An aim to provide an optimised keratoprosthesis, with excellent
biointegration, and all other properties meeting ideal requirements, is
one we share with the authors of the recent article entitled “Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials”.[1] However, the current paper includes some points that require clarificatio...
An aim to provide an optimised keratoprosthesis, with excellent
biointegration, and all other properties meeting ideal requirements, is
one we share with the authors of the recent article entitled “Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials”.[1] However, the current paper includes some points that require clarification.
PHEMA (spelled in full: poly(2-hydroxyethyl methacrylate)is a non-toxic polymer of the toxic monomer HEMA, though cytotoxicity is still possible if non-reacted monomer has not been fully removed. The ' polyhydroxyethyl methacrylate' the authors obtained for their study was not fully described, and may have been contact lens blanks, unlikely to have been processed for 'implantable quality'. Whether the samples had been fully extracted was not stated, nor was the hydration of the samples when used for the study. Contact lens blanks are not designed for cell adhesion and the results of this study, with regard to PHEMA, are entirely predictable and have been previously reported.
The commercially available keratoprosthesis AlphaCor is made from a form of PHEMA, specifically modified for its intended purpose within the cornea. In particular, the AlphaCor OPTIC is made from a relatively low water content, but hydrated, microporous form, similar to the samples evaluated by the authors, specifically because it does not encourage cellular adhesion (epithelial coverage is not desired for this model, nor would adherent posterior cells and membranes be desirable).
In contradistinction, the biointegratable SKIRT region of AlphaCor is
made from a macroporous form of PHEMA with a very high water content; this material, with its interconnecting channels, has been optimised to promote viable biocolonisation, which has been extensively described in the literature. The authors of the present article do concede that cells 'may behave differently in colonising a 3-D porous keratoprosthesis skirt': indeed they do. Further, very subtle modifications of the sponge structure significantly affect all aspects of biointegration.
Both early trial results, such as the preliminary cases cited by the authors, and current results for over 250 AlphaCor devices, have been extensively presented and made available to all device users. Histology now available from AlphaCor devices explanted from human recipients confirms that the biointegration process in humans is similar to that previously shown in the animal model, and maintained in the long term. As expected, specific inflammatory processes can cause localised reversal of biointegration in areas of stromal melting. Certainly, porosity itself does not prevent melting processes, as is also seen in relation to hydroxyapatite keratoprostheses and orbital implants.
There is no argument that keratoprosthesis materials and design
require ongoing revision and improvement. The authors' findings in
relation to hydroxyapatite are interesting, although as they note, this
rigid material has its own limitations. Novel approaches are undergoing early evaluation and may offer benefits. However, at present,
in our view, AlphaCor is a device worthy of consideration for those in whom a donor graft would fail.
Disclosure: Celia Hicks is Medical Director of CooperVision Surgical,
manufacturer of AlphaCor. The Biomaterials and Polymer Research department of the Lions Eye Institute has a financial interest with CooperVision Surgical through support of departmental funding, travel and research.
References
1. J S Mehta, C E Futter, S R Sandeman, R G A F Faragher, K A Hing, K E Tanner, and B D S Allan. Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials. Br. J. Ophthalmol. 2005; 89: 1356 – 1362.
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 thank Dr. Shoaib for his interest in our article.1 We agree that
there are various causes of graft rejection and that performing an
endothelial keratoplasty (EK) would not resolve the rejection. To clarify
our wording for the article, patients who developed endothelial graft
rejection with subsequent endothelial failure were offered EK under their
penetrating keratoplasty (PK). The rejection episode was resolved at...
We thank Dr. Shoaib for his interest in our article.1 We agree that
there are various causes of graft rejection and that performing an
endothelial keratoplasty (EK) would not resolve the rejection. To clarify
our wording for the article, patients who developed endothelial graft
rejection with subsequent endothelial failure were offered EK under their
penetrating keratoplasty (PK). The rejection episode was resolved at the
time of the EK. There were a total of 9 patients that fulfilled this
requirement and were included in the study. These patients did not have
any epithelial or stromal rejection and did not have stromal opacities. We
do feel that EK under PK for immunological endothelial failure is a viable
treatment option that should be considered in cases where there are not
any stromal opacities.
