We would like to thank Zaidi et al. for their interest in our
publication titled, "Sustained elevation of intraocular pressure after
intravitreal injections of anti-VEGF agents." [1] As stated in our
publication, we believe anti-VEGF agents revolutionized the treatment of
ocular neovascular disease and their overall safety profile is excellent.
The points by Zaidi et al. are valid and we take this opportunity to
expand...
We would like to thank Zaidi et al. for their interest in our
publication titled, "Sustained elevation of intraocular pressure after
intravitreal injections of anti-VEGF agents." [1] As stated in our
publication, we believe anti-VEGF agents revolutionized the treatment of
ocular neovascular disease and their overall safety profile is excellent.
The points by Zaidi et al. are valid and we take this opportunity to
expand on recent developments related to ocular hypertension (OHTN) post
intravitreal injection of anti-VEGF agents.
Additional evidence has been published regarding the potential causes
of OHTN post anti-VEGF injections. Kahook et al.[2] examined particulate
material in samples of bevacizumab from different compounding pharmacies
and found significantly less functional IgG and correspondingly more large
particulate matter in samples from certain pharmacies. The authors
concluded that large particulate material might result in aqueous outflow
obstruction. The fact that particular compounding pharmacies were more
likely to have contaminants in their syringes could explain why our group
and others have noted clusters of OHTN cases, a phenomenon which then
lessens after switching to a different compounding pharmacy.[3]
A second study by Lui et al. examined the affects of handling
procedures used by pharmacies when repackaging both bevacizumab and
ranibizumab.[4] The repackaged samples of anti-VEGF agents had
significantly higher particle counts after mishandling of syringes. The
contaminants were consistent with silicone droplets. It is important to
note that these silicone droplets are sub-visible leading some to negate
their existence erroneously due to not observing them on slit lamp exam.
This study also highlighted that the existence of silicone droplets was
not exclusive to repackaged bevacizumab but was also observed in
mishandled ranibizumab samples. Our group has acknowledged that other
causes of OHTN in this setting likely exist and require further
exploration.[2,4] Other potential causes include repeated volume changes
with multiple injections or an idiosyncratic response by the trabecular
meshwork.[5]
The design of our study, a retrospective chart review, is a
reflection of the early stage of our understanding of this phenomenon.
Recently, Dr. Sophi Bakri reported, "In the pooled ANCHOR and MARINA
population, those treated with 24 monthly ITV injections of ranibizumab
were more likely than sham injection/PDT patients to have [higher rates of
glaucoma, new glaucoma medications, and OHTN]" and recommended "close
monitoring of IOP in patients receiving intravitreal injections with
Lucentis with special attention paid to those patients who have
preexisting glaucoma or glaucoma risk factors."[6] Dr. Bakri cautioned
that these findings could not be attributed directly to ranibizumab
independent of repeated intravitreal injections being a possible cause. It
appears that cases of OHTN may indeed be linked to intravitreal anti-VEGF
therapy. We hope that our data and recent publications have brought
attention to this phenomenon and that others continue to build upon this
knowledge so that we can better counsel and treat our patients.
References
1. Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of
intraocular pressure after intravitreal injections of anti-VEGF agents. Br
J Ophthalmol. 2010 Aug 11. Epub ahead of print.
2. Kahook MY, Liu L, Ruzycki P, et al. High-molecular-weight
aggregates in repackaged bevacizumab. Retina. 2010 Jun;30(6):887-92.
3. Carver J, Bouska C, Corey R. Avastin and Risk of Glaucoma
[abstract]. Retina Congress 2009 New York, September 30th-October4th,
2009. New York, NY.
4. Liu L, Ammar DA, Ross LA, et al. Silicone oil microdroplets and
protein aggregates in repackaged bevacizumab and ranibizumab: effects of
long-term storage and product mishandling. Invest Ophthalmol Vis Sci.
2011 Feb 22;52(2):1023-34.
5. Kahook MY, Ammar DA. In vitro effects of antivascular endothelial
growth factors on cultured human trabecular meshwork cells. J Glaucoma.
2010 Sep;19(7):437-41.
6. Bakri SJ. IOP in Eyes Treated with Monthly Ranibizumab (Ran): a
Post-hoc Analysis of Data From the MARINA and ANCHOR Trials. American
Academy of Ophthalmology Annual Meeting 2010, October 16th-19th, 2010,
Chicago, IL.
Conflict of Interest:
MYK has received research support from Genentech in the past.
In your September 2010 issue, I read with interest the article about
amblyopia by D J Hwang.1 The group has also previously published a
similar article in Korean Journal of Ophthalmology 2 but it was not
mentioned in the references. Both articles included their participants
from the same hospital since 2000 and the eligibility criteria were nearly
identical. I was wondering if both articles share the same group of
parti...
