Uveitis is a common ophthalmic condition encountered in horses, with an estimated prevalence of 2–25% in the USA and 8–10% in Europe (Schwink, 1992). In the UK, Chandler et al (2003) reported findings from 83 geriatric horses, and found five animals to show signs of previous inflammatory disease of the iris, consistent with previous uveitis. Reports from the National Equine Health Survey 2013 reported a uveitis prevalence rate of 0.3% (Slater, 2014).
Data surrounding ophthalmic assessment and disease in the donkey are scarce, with only a small number of papers reporting on normal ophthalmic parameters in this species, namely tonometry values (Selk Ghaffari et al, 2017; Hibbs et al, 2019; Ali et al, 2020) and Schirmer Tear Test 1 values (Selk Ghaffari et al, 2017). A study investigating the prevalence of uveitis in a population of donkeys in the UK has been published, with a reported prevalence rate of of 2.9% reported (Bradley et al, 2020).
Clinical signs consistent with uveitis include:
- Miosis
- Corpora nigra atrophy
- Synechia
- Iris hyperpigmentation
- Lens luxation or subluxation
- Cataract
- Aqueous flare
- Keratic precipitates
- Retinal detachment
- Hyalitis (Deeg and Gilger, 2011).
Recurrent uveitis, as frequently encountered in horses, is not reported in veterinary literature in donkeys. However, in the author's opinion, donkeys do also suffer from classic ‘equine recurrent uveitis’ syndrome, in spite of the lack of published reports. Uveitis is a potentially catastrophic disease, and is cited as the leading cause of blindness in horses (Schwink, 1992; Gerding and Gilger, 2016). It is prudent for vets working with donkeys to be aware of this condition, and to instigate prompt therapy when uveitis is present.
Anatomy and physiology of the uveal tract
The eye is recognised as an immune privileged organ, with numerous adaptive mechanisms and barriers, such as the so-called anterior chamber-associated immune deviation, the blood-aqueous barrier and the blood–retinal barrier. The uveal tract is a highly vascularised structure, comprising the iris, ciliary body and choroid. Given its close proximity to the peripheral circulation, damage to any part of the uveal tract leads to disruption of the intrinsic barriers and ACAID, leading to signs of uveitis (Gilger and Hollingsworth, 2017).
The clinical signs of both acute and chronic uveitis reflect the different phases of uveal inflammation. With initiation of intraocular inflammation, the release of inflammatory mediators leads to vascular congestion and increased vascular permeability, with subsequent leakage of proteins and fluid into the surrounding connective tissue. Non-cellular exudates accumulate and lead to reduced production of aqueous humor by the ciliary body. Prostaglandin release results in ciliary and iris sphincter muscle spasm, while disruption of the corneal endothelial Na+/K+ -AT pase pump results in corneal oedema (Gilger and Hollingsworth, 2017).
With chronicity, alterations in aqueous humor together with synechiae formation may result in cataract formation. The vitreous loses clarity because of the accumulation of inflammatory cells and debris, and vitreal membranes may form, predisposing tractional retinal detachment. Retinal function becomes disrupted as a result of a reduced supply of oxygen and other essential nutrients (Gilger and Hollingsworth, 2017).
Recognition and classification of uveitis
It is important for veterinary surgeons to appreciate the differences between horses and donkeys, with respect to identifying pain. Donkeys are known for their ‘stoic’ nature, and may not readily show obvious signs of ocular discomfort. Signs which should alert the clinician to ophthalmic discomfort include excessive lacrimation, rubbing of one or both eyes, an increased blink rate and in increased downward slope of the eyelashes. Some donkeys may simply show reduced activity and interaction within the herd. Visual deficits may manifest as the development of ‘stubborn’ behaviours, with a reluctance to move as asked.