Jennifer Nottage, MD
Verinder Nirankari, MD
Eye Consultants of Maryland, Owings Mills, MD
1. Nottage JM, Nirankari VS. Endothelial keratoplasty without
Descemet's stripping in eyes with previous penetrating corneal
transplants. Br J Ophthalmol. 2012 Jan;96(1):24-7
Saito et al. present a patient with Terson’s syndrome and vitreous
hemorrhage who underwent pars plana vitrectomy and was noted
postoperatively to have developed an ophthalmic artery occlusion. They
propose that the ophthalmic artery was occluded by the spontaneous release
of an embolus from an atheromatous plaque in the internal carotid artery.
This seems unlikely in a 39-year-old male without a...
Saito et al. present a patient with Terson’s syndrome and vitreous
hemorrhage who underwent pars plana vitrectomy and was noted
postoperatively to have developed an ophthalmic artery occlusion. They
propose that the ophthalmic artery was occluded by the spontaneous release
of an embolus from an atheromatous plaque in the internal carotid artery.
This seems unlikely in a 39-year-old male without a prior history of
symptomatic atherosclerotic disease. Although the authors identified
plaques in the patient’s carotid artery by ultrasound, these can be seen
in 11% of asymptomatic males under age 40 and may therefore be an
incidental finding in this case.[1]
An alternate explanation for the patient’s ocular findings is trauma
from the retrobulbar injection. Intravascular injection into the
ophthalmic artery has been reported as a complication of retrobulbar
anesthesia.[2] It is possible that either an intravascular injection or
simply needle-tip trauma resulted in thrombus formation with obstruction
of flow in the ophthalmic artery. It should also be noted that although
acute ophthalmic artery occlusion is the presumed diagnosis, the same
findings could result from simultaneous obstructions of the retinal and
choroidal circulations,[3] also a potential consequence of errant
retrobulbar injection. The possibility that the patient’s chorioretinal
disturbance could have been iatrogenic highlights the importance of a
thorough preoperative discussion with patients about the risks and
benefits of different methods of delivering anesthesia for ophthalmic
surgery.
References
(1) Sun Y, Lin CH, Lu CJ, et al. Carotid atherosclerosis, intima
media thickness and risk factors—an analysis of 1781 asymptomatic subjects
in Taiwan. Atherosclerosis 2002;164:89-94.
(2) Morgan CM, Schatz H, Vine AK, et al. Ocular complications
associated with retrobulbar injections. Ophthalmology 1988;95:660-665.
(3) Brown GC, Magargal LE, Sergott R. Acute obstruction of the
retinal and choroidal circulations. Ophthalmology 1986;93:1373-1382.
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmat...
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmatory data, Cantor et al1 appear to reach conclusions that are not supported by their own data. Whereas the 2 previous studies(2,3) conclude that BP is a prodrug that is hydrolyzed to its free acid to account for its ocular hypotensive effect by activation of known FP prostanoid receptors, the current publication1 surprisingly concludes that BP is not a prodrug and acts directly as an amide to reduce intraocular pressure (IOP).
