Dear Editors

We read with great interest, the illuminating article by Drs Gomi, Sawa and Tano. Our limited experience (4 Afro-American patients) with intravitreal bevacizumab (IVB) for polypoidal vasculopathy (PPV) has been more positive.

We had reported the first success early this year in terms of lasting remission [1]. Furthermore, I enclose details on another patient who had PPV OU, in all likelihood clinically. ICG confirmation was not possible due to dye non availability. The details are evident in the legend and the therapeutic approach was IVB Q 6 weeks OD x 4 and intravitreal triamcinolone x1.OS was managed with IVB alone X 3. Verteporfin (PDT) was not a consideration OD and the pigment epithelial detachment OS forced the use of an anti VEGF agent empirically off label. There are no active lesions OU for about 3 months.

It is unclear to us if our results were a function of ethnicity or more limited disease (OS).We respectfully opine that a prospective trial IVB +/- PDT may be useful, possibly more so in the US population with a wide ethnic base. We are in the process of finalizing such a study.

Fig 1 A. Visual acuity (VA) OD: Hand motion, with massive subretinal hemorrhage (SRH). VA OS 20/30, superonasal hemorrhagic pigment epithelial detachment (HPED)

Fig 1 B. OD VA 20/200, with significant clearing of the SRH and fibrosis of HPED. OS VA unchanged, HPED resolved entirely with minimal fibrosis

References

1.Ghajarnia M, Kurup S et al: The therapeutic effects of intravitreal bevacizumab in a patient with recalcitrant idiopathic polypoidal choroidal vasculopathy.Semin Ophthalmol. 2007 Apr-Jun;22(2):127-31. PMID: 17564935

Dear Editor,

We want to congratulate Drs. S.L. Liao, et al., on their excellent paper entitled "Surgical coverage of exposed hydroxyapatite implant with retroauricular myoperiosteal graft". 1 In the paper they described "a newly developed technique with an autogenous retroauricular myoperiosteal graft" to repair defects with exposed hydroxyapatite implants.

However, they did not mention our retrospective, multicentered work published in 1999 in The American Journal of Ophthalmology. 2 In this paper we discussed a technique very similar to that of Dr. Liao and coworkers in which we covered exposed hydroxyapatite implants with a retroauricular muscle complex graft (complex refers to muscle, fascia, and vascular tissues). As with Dr. Liao's, et al., technique, we placed our retroauricular graft between the implant and the overlying Tenon's capsule and conjunctiva and the latter tissues migrated over the graft within several weeks.

We also used the thicker, stronger, retroauricular tissues anteriorly combined with the thinner tissues overlying the pinna for additional volume post-enucleation. This also facilitated the insertion of the spicular hydroxyapatite into the orbit post-enucleation. Additionally, we used only the thicker tissue between the mastoid and the overlying dermal flap anteriorly as a "cap graft" post-enucleation. Our techniques involved 83 patients with a mean follow-up of 36 months.

One difference in our technique and that of Dr. Liao and associates was that they used periosteum in their retroauricular complex graft for added strength and vascularity. We were reluctant to use periosteum in our grafts for fear of unduly compromising the vascularity of the underlying mastoid bone and the overlying dermal flap. The authors do not state that this occurred in their series of 9 patients in the duration of over one year. Accordingly, this may be a non-problem and it would appear that both techniques are efficacious. However, incorporation of the periosteum in the retroauricular myoperiosteal graft may not be necessary because of the strong, thick complex of muscle and fascia and vascular tissues between the underlying periosteum and overlying dermal flap.

Another difference in our technique is that we did not have to encounter active infections at the time of surgery and did not find it necessary to burr down the implant anteriorly. By undermining conjunctiva and Tenon's capsule the approximate distance of the equator of the globe, we have found that there is sufficient space for the graft to fit "flush tight" in the recipient bed.

The authors and readers might read with interest an article entitled "Variability of the postauricular muscle complex - analysis of 40 hemi-cadaver dissections" by Guerra, et al., including myself. 3 This article identifies and analyzes variations in the patterns of the posterior auricular muscle complex and the relations of the fascial contributions.