In your September 2010 issue, I read with interest the article about
amblyopia by D J Hwang.1 The group has also previously published a
similar article in Korean Journal of Ophthalmology 2 but it was not
mentioned in the references. Both articles included their participants
from the same hospital since 2000 and the eligibility criteria were nearly
identical. I was wondering if both articles share the same group of
participants. If so, a clarification will help to determine the
eligibility of either studies into future systematic reviews.
I look forward to your reply.
Sincerely yours,
Vannarut Satitpitakul, MD
References
1. Hwang DJ, Kim YJ, Lee JY. Effect and sustainability of part-time
occlusion therapy for patients with anisometropic amblyopia aged ? 8
years. Br J Ophthalmol 2010;94(9):1160-4.
2. Lee YR, Lee JY. Part-time occlusion therapy for anisometropic
amblyopia detected in children eight years of age and older. Korean J
Ophthalmol 2006;20(3):171-176.
Treatments for age-related macular degeneration (AMD) are lively
being debated. One controversy is that all randomized controlled studies
published thus far have used placebo or verteporfin in the control group
[1,2]; hence, direct head-to-head comparisons between the newest active
agents are lacking. The only randomised trial comparing ranibizumab vs
bevacizumab (CATT study [3]) is still ongoing and its results are...
Treatments for age-related macular degeneration (AMD) are lively
being debated. One controversy is that all randomized controlled studies
published thus far have used placebo or verteporfin in the control group
[1,2]; hence, direct head-to-head comparisons between the newest active
agents are lacking. The only randomised trial comparing ranibizumab vs
bevacizumab (CATT study [3]) is still ongoing and its results are
eagerly been awaited.
Network meta-analysis (NMA) can carry out indirect comparisons when
head-to-head controlled trials are not available [4]. Another advantage
of this technique is that a single graph can effectively summarise all
information available on comparative effectiveness [5].
We have conducted a simplified NMA to examine all controlled trials
in which all AMD therapeutic options were evaluated. For this purpose, a
standard PubMed search identified a total of 5 studies (acronyms: ANCHOR,
FOCUS, MARINA, VISION and ABC, see Figure 1 below for details) that
shared the end-point of the loss of fewer than 15 letters on the ETDRS
chart at one year. The data of comparative effectiveness were
incorporated in a simplified NMA graph (Figure 1). While these results
confirm that ranibizumab is likely to determine the best outcomes, the
indirect comparison of ranibizumab vs bevacizumab shows no significant
difference.
In conclusion, the evidence currently available indicates that the
class of anti-VEGF agents can significantly improve the outcome of
patients with AMD. However, the choice between bevacizumab and ranibizumab
remains a matter of controversy because current data show no difference in
indirect comparisons, but the former agent is much less expensive than the
latter.
References
1. Takeda A L, Colquitt J, Clegg A J, Jones J. Pegaptanib and
ranibizumab for neovascular age-related macular degeneration: a systematic
review. Br J Ophthalmol 2007;91:1177-1182.
2. Tufail A et al. Bevacizumab for neovascular age related macular
degeneration (ABC Trial): multicentre randomised double masked study. BMJ
2010;340:C2459.
The article by Hennessy and co-authors is important and interesting,
and the last three words of the abstract are essential (The utility of
relative afferent pupillary defect as a screening tool for glaucoma:
prospective examination of a large population-based study in a south
Indian population. BJO Online First, February 24, 2011, DOI: 10.1136/BJO.
2010.194217). Their conclusion is, "The authors...
The article by Hennessy and co-authors is important and interesting,
and the last three words of the abstract are essential (The utility of
relative afferent pupillary defect as a screening tool for glaucoma:
prospective examination of a large population-based study in a south
Indian population. BJO Online First, February 24, 2011, DOI: 10.1136/BJO.
2010.194217). Their conclusion is, "The authors find that APD assessed by
the swinging flashlight test is a poor screening tool for glaucoma in this
setting." The authors state, ". . . the low prevalence of afferent defect
. . . 60/5150 (1.2 percent in those referred for evaluation) led to a
large number of true negatives. It was previously reported by
Ramakrishnan and colleagues15 that "the prevalence of any glaucoma in the
same population was 2.6 percent." However, the authors only found 77
cases of glaucoma in their 5150 referred cases. Thus, the percentage of
patients found with a simple test performed by individuals who are not
expert came up with a percentage of 1.2 percent, and in that study
population the expert glaucoma specialist found a percentage of 1.5
percent with glaucoma, not the 2.6 percent they mention. Furthermore, it
is clear that the technicians screening for afferent pupillary defects
were not highly reliable in recognizing afferent pupillary defects. The
technicians found 11 afferent pupillary defects, but ". . . only one was
verified to have a pupil defect at the time of the comprehensive
examination. . ." My major concern is that clinicians around the world
will generalize unwisely from a comment made by this group of highly-
respected authors. Specifically, they state, "Many academic institutions.