The clinical studies cited above(1-3) are not the only ones that have demonstrated the hydrolysis of BP in ocular tissues. Previous studies have demonstrated its hydrolysis in vitro in rabbit, bovine, and human ocular tissues(4-7) and after topical application in vivo in rabbit and monkey ocular tissues.(8) The hydrolysis of BP to produce sufficient concentrations of its very potent free acid, a well-described FP receptor agonist, provides clear evidence of its prodrug properties. Studies in FP receptor knockout mice have clearly demonstrated the importance of FP receptors for effective IOP reduction after topical application of FP receptor agonists, including BP.(9-12)
The 3 clinical studies1-3 provide very consistent data. Each demonstrates equal or higher levels of the free acid than the intact amide of BP in aqueous humor. Each demonstrates peak levels occurring within the first few hours after topical application of BP, with lower levels afterwards. Peak concentrations of the free acid were 35 nM,3 22 nM,2 and 7 nM1 in each of the 3 studies. After topical application of latanoprost (LP), Cantor et al1 demonstrated a free acid concentration in aqueous of 41 nM at 3 hours, which is less that half of the 100 nM concentration found in a previous study.13 Therefore, when assessing the 4 clinical studies1-3,(13) which evaluated the hydrolysis of LP and/or BP, the lowest concentrations (2 to 5-fold less than the other studies) of the free acids of either LP or BP were consistently demonstrated by Cantor et al.1 Cantor et al1 suggest that the lower levels might be partially explained by single dose administration of BP or LP in their study, compared with multiple dosing in other studies. However, another clinical study also involved single dose administration and yet found approximately 2-fold higher concentrations of LP acid.(13)
The key and unambiguous observation that we believe is critical is that, no matter what values were obtained in each and every study, all of the concentrations, including the lower concentrations of the free acid of either LP or BP found by Cantor et al,1 are sufficiently high enough to account for their activity at FP prostanoid receptors. At 24 hours after LP, the aqueous humor concentration of the free acid was found to be well less than 1 nM,13 demonstrating that very low aqueous concentrations are found during periods of substantial IOP reduction. Therefore, the lower limits of quantitation of 1.3 nM for BP acid and 2.6 nM for LP acid in the current study1 apparently are not sensitive enough to detect substantial, clinically significant aqueous concentrations of the free acids of these prodrugs.
Although lower than the free acid concentrations, the relatively high concentrations of the amide of BP in the aqueous1-3 compared with nondetectable levels of the LP ester is hardly an adequate criterion to support the hypothesis that BP is not a prodrug. These data instead demonstrate that BP amide is an inefficient prodrug compared with LP ester simply because the ester bond is more labile than the amide bond. BP is topically applied at 6 times the concentration of LP, but, unlike LP, is not completely hydrolyzed. 1-3,13 Despite its 6-fold higher concentration, BP yields peak free acid concentrations in the aqueous 3 to 6 times lower than LP acid, 1-3,13 clearly demonstrating the inefficiency of hydrolysis of the amide compared with ester prodrug. Despite these lower concentrations of the BP free acid, they appear to be sufficient to fully account for the effect of BP. Studies have repeatedly demonstrated that the free acid of BP is 3 to 10 times more potent at the FP receptor than the free acid of LP.(14-23) Therefore, the 3 to 6-fold lower concentrations of BP, compared with LP, acid in aqueous still can account for similar activation of FP receptors when their differences in potency are considered.
Despite the overwhelming evidence for greater potency of the acid of BP compared with LP, (14-23) Cantor et al1 claim that the acids are equally potent and cite a single published study(19) using trabecular meshwork cells from a limited number of donor eyes to support their claim. Cantor et al fail to acknowledge that BP acid exhibits a potency (EC50) of 2.8 to 3.8 nM in numerous cell-types derived from several different species (e.g. human ciliary muscle cells, mouse fibroblast, and rat smooth muscle cells)(18) such that even the amount of BP acid they detected (7 nM) would be sufficient to occupy and stimulate many of the FP receptors in the target tissues. In more comprehensive studies using trabecular meshwork cells derived from numerous donor eyes,(18) BP acid still exhibits a relatively high potency (EC50 = 26 ± 10 nM) at the FP receptor that could help account for the observations of Cantor et al.(1) By citing and concentrating on only a single reference as opposed to the many other published studies, Cantor et al1 appear to bias their interpretation of their data.
We fully agree that drugs might reach target tissues via routes independent of aqueous humor. However, in the case of prostaglandin analogs, including both LP and BP, drug concentrations measured in the aqueous will leave the eye via trabecular or uveoscleral outflow pathways, thereby providing active drug to these tissues. These drugs also might enter these outflow tissues by other routes, and also might be hydrolyzed to their active free acids either along these alternative routes or after they arrive at their target tissue. Therefore, the possibility of alternative routes of delivery of these drugs to target tissues does not negate their action as prodrugs.