A complete ophthalmic examination should always include assessment of globe and eyelid positioning, assessment of pupil size and symmetry, and a full neuro-ophthalmic assessment (including menace response, dazzle reflex, palpebral reflex and direct pupillary light reflex as a minimum). Donkeys may anticipate pain and, while both eyes may be open and comfortable when viewed from a distance, they can show intense blepharospasm when approached, thus highlighting the importance of initiating an ophthalmic examination when first entering the animal's environment. A dark setting is necessary to identify subtle signs of uveitic disease (such as aqueous flare), and the pupil should be dilated using a shortacting mydriatic agent (for example, tropicamide) to enable full examination of the lens, vitreous and fundus. Retroillumination can be helpful to identify keratic precipitates and lens changes, as well as pupil abnormalities. Tonometry readings should be obtained in both eyes, using either applanation or rebound tonometry. Fluorescein staining should always be performed, particularly as topical steroid therapy may be required. Some patients may require sedation and/or periocular nerve block administration to enable a thorough examination, although in the author's experience, donkeys tolerate a complete ophthalmic examination much better than horses, and sedation is infrequently required. Ensuring that the donkey's bonded companion remains present during the examination can further help to calm the patient, and enable a thorough examination with minimal stress to the donkey.
The first step towards successful treatment of uveitis in donkeys is to recognise its presence and distinguish between acute and chronic disease.
Acute signs of uveitis include epiphora, aqueous flare, miosis, corneal oedema, keratic precipitates and vitreal inflammation (Figure 1). Signs consistent with chronic or previous uveal tract inflammation include posterior synechiae formation, cataract formation, lens luxation or subluxation, peripapillary scarring and retinal detachment (Figures 2, 3, 4 and 5). Donkeys may present with a combination of acute and chronic changes.
There are two studies investigating the normal intraocular pressure in donkeys. Selk Ghaffari et al (2017) reported a range between 13.5–24.5mmHg, with a median of 17.8+/-3.7mmHg in normal adults, using applanation tonometry. A study by Hibbs et al (2019) reported a reference range of 12.82–33.38mmHg in miniature donkeys, using applanation tonometry, and a range of 14.34–37.15mmHg, using rebound tonometry. A study by Ali et al (2020) reported the presence of diurnal variation, with a higher intraocular pressure recorded in the early mornings. In cases with acute uveitis, reduced aqueous humour production leads to hypotony, with the intraocular pressure frequently below 10mmHg. In some cases, the intraocular pressure may be greater than 10mmHg, but show significant deviation from the contralateral eye. Whenever there is a significant discrepancy in the intraocular pressure value between eyes, a thorough ophthalmic examination should be undertaken. Alternatively, cases with chronic uveal inflammation may present with an elevated intraocular pressure, as a result of the formation of inflammatory membranes and/or pupillary block.
Equine recurrent uveitis syndrome can be sub-divided into classic, insidious or posterior uveitis. A similar classification system can be used in donkeys. The classic equine recurrent uveitis patient will have periods of active painful intraocular inflammation, followed by periods of minimally observable inflammation. Insidious equine recurrent uveitis (commonly seen in the Appaloosa and Draft horse breeds) is characterised by persistent low-grade uveal inflammation, without overt signs of discomfort. Posterior equine recurrent uveitis, as the name suggests, primarily affects only the structures of the posterior segment (vitreous, retina and choroid). Reports describing the frequency of each of the above equine recurrent uveitis classifications in donkeys are currently lacking. Before reaching a diagnosis of recurrent uveitis, it is essential to confirm that acute uveitis has been successfully treated. Ongoing low grade acute uveitis that is treated inappropriately, or for too short a treatment period, can be mistaken for recurrent uveitis. This can lead to frustration for both the veterinarian and owner, and can lead to long-term complications for the patient.
