, and/or vomiting, associated with
blurred vision include: PRES, cerebrovascular accidents,
intracranial haemorrhage, space-occupying lesions,
raised intracranial pressure (idiopathic or secondary to
other
pathology),
hypertensive
encephalopathy,
meningitis, encephalitis, and migraine.
PRES is a neurotoxic state which results in a unique
45
CasEd
Case
Report
brain imaging appearance. The basic PRES pattern
shows changes in the cortex, with subcortical and deep
white matter involved to varying degrees. 4-8
Various aetiological factors have been implicated in
the pathophysiology of PRES. These lead to blood-brain
barrier injury either by hyper- or hypo-perfusion,
endothelial dysfunction, changes in blood vessel
morphology, hypocapnea, or immune system
activation.3,9-10
In hypertension-induced PRES, there is failure of
cerebral autoregulation which predominantly affects the
vertebrobasilar system, probably due to sparse
sympathetic innervation of the posterior circulation. As a
result, the parietal and occipital lobes are most
commonly affected.11-12
PRES is also associated with sepsis, usually due to
Gram-positive organisms. In these patients blood
pressure is often normal or only minimally increased. On
imaging, vasogenic oedema is greater in normotensive
patients than in severely hypertensive ones. 13
The autoimmune diseases that have been associated
with PRES include systemic lupus erythematosus,
Wegener’s granulomatosis, systemic sclerosis, and
polyarteritis nodosa. These patients are usually managed
with intermittent courses of immunosuppressants to keep
the disease under control.14-19
PRES is also recognized in patients undergoing
bone marrow or stem cell transplants, especially when
high-dose myeloablative regimens are applied.20-26 It
usually occurs in the first month after allogeneic bone
marrow transplantation, with the rest occurring in the
subsequent year.20,24,26-27 Several PRES-related risks coexist in post-transplant patients. Immunosuppressive
drugs, such as cyclosporine, can induce endothelial
injury that leads to vasoconstrictive effects, increased
sympathetic activation, and coagulation abnormalities. 2833
Effects of chemotherapy and infection in
immunosuppressed patients further contribute to
toxicity.
PRES has also been strongly associated with
toxaemia of pregnancy.34-39 Although blood pressure is
high in the majority of cases, it has also been reported to
be normal in others.40-41
Histopathological changes in PRES include
activated astrocytes, scattered macrophages and
lymphocytes, often in the absence of inflammation,
ischaemia or neuronal damage. Demyelination, neuronal
anoxic damage, laminar necrosis and old haemorrhage in
the white matter and cortex have also been shown to
occur on autopsy.20,42
MRI is the gold standard imaging modality to
diagnose PRES. The commonest findings on MRI are
focal areas of vasogenic oedema in the white matter of
the posterior cerebral hemispheres. These changes are
usually in a watershed distribution.4-8 The medial part of
the occipital lobe is not affected in PRES, therefore
Malta Medical Journal
Volume 27 Issue 05 2015
differentiating it from bilateral posterior cerebral artery
infarcts.43 The aetiological factor of PRES does not seem
to affect the radiological appearance. 44
In hypertension-induced PRES, repeat MRI after
blood pressure control usually shows improvement or
complete resolution of the radiological findings.
Conclusion
The pathophysiology of PRES is not completely
understood. Hypertension with failed autoregulation and
hyperperfusion is the primary theory for the mechanism
of brain oedema.21,45-47 Other mechanisms proposed
include endothelial dysfunction, hypoperfusion, and
vasoconstriction which compromise the blood-brain
barrier. 48-49
The controversies with the hypertensionhyperperfusion theory are highlighted by the absence of
hypertension in 20-40% of patients.8,13,42 And in mild
hypertension, the blood pressure does not typically reach
the limit of autoregulation.50
The outcome of this condition depends on timely
diagnosis and prompt management. Treating the
underlying cause is usually enough to reverse the
condition. However, if the brain insult is prolonged,
irreversible infarction can occur. Cerebral damage is
augmented if haemorrhage and raised intracranial
pressure ensue. 51
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48
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Report
Primary CNS Lymphoma with Intravitreal
Metastasis – using vitreous cavity samples to
monitor response to therapy
Matthew Fenech, Nicola Aquilina, John Grech Hardie, Suzanne Pirotta,
Thomas Fenech, Patricia Debono
Abstract
A fifty-eight year old male patient presented to the
ophthalmic department with a 3 day history of reduced
visual acuity, blurred vision and floaters, associated with
recent lethargy, headaches and behavioural changes.