While the manufacturer of BP has repeatedly tried to present data to support the hypothesis that BP’s mechanism of action does not rely on FP receptor agonism of the free acid but rather is due to intrinsic receptor occupancy of the amide, their arguments fail to be convincing for several reasons. First, as previously reported, the presence of FP receptors are essential for BP’s hypotensive action as demonstrated by experiments in FP knockout mice.(10,11) More importantly, there has not been, to the best of our knowledge, any putative receptor that has been adequately identified that can explain the actions of BP at a unique non-FP receptor. The elusive, mystery receptor in question has never been cloned or characterized by receptor binding kinetics. In short, BP’s hypotensive action appears to require FP receptor agonism that occurs following the hydrolysis of the prodrug that liberates the free acid that then activates the classic FP receptors in the target tissues. The shared characteristics of BP with other prostaglandin analogs, including the side effects of iris color darkening and eyelash changes, also would argue that BP exerts its biological actions by activating the FP receptor. Even if “prostamide” receptors were demonstrated to exist in the anterior uvea, the IOP effect of BP still can be more reasonably explained by its ability to activate FP prostanoid receptors following its demonstrated hydrolysis to its potent free acid.
In conclusion, we agree with the data presented by Cantor et al1 finding substantial, albeit somewhat lower,(2,3,13) concentrations of the free acid of BP or LP in aqueous after topical application in humans. However, we strongly disagree with their conclusions. Cantor et al,(1) like others,(2,3,13) have confirmed that BP is an inefficient prodrug that is hydrolyzed to its free acid to activate well-described FP prostanoid receptors resulting in IOP reduction. Postulation of the existence of enigmatic “prostamide” or yet to be identified unknown receptors is not necessary or warranted.
Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
Najam A. Sharif, Ph.D., Molecular Pharmacology Unit, Alcon Research, Ltd. Fort Worth, TX
Martin B. Wax, M.D., Research and Development, Ophthalmology Discovery Research, Alcon Laboratories, Fort Worth, TX; Department of Ophthalmology and Visual Sciences, University of Texas Southwestern Medical School, Dallas, TX
Johan Stjernschantz, M.D., Ph.D., Department of Neuroscience, Uppsala University Biomedical Center, Uppsala, Sweden
Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.
Dr. Camras was a consultant to Pfizer Ophthalmics. Drs. Sharif and Wax are employees of Alcon Laboratories. Dr. Stjernschantz was an employee of Pharmacia Ophthalmics.
Correspondence to: Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, 985540 Nebraska Medical Center, Omaha, NE 68198-5540
References:
1 Cantor LB, Hoop J, WuDunn D, et al. Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract. Br J Ophthalmol 2007;91:629-32.
2 Camras CB, Toris CB, Sjoquist B, et al. Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery. Ophthalmology Same 2004;111:2193-8.
3 Dahlin DC, Craven ER, Moster M, et al. Human aqueous humor concentrations of bimatoprost and bimatoprost free acid following topical ocular dosing of Lumigan (bimatoprost (17-phenyl-trinor-PGF2a) 0.03% ophthalmic solution) [abstract]. Invest Ophthalmol Vis Sci 2004;45:ARVO E-Abstract 2096.
4 Maxey KM, Johnson JL, LaBrecque J. The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist. Surv Ophthalmol 2002;47(Suppl 1):S34-S40.
5 Davies SS, Ju WK, Neufeld AH, et al. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther 2003;19:45-54.
6 Hellberg MR, Ke TL, Haggard K, et al. The hydrolysis of the prostaglandin analog prodrug bimatoprost to 17-phenyl-trinor PGF2a by human and rabbit ocular tissue . J Ocul Pharmacol Ther 2003;19:97-103.
7 Kriatchko A, Zhan G, Cheruvu N, et al. In vitro transport and hydrolysis of bimatoprost in bovine cornea [abstract]. ARVO 2003;B81.