In our opinion, a signature thought would be to wrap a hydroxyapatite orbital implant with a strong autogenous graft of the surgeon's choice anteriorly to create a barrier between the implant and the overlying conjunctiva and Tenon's capsule to significantly decrease the chance of implant exposure.

Our technique has been discussed in a presentation of the 9th annual meeting of the European Society of Ophthalmic Plastic and Reconstructive Surgery in Dublin, Ireland, 1991, a presentation at the 23rd annual Scientific Symposium of the American Society of Ophthalmic, Plastic, and Reconstructive Surgery in Dallas, Texas, 1992, and discussed as a scientific video presentation at the annual meeting of the American Academy of Ophthalmology, 1994.

References

1. Liao S.L., Kao S.C.S, Tseng J.H.S., et al. Surgical coverage of exposed hydroxyapatite orbital implants with retroauricular myoperiosteal graft. Br J Ophthalmol 2005;89:92-95.

2. Naugle T.C., Lee A.M., Haik B.G., et al. Wrapping hydroxyapatite orbital implants with posterior auricular muscle complex grafts. Am J Ophthalmol 1999;128:495-501.

3. Guerra A.B., Metzinger S.E., Metzinger R.C., et al. Variability of the postauricular muscle complex - analysis of 40 hemicadaver dissections. Arch Facial Plast 2004;6:324-344.

Thomas C. Naugle Jr, M.D.
Department of Ophthalmology,
Tulane University School of Medicine,
New Orleans, LA, USA.

Dear Editor,

We thank Dr. Camras for his interest in our report on levels of bimatoprost and its free acid in the aqueous humour of cataract patients after a single topical dose of bimatoprost [1] and welcome the opportunity to respond to his comments. We are in agreement with Dr. Camras that the results of our study [1] and those of his previously reported study [2] are similar, showing low nanomolar concentrations of 17-phenyl PGF2alpha (bimatoprost acid) in the aqueous humour. There is no question that bimatoprost acid is a metabolite of bimatoprost. The issue is whether bimatoprost acid levels account for the IOP-lowering activity of bimatoprost. The evidence suggests that they are insufficient to do so. As Dr. Camras stated in his correspondence: “bimatoprost yields peak free acid concentrations in the aqueous 3 to 6 times lower than latanoprost acid”. It is accepted that the biological effects of latanoprost are exerted by latanoprost acid: the relatively high concentration of latanoprost acid achieved after latanoprost dosing [1-3] is sufficient to activate a substantial proportion of the prostaglandin FP receptors present in the target tissues and account for the IOP-lowering effect of latanoprost. It is difficult to understand, however, how the much lower levels of bimatoprost acid achieved could be believed to account for the IOP-lowering effect of bimatoprost, particularly since bimatoprost has reduced IOP more effectively than latanoprost in some clinical studies [4,5] and is effective in patients who fail to respond to latanoprost [6,7].

Dr. Camras contends that there is overwhelming evidence that bimatoprost acid is more potent than latanoprost acid at prostaglandin FP receptors, but the 10 references he cites to support this statement [8-17] include 3 studies in which bimatoprost acid and latanoprost acid were not compared [8-10], 3 reviews from a single laboratory that reported greater functional potency of bimatoprost acid compared with latanoprost acid in the cat iris sphincter preparation [11-13], and a study that found 3-fold lower functional potency of bimatoprost acid compared with latanoprost acid in human trabecular meshwork cells (EC50 of 112 nM vs 34.7 nM) [14]. Dr. Camras fails to note that the study showing very high functional potency of bimatoprost acid in human HEK-293 cells [15] used transfected cells with overexpression of the FP receptor. Bimatoprost acid was reported to be very potent in stimulating phosphoinositide hydrolysis in nontransfected mouse 3T3 and rat A7r5 cells [16]. However, in other studies by the same laboratory, bimatoprost acid was 10-fold less potent in mobilizing intracellular Ca++ in these cell lines [9,18]. Reported potency values in human ciliary muscle cells were 3.8 nM and 3.6 nM for bimatoprost acid and 124 nM and 198 nM for latanoprost acid [16,17], but bimatoprost acid was less effective than latanoprost acid in stimulating MAP kinase at 100 nM [17]. In summary, review of the literature does not reveal compelling evidence that bimatoprost acid is more potent than latanoprost acid. In fact, in human trabecular meshwork cells as well as human fibroblasts expressing endogenous, nontransfected prostaglandin FP receptors, bimatoprost acid and latanoprost acid have shown similar functional potency [1,14,16]. The results with trabecular meshwork cells are more clinically relevant because one pathway by which bimatoprost is believed to reduce IOP is through effects on the trabecular meshwork [19]. Wan et al [20] have shown that bimatoprost produces a decrease in outflow facility, which is blocked by a prostamide antagonist, in a human anterior segment organ culture model.

