The eye has long been recognised as an immune-privileged organ, whereby immune responses to foreign antigens are suppressed or inhibited. This allows the preservation of normal function within such a highly specialised organ. Immune privilege is maintained by both structural barriers and a complex array of active homeostatic mechanisms. Despite this, immune-mediated diseases of the eye are relatively common and frequently encountered in practice. This is the second of two articles on immune-mediated diseases of the equine eye and will focus on equine recurrent uveitis (ERU). Again, the emphasis will be on the principles and practicalities of treatment and long-term management, with emphasis on a collaborative approach between owner and veterinary surgeon.
There are no treatments licensed for the treatment of uveitis in the horse and clinicians are advised to refer to the cascade when selecting appropriate medications. Proprietary ophthalmic formulations of all of the topical medications discussed are (intermittently) available in the UK, licensed for either human or animal use. These should always be used in place of non-ophthalmic preparations, which can cause severe damage to the eye. Some compounded preparations are now also available. Sustainedrelease ciclosporin A (CsA) implants require a special treatment certificate for importation into the UK. Many preparations are also prohibited in competition horses.
Aetiopathogenesis
All equine practitioners will be familiar with ERU as it is the most common cause of blindness in horses worldwide (Gilger and Hollingsworth, 2017). While it is agreed to be an immune-mediated disease, details of the aetiopathogenesis of ERU remain unknown. However, as it is clinically a heterogenous disease, the mechanism is likely to vary in each case. Substantial steps toward understanding the details have been made and are reviewed in detail elsewhere (Deeg, 2008; Gilger and Hollingsworth, 2017). Briefly, ERU appears to be primarily mediated by Th1 and Th17 CD4+ T lymphocytes, with almost all cases having autoantigens directed against retinal antigens detectable in the serum or vitreous (Gilger et al, 1999; Regan et al, 2012; Gilger and Hollingsworth, 2017). Epitope spreading (simplistically, a shift in the immune response from targeting an initial self or foreign antigen epitope, to targeting epitopes on other antigens) is a very important part of autoimmunity that occurs in ERU and may well account for the induction, progression and relapsing nature of the disease (Deeg et al, 2006; Gilger and Hollingsworth, 2017). A variety of factors, including genetic predisposition and antigens encountered, will determine how an individual case progresses.
There is no universal triggering antigen for ERU. However, most clinicians are aware that Leptospira are potent triggers and have received the most attention. Leptospira are spirochete bacteria that infect horses when they consume contaminated water that contains urine from a carrier species. The mechanism of disease is unknown, although one theory is that persistent inflammation associated with bacterial deposition in the intraocular tissue allows exposure of the immune privileged site to the immune system, with subsequent epitope spreading (Malalana et al, 2015). Exposure to leptospires (based on seroconversion) appears to be high in most places, but any clinical disease (including ERU) is rare (Malalana, 2019). In horses, the uveitis associated with both naturally occurring and experimental Leptospira infection is usually only clinically apparent (although some inflammation can occur acutely) 12–24 months after exposure. Therefore, it is often impossible to know when the infection occurred (Williams et al, 1971; Gilger and Hollingsworth, 2017). The measurement of serum antibodies alone is of little benefit for the diagnosis of Leptospira-induced ERU, and vitreocentesis with subsequent antibody assessment is required for a more convincing diagnosis (Gilger and Hollingsworth, 2017; Malalana et al, 2017). This is only really indicated if pars plana vitrectomy (PPV) is being considered, as will be discussed later.
There is convincing evidence of an association between ERU and Leptospira in western mainland Europe and the USA, but Leptospira-associated ERU appears to be very uncommon in the UK (Malalana et al, 2017). In addition, the overall prevalence of ERU in the UK is thought to be much lower than in the USA and parts of mainland Europe, although no accurate data exist (Malalana et al, 2020). The reasons for these differences are unknown, particularly as exposure of UK horses to leptospirosis (based on serology) appears similar to that in other countries with much higher ERU rates (Malalana et al, 2017). It is likely the explanation is multifactorial and involves individual horse factors (genetics), involvement of other environmental antigens/triggers and the triggering capacity of the different Leptospira serovars that have been shown to be involved in the UK (Malalana et al, 2017). Overall, though, it is increasingly apparent that Leptospira are only the trigger for a small number of the ERU cases seen in the UK, and routine antibody assessment in serum and vitreous is not advocated.
Clinical signs and diagnosis of ERU
The typical signs of acute uveitis are familiar and easily recognisable to equine clinicians (Figure 1): pain, blepharospasm, epiphora, miosis, aqueous changes (flare, hypopyon and occasionally hyphaema), conjunctival and episcleral hyperaemia, corneal oedema and neovascularisation (usually short, deep, circumferential vessels around the limbus, not the extensive neovascularisation seen with corneal immune mediated keratopathies) and a hazy appearance to the anterior vitreous (if visible). When presented with such a case, the clinician must try to determine two things: first, whether or not the uveitis is primary (endogenous uveitis) or secondary to another condition (which might be ocular, such as ulcerative keratitis, or systemic, such as Rhodococcus equi infection (Figure 2); and secondly, whether or not there is any clinical or historical evidence of chronicity that suggests ERU.
