Dear Editor,

We read with great interest the article by Bernauer et al [1] on the use hyaluronate artificial tear formulation �Hylo-Comod� favours the formation of corneal calcification related to the phosphate content of eye medications and frequent instillation. We agree with their conclusion and would like to highlight that in the setting of dry chronically inflamed eyes phosphate containing topical preparations should be used with caution. Even less frequent instillation of phosphate containing topical preparation [prednisolone phosphate (0.5%) four times a day] in our experience has resulted in calcium deposits within 48 hours in an eye with secondary Sjogren�s syndrome (following Graft versus Host disease) in a 23 year old Caucasian lady following penetrating keratoplasty. This lady underwent a total of three penetrating keratoplasties. The first was due to a perforating corneal ulcer (unassociated with any calcification), the second and third were due to infection of graft via epithelial defect over calcium plaques leading on to perforation. Interestingly, she had intensive topical �Hylo-prompt� preoperatively prior to her first graft. In retrospect, we believe topical phosphate use following the first and second corneal transplant in this setting along with an epithelial defect resulted in the formation of a band keratopathy. Histopathological analysis of the both corneal button specimen showed extensive mineralisation 2 mm from the margin extending through the entire thickness of corneal stroma with associated nuclear debris gram positive cocci and inflammatory cells. The role of phosphate being the offending agent in our case was amply demonstrated by the maintenance of clear cornea on switching to prednisolone acetate preparation following the third transplant.

As mentioned by Bernauer et al, Huige et al in 1991[2] first described an association of band keratopathy in his series of eight patients to a combination of steroid (with and without preservatives) and beta blocker use and suggested an interaction between simultaneously given steroid and beta-blocking agents, giving rise to calcium phosphate precipitates in cornea. Taravella et al in 1994 [3] first reported five case of topical steroid-phosphate induced band keratopathy. Scholtzer- Schrehardt et al implicated topical steroid-phosphate preparation to the formation of calcareous degeneration instead [4] and Lavid and co authors described two cases with spontaneous calcific band keratopathy and calcareous degeneration coexisting and occurring in eyes with severe dry eyes secondary to GVH disease and Sjogren�s syndrome [5]. In a double- masked experimental animal model Schrage et al [6] induced corneal calcification following topical phosphate buffer irrigation of eyes after alkali burn. Common to most reported cases including by Bernauer et al [1] of either band keratopathy or calcareous degeneration are inflamed and dry eyes due to variety of reasons with epithelial defect and normal serum biochemistry. We feel that chronically inflamed and dry eyes are at risk of developing calcium deposition when exposed to phosphate containing topical preparations. We recommend that in this setting such preparation should be used with caution especially in cases with epithelial defect. Should such medication be unavoidable they should be withdrawn at the first hint of mineralisation. We commend and support Bernauer et al�s recommendation that declaration of the amount of phosphate buffers on drop bottles and in the inserted leaflets should be introduced.

References

1. Bernauer, W., et al., Corneal calcification following intensified treatment with sodium hyaluronate artificial tears. Br J Ophthalmol, 2006. 90(3): p. 285-8.

2. Huige, W.M., et al., Unusual deposits in the superficial corneal stroma following combined use of topical corticosteroid and beta-blocking medication. Doc Ophthalmol, 1991. 78(3-4): p. 169-75.

3. Taravella, M.J., et al., Calcific band keratopathy associated with the use of topical steroid-phosphate preparations. Arch Ophthalmol, 1994. 112(5): p. 608-13.

4. Schlotzer-Schrehardt, U., et al., Corneal stromal calcification after topical steroid-phosphate therapy. Arch Ophthalmol, 1999. 117(10): p. 1414 -8.

5. Lavid, F.J., et al., Calcareous corneal degeneration: report of two cases. Cornea, 1995. 14(1): p. 97-102.

6. Schrage, N.F., et al., Phosphate buffer in alkali eye burns as an inducer of experimental corneal calcification. Burns, 2001. 27(5): p. 459- 64.

Dear Editor,

Thank you for writing and giving us the opportunity to further comment on our case series and investigations. We wish to put several misquotations right, respond to the accusation of inappropriate dosage, comment on the declaration of ingredients, explain our case description and substantiate the necessity to publish this case series.

Please note that we described five and not six cases. The patient described as case 1 used at some stage the Hylo-Comod drops every ten to fifteen minutes, summarised in Table 1 as "up to 100x/day". This is not the same as "more than 100 times" as you quote. Ofloxacin (Floxal) was used and not norfloxacin. Dexamytrex eye drops were only used in a small dosage in case 3 and 4. Several measures were taken when corneal calcification occurred: EDTA drops were introduced, phosphate-buffered Hylo-Comod stopped, dexamethasone phosphate replaced by prednisolone acetate, superficial keratectomy attempted and finally penetrating keratoplasties carried out. In contrast to what you indicate, we did not warn that phosphate containing drops may lead to corneal epithelial defects, but we stated: "that topical preparations, high in phosphate, may cause severe adverse effects when used very frequently and on a damaged corneal surface".