Camras et al proposed that the 22 nM aqueous humour concentration of bimatoprost acid is sufficient to lower IOP based on its agonist potency. Following his line of reasoning, the 100 nM aqueous humour concentration reported for latanoprost acid should not be sufficient to account for the IOP lowering, based on EC50 potency values of 124 nM and 198 nM in ciliary muscle cells. In fact, the data suggest that aqueous humour concentrations of bimatoprost acid are not sufficient to activate the FP receptor for effective diurnal IOP lowering, particularly taking into account the aqueous humour concentration of latanoprost acid and respective agonist potencies. The most plausible explanation for the greater efficacy of bimatoprost, despite lower levels of bimatoprost acid in the aqueous humor, is that bimatoprost reduces IOP through a mechanism other than or in addition to production of bimatoprost acid. There is excellent evidence from animal studies that the intact bimatoprost molecule has biological activity distinct from the activity of prostaglandin FP agonists [21]. For example, in a dissociated cat iris preparation, a specific population of cells responds to bimatoprost with an increase in calcium levels, and a separate and distinct population of cells responds to bimatoprost acid with an increase in calcium levels [22]. The selective stimulation of different cells in the same preparation by bimatoprost and prostaglandin FP agonists suggests the involvement of receptors for bimatoprost distinct from prostaglandin FP receptors. The recent identification of an antagonist that blocks the effects of bimatoprost, but not bimatoprost acid or latanoprost acid, in the cat iris preparation has provided additional evidence for biological activity of bimatoprost mediated through novel receptors [23]. Although studies in prostaglandin FP receptor knockout mice have shown that the intact FP receptor gene is needed for the IOP response to bimatoprost in the mouse eye [24,25], the IOP response does not appear to be mediated by interaction of bimatoprost acid with prostaglandin FP receptors, because there is minimal hydrolysis of bimatoprost in the mouse eye [25]. Instead, intact bimatoprost may interact with an alternatively spliced prostaglandin FP receptor pharmacologically distinct from the well-characterized FP receptor [26].

The mechanism of action of bimatoprost is of considerable interest because bimatoprost appears to be the most effective medication now available for reducing IOP [4,27]. Further drug discovery may well aim to develop drugs that take advantage of a similar mechanism of action. For this reason it is important to consider the data from both clinical and laboratory studies and to be open-minded in reaching reasonable conclusions. To assume that the mechanism of action of bimatoprost is the same as that of latanoprost and ignore or misinterpret evidence inconsistent with that assumption is neither good science nor helpful to clinical advancements in lowering IOP.

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 2004;111:2193-8.

3. Sjöquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 2002;47(Suppl 1):S6-12.

4. Denis P, Lafuma A, Khoshnood B, et al. A meta-analysis of topical prostaglandin analogues intra-ocular pressure lowering in glaucoma therapy. Curr Med Res Opin 2007;23:601-8.

5. Dirks MS, Noecker RJ, Earl M, et al. A 3-month clinical trial comparing the IOP-lowering efficacy of bimatoprost and latanoprost in patients with normal-tension glaucoma. Adv Ther 2006;23:385-94.

6. Gandolfi SA, Cimino L. Effect of bimatoprost on patients with primary open-angle glaucoma or ocular hypertension who are nonresponders to latanoprost. Ophthalmology 2003;110:609-14.

7. Williams RD. Efficacy of bimatoprost in glaucoma and ocular hypertension unresponsive to latanoprost. Adv Ther 2002;19:275-81.