Clinical signs consistent with chronicity include the following: corneal changes (mild oedema, usually without the prominent neovascularisation associated with corneal disorders), iris rests (small pigmented deposits, usually on the anterior lens capsule), anterior and posterior synechiae (attachments of the iris to the cornea and anterior lens capsule, respectively), atrophy and irregularity of the granula iridica (a hallmark sign, particularly important at PPE), iris pigment changes, iris thinning, dyscoria (abnormal pupil shape), cataract, vitreal clouding and floaters, chorioretinal scarring, evidence of glaucoma (enlarged globe, linear corneal opacities, corneal oedema and elevated intraocular pressure) and, during the end-stage, phthisis bulbi (Figures 3, 4, 5, 6). It is worth noting that horses with depigmented punctate chorioretinal foci (bullethole lesions) without other signs of chronicity are now not considered more likely to have ERU than horses with clinically normal fundi (Mathes et al, 2012).
Three types of ERU
Three different clinical syndromes of ERU are recognised: classic, insidious and posterior (Gilger and Michau, 2004; Gilger and Hollingsworth, 2017).
- Classic ERU is the most common type reported, with obvious episodes of active inflammatory uveitis separated by periods of minimal ocular inflammation (quiescent phase). The iris, ciliary body and choroid are most prominently affected, with varying involvement of all other parts of the eye. Repeated episodes tend to be increasingly severe with progressive development of chronic signs.
- Insidious ERU involves low-grade inflammation of the entire eye, that does not manifest as obvious discomfort. It leads in time to development of chronic signs and corpora nigra degeneration is considered a hallmark sign. Insidious ERU is most commonly seen in Appaloosas and draft breeds.
- Posterior ERU involves primarily the vitreous, retina and choroid (with mild inflammation only in anterior parts). Again, there is rarely any obvious ocular discomfort and the clinical signs include vitreal cloudiness and floaters, retinopathy and retinal detachment. Cataracts can also develop. Posterior ERU is seen most commonly in draft breeds.
All horses that have an episode of uveitis are considered at increased risk of developing ERU for several years (Gilger and Hollingsworth, 2017). Horses are classified as having ERU if they have had two or more documented episodes of uveitis, or, where there is no documented veterinary history, at least three clinical signs of chronicity and a history of some sort of ocular disease (Gilger and Hollingsworth, 2017). A diagnosis cannot be made on a single examination with no known history at all (an important fact for prepurchase examination). Genetic testing to support a diagnosis of insidious ERU is available for Appaloosas (Fritz et al, 2014). Uveitic episodes can affect one, or both eyes. A long-term study revealed that 66% of horses with ERU (any type) were eventually bilaterally affected (Gerding and Gilger, 2016). Most cases of insidious ERU are bilateral and tend to occur with no known history of ocular disease.
Treating acute endogenous uveitis
Aggressive implementation of anti-inflammatory and analgesic therapy is essential for any case of acute uveitis to minimise the development of chronic sequalae and vision loss. This is based primarily on mydriatics and anti-inflammatories (systemic NSAIDs and topical anti-inflammatories). Key points are as follows:
- Attempts to dilate the pupil should be as aggressive as safely possible to minimise the chance of sequalae, such as synechiae and cataract, as well as providing analgesia by relieving iridial muscle spasm. Topical 1% atropine is initially given every 6–8 hrs until mydriasis is achieved or the contralateral pupil becomes mydriatic (indicating systemic atropinisation and increased risk of adverse effect). Once the pupil is atropinised, the frequency of administration is reduced according to requirements (usually once daily) and cases monitored for adverse effects (colic). If the atropinisation of the affected pupil is not achieved, then 10% phenylephrine can be used topically in addition to the atropine. However, this is usually a sign of severe inflammation and attention should be focused on antiinflammatories.
- Systemic NSAIDs are usually more effective at treating uveitis than topical corticosteroids, and this must not be forgotten. Flunixin meglumine (up to 1.1 mg/kg intravenously once or twice daily initially, followed by up to 1.1 mg/kg orally once daily) is one of the most potent therapies for equine uveitis. Phenylbutazone, meloxicam or firocoxib are potential alternatives. Consideration of the adverse effects of NSAIDs is important and the use of gastroprotectants should be considered alongside owner advice on the signs of ulcerative gastrointestinal disease.
