We thank Cheng and Tham for their interest in our systematic review
of global variations and time trends in primary open angle glaucoma
(POAG).[1] The comments raise some important issues relating to the
assimilation of evidence from observational studies, particularly in
summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resu...
We thank Cheng and Tham for their interest in our systematic review
of global variations and time trends in primary open angle glaucoma
(POAG).[1] The comments raise some important issues relating to the
assimilation of evidence from observational studies, particularly in
summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resulted
in us having a greater number of studies, number of POAG cases and
population denominator, and led to more precise estimates of POAG
prevalence compared to their earlier review.[2] The purpose of our more
complex approach was to explicitly model and quantify the heterogeneity
between population surveys, which used different survey methods and case
definitions of POAG. By quantifying these differences we are able to
provide estimates of POAG prevalence standardised to studies which use
optimal methods, i.e., that did not rely on intraocular pressure and
routinely performed visual field assessments on all participants, while
allowing studies with suboptimal methods to contribute to overall
estimates by accounting for the differences in study methods. This is
particularly important when attempting to appreciate time trends in POAG,
given changes in study methods over time. Moreover it allows greater
global representation of studies, allowing more recent studies,
particularly from less developed countries often with suboptimal methods,
to contribute. This would not have been the case if a more exclusive
approach had been adopted.
Cheng and Tham also raise the issue of examining response rates.
However, we examined differences in response rates in our earlier
review,[3] and found that these had little effect on our prevalence
estimates. We acknowledge in the paper the difficulty of extracting
response rates, as these are not routinely reported, and sometimes
confused with participation rates, i.e., the number who took part and
completed an examination out of those who agreed to take part. In general,
our experience is that assessment of study quality of observational
studies is complex, compared to established methods in experimental
studies. Attempts were made to judge the quality of studies on criteria
such as response rates and methods used. However, it is difficult to
extract measures of study quality in a meaningful way; for example well-
designed studies may have low response rates. Our experience suggests that
subjective assessments of study quality can sometimes be arbitrary and may
not capture characteristics which may influence the outcome of interest.
Hence, we have chosen an approach which seeks to understand variability by
explicitly modelling differences in study methods. We believe that this
makes for a fuller assessment, providing evidence based guidance for the
conduct of future studies. For instance, our work suggests that a recent
shift away from routine visual field testing, perhaps as an inadvertent
consequence of recent ISGEO guidelines,[4] may have artefactually
influenced prevalence estimates; such an effect would not have been
identified and quantified by a more exclusive approach.
Cheng and Tham also question whether our more inclusive strategy may
have led to lower global estimates of POAG prevalence; 2.2% (95% CrI 1.8%
to 2.8%) in our study [1] versus 3.1% (1.7% to 5.3%) in their earlier
review.[2] However, we would like to point out that these estimates are
not dissimilar, with our more precise estimate being encapsulated within
the much wider confidence interval of their earlier estimate.[2] That our
estimate is marginally lower may in part be attributable to our different
ethnic/regional categorization of studies, particularly amongst Asians.
The earlier review simply treated Asians as one population.[2] However, we
found evidence suggesting that the age specific prevalence differed across
Asian populations,[1] which needs to be accounted for when deriving global
estimates, especially given the large population size of Asia. Moreover,
our review includes more recent studies from Asian populations, where POAG
numbers are high given the large population, but age-specific prevalence
is actually lower compared to other ethnic groups. We feel that our
modelling approach is justified and provides an important corrective to
earlier work. For example, the earlier review suggested urban-rural
differences in disease prevalence,[2] where we showed no effect as urban-
rural associations were inextricably linked to ethnicity and the ethnic
specific associations with age.[1]
We hope that these estimates provide greater certainty and
transparency so we understand how the global and regional estimates of
POAG prevalence are derived. Greater precision allows for more accurate
and appropriate planning of health care service needed to care for those
with the condition. We also believe that our work will assist with the
design of future population based studies, which seek to describe the
population prevalence of glaucoma.
Authors: Dr Alicja R Rudnicka,* Dr Venediktos V Kapetanakis,* Miss
Michelle P Y Chan,# Professor Paul J Foster,#** Professor Derek G Cook,*
Professor Christopher G Owen
*Population Health Research Institute, St George's, University of
London, Cranmer Terrace, London, SW17 0RE, UK
#Division of Genetics and Epidemiology, UCL Institute of
Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
**NIHR Biomedical Research Centre Moorfields Eye Hospital NHS
Foundation Trust, 162 City Road, London EC1V 2PD, UK.
References:
1. Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR.