. . still teach residents and fellows to consciously look for an APD as
part of any initial clinical examination. . ." The authors are clearly
suggesting that is inappropriate. However, there are few tests that are
as quick and as inexpensive, and whose results are so important. The
presence of an afferent pupillary defect is a sure sign of significant
disease. The clinical significance of its presence, then, is close to 100
percent. To test for an afferent pupillary defect properly requires that
the room be dark, that the light be bright, that the patient be looking in
the distance, and the light be held in each eye for three seconds. The
authors have verified themselves that clearly the testing was not well
done. The overwhelming majority of individuals seen by physicians have
borderline findings, in which it is not clear whether the involved person
is merely a variant of normal or has actual disease. To discard a test
that can quickly and inexpensively solve that common dilemma seems unwise.
We appreciate the interest of Dr. Kahn and Dr. Philip [1] in our
paper describing pilot results from a retrospective study in patients with
retinitis pigmentosa (RP) treated with valproic acid (VPA) [2], and we
would like to comment on the points raised by them.
Length of treatment. As mentioned in our recent reply to another
letter regarding the same article [3], the length of treatment...
We appreciate the interest of Dr. Kahn and Dr. Philip [1] in our
paper describing pilot results from a retrospective study in patients with
retinitis pigmentosa (RP) treated with valproic acid (VPA) [2], and we
would like to comment on the points raised by them.
Length of treatment. As mentioned in our recent reply to another
letter regarding the same article [3], the length of treatment reported in
our study was dictated by the logistical circumstances, not by any
limitations imposed by any institutional review board. Attempts to limit
the duration of treatment would be unfounded, as VPA has an excellent,
long-standing safety record [4, 5].
Status of the retina. There is tremendous genotypic and phenotypic
heterogeneity in RP, and fundus appearance can be quite variable--from
almost normal retina to very significant changes such as retinal
arteriolar narrowing, optic nerve head pallor, progressive chorioretinal
atrophy and highly variable geographic involvement [6]. Therefore, we felt
that photographic evidence of the degree to which the retina was affected
by RP would not be particularly helpful. Indeed, the design of new
clinical trials for RP do not include changes in fundus characteristics.
In contrast to visual field and visual acuity, electroretinographic
records were not available for all the patients in the study at the time
of article development. Where available, electroretinographic records were
profoundly reduced and consistent with the diagnosis of retinitis
pigmentosa.
Age-matched controls. As stated previously [4], we agree that a case-
control study would have been a better design. This problem will be
resolved with the randomized clinical trial, in which the treatment group
and the control group are age-matched [7].
Conversion of Snellen BCVA to logMAR, and reporting improvement in
visual acuity and visual field. We agree that the Snellen chart has
numerous disadvantages and we support the notion that the ETDRS chart
should be the preferred method for clinical research. At the same time, it
is a fact of life that the Snellen chart remains a very popular choice
(and probably number one choice) by ophthalmologists in most countries of
the world and has been for more than 140 years. Conversion of Snellen best
-corrected visual acuity to logMAR is an accepted and widely used method
[8]. Furthermore, a method to convert Snellen acuity to approximate ETDRS
letter scores was also recently developed and considered appropriate [9].
Therefore, reporting change in mean visual acuity, although limited by the
small sample size of this study as stated in the article [2], is
appropriate. Reporting an improvement in mean visual field area was
discussed in our previous reply [4] and we consider its use appropriate,
although limited by sample size.
Visual field learning effect. We agree that visual field learning
effect should be accounted for in a rigorous clinical research study, and
this is exactly how the subsequent clinical trial is designed. In
contrast, our study, as pointed out in our previous communications [3,4],
was a pilot, retrospective chart review based on clinical impressions, and
there was no initial intent for this to be designed as a prospective
study. As we emphasized in the article, we feel that VPA is exerting some
biological effect on the retina of patients with RP. There are other
anecdotal, unpublished (at this time) observations by others that appear
to be consistent with ours.
Mode of action of VPA. Although we find the cited article by Osakada
et al. [10] very interesting and important in supporting the role of VPA
as a potential treatment in retinitis pigmentosa, the information provided
in it is insufficient to support a claim for "neuroprotection and
neuroregeneration in a histone-acetylation- independent manner". The part
of the study by Osakada et al. using VPA was conducted in a retina explant
culture setting and limited to demonstrating that VPA promoted the
differentiation of proliferating cells stimulated by Wnt3a into rhodopsin-
positive photoreceptor cells. Valproic acid can act through multiple
mechanisms in terms of neuroprotection (11), and it is presently uncertain
which of these mechanisms is the leading one when the substance is applied
in the diseased retina. Significant effort is underway in our (12) and
other laboratories (13, 14) to elucidate the mechanisms by which VPA is
exerting neuroprotective action in in vitro and in vivo models of retinal
degenerations. We will be publishing those findings in the future.
In summary, we agree with the title of the letter by Drs. Khan and
Philip and concur with their statement that "VPA and related HDAC
inhibitors could potentially be valuable drugs for patients with retinal
degenerative disorders".
1. Khan S., Philip S. Need to further investigate the efficacy of
valproic acid therapy in retinal degenerative disorders (letter). Br J
Ophthalmol 7 February 2011.