- Topical corticosteroids are frequently administered to reduce ocular inflammation (unless contraindicated due to the presence of ulcerative keratitis). A combined 0.1% dexamethasone/polymyxin B/neomycin ointment/solution (Maxitrol; Novartis Pharmaceuticals UK) and a 1% prednisolone acetate (Predforte; Allergan) solution are available. Both are usually applied 3–4 times daily if possible.
- Topical NSAID application (including 0.09% bromfenac sodium and 0.1% diclofenac sodium) can be considered where ulcerative keratitis is present, but it is not as effective as corticosteroid.
- Treatment should be prolonged and tapered to ensure that rebound recurrence does not occur, as all cases of acute uveitis could become recurrent (Gilger and Hollingsworth, 2017). Initial intensive treatment is usually required for at least 1–2 weeks, before tapering off gradually over another 2–4 weeks. Again, the importance of systemic NSAID medication during this tapering phase should not be forgotten and is often much easier than continuing topical medication.
Treating equine recurrent uveitis
When a diagnosis of ERU is made (according to the guidelines above), then the treatment options must be carefully considered for each case. The prognosis for vision in an eye with ERU is considered to be poor, even with treatment, particularly for Appaloosas. A large North American study of 224 horses (338 eyes) found that ERU had a significant detrimental effect on both horses and owners (Gerding and Gilger, 2016). Owners reported that 46.9% of horses were blind in affected eyes, 29.4% could not return to their previous roles and 19.1% changed hands. Around 9% of horses were euthanased because of the ERU. Enucleation occurred in 14.1% of eyes. This is higher than many previous studies but similar to the 20% enucleation recently reported in a UK study, albeit with fewer eyes and inclusion of non-recurrent cases (Malalana et al, 2020). Other ocular complications including corneal ulceration and glaucoma occur more commonly in horses with ERU, and often these are the reason for enucleation (Dwyer et al, 1995). Owners should be counselled on the prognosis for vision and the likely necessity of repeated treatments for various ocular problems. No ERU treatment is considered suitable for eyes with advanced chronic pathology (retinal detachment, glaucoma, phthisis bulbi). Where treatment is attempted, the following options are available:
- Long-term anti-inflammatory use (corticosteroid). This is a possibility where compliance is not a problem and finances are limited. There is no evidence at all to determine whether or not this makes any difference to the likelihood of recurrence in any form of ERU, although it probably makes most sense in classic cases. Long-term administration of corticosteroid to the eye can potentiate infection, delay healing of ulceration and increase the chance of calcific band keratopathy.
- Long-term systemic NSAID. Similarly to corticosteroid, there is no evidence to support the use of long-term NSAID in the management of ERU. In addition, there is the risk of long-term adverse effects to the gastrointestinal tract and kidneys. However, there is some logic to the idea and many horses remain on long-term NSAID due to orthopaedic disorders for years without apparent adverse effects.
- Suprachoroidal ciclosporin A (CsA) implants. Sustained-release CsA devices have long been used for the control of ERU. The implants are surgically positioned between the sclera and the choroid (usually under general anaesthesia) and release CsA directly into the ciliary body (topical formulations of CsA do not penetrate to the uvea). Side-effects of the implantation are rare and usually not vision-threatening when they do occur. The mechanism of action of CsA means that it is effective at reducing the recurrence of uveitic episodes, but not in suppressing them when they occur. Occasional flare-ups should be expected and owners must always be made aware of this; implants are only of use in ERU cases in which inflammation can be readily controlled using systemic NSAIDs, atropine and topical steroid. Flare-ups are, anecdotally, easier to control after implant placement. The implants must be placed when the eye is quiescent. A North American study reported that suprachoroidal implants improved the prognosis for vision (85% of eyes remained visual long-term), and reduced, but did not eliminate, the frequency of uveitis flare-ups (Gilger et al, 2010). The duration of medication delivery from implants is reported to be around 36 months; however, most horses do not require repeated treatments after 3–4 years, indicating an immunomodulatory effect of the treatment (Gilger and Hollingsworth, 2017).
- Pars plana vitrectomy (PPV). PPV involves surgically removing and replacing the vitreous. This removes the inflammatory cells responsible for ERU and also clears opacities within the vitreous, helping restore vision. Complications of the procedure are rare, but when they occur often result in vision loss (cataract and retinal detachment). Where successful, PPV appears to reduce the chances of recurrence far more than the CsA implant; however, it appears that this depends on the presence of intravitreal antibodies to Leptospira. In one study, 82.5% of horses testing positive for intravitreal antibodies against Leptospira showed no further episodes of ERU, while 85.7% of horses testing negative continued to experience recurrence (Tömördy et al, 2010). This has led to the widespread recommendation that PPV should only be carried out in eyes with Leptospira-associated ERU, with CsA implants used in those that are not (Gilger and Hollingsworth 2017). It should be noted that some groups advocate PPV as the most effective treatment for all cases of ERU (Baake et al, 2019); however, this is mostly in countries where there are significant difficulties in acquiring CsA implants and Leptospira-associated disease is common. In one study, where treatment was allocated based on Leptospira association, recurrence of acute uveitis was more common with the implants, although blindness and visual impairment were equally likely to occur in both treatment groups (Voelter et al, 2020). Based on previous comments regarding the very low incidence of Leptospira-associated ERU in the UK, it seems reasonable to say that the case for PPV as the recommended treatment in this country is unconvincing. Given the reduced incidence of severe adverse effects, CsA implant should probably be attempted first, unless there is significant opacification of the vitreous.