Global variations and time trends in the prevalence of primary open angle
glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol
2015.
2. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global
prevalence of glaucoma and projections of glaucoma burden through 2040: a
systematic review and meta-analysis. Ophthalmology 2014; 121(11):2081-
2090.
3. Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in
primary open-angle glaucoma prevalence by age, gender, and race: a
Bayesian meta-analysis. Invest Ophthalmol Vis Sci 2006; 47(10):4254-4261.
4. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and
classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;
86(2):238-242.
We read with interest the article by Kapetanakis et al.[1] The
authors presented a systemic review of published population-based surveys
to provide estimates of global and regional prevalence of primary open-
angle glaucoma (POAG). The authors claimed that this review provided the
most precise estimates of POAG prevalence thus far, as they adopted a more
"inclusive" approach, compared to previous re...
We read with interest the article by Kapetanakis et al.[1] The
authors presented a systemic review of published population-based surveys
to provide estimates of global and regional prevalence of primary open-
angle glaucoma (POAG). The authors claimed that this review provided the
most precise estimates of POAG prevalence thus far, as they adopted a more
"inclusive" approach, compared to previous review.[2] As a result of this
inclusive approach, more publications were included in this review with
greater total number of cases and participants, and thus the authors
believed that these estimates provided greater certainty compared to
previous reviews.[2 3]
Nevertheless, while an 'inclusive' approach adopted in this review
generated a 'seemingly' more precise estimate (slightly narrower credible
intervals), it may not necessarily provide estimates which 'accurately'
reflect the trends of POAG prevalence. This is mainly because, the review
also included older studies with improper definition/ diagnosis of POAG
which used raised IOP (i.e. greater than 21mmHg) as a key diagnostic
criterion for POAG. It has been widely recognized that using IOP as a
diagnostic criterion is not appropriate and may miss POAG cases with lower
levels of IOP.[4] This point has also been reiterated and acknowledged by
the authors themselves in the manuscript. Furthermore, in Table 2, the
authors showed that reliance on IOP in POAG diagnosis was associated with
lower POAG prevalence. This finding befittingly concurs with the point
that studies which used IOP as a diagnostic criterion would indeed
underestimate the prevalence of POAG. Thus, inclusion of older studies
with improper POAG definition in the meta-analysis would naturally result
in an underestimated overall pooled estimate despite having a seemingly
narrower range of credible intervals (mainly due to higher number of POAG
cases). This is evident when comparing the global POAG prevalence in this
review (2.2%) with the prevalence estimated in our group's recent meta-
analysis project (3.05%).[2]
The idea to include more studies in order to have 'greater power' but
at the expense of compromised study quality inclusion criteria, is
fundamentally flawed in the context of conducting a reliable meta-
analysis. Estimation errors caused by inclusion of poor quality studies
may not be sufficiently accounted for by using modeling method to adjust
for study design factor. Thus, the authors' claim that 'more precise and
accurate estimates were produced in this review' appears to be
unconvincing and overly stated.
Secondly, response rate was not taken into account when identifying
studies to be included in this meta-analysis. It was noticed that studies
of low response rates (i.e. less than 60% or 70%) were also included in
the analysis. It should be noted that population-based studies with
suboptimal response rate can give rise to sampling bias even though random
sampling method was adopted. Thus, estimates from these studies may not be
accurately representative of their respective underlying populations.
Inclusion of such studies may further introduce error to the overall
pooled estimate. Furthermore, if greater weights were attributed by
studies which relied on IOP diagnostic criterion or by studies with poor
response rate in this meta-analysis, the impact on the overall pooled
estimate would be even greater. With regards to this, a forest plot ought
to be included in this meta-analysis to illustrate the effect size and the
weight rendered by each study. Such illustration with additional
sensitivity analyses (stratified by study design factors or response rate)
may help to further validate or refute the approach adopted in this
analysis.
Taken together, we humbly opine that a more 'inclusive' approach but
without adequate screening of study quality, may not necessarily yield
more accurate estimates. The seemingly more precise estimate (i.e.
slightly narrower credible intervals) was simply due to increase in sheer
number of POAG cases from studies of inadequate quality. Robust and
comprehensive assessments of study quality are central to a valid, high
quality meta-analysis.
Thank you.
References:
1. Kapetanakis VV, Chan MP, Foster PJ, et al. Global variations and
time trends in the prevalence of primary open angle glaucoma (POAG): a
systematic review and meta-analysis. Br J Ophthalmol 2015.
2. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and
projections of glaucoma burden through 2040: a systematic review and meta-
analysis. Ophthalmology 2014;121(11):2081-90.