Frequent application of artificial tear products is an important measure in the treatment of ocular surface disease with keratoconjunctivitis sicca. In severe cases, artificial tears are typically applied hourly or more frequently. The Swiss data sheet for Hylo -Comod suggests a dosage individualised to the patient's needs [1]: "In general, Hylo-Comod is instilled three times per day in both eyes. With more severe symptoms Hylo-Comod can be applied without reservations more frequently". This recommendation was followed. We do not share your view that we used the artificial tear preparation Hylo-Comod off label.

The ingredients of Hylo-Comod are declared on the data sheet and the inserted information leaflet. Unfortunately, European legislation does intend a quantitative declaration of the pharmaceutically active agent only, but no quantification of the adjuvants. The lack of such information on the buffering system led to the described severe corneal complications [2]. We did not expect that the phosphate concentration in Hylo-Comod exceeds the concentration of alternative artificial tear products or of the physiological tear film more than fifty times [3]. Such concentrations put the time interval between applications into perspective.

Full-thickness corneal calcification following phosphate-rich eye drops may develop as rapidly as within 48 hours. Table 1 gives an overview on the time course of corneal calcification, and highlights the difference to the well-known (post-)inflammatory superficial band keratopathies that form over months and years. Please note that this table summarises the process of corneal calcification, whereas the text section describes the time course of ocular disease.

There are indeed several clues in the ophthalmic literature that point to the hazard of high phosphate concentrations on a damaged corneal surface. Whereas the role of phosphate buffers in irrigating solutions has been studied systematically by your group [4], the investigation of topical medications has only started. To our knowledge, our papers are the first that provide information on the phosphate concentrations in ophthalmic drop preparations [2,3]. This does not only help in the interpretation of our case series, but also in the selection of eye medication and in the clarification of previous studies. The combination of amniotic membrane transplantation and phosphate-rich lubrication bears a particular risk for corneal calcification: Anderson et al. described fifteen patients (12.8%) that developed calcification on phosphate-rich lubrication (Hylo-Comod among others) [5], whereas other groups have not encountered such problems (J.K.G. Dart, personal communication).

The aim of our publication is the prevention of sight threatening corneal complications. Ethical considerations prompted us to inform also the Head of Ursapharm Arzneimittel well ahead of publishing, hoping that the company would consider our advice to reformulate their products which contain phosphate concentrations as high as 160 mmol/l [6].

Good pharmaceutical practice would mean that the product information gives a quantitative declaration of the phosphate buffers, particularly so, if their concentration allows restricted use only.

References

1. Arzneimittelkompendium der Schweiz 2006. Documed, Basel, Switzerland 2006; 1538-1539.

2. Bernauer W, Thiel MA, Kurrer M, Heiligenhaus A, Rentsch KM, Schmitt A, Heinz C, Yanar A. Corneal calcification following intensified treatment with sodium hyaluronate artificial tears. Br J Ophthalmol 2006; 90: 285- 288

3. Bernauer W, Thiel MA, Langenauer UM, Rentsch KM (2006) Phosphate concentration in artificial tears. Graefe's Arch Clin Exp Ophthalmol DOI: 10.1007/s00417-005-0214-1

4. Schrage NF, Schloßmacher B, Aschenberner W, et al. Phosphate buffer in alkali eye burns as an inducer of experimental corneal calcification. Burns. 2001;27:459-464.

5. Anderson SB, de Souza RF, Hofmann-Rummelt C, Seitz B. Corneal calcification after amniotic membrane transplantation. Br J Ophthalmol 2003; 87: 587-591.

6. Bernauer W, Thiel MA, Rentsch KM. Phosphate in ophthalmologischen Präparaten. Ophthalmologe (in press).

W. Bernauer1, M. A. Thiel1, A. Heiligenhaus2, A. Yanar1 , K. M. Rentsch3

1 Department of Ophthalmology, University of Zürich, Switzerland
2 Department of Ophthalmology at St. Franziskus Hospital, Münster, Germany
3 Institute of Clinical Chemistry, University of Zürich, Switzerland

Correspondence
Prof. Dr. Wolfgang Bernauer
OMMA Eye Center and University of Zürich
Theaterstrasse 2
CH-8001 Zürich
SWITZERLAND

Tel ++41 44 256 80 10
Fax ++41 44 256 80 19
e-mail: wolfgang.bernauer@hin.ch

All the authors, W. Bernauer, M. A. Thiel, A. Heiligenhaus, A. Yanar, and K. M. Rentsch, confirm herewith that there are no competing interests.