2. Clemson CM, Tzekov R, Krebs M, Checchi JM, Bigelow C, Kaushal
S. Therapeutic potential of valproic acid for retinitis pigmentosa. Br J
Ophthalmol 2011; 95:89-93.
3. Clemson CM, Tzekov R, Krebs M, Checchi JM, Kaushal S. Re:
Conclusions of Clemson et al. concerning valproic acid are premature. Br J
Ophthalmol 2011; 95:153-154.
4. Tzekov R, Bigelow C, Clemson C, Krebs M, Checchi JM, Kaushal S.
Re: Lack of scientific rationale for use of valproic acid for retinitis
pigmentosa Br J Ophthalmol Online First: 22 December 2010.
5. Peterson, GM, Naunton, M. Valproate: a simple chemical with so
much to offer. Journal of Clinical Pharmacy and Therapeutics 2005;30:417-
421.
6. Carr, RE, Noble KG. Retinitis pigmentosa and allied diseases.
In: Guyer DR, Yannuzzi LA, Chang S, et al., eds. Retina-Vitreous-Macula
1st ed. Vol. 2. Philadelphia: W.B. Saunders, 1999:891-922.
7. ClinicalTrials web site. Trial entry: NCT01233609.
http://clinicaltrials.gov/ct2/results?term=NCT01233609
8. Holladay JT. Proper method for calculating average visual
acuity. J Refract Surg. 1997 Jul-Aug;13(4):388-91.
10. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt
signalling promotes regeneration in the retina of adult mammals. J
Neurosci. 2007;27:4210-9.
11. Monti B, Polazzi E, Contestabile A. Biochemical, molecular and
epigenetic mechanisms of valproic acid neuroprotection. Curr Mol
Pharmacol. 2009 Jan;2(1):95-109.
12. Noorwez SM, Kaushal S. Dose-Dependent Differential Effect of
HDAC Inhibitors on Yields of Folded P23H and WT Rhodopsin. Invest
Ophthalmol Vis Sci 2010;51: E-Abstract 5979.
13. Alsarraf O, Mani SK, Menick DR, Crosson CE. Reduced Histone
Deacetylase Activity Protects the Retina From Ischemic Injury. Invest
Ophthalmol Vis Sci 2010;51: E-Abstract 4714.
14. L. Yang. Valproic Acid Prevents Photoreceptor Cell Apoptosis in
Retinitis Pigmentosa Mice by Increasing Bcl-2 Expression. Invest
Ophthalmol Vis Sci 2010;51: E-Abstract 3691.
We read with great interest the article by Kumar et al. We have
audited our 1-year results using a slightly different clinical model: a
nurse-led optical coherence tomography (OCT)-guided macula service.
Following wet AMD diagnosis in the consultant-led macula clinic,
three consecutive monthly ranibizumab injections are administered.
Thereafter, patients are reviewed 4-6 weekly in the nurse-led clinic for 2
visi...
We read with great interest the article by Kumar et al. We have
audited our 1-year results using a slightly different clinical model: a
nurse-led optical coherence tomography (OCT)-guided macula service.
Following wet AMD diagnosis in the consultant-led macula clinic,
three consecutive monthly ranibizumab injections are administered.
Thereafter, patients are reviewed 4-6 weekly in the nurse-led clinic for 2
visits (visual acuity, fundus photography and spectral domain-OCT), and
then in the consultant-led clinic, where dilated fundoscopy is also
undertaken. After each nurse-led clinic, medical notes and scans are
reviewed by the clinician in a 'virtual' clinic, only if any of the
criteria below is met:
1. Reduced LogMar VA of >=5 letters.
2. Increased OCT intraretinal or subretinal macular fluid.
3. Increase in OCT central retinal thickness >=100 microns.
4. New macular haemorrhage on colour fundus photograph.
5. Persistent OCT fluid >=1 month after the previous ranibizumab
injection.
85 patients (91 eyes) with a mean age of 81 (range 52-94) completed
the 12-month follow-up in our audit. All patients were treatment naive for
wet AMD. Patients attended a mean of 4 nurse-led clinics and 3 consultant-
led clinics. The mean number of intravitreal injections was 4.8 (range 3-
9). The mean pre-treatment VA was 0.69 (range 0.2-1.2) and at 12 months
was 0.58 (0.0-1.5). 31.5% of eyes gained >=15 letters, comparable to
the PrONTO 1-year study, but in our audit 91.3% lost <15 letters
compared to Kumar (97.4%).
Our results suggest that using vision and OCT scans can provide a
basis for effective retreatment in year-1 outside of a randomised
controlled trial. It is difficult to explain the differences in our
results as our retreatment criteria are similar to Kumar et al, but
perhaps using nurses and virtual clinics has necessitated strict protocols
with less flexibility in retreatment decisions.
Conflict of Interest:
Dr Caroline Styles has been on an advisory board for Novartis.