3. Quigley HA, Broman AT. The number of people with glaucoma
worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3):262-7.
4. Quigley HA. Glaucoma. Lancet (London, England) 2011;377(9774):1367
-77.
We congratulate Holz et al.1 on their most important contribution to
anti-vascular endothelial growth factor therapy in neovascular age-related
macular degeneration (n-AMD).
We think it is important to note that their main finding "visual acuity
improved until about day 120; thereafter visual acuity changes were not
maintained" does not contradict the findings of the MARINA2 [Ranibizumab
Vs sham in...
We congratulate Holz et al.1 on their most important contribution to
anti-vascular endothelial growth factor therapy in neovascular age-related
macular degeneration (n-AMD).
We think it is important to note that their main finding "visual acuity
improved until about day 120; thereafter visual acuity changes were not
maintained" does not contradict the findings of the MARINA2 [Ranibizumab
Vs sham injection] clinical trial.
We have previously re-evaluated3 the published results of the MARINA study
to assess the absolute risk reduction (The absolute difference of outcome
between experimental - i.e. ranibizumab treated - and control participants
in the MARINA trial). This being the approach specified in The ABPI Code
of Practice4 Clause 7; Information, Claims and Comparisons
"Referring only to relative risk, especially with regard to risk
reduction, can make a medicine appear more effective than it actually is.
In order to assess the clinical impact of an outcome, the reader also
needs to know the absolute risk involved. In that regard relative risk
should never be referred to without also referring to the absolute risk.
Absolute risk can be referred to in isolation."
We set out in the graph below our evaluation of mean letter change from
baseline (visual acuity change) derived from MARINA Figure 2 A results
page 14262. The published change in letter score is at 3 month intervals
rather than for each monthly injection as our efforts to acquire the raw
data from the authors of the MARINA study2 have been unsuccessful.
The best we can do is to show the letter change for the ranibizumab
treated patients (we have confined our analysis to 0.5 mg group) letter
score is in green, sham injection is in blue and the difference between
the groups is in pink - this being the absolute risk reduction at every
time we have data for.
Our re-analysis seemingly confirms Holtz's findings1; ranibizumab is
apparently most beneficial in the initial stages of treatment of n-AMD and
visual gains cease between 3 - 6 months.
Figure 1 -
Green line - Ranibizumab treated patients (0.5mg) - change in letters read
since last injection.
Blue line - Sham-injection treated patients - change in letters read since
last injection.
Pink line - Absolute risk reduction (The arithmetic difference between the
Ranibizumab and sham groups for each 3-monthly time point.)
We note that Holtz and colleagues presented the mean change in visual
acuity score after start of anti-VEGF as their primary endpoints. Our
graph demonstrates the change in visual acuity score since previous visit
and we note the striking resemblance in that both the analysis plots a
very similar graph. While the patient demographics include the various
subsets of n-AMD, we could not find any mention of visual acuity outcomes
for these subset groups of patients. As MARINA showed visual benefits
(stabilization or improvement of letters read) due to Ranibizumab
treatment was achieved in only 27.6% of patients, we ask the authors if
they are able to predict likely responders based on any base-line
characteristics that would distinguish them from non-responders. Also
would the authors be able to share if available their analysis of change
in visual acuity from the previous visit. This could help in the early
identification of those patients unlikely to benefit either prior to
treatment or as the treatment progresses and avoid exposing patients
unlikely to benefit to the risks of treatment.
References
1. Frank G Holz, Ramin Tadayoni, Stephen Beatty et al. Multi-country
real-life experience of anti-vascular endothelial growth factor therapy
for wet age-related macular degeneration.Br J Ophthalmol
doi:10.1136/bjophthalmol-2014-305327
2. Philip J. Rosenfeld, M.D., Ph.D., David M. Brown, M.D., Jeffrey S.
Heier, M.D. et al. for the
MARINA Study Group. N Engl J Med 2006; 355:1419-1431.
3. B. Ramasamy, S Tiew, J Wason, L Clearkin . Absolute Risk
Reduction and Natural Frequencies of Ranibizumab treatment in neovascular
Age-Related Macular Degeneration (nvAMD). Poster and rapid fire
presentation, Oxford Ophthalmological Congress ( 7/7/2015)
4. ABPI Code of Practice for The Pharmaceutical Industry
https://www.bsped.org.uk/resources/docs/ABPIguidelines
Dear Editor;
We have read the article entitled "Amniotic membrane graft to conjunctival
flap in treatment of non-viral resistant infectious keratitis: a
randomised clinical study" by Abdulhalim et al. with interest.1 The
authors compare the results of bipedicle conjunctival flap and
cryopreserved amniotic membrane graft in the treatment of non-viral
infectious keratitis resistant to medical treatment. We want to express...