Causes of uveitis
The list of aetiologies for uveitis in the donkey is extensive, including but not limited to, trauma, infection (bacterial, viral or parasitic), endotoxaemia, septicaemia, and neoplastic causes. Donkeys with corneal ulceration may present with a painful secondary reflex uveitis. In the case of traumatic uveitis, so long as the integrity of the globe remains intact, and there is no damage to the anterior lens capsule, the uveitis can usually be treated successfully. Cases suffering from endotoxaemia or septicaemia will present with significant systemic illness, and further investigations and treatment will be aimed primarily at addressing the underlying disease.
Infectious causes of uveitis in horses and donkeys are varied. Parasites such as Onchocerca cervicalis, Strongylus and toxoplasma have been reported in association with uveitis in horses, although these are rare. Reported viral causes include equine viral arteritis, and putatively, equine herpes virus 1 and 2, parainfluenza type 3 and equine influenza. Bacterial organisms are perhaps the most common infectious cause of uveitis. In young foals presenting with uveitis, Rhodococcus equi should be suspected, and appropriate diagnostics performed. Other potential infectious agents include Leptospira spp., Brucella, Streptococcus and Borrelia burgdorferi.
Much research to date has investigated the role of leptospiral organisms in the initiation and propagation of ERU in the horse (Dwyer et al, 1995; Malalana et al, 2017; Sauvage et al, 2019; Himebaugh et al, 2021). Studies from the UK suggest that this is not a frequent cause of uveitis in horses within the UK, with no difference in seroprevalence between horses with uveitis and controls. One study found only 2/30 eyes with uveitis to have a positive Cvalue, suggestive of active Leptospiral antibody production within the eye (Malalana et al, 2017). To date, no published studies have investigated the role of Leptospiral organisms as a causative agent in donkeys. Clinical work previously performed by the author in Europe showed a significantly higher incidence of sight-threatening uveitis in donkeys, and a link with Leptospira infection was considered likely (unpublished data). Thus, knowing the import status of the patient is important, as a travel history may increase the clinician's index of suspicion for an underlying infectious cause.
Heterochromic iridocyclitis
A novel form of uveitis recently reported in horses is termed heterochromic iridocyclitis. This is characterised by the presence of pigmented keratic precipitates adherent to the corneal endothelium, depigmentation of the iris, dense corneal oedema and the formation of retrocorneal membranes (Pinto et al, 2015). This appears to be an aggressive disease, which requires persistent local immune suppression, and carries a guarded prognosis. While no histopathological studies of this have been reported in donkeys, the author has seen one donkey suspected to have this condition, and is aware of another suspected case seen by another UK veterinary ophthalmologist (personal communication). Early referral to a veterinary ophthalmologist is recommended for cases with suspected heterochromic iridocyclitis.
Treatment
Treatment of uveitis is aimed at addressing the underlying cause (where known), and stabilising the blood–ocular barriers through suppression of inflammation. Cases of acute uveitis warrant intensive initial therapy, while a case presenting with signs of chronic or previous uveitis may not require aggressive treatment in the first instance.
For acute uveitis, treatment should be administered both topically and systemically (except for cases with posterior uveitis only, where systemic medication alone may be sufficient because of the poor penetration of topical drugs into the posterior segment). Topical medications frequently used include prednisolone acetate 1% and bromfenac 0.1% (except in cases with corneal ulceration, in which their use is contraindicated). Frequency of use is dependent on the level of inflammation present, with severe cases benefitting from administration every 2 hours, and milder cases requiring administration 2–3 times daily. Topical atropine should be administered to all patients with uveitis, to relieve the pain associated with iris muscle spasm. This should be dosed to effect, to keep the pupil dilated. While there is a risk of decreased gut motility with repeated use (Williams et al, 2000), a later study in horses failed to detect atropine within the serum of treated horses, and no ileus was detected in any patients (Wehrman et al, 2017). A more recent study by Ström et al (2021), investigating the pharmacokinetics of topical atropine sulphate, showed that atropine has a short half-life with rapid clearance from plasma. Administration of topical atropine hourly or every 3 hours led to detectable levels of atropine in serum, and decreased gut motility. However, allowing a 6-hour interval between administrations allowed complete wash-out between treatments.