- Intravitreal low-dose gentamicin injection. This technique should not be confused with the use of high doses of gentamicin to ablate the ciliary body in end-stage glaucoma (often following ERU). Gentamicin is included within the irrigation fluid used during PPV and this led to speculation that it could be used alone to treat ERU at low-doses. A possible mechanism of action is unknown, and it has been suggested that it may be a direct immune-modulating effect rather than an antibacterial effect on Leptospires (Fischer et al, 2019). However, at the time of writing this is purely speculation. A study in Germany evaluating the effect of intravitreal injection of 4 mg of gentamicin on ERU cases reported non-recurrence of ERU in 88.1% in the absence of medical treatment, with a minimum follow-up period of 30 days (Fischer et al, 2019). The Leptospira status of the eyes had no effect on outcome. Another recent European paper also reported significant improvement after the technique in several ERU cases, although the authors were clear that the report should be read with reservation (Launois et al, 2019). Further work is required before advocating the treatment ahead of CsA implant or PPV, but it appears promising.
- Systemic antibiotics. There are anecdotal reports of the use of prolonged courses of oral doxycycline or enrofloxacin to treat suspected Leptospira-associated ERU, but there are no reports of success (Gilger and Hollingsworth, 2017). In line with current advice on responsible use of antimicrobials, the use of oral antimicrobials cannot be recommended for treatment of ERU.
- Autologous mesenchymal stem cells (MSCs). An immunomodulatory role of MSCs has been demonstrated in other species and there is some evidence of therapeutic efficacy in treating autoimmune uveitis in rats (Tasso et al, 2012). A recent in vitro study using cells from horses with ERU demonstrated that MSCs were able to reduce CD4+ T-cell activation (Saldinger et al, 2020). No clinical data was available at the time of writing, but future applications of MSCs appear promising.
- Adjunctive treatments and management advice. Many straightforward management changes can be implemented to try and reduce the likelihood of ocular irritation, inflammation or injury, all of which may trigger recurrent episodes of uveitis. These include the use of fly/UV masks, maintenance of a low-dust stable environment (using similar methods as for equine asthma), restricting access to hedgerows and low-hanging branches and minimising transport. There are anecdotal reports of flare ups of ERU following administration of multiple or multi-valent vaccines, and in North America it is recommended that horses with ERU are given annual vaccines in two or more sessions (at least a week apart) or pre-treated with NSAID (Gilger and Hollingsworth 2017). It should be noted that in North America there are five core vaccines (not including influenza), with many horses receiving several more risk-based vaccines as well. In the UK, there is essentially only one core vaccine (tetanus) and, as most horses receive only influenza in addition to this, the advice is probably not as applicable to most cases in this country. A vaccine is available for the prevention of Leptospira-associated ERU and abortion in North America and can be used in known high-risk zones. Based on previous comments regarding the very low incidence of Leptospira-associated ERU in the UK, the vaccine is not recommended for use in this country.
Conclusions
ERU presents in three different forms that vary greatly in their overtness, but all progressively lead to destruction of intraocular structures and loss of vision. Advice on the treatment of the painful, acutely uveitic eye has not changed significantly; however, there is now more of an emphasis placed on prolonged courses of treatment to minimise the chances of recurrence. Various options are available for long-term management, which must be tailored to the individual case. Early detection of ERU cases by attending veterinary surgeons is vital to allow implementation of advanced treatments before the development of chronic ocular changes and the depletion of available funds.
KEY POINTS
- Equine recurrent uveitis is the most common cause of blindness in horses around the world and occurs in three forms: classical, insidious and posterior.
- Classical equine recurrent uveitis is associated with overt ocular pain; however, the other forms of the disease cause are often associated with severe damage in the absence of obvious clinical signs.
- Equine recurrent uveitis is an autoimmune disease; however, many details of the aetiopathogenesis are unknown and likely vary between cases.
- While leptospirosis is a cause of equine recurrent uveitis in some areas, it likely only has a very limited role in the UK.
- Currently the long-term control options include topical therapy, systemic NSAIDs, suprachoroidal ciclosporin A implants, pars plana vitrectomy and intravitreal low-dose gentamicin injection.