Dear Editor;
We have read the article entitled "Amniotic membrane graft to conjunctival
flap in treatment of non-viral resistant infectious keratitis: a
randomised clinical study" by Abdulhalim et al. with interest.1 The
authors compare the results of bipedicle conjunctival flap and
cryopreserved amniotic membrane graft in the treatment of non-viral
infectious keratitis resistant to medical treatment. We want to express
our reservation about using amniotic membrane in the acute stage of fungal
keratitis.
The main immune mechanism against fungal keratitis depends on
neutrophils.2 Karthikeyan et al. revealed that neutrophils constitute the
vast majority (90%) of cellular infiltrates in fungus-infected human
corneas.3 In the course of the anti-fungal immune activity reactive oxygen
species secreted through the infected tissues play very critical roles.
Furthermore, the balance between the host oxidant and the fungal anti-
oxidant substances has been studied in order to decrease hyphal survival.
Besides that; the balance between the host oxidant and the fungal anti-
oxidant substances has lately been discussed to be targeted for
diminishing hyphal survival.2
On the other hand, Lockington et al. recently reported that amniotic
membrane can scavenge reactive oxygen species because of abundant
hyaluronic acid.4 Besides, amniotic membrane may suppress immune defense
by absorbing live inflammatory cells into its stroma and force them to
apoptosis.5 Therefore, we suppose that antioxidant and anti-inflammatory
properties of amniotic membrane could be objectionable during the acute
phase of fungal keratitis in which fungicidal activity is essential. We
propose that amniotic membrane transplantation should be delayed until the
infection is limited to a certain location.
We read with great interest the study" Recovery of photoreceptor
inner and outer segment layer thickness after reattachment of
rhegmatogenous retinal detachment" by Terauchi G, et al.[1] Authors
concluded that thickness of inner segment layer (20.4 +/- 5.0 microns) at
one month after surgery was significantly less than fellow eye (28.9 =/-
2.9 microns). However, we know that the axial resolution of Spectral
Domain(SD)...
We read with great interest the study" Recovery of photoreceptor
inner and outer segment layer thickness after reattachment of
rhegmatogenous retinal detachment" by Terauchi G, et al.[1] Authors
concluded that thickness of inner segment layer (20.4 +/- 5.0 microns) at
one month after surgery was significantly less than fellow eye (28.9 =/-
2.9 microns). However, we know that the axial resolution of Spectral
Domain(SD)-OCT is approximately 5 microns i.e. one pixel on the scan image
would represent for 5 microns. This would lead to a difference between the
outer segment measurements in operated eye and fellow eye in the range of
1-2 pixels, leaving very little room for error. Although, coefficient of
repeatability for total macular thickness in Diabetic Macular Edema was
found as high as 9 micron.[2] The measurement error and coefficient of
repeatability of outer segment and inner segment measurements using SD-OCT
is still not known. Keeping this in account, would the results still
remain statistically significant? Hence, if measurements were taken by
Adaptive optics-OCT with axial resolution of 3micron[3]there would be
greater reliability of measurements and results compared to SD-OCT
especially considering smaller measurements like outer and inner segment
layer thickness.
We keenly wait authors' reply.
References
1. Terauchi, G., et al., Recovery of photoreceptor inner and outer
segment layer thickness after reattachment of rhegmatogenous retinal
detachment. Br J Ophthalmol, 2015. 99(10): p. 1323-7.
2. Sohn, E.H., et al., Reproducibility of diabetic macular edema estimates
from SD-OCT is affected by the choice of image analysis algorithm. Invest
Ophthalmol Vis Sci, 2013. 54(6): p. 4184-8.
3. Miller, D.T., et al., Adaptive optics and the eye (super resolution
OCT). Eye (Lond), 2011. 25(3): p. 321-30.
The authors have investigated the and compared the chromosome 3
aberrations of Choroidal melanoma (CM) as determined by multiplex ligation
probe amplification (MLPA) or microsatellite analysis (MSA)in intra ocular
tumor biopsies with those results obtained from subsequent
endoresection/enucleation of the same Choroidal melanoma. However few
points need clarification from the authors:
1. Since the investigators used few ma...
The authors have investigated the and compared the chromosome 3
aberrations of Choroidal melanoma (CM) as determined by multiplex ligation
probe amplification (MLPA) or microsatellite analysis (MSA)in intra ocular
tumor biopsies with those results obtained from subsequent
endoresection/enucleation of the same Choroidal melanoma. However few
points need clarification from the authors:
1. Since the investigators used few markers on chromosome 3, technically
speaking the use of the word "Monosomy" is not appropriate to describe
the generic findings. This is at best can be called "Partial monosomy" or
even better, just describe the chromosome 3 locations of the deletions or
chromosome 8 duplications.