Fundal examination revealed a bilateral vitritis. Steroid
therapy was started. MRI of the brain revealed multiple
hypodense and hyperdense lesions. Vitrectomy was
performed in view of the poor response to steroids. A
biopsy showed non-hodgkin B-Cell lymphoma. The
patient was started on intravenous Methotrexate and
Cytarabine. Repeat vitreous cavity biopsies were
performed in order to assess response to therapy. All
biopsies to date have revealed evidence of on-going
lymphoma.
Matthew Fenech, MD*
Email: fenech.mat@gmail.com
Nicola Aquilina MD, M. Sc, MRCP (MD)
Department of Neurosciences,
Mater Dei Hospital
Msida
John Grech Hardie MD, FEBO
Ophthalmic Department,
Mater Dei Hospital
Msida
Suzanne Pirotta MD, MRCOphth, FEBO
Ophthalmic Department,
Mater Dei Hospital
Msida
Thomas Fenech MBBS, FRCS, FRCOphth
Ophthalmic Department,
Mater Dei Hospital
Msida
Patricia Debono
Pathology Department,
Mater Dei Hospital
Msida
*Corresponding Author
Malta Medical Journal
Volume 27 Issue 04 2015
Key words
Lymphoma, Vitreal
Methotrexate, Vitrectomy
Metastasis,
Cytarabine,
Background
Primary CNS Lymphoma is a high-grade extra
nodal non-Hodgkin B-cell neoplasm that commonly
masquerades as benign conditions that mimic an uveitislike picture. It is to our knowledge that this is the first
reported case on the Maltese Islands in which vitreal
metastases have occurred. Due to the location of the
lesions, stereotactic brain biopsies were not possible to
perform in order to make a diagnosis. Vitrectomy served
as both a diagnostic and therapeutic tool, where repeat
vitreous cavity biopsies have also been used as a means
of assessing response to therapy. Fortunately, all
samples so far have confirmed the presence of
lymphoma, making vitrectomy the only accurate and
feasible means of assessing prognosis and response to
therapy despite the well-documented poor positive
predictive value of such techniques due to the fragility of
the lymphoma cells in question.
Case presentation
A 58 year old male patient presented to the accident
and emergency department with a three day history of
left sided tunnel vision, distortion, blurring and floaters.
There was no ocular pain or tenderness. Visual acuity on
examination was 6/9 bilaterally. Pupils were reactive
with no relative afferent pupillary defect seen.
Fundoscopy revealed mild vitritis on the right and severe
vitritis on the left. Intra-ocular pressures were 18mmHg
bilaterally.The patient was started on topical steroids.
Review 6 weeks later revealed no change in the
degree of vitritis. There was a quiet anterior segment and
no evidence of retinitis or choroiditis. Visual acuity
remained unchanged.
B scan of the retina was
unremarkable except for a very hazy vitreous. Subtenon
Triamcinolone (Kenalog), with a view for follow up was
given. An MR Brain was done.
Two weeks later, the patient was advised to return
to the emergency department in view of his MR Brain
findings. A thorough history revealed the patient had a
49
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Report
two week history of worsening confusion associated
with weakness, lethargy, headaches and night sweats.
Relatives noted a gradual change in behaviour.
Neurological examination was grossly normal. Repeat
MR Brain on admission to A&E revealed no changes
from the previous MR Brain. Lumbar punctures were
insignificant.
A working diagnosis of lymphoma was made.
Multiple sclerosis was also being considered. A concrete
diagnosis was not possible without histological samples.
The diagnosis was clinched when a left vitreous
body biopsy after a pars plana vitrectomy revealed Blymphocystoid lymphocytes within the vitreous, in
keeping with a high grade diffuse Non-hodgkin B-Cell
lymphoma.
A central line was inserted and the patient was
started on high-dose intravenous methotrexate and
Cytarabine according to the Ferreri Protocol. Repeat
vitreous cavity samples were taken in order to assess the
response to therapy. Unfortunately due to the aggressive
nature of the lymphoma, repeat vitreous biopsies
continued to show evidence of ongoing lymphoma.
Investigations
Slit lamp examination usually reveals vitreous cells
forming clumps or sheets in the posterior segment.