8. Sharif NA, Kelly CR, Williams GW. Bimatoprost (Lumigan®) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracellular Ca2+ mobilization studies. Prostaglandins Leukot Essent Fatty Acids 2003;68:27-33.

9. Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol 2001;432:211-3.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. Brubaker RF. Mechanism of action of bimatoprost (Lumigan). Surv Ophthalmol 2001;45(Suppl 4):S347-51.

20. Wan Z, Woodward DF, Stamer WD. Bimatoprost effects on conventional drainage tissues. Invest Ophthalmol Vis Sci 2007;48:E- Abstract 3919. Full manuscript in press.

21. Chen J, Senior J, Marshall K, et al. Studies using isolated uterine and other preparations show bimatoprost and prostanoid FP agonists have different activity profiles. Br J Pharmacol 2005;144:493-501.

22. Spada CS, Krauss AH, Woodward DF, et al. Bimatoprost and prostaglandin F(2 alpha) selectively stimulate intracellular calcium signaling in different cat iris sphincter cells. Exp Eye Res 2005;80:135- 45.

23. Woodward DF, Krauss AH, Wang JW, et al. Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris. Br J Pharmacol 2007;150:342-52.

24. 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.

25. 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.

26. Liang Y, Li C, Guzman VM, Woodward DF. Identification of alternatively spliced variants of human prostaglandin FP receptor mRNA [Abstract 639.4]. Presented at: Experimental Biology 2005 and XXXV International Congress of Physiological Sciences, March 31-April 6, 2005; San Diego, CA.

27. Cantor LB, Hoop J, Morgan L, et al. Intraocular pressure-lowering efficacy of bimatoprost 0.03% and travoprost 0.004% in patients with glaucoma or ocular hypertension. Br J Ophthalmol 2006;90:1370-3.

Dear Editor,

We read with great interest the paper by Senoo et al1 and we would like to draw your attention to a complication of the approach described. Some years ago, relying on our experience in deep sclerectomy, we tried a similar approach in two cases: we first performed a double scleral flap exposing Descemet membrane at limbus and then started the dissection. Although in both cases we had a good exposure of Descemet's membrane at surgery without perforation, in one patient we observed an unusual complication on the first postoperative day: blood was present between the donor cornea and the recipient Descemet's membrane marking a channel from the sclerotomy site. We had to reopen the scleral flaps and wash out the blood in the interface by introducing air in the anterior chamber. The patient did not suffer any further complications after this treatment.

We discontinued this approach not only for the possibility of this complication but also because in our experience the time required to prepare the limbal access is equal to that of a classical mechanical procedure. The high percentage of double anterior chamber reported for the limbal approach (45%) is another point worth consideration. Since we observe a rate of less than 3% with mechanical dissection, the suspecion arises that the higher rate reported for the new technique may be due to either viscoelastic persistence in the interface or filtration through trabeculodescemetic membrane at the sclerotomy site: in the presence of an intact descemetic membrane and functioning endothelium, percolation of aqueous humor at the sclerotomy site may maintain a double chamber. It would be of interest to verify this hypothesis with ultrasound biomicroscopy.

Finally, we wonder why the author did not try to resolve the long persistence of a double chamber (often a sign of unrecognized perforation) by introducing air in the anterior chamber. In this procedure, the risk of a pseudo Urrets-Zavalia syndrome2 may be controlled by both avoiding overinflation of the chamber and strictly monitoring the patient over hours.

Marco Nardi, Gianluca Guidi, Marino De Luca
Neuroscience Department, University of Pisa, Pisa, Italy

Correspondence to:
M Nardi MD
Pza Varanini 2
55100 Lucca Italy
marco.nardi@med.unipi.it

References:

1. Senoo T, Chiba K, Terada O et Al. Deep lamellar keratoplasty by deep parenchima detachment from the corneal limbs. Br J Ophthalmol 2005; 89:1597-1600.

2. Maurino V, Allan BD, Stevens JD, Tuft SJ. Fixed dilated pupil (urrets-Zavalia syndrome) after air/gas injection after deep lamellar keratoplasty for keratoconus. Am J Ophthalmol 2002; 133(2): 266-8.