2. There are better genetic techniques currently available to detect
chromosomal deletions(s) and/or duplication(s) than multiplex ligation
probe amplification (MLPA) or micro-satellite markers. For example, array
comparative genomic hybridization (arrayCGH) high definition can be used
to screen the full genomic for chromosomal abnormalities and even detect
deletion(s) and/or duplication(s) as small as 10 Kb in size. The 100 ng of
DNA which was used by the investigators for MLPA can be easily used for
arrayCGH with small alterations to the protocol. This would make the
results more comprehensive and may able to detect other alterations on
other chromosomes.
3. The use of microsatellite markers to measure chromosomal abnormalities
(duplication or deletion) is not appropriate. Microsatellite markers, if
informative, can give you whether the tested individual is homozygous or
heterozygous for a particular allele. They are not design to give you a
quantitative answer and the peak height cannot be used for quantitative
measure.
4. It will be great if the authors can elaborate on the genes encompassed
in the deleted areas of chromosome-3 and how those genes may contribute to
the development and/or metastatic effect on the melanoma. For example, are
those genes involved in suppressing the tumor? or do they play some other
role ?
5. In Table-2, the authors list 13 patients with Chr3 loss vs. 12 patients
with no chr3 loss, can we actually use the deletion(s) on chr3 as a
genetic marker for choroidal melanoma?
We read the article '3D printed reproductions of orbital dissections:
a novel mode of visualising anatomy for trainees in ophthalmology or
optometry' by Adams JW. et al with great interest. The authors have
successfully identified the need for experience handling and navigating
through anatomical material to understand clinical ophthalmology.
Furthermore, they have brilliantly created a means for th...
We read the article '3D printed reproductions of orbital dissections:
a novel mode of visualising anatomy for trainees in ophthalmology or
optometry' by Adams JW. et al with great interest. The authors have
successfully identified the need for experience handling and navigating
through anatomical material to understand clinical ophthalmology.
Furthermore, they have brilliantly created a means for this teaching to
occur due to the difficulties obtaining cadaveric specimens, and the
similar issues and expense of using plastinated models.
We were particularly interested in the preparation of the orbital
dissections, and the choice of views to optimise the teaching value of the
prosections. In the paper, it is stated quite rightly that 'it is
essential to optimise the number of features displayed' (1). Given the
authors' expertise in recreating the best from the cadaveric specimens to
generate models, we would like the authors' opinion on how best to conduct
an ophthalmic anatomy teaching session for students using approximately
ten cadaveric heads which we will be running next year. What do the
authors think would be the most important teaching aims, and how do the
authors recommend specimens should be approached to maximise educational
effectiveness? Furthermore, other than using techniques outlined in their
paper to create the best views for models, are there any other ways in
which we should take advantage of this privileged access to cadaveric
tissue?
We would very much appreciate some advice and guidance with regards
to this, and once again we commend the authors for this innovative method
of teaching dissection.
References:
1. Adams JW, Paxton L, Dawes K, Burlak K, Quayle M, McMenamin PG, 3D
printed reproductions of orbital dissections: a novel mode of visualising
anatomy for trainees in ophthalmology or optometry, Br J Ophthalmol, 2015;
99(9): 1162-7
Dr. Sagar and colleagues made reference to our paper "Significance of
the Hyperautofluorescent Ring Associated with Choroidal Neovascularization
in Eyes Undergoing Anti-VEGF therapy for Wet Age-Related Macular
Degeneration", and pointed out the fact that they did not find a
statistically significant difference in subretinal fluid (SRF) between
eyes with and without a hyperautofluorescent ring (HAF) i...
Dr. Sagar and colleagues made reference to our paper "Significance of
the Hyperautofluorescent Ring Associated with Choroidal Neovascularization
in Eyes Undergoing Anti-VEGF therapy for Wet Age-Related Macular
Degeneration", and pointed out the fact that they did not find a
statistically significant difference in subretinal fluid (SRF) between
eyes with and without a hyperautofluorescent ring (HAF) in their studied
population.