Systemic medications used in the treatment of uveitis frequently include oral prednisolone 1–2mg/kg twice daily, or flunixin meglumine 1.1mg/kg once daily. Phenylbutazone is rarely of sufficient potency to suppress moderate to marked uveitis. While prednisolone is often the drug of choice, it is not without risk of causing laminitis, thus its use will not be appropriate in all cases. Patients requiring prolonged flunixin administration should be monitored for gastric and renal complications. Although flunixin is useful to address the reflex uveitis seen in cases of corneal ulceration, clinicians should use this drug judiciously, given its ability to significantly impair the rate of vascularisation and corneal re-epithelialisation.
For donkeys showing confirmed recurrent uveitis, that respond well to treatment in between flare ups of disease, placement of a suprachoroidal cyclosporin implant may be considered. This can increase owner and patient compliance, and allows high concentrations of the drug to be achieved, with constant delivery of therapeutic drug levels (Gilger and Michau, 2004; Gilger et al, 2010). The implants should be placed during a quiescent period (not when the eye is actively inflamed). Donkeys that cannot be controlled with typical anti-inflammatory medications are not a candidate for implant placement. While cyclosporin placed in the suprachoroidal space shows efficacy in the treatment of uveitis, use of topical cyclosporin (Optimmune) is ineffective because of the poor ocular penetration of the hydrophobic preparation.
In cases with significant posterior segment inflammation, or where Leptospira is highly suspected, pars plana vitrectomy may be considered. A number of studies have shown promising results for long-term control of leptospiral-induced equine recurrent uveitis in horses, using this method (Frühauf et al, 1998; Tömördy et al, 2010; Dorrego Keiter et al, 2017; Baake et al, 2019; Voelter et al, 2020). Another treatment option which has shown some success involves the use of a single intravitreal gentamycin injection (Fischer et al, 2019; Kleinpeter et al, 2019; Launois et al, 2019). This is not without risks, and can lead to both cataract formation and retinal degeneration.
Donkeys suffering from chronic uveal inflammation frequently develop cataract formation. Lens extraction via standard phacoemulsification may be considered, although, based on results reported in horses, donkeys with chronic preoperative uveitis are likely to carry a poor long-term prognosis for vision (Edelmann et al, 2014). Where lens luxation or subluxation occurs secondary to chronic inflammatory changes, intra-capsular lens extraction may be considered. However, the reported surgical success rate associated with this procedure in horses is very low (Brooks et al, 2014). In the absence of successful treatment for ongoing uveitis, phthisis bulbi may result and enucleation may need to be considered.
Prognosis
The prognosis for uveitis in donkeys is dependent on the underlying cause. It is essential that therapy is extended well beyond resolution of the clinical signs, and that therapy (including topical therapy) is tapered slowly. With early discontinuation of treatment, a rebound uveitis can occur, mimicking recurrence. With appropriate medication and monitoring, uveitis can often be managed successfully. However, if missed or left untreated, or if the disease shows progression despite therapy, there is a risk of vision loss and/or the globe itself through mature cataract formation, lens luxation, retinal detachment and/or phthisis bulbi.
KEY POINTS
- Uveitis is a potentially blinding disease if left untreated.
- Signs of uveitis can be subtle, and easily missed if a full ophthalmic examination is not performed.
- Clinical signs associated with acute uveitis include epiphora, aqueous flare, miosis, corneal oedema, keratic precipitates and vitreal inflammation.
- Clinical signs associated with chronic uveitis include posterior synechiae formation, cataract formation, lens luxation or subluxation, peripapillary scarring and retinal detachment.
- Treatment involves both systemic and topical anti-inflammatory therapy, and a prolonged course may be required to achieve good control.
- Surgical treatment options including suprachoroidal cyclosporin implant placement and pars plana vitrectomy may be considered in selected cases.