8 Dahlin DC, Bergamini MVW, Curtis MA, et al. Bimatoprost hydrolysis to 17-phenyl PGF2a by rabbit and monkey ocular tissues, in vivo [abstract]. Invest Ophthalmol Vis Sci 2002;43:ARVO E-Abstract 4109.
9 Ota T, Aihara M, Saeki T, et al. The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice. Br J Ophthalmol 2007;91:673-6.
10 Crowston JG, Lindsey JD, Morris CA, et al. Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol Vis Sci 2005;46:4571-7.
11 Ota T, Aihara M, Narumiya S, et al. The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci 2005;46:4159-63.
12 Crowston JG, Lindsey JD, Aihara M, et al. Effect of latanoprost on intraocular pressure in mice lacking the prostaglandin FP receptor. Invest Ophthalmol Vis Sci 2004;45:3555-9.
13 Sjöquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 2002;47(Suppl 1):S6-S12.
14 Resul B, Stjernschantz J, Selén G, et al. Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids. Surv Ophthalmol 1997;41(Suppl 2):S47-S52.
15 Stjernschantz JW. From PGF2a-isopropyl ester to latanoprost: a review of the development of Xalatan: the Proctor Lecture. Invest Ophthalmol Vis Sci 2001;42:1134-45.
16 Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol 2001;432:211-3.
17 Sharif NA, Kelly CR, Crider JY, et al. Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells. J Ocul Pharmacol Ther 2003;19:501-15.
18 Sharif NA, Crider JY, Husain S, et al. Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation. J Ocul Pharmacol Ther 2003;19:437-55.
19 Sharif NA, Kelly CR, Crider JY. Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues. Invest Ophthalmol Vis Sci 2003;44:715-21.
20 Sharif NA, Kelly CR, Williams GW. Bimatoprost (Lumigan®) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracelluar Ca2+ mobilization studies . Prostaglandins Leukot Essent Fatty Acids 2003;68:27-33.
21 Sharif NA, Kelly CR, Crider JY. Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor. J Ocul Pharmacol Ther 2002;18:313-24.
22 Kelly CR, Williams GW, Sharif NA. Real-time intracellular Ca2+ mobilization by travoprost acid, bimatoprost, unoprostone, and other analogs via endogenous mouse, rat, and cloned human FP prostaglandin receptors. J Pharmacol Exp Ther 2003;304:238-45.
23 Stjernschantz J, Albert D, Hu D, et al. Mechanism and clinical significance of prostaglandin-induced iris pigmentation. Surv Ophthalmol 2002;47 (suppl 1):S162-S175.
When reading the article we were a bit surprised by the
extremely positive declaration of the clinical results after subthreshold
diode micropulse photocoagulation. The authors stated that
subthreshold diode micropulse laser photocoagulation minimises
chorioretinal damage in the management of CSMO and demonstrates a
beneficial effect on visual acuity and CSMO resolution (in 96% of all
treated eyes, n=...
When reading the article we were a bit surprised by the
extremely positive declaration of the clinical results after subthreshold
diode micropulse photocoagulation. The authors stated that
subthreshold diode micropulse laser photocoagulation minimises
chorioretinal damage in the management of CSMO and demonstrates a
beneficial effect on visual acuity and CSMO resolution (in 96% of all
treated eyes, n=95). However, we have
the strong feeling that the presented results may not support this
conclusion. Moreover, the basic mechanism of the proposed laser
interaction is unclear. It is most likely that
nothing than marginal thermal side effects occurred in the retina
during treatment.
Conventional laser therapy is regarded as effective in treating CSMO.
Unwanted side effects as e.g. induction of CNV or subretinal fibrosis
principally do not appear if laser parameters for threshold exposition are
carefully used. Generally a new laser method must measure against this gold
standard, so that at least comparable results are obtained. This seems not to be the case in the present article.
Conclusions such as "visual acuity was stable or improved in 85% of treated eyes" are questionable if Tab.2 shows stabilization in only 76.8% of eyes (+ < 3 ETDRS lines) and only 8.4% achieved significant better visual acuity (also 14.7% lost more
than 3 lines). Regarding Tab.1 and Tab.3 overall visual acuity
became worse and not better and nearly none of the p-values showed
significance (if p-value was significant visual acuity was worse).