We would first like to thank Dr Sagar et al. for their interest in
our publication and in this newly reported autoflourescence phenomenon,
which as was mentioned, is quite common among eyes diagnosed with
neovascular AMD. Our rigorous data collection, measurements (including
vertical and horizontal SRF extend, as well as SRF area) and analysis led
to our results showing that the HAF ring had a positive correlation with
baseline subretinal fluid and outer retinal disruption. Similar to their
findings, our study did not show a statistically significant association
with visual acuity.
Despite our thorough research on this topic, we agree that more work
is indicated on this subject to fully understand the meaning and
importance of the HAF ring.
Sincerely,
William R. Freeman, MD
Distinguished Professor and Director
UCSD Jacobs Retina Center
Vice Chairman
Department of Ophthalmology, UCSD
Shiley Eye Center
9415 Campus Point Drive
La Jolla, CA 92093-0946
We thank the authors for their prompt reply and do want to thank them
for this wonderful paper which definitely serves as an excellent
continuing professional development(CPD) module for us and will also be
used by many CPD providers immediately after its publication
But another CPD module one engages in, is the GRADE system. And that
has set me thinking trying to fill my learning gaps and the following is
ju...
We thank the authors for their prompt reply and do want to thank them
for this wonderful paper which definitely serves as an excellent
continuing professional development(CPD) module for us and will also be
used by many CPD providers immediately after its publication
But another CPD module one engages in, is the GRADE system. And that
has set me thinking trying to fill my learning gaps and the following is
just my reflection in an attempt to improve my own understanding and I add
that I realise that I could be completely wrong
The GRADE system can be used to grade the quality of evidence and
strength of recommendations for diagnostic tests or strategies. (BMJ
2008;336:1106) which entails that "Inferring from data on accuracy that a
diagnostic test or strategy improves patient-important outcomes will
require the availability of effective treatment, reduction of test related
adverse effects or anxiety, or improvement of patients' wellbeing from
prognostic information"
Vascular malformations may be single vessel form ( arterial,
capillary, lymphatic or veinous) or combined. Their flow characteristics
may give a clue as to whether there is going to be an involution or not.
The clinical characteristics are also important and Orbital LMs are
reported to cause proptosis in 85%, ptosis in 73%, and restrictive eye
movements in 46% of patients (Tunc M, Sadri E, Char DH. Orbital
lymphangioma: an analysis of 26 patients. Br J Ophthalmol 1999; 83:76 -
80.). There is also a real risk of bleeding in such cases .Hence a
diagnostic modality to be used may include one which gives maximum
information in terms of whether vision can be potentially lost, extra
ocular muscles are involved or not and if one needs to intervene
surgically , then what are the planes involved; in addition to the fact
whether bleeding is already present and in presence of bleeding an
angiography hardly gives any information . One definitely doesn't want to
make the patient spend money over multiple imaging modalities and would
want the modality to be safe and repeatable and the repeat imaging
comparable to look for changes in size ,homogeneity and other issues like
evidence of inflammation, post procedure bleeding or infection and
inflammation.So one tends to do an MRI in my opinion and I agree that it
is open to interpretation since as an ophthalmologist I would love to look
at extra ocular muscle involvement and possibility of amblyopia and would
want to institute therapy based on prognosis which in turn is based on
imaging.. A digital subtraction angiography thus becomes a secondary
investigation which needs to be carefully selected keeping in mind risks
both present and future besides economic considerations of a second test
which is invasive and needs radiation which may potentially cause cancers
We do know that even after meticulous extensive surgical ligation of
feeder , we do get recurrences and also have complications like
perioperative haemorrhage(1) . Both these conditions do need follow up
imaging at times . We have been following the reports of success with
transarterial embolisation and do realise that some authors do a repeat
digital subtraction angiography to check for resolution (2)
We realise that it may not be possible to scientifically conclude
that a modality is a gold standard or the preferred treatment modality
unless we evaluate the resolution of lesions by follow up imaging to prove
that the same imaging shows complete resolution of malformation in the
long term and that would be risky with a digital subtraction angiography
since even the first imaging or treatment is associated with radiation
risks which in itself is under investigation for leukaemia and head
cancers which are projected even for CT scan in childhood
It has been suggested that " Use of CT scans in children to deliver
cumulative doses of about 50 mGy might almost triple the risk of leukaemia
and doses of about 60 mGy might triple the risk of brain cancer" and so ",
radiation doses from CT scans ought to be kept as low as possible and
alternative procedures, which do not involve ionising radiation, should be
considered if appropriate." (3)
The risk of leukemia is reported highest from head scans for
children younger than 5 years of age at a rate of 1.9 cases per 10,000 CT
scans (4)
The dose for digital subtraction angiography can be high (5)
For the imaging of cerebral vessels, the effective dose according to
some authors is calculated as 0.67 mSv for CTAngiography(CTA) and 2.71
mSv for Digital subtraction angiography(DSA) . For the imaging of
cervicocerebral vessels, the effective dose is 4.85 mSv for CTA and 3.60
mSv for DSA. The maximum absorbed dose (milligray) for skin, brain,
salivary glands, and eyes is 166.2, 73.5, 35.6, and 21.8 mGy for DSA and
19.0, 16.9, 20.4, and 14.8 mGy for CTA, respectively.
