33rd Annual Scientific Meeting proceedings

Cyclosporine A (CsA) is a cyclic peptide that works as an immunosuppressant as it inhibits T-lymphocyte activation (1-3). It is commonly used in human medicine to prevent organ transplant rejection and in dogs for treatment of keratoconjunctivitis sicca (KCS), or dry eye (2). Cyclosporine is an ideal drug for immune-mediated ophthalmic diseases in horses and it is for example often used in horses with immune-mediated keratitis (IMMK) (2). However, as it does not penetrate the cornea when administered topically, it cannot be used as a topical medication for intraocular immune-mediated diseases such as Equine Recurrent Uveitis (ERU) (1-3). Systemic use of cyclosporine, as commonly used in humans with endogenous uveitis, is limited in the horse as it is possibly toxic and too expensive (2).

Two slow release CsA devices have been developed for use in the horse: the suprachoroidal CsA implant for ERU and the episcleral CsA implant for IMMK (1).

The use of cyclosporine ophthalmic preparations and cyclosporine implants in horses is permitted by the FEI and can therefore be used in sport horses. Both implants are experimental devices and not approved for use in horses by the FDA.

Suprachoroidal CsA implant
ERU, a progressive recurring immune-mediated ophthalmic inflammatory disease, is one of the most common and devastating equine ophthalmic conditions and the leading cause of blindness in horses (1,4,5). As ERU is often difficult to control, treatment is challenging and often frustrating, and a cure for ERU remains elusive at this moment (4,5). Different treatment options, medical as well as surgical, have been described (1,4-6). Placement of a suprachoroidal CsA implant is one of the surgical treatment options for horses with ERU (1,5,7).

Placement of a suprachoroidal CsA implant is usually performed with the horse under general anaesthesia (1,7). It will be possible to place these implants under standing sedation with adequate local blocks, although a very significant level of experience is needed as proper placement of the implant is imperative to have a good outcome.

After surgical aseptic preparation of the eye, a 1cm conjunctival incision is made in the dorsolateral bulbar conjunctiva. A 7-mm-wide scleral flap is prepared approximately 8mm posterior to the limbus, exposing the black uvea. The CsA-containing device is placed into the incision, in full contact with the uvea (1,7). The scleral flap and conjunctival incision are closed using 5-0 or 6-0 polyglactin 910 suture material (Vicryl).

It takes approximately 30-45 days after implantation to get adequate ocular concentrations (1,7). The duration of delivery of medication is approximately 36-48 months (1,7). Long-term studies following implantation of these suprachoroidal implants in horses have shown a reduction in the number and severity of uveitis episodes with minimal complications, although good patient selection is key (8,9). Especially as other surgical options for ERU often have a better outcome (10-13). 

Episcleral CsA implant
The implantation of episcleral (subconjunctival) cyclosporine devices is a surgical method to treat immune-mediated keratitis (IMMK) in horses. IMMK is a collective term to describe a group of idiopathic, often non-ulcerative corneal inflammatory diseases that presumably have an immunoinflammatory origin (3,14-16). IMMK should be regarded a ‘catch-all concept’ as the clinical spectrum is very diverse (3,14-16). Treatment of IMMK can be frustrating as different cases tend to react differently to treatment and the outcome of treatment is variable. The placement of episcleral CsA implants can be effective if topical CsA is useful and has the best outcome in horses with superficial or (anterior) stromal forms of IMMK (3,17,18).

Episcleral CsA implants are used in horses to deliver cyclosporine in a sustained release matter (18). The implant is designed to release cyclosporine for 12-18 months (3,17,18). When the implant is successful it reduces or even eliminates topical medication and this is helpful for patient and owner compliance. The surgical implantation of the episcleral CsA implants can be performed in the standing sedated horse with local anaesthesia. After surgical aseptic preparation of the eye a 2-3mm incision is made in the dorsal bulbar conjunctiva 5mm posterior to the limbus (17). A pocket is formed and two to four implants are placed parallel to the limbus (in one or more pockets) (17). The incision is closed with a single interrupted or cruciate suture pattern with absorbable suture material (17). Depending on the aspect of the IMMK additional implants can be placed in the ventral bulbar conjunctiva. The procedure is often well tolerated by horses and complications are very rare.