Dear Editor,

We read with interest the article by Wong T.Y. et al[1], which studied a non-diabetic population consisting of 7992 people aged 49-73 years. Non-mydriatic retinal photographs of one eye were taken and graded for retinopathy lesions using to standardised protocols. Surprisingly, the presence of typical retinopathy lesions (microaneurysms or retinal haemorrhages) in persons without diabetes did not significantly predict subsequent development of diabetes over a period of 3.5 years. Incident diabetes developed in 4.7% and 3.6% of persons with and without retinopathy lesions at baseline, respectively, with a multivariate adjusted odds ratio, OR, 1.1, 95% confidence interval, CI, 0.7-1.9. However, in persons with a family history of diabetes, presence of retinopathy lesions at baseline predicted a doubling of the risk of incident diabetes (OR 2.0, CI 1.1-3.8).

We previously reported findings from the Blue Mountains Eye Study cohort (BMES, n=3654) that the 5-year risk of developing diabetes in persons without diabetes but with retinopathy lesions at baseline was 3.5% (7/202).[2] The BMES examined 3654 participants at baseline (1992-94) and re-examined 2335 participants (75% of survivors) 5 years later (1997-99). Dilated 6-field retinal photographs of all participants were taken at the baseline and follow up examinations. Diabetes was diagnosed either from medical history or fasting blood glucose >=7.0 mmol/L at examination. Of the baseline participants without diabetes, 202 had retinopathy lesions (haemorrhages, microaneurysms, soft and hard exudates). Our 3.5% diabetes incidence over 5 years in this group is relatively similar to the 4.7% diabetes incidence over 3.5 years reported by Wong T.Y. et al[1] in persons with retinopathy lesions at baseline. These consistent findings suggest that retinopathy lesions occurring in persons without diabetes are likely to have multiple aetiologies. In persons with a family history of diabetes, retinopathy lesions may indicate a pre-clinical stage of diabetes. In the great majority of persons without diabetes, however, retinopathy lesions are not necessarily linked to blood glucose. Reports from the BMES[3] and Hoorn Study[4] showed that baseline impaired fasting glucose or impaired glucose metabolism did not predict incident retinopathy lesions in persons without diabetes. Older age and blood pressure, however, were strongly related.[2,5] It is possible that the same phenotype can result from different pathogenic conditions (such as hypertension[6]) that damage the microvasculature. Given that retinopathy lesions predict systemic vascular outcomes,[7] further research to clarify the causes of these lesions is warranted.

References

1. Wong TY, Mohamed Q, Klein R, Couper DJ. Do retinopathy signs in non-diabetic individuals predict the subsequent risk of diabetes? Br J Ophthalmol 2006;90:301-3.

2. Cugati S, Cikamatana L, Wang JJ, Kifley A, Liew G, Mitchell P. Five-year incidence and progression of vascular retinopathy in persons without diabetes: the Blue Mountains Eye Study. Eye 2005 Sep 16; [Epub ahead of print].

3. Babisch W, Beule B, Schust M, Kersten N, Ising H. Traffic noise and risk of myocardial infarction. Epidemiology 2005;16:33-40.

4. van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, Bouter LM et al. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Arch Ophthalmol 2003;121:245-51.

5. Yu T, Mitchell P, Berry G, Li W, Wang JJ. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch.Ophthalmol. 1998;116:83-9.

6. Wong TY, Klein R, Sharrett AR, Manolio TA, Hubbard LD, Marino EK et al. The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study. Ophthalmology 2003;110:658-66.

7. Wong TY, Mitchell P. Hypertensive retinopathy. N.Engl.J.Med. 2004;351:2310-7.

Dear Editor,

We congratulate Kogure et al,[1] on a well designed longitudinal study, which confirms the suspicions of many earlier investigators, who conjectured that Frequency Doubling Perimetry (FDP) may be able to detect visual field loss earlier than Achromatic Automated Perimetry (AAP) based on cross-sectional data. In their text they refer to our longitudinal study[2] as a cross-sectional one and go on to say that there have only been two other papers, which have demonstrated that FDP predicts future AAP visual field loss in a longitudinal fashion. Our paper was conducted over a four-year period, with the first-year data presented as a cross- sectional study[3] and the final data showing the relationship between FDP and AAP longitudinally.[2]

In addition, Kogure et al. have shown quantitatively that the location of FDP field loss can predict the location of future AAP field loss. We also noted qualitatively a topographical relationship between the two perimeters, however our original methodology had not included this premise. Their topographical analysis adds credence to the principle that these early FDP changes are the same visual field loss seen several years later on AAP.

References

1. Kogure S, Toda Y, Tsukahara S. Prediction of future scotoma on conventional automated static perimetry using frequency doubling technology perimetry. Br J Ophthalmol. 2006;90:347–52.

2. Landers J, Goldberg I, Graham S. Detection of Early Visual Field Loss in Glaucoma Using Frequency Doubling Perimetry and Short Wavelength Automated Perimetry. Arch. Ophthalmol. 2003;121:1705-10.

3. Landers J, Goldberg I, Graham S. A Comparison of Short Wavelength Automated Perimetry with Frequency Doubling Perimetry for the Early Detection of Visual Field Loss in Ocular Hypertension. Clin. Exp. Ophthalmol. 2000;28:248-52.