Various authors have studied risks and projected risks of head
cancer and leukaemia with CT radiation (6) (7) (8)
As early as 2009 it has been estimated that 29000 cancers in future
may be caused due to CT Scan with 4000 cancers due to head CT with this
being more for radiation in children (9)
And so we wonder what would the strategy be, for reimaging , in case
some of these kids do come back with recurrent swelling which may be
inflammatory /infection /haemorrhage or simply recurrence because
inflammation may stimulate lymphatic memory and regrowth (10)
Some authors have looked at the utility of 4 D imaging instead of
repeat DSA even for small recurrences with small flow in brain AVMs (11)
and found that the " diagnostic accuracy of 4D MRA for residual brain
AVM compared with DSA, reached a sensitivity of 73.7%, specificity 100%,
positive predictive value 100%, and negative predictive value 78.3%" (11)
and so I wonder if this can be used to study the residual effects
scientifically over a long term in case repeated imaging is necessary. I
wonder if the GRADES approach is justified herein.
As far as the issue of anemia is concerned ,we know that inequalities
exist in all human societies, even so-called "egalitarian" ones and I
quote an American report that "An estimated 20 percent of American
children will have anemia at some point in their childhood"(12) and
another that states "Most children with mild anemia have no signs or
symptoms" and even the BMJ best practices reports that
"It is estimated that 3% of men and 8% of women in the UK have iron
deficiency anaemia" and that Infants and adolescents have an increased
risk as a result of high demand related to growth spurts besides the fact
that " Microangiopathic hemolytic anemia (MAHA), has also been described
with large capillary hemangiomas of the periocular region'wherein the
erythrocytes are destroyed from coagulation, or are sheared or fragmented
by high pressure forcing them through the abnormally small vessels of the
hemangioma" (13) and unless an imaging is done one doesn't know whether
the mass is a hemangioma or a lymphatic mass and some patients may benefit
from ruling out an anemia at the outset without much damage done in the
process
Besides it was long assumed anthropologically that iron deficiency
anemia has marked effects on the flat bones of the cranium of infants and
young children and that as the body attempts to compensate for low iron
levels by increasing red blood cell production in the young, sieve-like
lesions develop in the cranial vaults (termed porotic hyperostosis) and/or
the orbits (termed cribia orbitalia)(14) and so if one does detect anemia
there may be some reason though not strong enough to keep intracranial
extensions in mind
I guess routine haemoglobin may fit into GRADES considering the low
costs and relative safety in comparison to possible utility , but
considering the issue of cancers with radiation in childhood routine
digital subtraction angiography in every case may still need evaluation
and we are still far away from a sweeping conclusion that sclerotherapy
with digital subtraction angiography in all Paediatric cases should be the
first line of treatment of orbital lymphatic malformations because we
never do repeat angiography to prove resolution and neither are we sure
whether the use of digital subtraction angiography is safe In terms of
projected head and neck cancers and leukaemia which any radiation has the
potential to cause in a child population ,where this condition is
predominant
We agree to the wonderful results presented , but object to the
conclusion of stating that sclerotherapy should be a first line of
treatment of orbital malformations without long term efficacy
scientifically proven by repeat imaging and long term risk of cancers with
radiation associated with this being evaluated and discussed because
sclerotherapy as is mutually agreed is dangerous without a digital
subtraction angiography which being a radiation based modality carries
with it the risks of cancers
References :-
1) Warrier S, Prabhakaran VC, Valenzuela A, Sullivan TJ, Davis G, Selva
D.Orbital arteriovenous malformations. Arch Ophthalmol. 2008
Dec;126(12):1669-75.doi: 10.1001/archophthalmol.2008.501.
2) Sato K, Matsumoto Y, Kondo R, Tominaga T. Intraorbital
arteriovenousmalformation treated by transarterial embolization: technical
case report.Neurosurgery. 2011 Jun;68(2 Suppl Operative):383-7; discussion
387. doi:10.1227/NEU.0b013e31821522ec.