Yamamoto and coworkers present in their paper the effect of
simultaneous intravitreal injection of a mixture of 4mg triamcinolone
acetonide (TA) and 25?g tissue plasminogen activator (tPA) to treat
macular edema due to central retinal vein occlusion (CRVO) ?1?. The
authors included 20 eyes. Best corrected visual acuity (BCVA) improved
three lines or more in 65%, 55%, 55% and 53% of eyes and the mea...
Yamamoto and coworkers present in their paper the effect of
simultaneous intravitreal injection of a mixture of 4mg triamcinolone
acetonide (TA) and 25?g tissue plasminogen activator (tPA) to treat
macular edema due to central retinal vein occlusion (CRVO) ?1?. The
authors included 20 eyes. Best corrected visual acuity (BCVA) improved
three lines or more in 65%, 55%, 55% and 53% of eyes and the mean macular
thickness decreased from 1072 ?m to 455, 450, 480 and 409 ?m (p<0.001)
at 1, 3, 6 and 12 months, respectively. Fifteen (75%) of the 20 eyes
required at least one additional injection to prevent a recurrence of
macular edema.
We congratulate the authors for their important study and want to add two
aspects from our clinical experience.
In a previous study we investigated the vitreomacular interface in
patients with a history of CRVO or branch retinal vein occlusion (BRVO).
We demonstrated that the posterior vitreous cortex stays attached more
frequently in cases of retinal vein occlusion in comparison to healthy age
-related controls. Hence, there is explicit evidence, that an attached
posterior vitreous might be a co-factor in the development of CRVO or BRVO
[2]. Recently, the vitreomacular interface and the adhesion status of the
posterior vitreous cortex towards the internal limiting membrane (ILM) of
the retina is getting more and more into the focus of interest as the
adhesion status of the posterior vitreous may play an important role in
the pathogenesis of different posterior pole pathologies [3].
Evidence could be demonstrated by Charbonnel and coworkers demonstrating
vitrectomy with arterio-venous (AV) crossing sheathotomy to be of benefit
in the management of BRVO, particularly in eyes with no previous posterior
vitreous detachment (PVD) [4]. The effect of vitrectomy with or without
sheathotomy for macular edema associated with branch retinal vein
occlusion (BRVO) was compared in 36 eyes by Yamamoto and coworkers [5].
Both AV sheathotomy and simple PVD significantly reduced macular edema
associated with BRVO. However, there was no significant difference in the
improvement of macular function following either procedure. As a result,
the posterior vitreous may play an improtant role in the course of macular
edema secondary to retinal vein occlusion.
Tissue plasminogen activator (tPA) is a possible treatment option for
retinal vein occlusion despite the fact that venous thrombi are presumed
to play an important role in the pathogenesis of CRVO. The authors used in
their treatment a combination of intravireal steroids and tPA since
corticosteroids decrease fibrinolytic activity and blood flow may be
compromised. The authors describe that they used tPA in a local
application into the eye to avoid the serious complications associated
with systemic administration.
Tissue plasminogen activator may cause an additional
pathophysiological cascade when applicated in the vitreous cavity.
Depending on the presence of plasminogen, plasmin is generated due to
enzymatic activity by tPA. Due to blood-barrier breakdown secondary to
retinal vein occlusion, plasminogen may be present in higher
concentrations. Clinical studies presented by Murakami and coworkers could
demonstrate for 21 eyes with attached vitreous in CRVO that 16 eyes
developed PVD after intravitreal application of tPA followed by incease of
visual acuity and decrease of retinal thickness [6].
We congratulate Yamamoto and coworkers for their results and
recommend to evaluate additionally the vitreomacular interface in macular
edema secondary to retinal vein occlusion especially when intravitreal tPA
is administered, as PVD may be induced and the course of the desease
consecutively be influenced.
References:
1. Yamamoto T, Kamei M, Sayanagi K, Matsumura N, Nishida K, Sakaguchi H,
Tsujikawa M, Tano Y. Simultaneous intravitreal injection of triamci-nolone
acetonide and tissue plasminogen activator for central retinal vein
occlusion: a pilot study. Br J Ophthalmol. 2011;95:69-73.
2. Bertelmann T, Kicova N, Messerschmidt-Roth A, Irle S, Sekundo W,
Men-nel S. The vitreomacular interface in retinal vein occlusion. Acta
Ophthalmol. 2011 Feb 11. doi: 10.1111/j.1755-3768.2010.02101.x.