As stated by the authors, the validity of this pilot study is
limited by its small size and retrospective nature. In fact no uniform
postoperative patient follow-up was performed and only the "last available
visual acuity measure" was taken for outcome assessment. This value was
obtained between 3 and 29 (mean 12.2 months), which underlines a high variability. In other words, the results
might only reflect the spontaneous untreated course of CSMO. Also
questionable is the postoperative gradation of CSMO as "worse, better and
resolved". There were no OCT scans taken
either pre- or post-operatively to verify macular thickness. Also,
angiography seems to be performed only in patients who appeared to need
additional treatment. Thus from none of the presented results could it be
objectively concluded that CSMO improved in 96% of eyes.
Finally it is
stated in the results section that in "79% of eyes exhibiting complete
resolution of CSMO postoperatively had significantly better visual
outcomes compared to 17% of eyes with persistent and 4% of eyes with
worsening macular oedema (table 8)". However, Tab.8 clearly demonstrates
that only 8% (n=6) with resolved oedema (n=75) gained 3 or more lines,
which is significantly better, but that 84% (n=63) had only stable visual
acuity within + 3 lines visual acuity change, whereas also additional 8%
had significant vision loss (Tab.8). Thus the proposed positive clinical
result in terms of CSMO resolution and visual acuity improvement could not
been followed.
Independent of clinical results, the mechanism of the
micropulse laser method is unclear. Since there
were no ophthalmoscopically nor angiographically visible laser
damage in the tissue, one has to ask, what happens to the fundus
during treatment? As proven in many experimental
studies conventional laser photocoagulation leads to primary destruction
of the RPE since it absorbs about 60% of the energy from a green laser
beam. The RPE damage is repaired within 7 days by migration and
proliferation of neighbour cells and this seems to lead to an enhanced
pump-function of the new RPE cells leading to resolution of CSMO. Bruch´s
membrane usually stays intact, thus no potential CNV induction is
expected. Because of the long laser exposition times of about 100ms during
irradiation, thermal damage to photoreceptors leads to
irreversible laser scotoma.
In both laser treatments (thermal laser and SRT) the primary RPE
damage can be demonstrated by angiography revealing leakage from the
damaged RPE site, thus the mode of action of the laser treatment can
clearly be proven and is comprehensible. This is not the case in the
article by Luttrull et al. who used repetitive laser pulses of 100µs pulse
duration (which are - at required energies for RPE damage - too long to
spare photoreceptors) within an envelope of 300ms. Temperature
calculations for the laser parameters set in this article reveal an
increase of tissue temperature of 1.8°C per pulse within the laser spot
(taken into account that there is just a 20% energy absorption within the
RPE/choroid complex at 810nm wavelength). The mean temperature increase in
the centre of the laser spot is - due to heat accumulation at the high
repetition rate of 500Hz - about only 11°C after 300ms. Neither thermal
nor thermomechanical based tissue alterations are expected for this low
short time temperature increase. Consequently it might be not remarkable
that - as also stated in the discussion section - the angiographical
visible diabetic leakage after therapy mostly persisted. The discussion of possible mechanisms of this kind of
micropulse laser irradiation as e.g. up- and down- regulation of different
growth factors or heat-shock proteins is speculative.
We read with keen interest the article by CMG Cheung, OM Durrani and
PI
Murray on the safety of anterior chamber paracentesis in patients with
uveitis.[1]
We appreciate their efforts to describe a method that can be easily and
safely
performed on an out-patient basis.
Although the authors evaluated the safety of AC paracentesis
technique, the
volume of aqueous that can be safely collect...
We read with keen interest the article by CMG Cheung, OM Durrani and
PI
Murray on the safety of anterior chamber paracentesis in patients with
uveitis.[1]
We appreciate their efforts to describe a method that can be easily and
safely
performed on an out-patient basis.