3) Radiation exposure from CT scans in childhood and subsequent risk of
leukaemia and brain tumours: a retrospective cohort study.Pearce, Mark S
et al.The Lancet , Volume 380 , Issue 9840 , 499 - 505)
4) Miglioretti DL, Johnson E, Williams A, Greenlee RT, Weinmann S, Solberg
LI,
Feigelson HS, Roblin D, Flynn MJ, Vanneman N, Smith-Bindman R. The use
ofcomputed tomography in pediatrics and the associated radiation exposure
andestimated cancer risk. JAMA Pediatr. 2013 Aug 1;167(8):700-7.
doi:10.1001/jamapediatrics.2013.311.
5) Manninen AL, Isokangas JM, Karttunen A, Siniluoto T, Nieminen MT. A
comparisonof radiation exposure between diagnostic CTA and DSA
examinations of cerebral and
cervicocerebral vessels. AJNR Am J Neuroradiol. 2012Dec;33(11):2038-42.
doi:10.3174/ajnr.A3123.
6) Mathews John D, Forsythe Anna V, Brady Zoe, Butler Martin W, Goergen
Stacy K, Byrnes Graham B et al. Cancer risk in 680?000 people exposed to
computed tomography scans in childhood or adolescence: data linkage study
of 11 million Australians 2013; 346 :f2360)
7) Huang WY, Muo CH, Lin CY, Jen YM, Yang MH, Lin JC, Sung FC, Kao CH
(2014) Paediatric head CT scan and subsequent risk of malignancy and
benign brain tumour: a nation-wide population-based cohort study. Br J
Cancer 110(9): 2354-2360.
8) Meulepas JM, Ronckers CM, Smets AM, Nievelstein RA, Jahnen A, Lee C,
Kieft M, Lameris JS, van Herk M, Greuter MJ, Jeukens CR, van Straten M,
Visser O, van Leeuwen FE, Hauptmann M (2014) Leukemia and brain tumors
among children after radiation exposure from CT scans: design and
methodological opportunities of the Dutch Pediatric CT Study. Eur J
Epidemiol 29(4): 293-301
9) Berrington de Gonz?lez A, Mahesh M, Kim KP, Bhargavan M, Lewis R,
Mettler F, Land C. Projected cancer risks from computed tomographic scans
performed in the United States in 2007. Arch Intern Med. 2009 Dec
14;169(22):2071-7. doi: 10.1001/archinternmed.2009.440.
10) Kelley PM, Connor AL, Tempero RM. Lymphatic vessel memory stimulated
by recurrent inflammation. Am J Pathol. 2013 Jun;182(6):2418-28. doi:
10.1016/j.ajpath.2013.02.025.
11) Soize S, Bouquigny F, Kadziolka K, Portefaix C, Pierot L. Value of 4D
MR angiography at 3T compared with DSA for the follow-up of treated brain
arteriovenous malformation. AJNR Am J Neuroradiol. 2014 Oct;35(10):1903-9.
doi: 10.3174/ajnr.A3982.
12) Irwin JJ, Kirchner JT. Anemia in children. Am Fam Physician.
2001;64(8):1379-1386.
13) Haik BG, Karcioglu ZA, Gordon RA, Pechous BP. Capillary hemangioma
(infantile periocular hemangioma) Surv Ophthalmol. 1994;38(5):399-426.
14) Walker et al. 2009 "The Causes of Porotic Hyperostosis and Cribra
Orbitalia: A Reappraisal of the Iron-Deficiency-Anemia Hypothesis"
American Journal of Physical Anthropology.
The authors thank Mr Moreker for his letter regarding our series. We
agree that these are often complex cases and that each patient should be
assessed holistically and discussed individually, ideally in a
multidisciplinary setting. We do not check haemoglobin levels in all the
patients referred to us, in part because severe anaemia in otherwise well
children is rare in the UK population, but we agree that this should be...
The authors thank Mr Moreker for his letter regarding our series. We
agree that these are often complex cases and that each patient should be
assessed holistically and discussed individually, ideally in a
multidisciplinary setting. We do not check haemoglobin levels in all the
patients referred to us, in part because severe anaemia in otherwise well
children is rare in the UK population, but we agree that this should be
done pre-operatively in children where anaemia is suspected.
We acknowledge that a proportion of lymphatic malformations demonstrate a
venous component and that it is vital to exclude any intracranial vascular
connections before embarking on the injection of a sclerosing agent. In
our series, contrast was injected into the malformation and digital
subtraction imaging performed in every case prior to injection.
Yours sincerely,
Dr Alex M Barnacle BM MRCP FRCR
Consultant Interventional Radiologist
Great Ormond Street Hospital for Children
London
UK
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