3. Mennel S, Meyer CH & Schmidt JC (2010): The Role of the
Vitreous in the Pathogenesis of Age-Related Macular Degeneration. Klin
Monatsbl Augenheilk 227: 1-5
4. Charbonnel J, Glacet-Bernard A, Korobelnik JF, Nyouma-Moune E,
Pour-naras CJ, Colin J, Coscas G & Soubrane G (2004): Management of
branch retinal vein occlusion with vitrectomy and arteriovenous
adventitial sheato-tomy, the possible role of surgical posterior vitreous
detachment. Graefe`s Arch Clin Exp Ophthalmol 242:223-228
5. Yamamoto S, Saito W, Yagi F, Takeuchi S, Sato E, Mizunoya S.
Vitrectomy with or without arteriovenous adventitial sheathotomy for
macular edema associated with branch retinal vein occlusion. Am J
Ophthalmol. 2004;138:907-14
6. Murakami T, Takagi H, Ohashi H, Kita M, Nishiwaki H, Miyamoto K,
Watanabe D, Sakamoto A, Yamaike N & Yoshimura N (2007): Role of Pos-
terior Vitreous Detachment induced by Intravitreal Tissue Plasminogen Ac-
tivator in Macular Edema with Central Retinal Vein Occlusion. Retina
27:1031-1037
Bartlett et al. have reported on the clinical viability of the MPS
9000, a heterochromatic flicker photometry (HFP) device used to estimate
macular pigment optical density (MPOD).[1] Coefficient of repeatability
(CoR) values were used to determine the test-retest repeatability and
reproducibility of the MPS 9000. While the observed CoR of 0.33 is indeed
high, and, superficially at least, raises concern regarding the clin...
Bartlett et al. have reported on the clinical viability of the MPS
9000, a heterochromatic flicker photometry (HFP) device used to estimate
macular pigment optical density (MPOD).[1] Coefficient of repeatability
(CoR) values were used to determine the test-retest repeatability and
reproducibility of the MPS 9000. While the observed CoR of 0.33 is indeed
high, and, superficially at least, raises concern regarding the clinical
application and interpretation of the device, I would suggest that the
author's interpretation of their data, and resultant conclusion in this
paper, that a change in MPOD of less than 0.33 "is very likely to be due
to measurement noise", is both misleading and inaccurate.
The reported CoR (ranging from 0.25 to 0.33) is in fact a measure of
the 95% limits of agreement (LoA), as proposed originally by Bland and
Altman, and is calculated as the mean +/- 1.96SD.[2] By definition, this
value provides an interval, within which 95% of test-retest measurement
differences lie, in this case 0.33.[2-4]
On the basis of this reported coefficient of repeatability, the
authors suggest that any change in repeated measures of MPOD of less than
0.33 on the MPS 9000, should be interpreted as measurement noise, and
could not be assumed to be of clinical importance.[1] In other words, the
authors interpret their coefficient of repeatability values as an
indicator of the amount of change that can occur between readings and
still be classed as measurement noise. Such a conclusion would suggest a
fundamental lack of understanding of this useful statistical tool on the
Author's behalf. Confining the analysis to increases in MPOD (as would be
expected clinically in response to dietary modification or
supplementation), the simple interpretation of a CoR value of 0.33 is
that, in the test-retest data, the observed increase in MPOD was less than
0.33 for 97.5% of subjects, or conversely, that the probability of
detecting a test-retest increase in MPOD greater than 0.33 in the test
population is only 2.5%.
Expanding on this statistical interpretation further, it can be seen
that if the CoR value is halved to 0.17 (mean + 1SD), 84% of subjects
would be expected to exhibit retest increases less than this 0.17 value.
If, for example, during routine clinical practice, a retest increase in
MPOD of 0.17 was noted for a particular patient, on the basis of the
Bartlett et al. results,[1] one could interpret that the probability of
such a change being due to measurement noise is as little as 16%, and for
an increase of 0.33, the probability is as little as 2.5%. In other words,
on the basis of probability, such differences would more than likely
represent a genuine change in MPOD rather than measurement noise as is
suggested by Bartlett et al.[1]
Extracting the data from the Bartlett et al. paper, [1] it can be
observed that the test - retest difference is < 0.1 in close to two-
thirds of their subject data. The data also reveals a significant
influence of two outliers on the magnitude of the observed CoR. For one
subject, the difference in MPOD between visits is an incredible 0.69, and
for another, the difference is greater than 0.4 in the opposite direction.
Simple exclusion of these outliers dramatically improves the CoR to ~0.23.
Similar interpretations have been adopted by the same group in a number of
recent papers, and ultimately, the general validity of the HFP technique,
and its applicability to clinical practice have thereby been called into
question by the group.[5] Given that (a) the results here from just two
subjects are observed to have a significant and adverse effect on the
reported CoR, (b) the test-retest values are quite repeatable for a very
high percentage of subjects, and (c) the authors repeatedly demonstrate a
lack of understanding of the appropriate statistical interpretation of
their data, their broad conclusions would, therefore, seem neither
reasonable nor sustainable.
The suggestion that "any change less than 0.33 units should not be
considered clinically significant as it is very likely to be due to
measurement noise" is simply incorrect. A more appropriate conclusion to
this paper might have been to suggest that, for clinical practice, a
number of measurements of MPOD might be used to provide an average MPOD
value, to thereby ensure that the value obtained is maximally robust, and
that cases of obviously poor performance on the test can be identified.
References
1. Bartlett H, Stainer L, Singh S et al. Clinical evaluation of the
MPS 9000 Macular Pigment Screener. Br J Ophthalmol 2010;94:753-6.