Fundus examination commonly reveals large, multifocal,
bilateral, well-demarcated, yellow-coloured subretinal
infiltrates.1 Unfortunately no such lesions were seen in
this case (Fig 1).
Figure 1: Fundoscopy: Posterior segment photo showing hazy vitreous with poor fundal details
Figure 2: MR Brain: (A) Axial Diffusion Weighted Image (DWI) showing restricted diffusion predominantly in the frontal
areas (B) Axial T2FLAIR showing white matter hyperintensities (C) Axial T1 with contrast showing enhancement of the
left frontal lesions
Figure 3 - MR Brain at the level of the thalami: (A) Axial T2 FLAIR (B) Axial T1 with contrast showing a 1.5cm
enhancing lesion in the right
Malta Medical Journal
Volume 27 Issue 04 2015
50
CasedRe
Report
Fluorescein
angiography
may
show
hypofluorescent or hyperfluorescent lesions. 2 No such
lesions were seen in this case.
Ultrasound commonly reveals vitreous debris,
choroidoscleral thickening or chorioretinal lesions. 3 No
lesions were found on US examination.
Baseline blood investigations such as CBC, CRP,
ESR, routine blood biochemistries as well as a CXR
were found to be within normal limits.
MRI revealed hyperdense lesions in T1-weighted
images and hypodense lesions within deep structures of
the brain when using T2-weighted sequencing (Fig 2-3).3
Lymphoma cells may also be identified in the
cerebrospinal (CSF) fluid in 25 % of cases. Lymphoma
cells are usually large and pleomorphic with a scanty
basophilic cytoplasm. 4 No cells were isolated when
lumbar punctures were performed.
Cytometry with Cytospin preparation was carried
out using Wescor Stainer, while the remaining sample
was used for Flow Cytometric (FC) analysis. The cells
were stained with the following fluorochrome-labelled
monoclonal antibodies: CD20FITC, CD19APC,
CD10PE, CD22APC, CD79a, CD138, CD38, CD5FITC
CD4PE, CD8FITC, CD3APC and CD45PerCP.
Examination of the cytospin preparation showed the
presence of a homogenous cell population composed of
medium to large sized plasmacytoid cells with scanty
and bluish cytoplasm. (Fig 4).FC evaluation showed a
population of cells with moderate expression of CD45
and low Side Scatter. When gated on the cell population
the cells showed weak positivity to B-cell markers
CD19, CD20 and CD38, moderate positivity to CD22
and CD79a and light chain restriction with strong
positivity to Lambda but no expression of Kappa light
chain. CD10 was negative. All T-cell markers, CD5,
CD3, CD4 and CD8 were negative thus ruling out T-cell
phenotype and also CD138 showed lack of positivity
excluding a plasmacytoid malignancy.
Figure 4: Cells show medium expression of CD45 and moderate Side Scatter
Treatment
The initial management on presentation included
the use of high dose steroids. Unfortunately there was no
response and no change in the degree of vitritis.
On confirmation of the diagnosis the patient was
started on high-dose intravenous methotrexate and
Cytarabine according to the Ferreri Protocol. Repeat
vitreous cavity samples were taken in order to assess
response to therapy. Unfortunately, owing to the
aggressive nature of the lymphoma, biopsies showed
evidence of on-going lymphoma.
Maintenance treatment was alerted from a monthly
dose of methotrexate to a biweekly regimen. The
combined use of MTX and radiation has been shown to
decrease recurrence rates. However, it is associated with
a
60%
risk
of
developing
dementia
or
leukoencephalopathy. Such therapy is currently being
considered.
Outcome and follow up
Follow up is crucial, usually undertaken on a
monthly basis with repeat MRI examination or CSF
analysis from lumbar puncture. The following may
Malta Medical Journal
Volume 27 Issue 04 2015
constitute a failure in treatment:
Greater than 25% enlargement of previous areas of
gadolinium-contrast enhancement
Appearance of new contrast-enhancing lesions
Appearance of malignant cells in the CSF or
vitreous if not previously present
If treatment does in fact fail, there are several
options that may be used. Initially, maintenance
treatment may be altered from a monthly dose of
methotrexate to a biweekly regimen. Radiation therapy
may be implemented, often being the best second-line
anti-PCNSL treatment. One may also attempt
combination therapy. The combined use of MTX and
radiation has been shown to decrease recurrence rates.