Although the authors evaluated the safety of AC paracentesis
technique, the
volume of aqueous that can be safely collected was not addressed. Studies
have shown that compared to Caucasian and Black counterparts, the anterior
chamber angles of older Chinese are significantly narrower [2,3] and the iris joins the scleral wall more anteriorly.[4] Therefore, since a vast majority
of the
patients seen at our center are Asians, withdrawing 0.2 cc of aqueous may
not only be technically difficult but unsafe as well.
In addition, excessive withdrawal of aqueous may induce hypotony with
resultant hyphema. The latter complication occurred in 2 out of the 34
eyes
which underwent AC paracentesis at the Singapore National Eye Centre from
the year 2003 up to this writing. Hyphema, which has been found to occur
spontaneously in anterior uveitidies including herpetic iritis,[5] was
also
encountered post AC paracentesis in an eye with herpetic iritis in another
study.[6] Blood in the sample may be a source of contamination which
occurred in one of our specimens, requiring a repeat of the procedure;
this
time, withdrawing a smaller volume. The information regarding sample
volume recommendations would be of great clinical value not just to the
Uveitis specialist but to any ophthalmologist who performs the procedure
regardless of indication.
At our center, we utilize a similar method under slit lamp guidance
during
which patients experience very minimal discomfort. However, several
differences in technique are worth noting. 1. To prevent infection,
sterile
gloves are used. The surgeon also wears a surgical mask during the
procedure. 2. Eyelids are retracted using a lid speculum. 3. A gauge 30
instead of a gauge 27 needle is used. We note less resistance upon
corneal
penetration. 4. The corneal limbus is penetrated below the horizontal
meridian and aimed towards the 6 o’clock position to avoid lens puncture. 5.
We aspirate a 0.1 to 0.2 cc sample which is submitted for PCR and
intraocular
antibody analysis. If warranted, samples are submitted for additional
studies
such as fluid cytology or cultures. We stop aspirating before 0.2 cc is
withdrawn if we see the iris-lens diaphragm bowing anteriorly or corneal
folds appearing. Aspiration is preferred to passive withdrawal as this
procedure is less likely to be associated with aspiration of blood and is
also
comfortable for the patient. 6. A tuberculin syringe is managed single-
handedly by the surgeon. It is held between the thumb and middle fingers,
with the index finger along the rod adjacent to the flat end of the
plunger. 7. We instruct the patient to fixate on the surgeon’s ear opposite the eye
being
examined instead of stabilizing the globe with a pair of forceps.
Nevertheless, we commend the authors for emphasizing the value of a
seemingly simple and commonly performed procedure which greatly affects
the diagnosis and management of ocular pathologies.
References
1. C M G Cheung, O M Durrani, and P I Murray
The safety of anterior chamber paracentesis in patients with uveitis
Br J Ophthalmol 2004; 88: 582-583.
2. NG Congdon, PJ Foster, S Wamsley, J Gutmark, SK Seah, GJ Johnson
and AT
Broman. Biometric gonioscopy and the effects of age, race and sex on the
anterior chamber angle. Br J Ophthalmol 2002; 86: 18-22.
3. TY Wong, PJ Foster, TP Ng, JM Tielsch, GJ Johnson, SK Seah.
Variations in
ocular biometry in an adult Chinese population in Singapore: the Tanjong
Pagar Survey. Invest Ophthalmol Vis Sci 2001Jan; 42 (1): 73-80.
4. Y Oh, S Minelli, G Spaeth and W Steinman. The anterior chamber
angle is
different in different racial groups: a gonioscopic study. Eye 1994; 8: 104-108.
5. D Fong and M Raizman. Spontaneous hyphaema associated with
anterior
uveitis. Br J Ophthalmol 1993; 7: 635-638.
6. A Van der Lelij and A Rothova. Diagnostic anterior chamber
paracentesis
in uveitis: a safe procedure? Br J Ophthalmol 1997; 81: 976-979.
