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,

The article by Bernauer et al. takes a new focus on the topic of corneal calcification related to the phosphate content of eye medications. This topic has been addressed previously by our group, first with the observation in glaucoma patients published by Huige et al. (1) then on the normal eye (2), and finally on patients with eye burns receiving phosphate buffer treatment(3). Other reports of non physiologic elements being applied to the cornea, from silver deposits after accidental high exposure with silver (4), to particulate matter being observed from trauma and therapy on in eye burns (5), to corneal calcification in the case of damaged epithelium, have supported our recent study on phosphate-containing buffer therapy following eye burns (6).

Severe changes of the cornea as observed by Bernauer et al. are very likely due to high dosing. The application of Hylo Comod more than 100 times daily as reported in this paper might be sufficient to be declared at least "off label use" or misuse of artificial tears. Mostly astonishing is the fact that the appearance of white plaques on the cornea did not lead to a change in the management in any of the 6 patients described. The combination of norfloxacin (Floxal Edo), known to form precipitates itself as cited above, dexamethasone phosphate (Dexa sine) and Hylo comod in patient 1 of the study might have caused the calcified plaques, with the artificial tears being only contributory in this case. Case 3, 4, 5, and 6 received dexamytrex eye drops containing phosphate buffer with Hylo Comod. This might be an additional factor causative for the calcification.

The authors to warning that phosphate containing drugs may lead to corneal epithelial damage is very important. The other important aspect is that recommended dosing (10), must be taken into account. The old wisdom that "the dose makes the poison" applies to the need to advise our patients to use eye drops as well as oral medications under recommended dosing.

References

(1) Huige WM, Beekhuis WH, Rijneveld WJ, Schrage N, Remeijer L. Deposits in the superficial corneal stroma after combined topical corticosteroid and beta-blocking medication. Eur J Ophthalmol. 1991 Oct-Dec;1(4):198-9.

(2) Schrage NF, Flick S, Redbrake C, Reim M. Electrolytes in the cornea: a therapeutic challenge. Graefes Arch Clin Exp Ophthalmol. 1996 Dec;234(12):761-4. Erratum in: Graefes Arch Clin Exp Ophthalmol 1997 Apr;235(4):262.

(3) Schrage NF, Schlossmacher B, Aschenbernner W, Langefeld S: Phosphate buffer in alkali eye burns as an inducer of experimental corneal calcification. Burns. 2001 Aug;27(5):459-64.

(4) Schirner G, Schrage NF, Salla S, Teping C, Reim M, Burchard WG, Schwab B. Corneal silver deposits following Crede's prophylaxis an examination with electron dispersive x-ray analysis (EDX-analysis) and scanning electron microscope (SEM). Lens Eye Toxic Res. 1990;7(3-4):445- 57.

(5) Schrage NF, Reim M, Burchard WG. Particulate matter contamination in the corneal stroma of severe eye burns in humans. Lens Eye Toxic Res. 1990;7(3-4):427-44.

(6) Schrage NF, Kompa S, Ballmann B, Reim M, Langefeld S. Relationship of eye burns with calcifications of the cornea? Graefes Arch Clin Exp Ophthalmol. 2005 Aug;243(8):780-4. Epub 2005 Mar 9.

(7) Tanhehco TY, Chiavetta SV 3rd, Lee PP, Fowler AM, Afshari NA. "Cracked-mud" ciprofloxacin precipitates on a corneal graft. Ophthalmic Surg Lasers Imaging. 2005 May-Jun;36(3):252-3.

(8) Castillo A, Benitez del Castillo JM, Toledano N, Diaz-Valle D, Sayagues O, Garcia-Sanchez J. Deposits of topical norfloxacin in the treatment of bacterial keratitis. Cornea. 1997 Jul;16(4):420-3.

(9) Lopez JD, del Castillo JM, Lopez CD, Sanchez JG. Confocal microscopy in ocular chrysiasis. Cornea. 2003 Aug;22(6):573-5.

(10) http://www.rote-liste.de/Online/ search Hylo Comod Dos.

Financial statement: The Aachen Center of Technologytransfer in Ophthalmology "ACTO.de" is involved in research on corneal trauma with phosphate containing eye drops since 10 years and received several research funds from pharmaceutical industry.