Intravitreal methotrexate is also an option. This however
is not being considered as of yet due to the uncertainty
of any long term benefits keeping the aggressive and
recurrent nature of the lymphoma in question.
A vitrectomy was planned and performed on the
accompanying eye. Vitreous biopsy also revealed
evidence of lymphoma metastasis.
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Report
Repeated vitreous cavity samples are being taken in
order to assess response to the Ferreri Protocol
implemented. Unfortunately, due to the aggressive
nature of the lymphoma, response has been poor.
Repeated samples have shown evidence of ongoing
disease.
Repeat MRIs did not show marked regression of the
lesions. That being said, the patient is clinically stable
and has not suffered any set backs. Regular neurological
outpatients follow up showed no new focal or
widespread neurological deficit.
Discussion
PCNSL accounts for about 4-6% of all primary
brain neoplasms and 2% of all extranodal lymphomas. 5
It occurs mostly in patients aged between 50-60 years
Ocular dissemination occurs in 15-25% of patients being
bilateral in 80% of cases. 6
The average duration of symptoms prior to
diagnosis is usually 3 months. PCNSL with intra-ocular
involvement commonly presents in older patients with a
non-specific chronic uveitis like picture which is
unresponsive to topical and systemic corticosteroid
treatment.
Ocular symptoms tend to precede cerebral
symptoms by months or years in many cases. 7
Behavioural change is the most common neurological
symptom at presentation, occurring in 25-75% of
patients. 8 Initial assessment of MR Brain favoured a
demyelinating or inflammatory pathology. This was
excluded after repeat MR Brains showed no significant
interval change.
Adequate management and treatment of such
patients is dependent on early, accurate and timely
diagnosis. Corticosteroids must be avoided during the
initial workup and management because their
administration may have a direct antitumor effect.
Similarly, corticosteroids should be avoided during
chemotherapy as they stimulate repair of the blood-brain
barrier, decreasing the delivery of methotrexate into the
brain parenchyma. 9
The mainstay of treatment is chemotherapy.
However, the main difficulty with using chemotherapy
is the blood-ocular barrier. 10 Studies show that systemic
high dose chemotherapy resulted in relatively low drug
levels in the vitreous, implicating the importance to focal
ocular treatment. 11 Studies also show that intrathecal
MTX may also be beneficial when combined to systemic
MTX treatement. 12
It is crucial that ocular disease is seen to because if
left untreated, it may act as a reservoir of persistent
active disease. 13 Intravitreal MTX is able to maintain
cytotoxic levels in the vitreous for hours as opposed to
systemic MTX, also resulting in less complications.
Intravitreal MTX has not been initiated in the patient in
question but is being discussed as the next possible
Malta Medical Journal
Volume 27 Issue 04 2015
option in management.
While intravitreal MTX should be added to the
standard systemic chemotherapy regimen, ocular
treatment simply appears to improve local control, but
has no proven long term survival benefit. 14
Unfortunately, prognosis remains poor, commonly
as a result of the high degree of recurrence and late
diagnosis. 15
Learning points/take home messages
1. CNS lymphoma with vitreal metastasis may easily
masquerade as a benign uveitis.
2.
Lymphoma should be one of the differential
diagnosis in cases of uveitis resistant to steroid
treatment.
3.
A multidisciplinary approach to patient care and
management is vital in the proper follow up and
treatment of such cases. Adequate co-operation
between the ophthalmic and neurological
department was necessary.
4.
Vitreous samples should be handled with care to
protect fragile lymphoma cells. Unfortunately, 40%
of vitrectomy specimens remain non-diagnostic
after corticosteroid use as they are cytolytic to
lymphoma cells.
5.
A multidisciplinary team is essential. Neurological
and ophthalmic follow up must be accompanied by
adequate oncological input in order to keep up to
date with the attest chemotherapeutic protocols and
guidelines. Social services also play a role in
making sure the patient is comfortable and is
making use of all the services available.
Patient’s perspective
“Things happened very fast. Treatment was started
straight away but it was not the best treatment. More
tests were needed to finalize the diagnosis. I was happy
with the way I was treated and I thank everyone for
taking care of me. I worry because I am always in and
out of hospital and I can never get rid of this condition. I
underwent a vitrectomy in my other eye in order to help
with the hazy vision. To be honest, my vision was the
most important issue and had it not been for that, I do
not think we would have started to treat my cancer
condition so early because I felt fine.”
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