2. Bland J, Altman D. Statistical methods for assessing agreement
between two methods of clinical measurement. Lancet 1986;1:307-10.
3. Bland J, Altman D. Measuring agreement in method comparison
studies. Stat Methods Med Res 1999;8:135-60.
4. Atkinson G, Nevill AM. Statistical methods for assessing
measurement error (reliability) in variables relevant to sports medicine.
Sports Med 1998;26(4):217-38.
5. Bartlett H, Howels O, Eperjesi F. The role of macular pigment in
clinical practice: a review. Clin Exp Optom 2010;93(5):300-8
We read with great interest the article by Good et al. titled
"Sustained elevation of intraocular pressure after intravitreal injections
of anti-VEGF agents." Authors of other case series have reported
sustained intraocular pressure (IOP) elevation following bevacizumab and
ranibizumab injections. Good et al. conducted a retrospective chart
review of 215 eyes receiving anti-VEGF injections to answer the following
ques...
We read with great interest the article by Good et al. titled
"Sustained elevation of intraocular pressure after intravitreal injections
of anti-VEGF agents." Authors of other case series have reported
sustained intraocular pressure (IOP) elevation following bevacizumab and
ranibizumab injections. Good et al. conducted a retrospective chart
review of 215 eyes receiving anti-VEGF injections to answer the following
questions:
1) What is the frequency of sustained IOP elevation after anti-VEGF
injections?
2) What is the frequency of sustained IOP elevation in patients receiving
ranibizumab versus bevacizumab?
3) Is glaucoma a risk factor for sustained IOP elevation in these eyes?
With respect to the first question, the authors report that 13 of 215
(6%) eyes developed sustained IOP elevation after treatment with anti-VEGF
injections. Nine of the eyes with sustained IOP elevation were treated
with bevacizumab originating from a single compounding pharmacy. The
authors hypothesize that the bevacizumab molecule itself may not be the
cause of the IOP elevation, but rather the packaging, transportation, or
storage of the medication. If these 9 cases are excluded, only 4 of 206
(1.9%) developed sustained IOP elevation. The significance of this
number, too, must be interpreted with caution. In the absence of a
control group, it is impossible to determine if this number is different
from similarly matched untreated eyes followed over time. Indeed,
randomized controlled clinical trials have not reported increased rates of
sustained ocular hypertension after ranibizumab injections. ,
With respect to the second question, the authors report that three of
96 (3.1%) eyes treated with ranibizumab developed sustained IOP elevation
compared to 10 of 101 (9.9%) eyes of patients treated with bevacizumab
(p=0.049). When the eyes that received bevacizumab from the particular
pharmacy were excluded, only 2.4% of bevacizumab treated eyes developed
sustained IOP, which is similar to the 3.1% rate in ranibizumab treated
eyes. However, accurate comparison between the two groups requires
consideration of follow-up times, which the authors do not report. Unless
every patient had equivalent lengths of follow-up, these data would be
more appropriately summarized as cumulative incidence (events per eye per
year), or in a Kaplan-Meier curve, either of which would control for
varying follow-up time.
With respect to the third question, the authors report that seven of
21 (33%) eyes with glaucoma treated with anti-VEGF injections developed
sustained IOP elevation, which was higher than the overall rate of
sustained IOP elevation using a Fisher exact test (p<0.001). Again,
variable follow-up times must be considered when comparing these groups.
The Kaplan-Meier curve presented in figure 1 compares all patients to
glaucoma patients as a function of interval between injections, not as a
function of follow-up times. More importantly, in the absence of a
control group of untreated eyes with glaucoma, it is impossible to
determine if the IOP elevation is due to the anti-VEGF injections,
injection of fluid itself into the eye, or simply the natural course of
the disease.
In summary, not accounting for variable follow-up and the absence of
control eyes severely limits the conclusions that can be drawn from this
paper. Based on the results presented, one cannot conclude that anti-VEGF
injections result in increased risk of sustained IOP elevation. In
addition, one cannot conclude that glaucoma patients receiving anti-VEGF
injections are at increased risk of sustained IOP elevation compared to
glaucoma patients not receiving these injections.
In a recently published article by Chandra et al. the authors have
stated that they conducted a "case-controlled" study to examine the
anticoagulant effectiveness of warfarin in vitreoretinal surgery.(1)
However, this study was conducted on a cohort of patients receiving pars
plana vitrectomy (PPV); 60 patients who received warfarin (exposure) on
the day of PPV were selected. These 'exposed' pati...