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
We welcome the latest estimates of global visual impairment (VI). (1)
Posterior segment eye diseases (PSED): Glaucoma; Age-Related Macular
Degeneration (ARMD); and Diabetic Retinopathy (DR) are now recognised as a
major cause of VI worldwide and are more prevalent than infectious causes
of VI such as trachoma and corneal ulcers. The majority of data collated
in the last ten years from which these figures are estimated like...
We welcome the latest estimates of global visual impairment (VI). (1)
Posterior segment eye diseases (PSED): Glaucoma; Age-Related Macular
Degeneration (ARMD); and Diabetic Retinopathy (DR) are now recognised as a
major cause of VI worldwide and are more prevalent than infectious causes
of VI such as trachoma and corneal ulcers. The majority of data collated
in the last ten years from which these figures are estimated likely
underestimate the true prevalence of PSED for three reasons: (a) The
majority of surveys used the WHO coding instructions, which use the
"principal disorder responsible for visual loss in the individual after
considering disorders in either eye which are most amenable to treatment
or prevention"(2), i.e. if a patient has co-existent PSED with cataract it
will be deemed that cataract is the primary cause of VI. Therefore most VI
prevalence data available in which cataract is the primary cause will
underestimate the actual prevalence of PSED; (b) The Rapid Assessment of
Avoidable Blindness (RAAB) methodology, which forms one of the most
employed methods of gathering VI data in the last ten years (20 published
from Africa, Latin America and Asia) does not allow for accurate diagnosis
of PSED or differentiation between PSED; and (c) VI surveys have been
designed to diagnose the cause of disease in those with varying degrees of
visual impairment (?6/18 Snellen acuity) and thus pre-visually impairing
disease is not detected. This is particularly important in the detection
of PSED where cessation rather than cure is currently our only realistic
management option. If VISION 2020: The Right to Sight's aims of
alleviating suffering from avoidable blindness is to be met, the growing
impact of PSED needs to be a focus of policy makers.
Dear Editor,
An aim to provide an optimised keratoprosthesis, with excellent biointegration, and all other properties meeting ideal requirements, is one we share with the authors of the recent article entitled “Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials”.[1] However, the current paper includes some points that require clarificatio...
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...
We thank Dr. Shoaib for his interest in our article.1 We agree that there are various causes of graft rejection and that performing an endothelial keratoplasty (EK) would not resolve the rejection. To clarify our wording for the article, patients who developed endothelial graft rejection with subsequent endothelial failure were offered EK under their penetrating keratoplasty (PK). The rejection episode was resolved at...
Dear Editor
Saito et al. present a patient with Terson’s syndrome and vitreous hemorrhage who underwent pars plana vitrectomy and was noted postoperatively to have developed an ophthalmic artery occlusion. They propose that the ophthalmic artery was occluded by the spontaneous release of an embolus from an atheromatous plaque in the internal carotid artery. This seems unlikely in a 39-year-old male without a...
Dear Editor,
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmat...
Dear Editor,
When reading the article we were a bit surprised by the extremely positive declaration of the clinical results after subthreshold diode micropulse photocoagulation. The authors stated that subthreshold diode micropulse laser photocoagulation minimises chorioretinal damage in the management of CSMO and demonstrates a beneficial effect on visual acuity and CSMO resolution (in 96% of all treated eyes, n=...
Dear Editor
We read with keen interest the article by CMG Cheung, OM Durrani and PI Murray on the safety of anterior chamber paracentesis in patients with uveitis.[1] We appreciate their efforts to describe a method that can be easily and safely performed on an out-patient basis.
Although the authors evaluated the safety of AC paracentesis technique, the volume of aqueous that can be safely collect...
Dear Editor
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 welcome the latest estimates of global visual impairment (VI). (1) Posterior segment eye diseases (PSED): Glaucoma; Age-Related Macular Degeneration (ARMD); and Diabetic Retinopathy (DR) are now recognised as a major cause of VI worldwide and are more prevalent than infectious causes of VI such as trachoma and corneal ulcers. The majority of data collated in the last ten years from which these figures are estimated like...
Dear Editor
A question: can we safely say that in children with pure astigmatism cycloplegic refraction is not required?
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