References

1. Gilger, B.C., Hollingsworth, S.R. (2016). Diseases of the uvea, uveitis, and recurrent uveitis. In: Equine Ophthalmology. Gilger, B.C. editor. 3^rd edn. pp 369-415. John Wiley & Sons Inc. Ames, Iowa, United States of America.
2. Gilger, B.C., Allen, J.B. (1998). Cyclosporine A in veterinary ophthalmology. Veterinary Ophthalmology, 1: 181-187. 
3. Brooks, D.E., Matthews, A., Clode, A.B. (2016). Diseases of the cornea. In: Equine Ophthalmology. Gilger, B.C. editor. 3^rd edn. pp 252-368. John Wiley & Sons Inc. Ames, Iowa, United States of America.
4. Malalana, F., Stylianides, A., McGowan, C. (2015). Equine recurrent uveitis: Human and equine perspectives. Vet. J. 206:22–29.
5. McMullen, R.J., Fischer, B.M. (2017). Medical and Surgical Management of Equine Recurrent Uveitis. Vet. Clin. North Am.: Equine Pract. 33:465-481.
6. Gilger, B.C., Michau, T.M. (2004). Equine recurrent uveitis: New methods of management. Vet. Clin. North Am.: Equine Pract. 20:417–427.
7. Gilger, B.C., Salmon, J.H., Wilkie D.A., Cruysberg, L.P., Kim, J., Hayat, M., Kim, H., Kim, S., Yuan, P., Lee, S.S., Harrington, S.M., Murray, P.R., Edelhauser, H.F., Csaky, K.G., Robinson, M.R. (2006). A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis. Invest. Ophthalmol. Vis. Sci. 47:2596-605.
8. Gilger, B.C., Wilkie, D.A., Clode, A.B., McMullen, R.J. Jr, Utter, M.E., Komaromy, A.M., Brooks, D.E., Salmon, J.H. (2010). Long-term outcome after implantation of a suprachoroidal cyclosporine drug delivery device in horses with recurrent uveitis. Vet. Ophthalmol. 13:294-300.
9. Hermans, H., Ensink, J.M. (2013). Complication after implantation of a suprachoroidal Cyclosporine device in a horse: a wandering implant. Pferdeheilkunde. 29:712-715.
10. Baake, E.I.A., Borstel, M. von,  Rohn, K., Boevé, M.H., Ohnesorge, B. (2019). Long-term ophthalmologic examinations of eyes with equine recurrent uveitis after pars plana vitrectomy. Pferdeheilkunde. 35:220-233.
11. Frühauf, B., Ohnesorge, B., Deegen, E. Boevé, M. (1998). Surgical management of equine recurrent uveitis with single port pars plana vitrectomy. Vet Ophthalmol. 1:137-151. 
12. Fischer, B.M., McMullen, R.J., Reese, S., Brehm, W. (2019). Intravitreal injection of low-dose gentamicin for the treatment of recurrent or persistent uveitis in horses: Preliminary results. BMC Vet. Res. 15:29.
13. Launois, T., González Hilarión, L.M., Barbe, F., Leurquin, C., Bihin, B., Hontoir, F., Dugdale, A., Vandeweerd, J.M. (2019). Use of Intravitreal Injection of Gentamicin in 71 Horses With Equine Recurrent Uveitis. J. Equine Vet. Sci. 77:93-87.
14. Matthews, A., Gilger, B.C. (2009). Equine immune-mediated keratopathies. Vet. Ophthalmol.  12:10-16.
15. Matthews, A., Gilger, B. (2010). Equine immune-mediated keratopathies. Equine Vet. J. Suppl. 37:31-7.
16. Matthews, A. (2000). Nonulcerative keratopathies in the horse. Equine Vet. Educ. 12:271–278.
17. Gilger, B.C., Stoppini, R., Wilkie, D.A., Clode, A.B., Pinto, N.H., Hempstead, J., Gerding, J. Salmon, J.H. (2014). Treatment of immune-mediated keratitis in horses with episcleral silicone matrix cyclosporine delivery devices. Vet. Ophthalmol. 17:23-30.
18. Gilger, B.C., Michau, T.M., Salmon, J.H. (2005). Immune-mediated keratitis in horses: 19 cases (1998–2004). Vet Ophthalmol. 8:233–239.