In a recently published article by Chandra et al. the authors have
stated that they conducted a "case-controlled" study to examine the
anticoagulant effectiveness of warfarin in vitreoretinal surgery.(1)
However, this study was conducted on a cohort of patients receiving pars
plana vitrectomy (PPV); 60 patients who received warfarin (exposure) on
the day of PPV were selected. These 'exposed' patients were matched to
other patients receiving PPV but not taking warfarin (unexposed) on age,
sex, and presenting complaint. These patients were then followed for
perioperative and long term complications. Thus, this is not a case-
control study rather it is a matched cohort study. As a result, the
statistical analysis raises concerns. Matching in a cohort study does not
necessarily eliminate the need for control of matching factors in the
analysis; censoring (competing risks, death, loss to follow-up) can
produce imbalances thereby limiting the extent of matching only to those
among the original counts of persons for whom matching was applied.(2) In
other words, an association of exposure and the matching factors could be
observed for the remaining persons and the observed person-time.2
Furthermore, even if no censoring occurs and one examines risk, control of
matching factors would still be necessary to obtain valid standard
deviation estimates.(3,4) In contrast, case-control studies require
control of matching factors associated with exposure rather than risk.
Moreover, with variable follow-up duration and censoring a matched
survival (time-to-event) analysis producing hazard ratios would have been
a better strategy than reporting the p-values alone; censoring has not
been mentioned in the article.
REFERENCES
1. Chandra A, Jazayeri F, Williamson T. Warfarin in vitreoretinal
surgery: a case controlled series. Br J Ophthal 2010.
http://bjo.bmj.com/content/early/2010/11/11/bjo.2010.187526.full.html.
2010.
2. Rothman K, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 1998.
3. Greenland S, Robins J. Estimation of a common effect parameter
from sparse follow-up data. Biometrics. 1985;41:55-68.
4. Weinberg C. On pooling across strata when frequency matching has
been followed in a cohort study. Biometrics. 1985;41:103-116.
We would like to thank Zaidi et al. for their interest in our publication titled, "Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents." [1] As stated in our publication, we believe anti-VEGF agents revolutionized the treatment of ocular neovascular disease and their overall safety profile is excellent. The points by Zaidi et al. are valid and we take this opportunity to expand...
In your September 2010 issue, I read with interest the article about amblyopia by D J Hwang.1 The group has also previously published a similar article in Korean Journal of Ophthalmology 2 but it was not mentioned in the references. Both articles included their participants from the same hospital since 2000 and the eligibility criteria were nearly identical. I was wondering if both articles share the same group of parti...
Treatments for age-related macular degeneration (AMD) are lively being debated. One controversy is that all randomized controlled studies published thus far have used placebo or verteporfin in the control group [1,2]; hence, direct head-to-head comparisons between the newest active agents are lacking. The only randomised trial comparing ranibizumab vs bevacizumab (CATT study [3]) is still ongoing and its results are...
Dear Editor:
The article by Hennessy and co-authors is important and interesting, and the last three words of the abstract are essential (The utility of relative afferent pupillary defect as a screening tool for glaucoma: prospective examination of a large population-based study in a south Indian population. BJO Online First, February 24, 2011, DOI: 10.1136/BJO. 2010.194217). Their conclusion is, "The authors...
Dear Editor,
We appreciate the interest of Dr. Kahn and Dr. Philip [1] in our paper describing pilot results from a retrospective study in patients with retinitis pigmentosa (RP) treated with valproic acid (VPA) [2], and we would like to comment on the points raised by them.
Length of treatment. As mentioned in our recent reply to another letter regarding the same article [3], the length of treatment...
We read with great interest the article by Kumar et al. We have audited our 1-year results using a slightly different clinical model: a nurse-led optical coherence tomography (OCT)-guided macula service.
Following wet AMD diagnosis in the consultant-led macula clinic, three consecutive monthly ranibizumab injections are administered. Thereafter, patients are reviewed 4-6 weekly in the nurse-led clinic for 2 visi...
Dear editor:
Yamamoto and coworkers present in their paper the effect of simultaneous intravitreal injection of a mixture of 4mg triamcinolone acetonide (TA) and 25?g tissue plasminogen activator (tPA) to treat macular edema due to central retinal vein occlusion (CRVO) ?1?. The authors included 20 eyes. Best corrected visual acuity (BCVA) improved three lines or more in 65%, 55%, 55% and 53% of eyes and the mea...
Bartlett et al. have reported on the clinical viability of the MPS 9000, a heterochromatic flicker photometry (HFP) device used to estimate macular pigment optical density (MPOD).[1] Coefficient of repeatability (CoR) values were used to determine the test-retest repeatability and reproducibility of the MPS 9000. While the observed CoR of 0.33 is indeed high, and, superficially at least, raises concern regarding the clin...
We read with great interest the article by Good et al. titled "Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents." Authors of other case series have reported sustained intraocular pressure (IOP) elevation following bevacizumab and ranibizumab injections. Good et al. conducted a retrospective chart review of 215 eyes receiving anti-VEGF injections to answer the following ques...
To The Editor,
In a recently published article by Chandra et al. the authors have stated that they conducted a "case-controlled" study to examine the anticoagulant effectiveness of warfarin in vitreoretinal surgery.(1) However, this study was conducted on a cohort of patients receiving pars plana vitrectomy (PPV); 60 patients who received warfarin (exposure) on the day of PPV were selected. These 'exposed' pati...
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