James Wardrop and Equine Recurrent Uveitis

James Wardrop should be remembered not only as one of the founders ofocular pathology but also for his contributions to the field of comparativeophthalmology. He described a "specific inflammation" that veterinarians todayknow as equine recurrent uveitis. As described by Wardrop in the 19th century,this condition is known today to eventually lead to blindness.

In 1782, James Wardrop was born in Linlithgow, Scotland, a small townshipnear Edinburgh (Figure 1). He hadextensive training as a general surgeon, and by the age of 22 years had completeda 4-year surgical apprenticeship in Scotland; a 2-year appointment as housesurgeon in London, England; part of a year at a prestigious Paris, France,medical school; and a year under Georg Joseph Beer in Vienna, Austria. Beerhad established the first clinic limited to the practice of ophthalmologyin Europe some 17 years earlier. In 1823, Wardrop was appointed Surgeon Extraordinaryto the Prince Regent, who later became King George IV. Wardrop's reputationas one of the foremost surgeons in his day, however, rested more on the accuracyof his diagnoses, his ability to be an original and forceful thinker, andthe number and value of his publications rather than on his technical skills.¹

Although Wardrop was considered a general surgeon, his greatest contributionsincluded establishing the foundations for ophthalmic pathology and being thefirst to classify ocular diseases according to the anatomical parts involved.¹ One may speculate that at least some of his interestin ophthalmology was fostered by his having an exotropic left eye as a child.¹ In 1808, he published one of his most important works,entitled Essays on the Morbid Anatomy of the Human Eye,² and in it he coined the term keratitis. He also had a passion for hunting and horse racing and was considered"one of the best judges of horseflesh in the Kingdom."³ In1819, he combined his fascination for ocular pathology with his extensiveknowledge of horses in An Essay on the Diseases of the Eyeof the Horse.⁴ This important workhelped to build a foundation for equine ophthalmic anatomy and aided in thedifferentiation of inflammatory diseases of the equine eye based on the tissueof origin. More specifically, the essay is notable because it is among thefirst to differentiate a form of ocular inflammation that Wardrop termed specific inflammation from other forms of ocular inflammatorydisease in horses. Today this condition is called equine recurrent uveitis(ERU), and it affects 10% to 15% of all horses, making it the leading causeof blindness in horses then and now.^5-8 Theessay is also noteworthy for its allusion to the notion of sympathetic inflammationbetween the 2 eyes and its description of several surgical techniques fortreating ocular disease in horses, including the use of glass eyes to preventdeformity in horses that have lost an eye.³

Wardrop's interest in equine ophthalmology appears to stem from thecritical economic role horses played in his day, his innate scientific curiosity,and an aesthetic appreciation for the animal's strength and beauty. In 19th-centuryGeorgian society, human productivity and physical safety were heavily dependenton the animal having good vision. Wardrop recognized that chronic ERU wasthe most common cause of visual loss in horses and, hence, was of great economicimportance, because it often rendered the animal useless for its intendedpurpose and sometimes bankrupted its owner in the process. However, Wardropwas also insightful because as a physician-scientist, he saw human and veterinarymedicines as a single medicine in which a better understanding of the diseasesof one species would benefit the other, and vice versa. Although he erroneouslybelieved horses had fewer and more uniform ocular diseases than humans⁴ (perhaps in part because horses have a much more floridinflammatory response than do humans), his appreciation for the linkage betweenspecies allowed him to make significant contributions to both human and veterinarymedicine. It was also Wardrop's hope that differentiation between the varioustypes of ocular inflammation based on anatomy would facilitate improving theselection and breeding of quality animals.⁴

In An Essay on the Diseases of the Eye of the Horse, Wardrop elucidated 2 principal forms of ocular inflammation.⁴ The first form, which he called simple or common inflammation, was a keratoconjunctivitisthat was characterized by swollen eyelids, conjunctival hyperemia, oculardischarge, and diffuse or focal loss of "pellucidity and lustre" of the cornea.⁴ In advanced stages, corneal perforation and loss of"appearances and utility" of the eye occurred.⁴ Thecritical observation, however, was that anterior uveitis was secondary tocorneal disease. Systemic signs such as fever, loss of appetite, thirst, "frequencyof the pulse," unhealthy appearance of the coat, and alternate "heat and chills"often accompanied this form.⁴ Trauma was acommon cause, but it was also seen as a consequence of colds and fevers. Younghorses and those in "high condition" were more commonly affected,⁴ as they were under the greatest amount of stress.We can assume by "high condition" he meant horses that were used for racingpurposes and, hence, may have also been more commonly treated because of theirvalue.

Today's veterinary ophthalmologist would easily recognize the patientsthat Wardrop describes, and in addition to traumatic keratitis would includeas possible causes sterile corneal stromal abscesses, corneal foreign bodies,bacterial keratitis (especially due to Streptococcus species, Staphylococcus species, Acinetobacter species, and Pseudomonas species), fungalkeratitis (due to Aspergillus species and Fusarium species), viral keratitis (equine herpesvirus 2, equine influenzavirus A₂, and adenovirus), ocular parasites such as Onchocerca cervicalis and Thelazia species,and allergic and chemical irritations.^9-16 Thesimilarities between these causes and those seen in humans are striking andspeak to the validity of Wardrop's concept of applying medical principlesacross species lines.

Although the methods of treating these disorders have improved greatlyfrom the "bleeding, purging, and blistering" of Wardrop's day,⁴ herecognized that the outcome often depended on the immediate and aggressivetreatment of the inflammation if the course of the disease was not to be protractedor to result in long-term damage to the globe. As today, he also recognizedthe importance of "paying attention to the air of the stable; for this isoften impure." In addition, he recommended avoiding exposure to light andnot feeding the animal a large amount of grain.⁴ Modernequine medicine has recognized that housing in a stable increases fungal contaminationof the equine conjunctiva¹⁰ and that sunlightinduces intense ocular pain and photophobia in horses with keratitis. Wardropcorrectly argued against a common practice at the time of scarifying the eyesand removing the third eyelid, although in some circles in the United Statesthis unfortunate practice persisted until well into the 1900s. He advocatedextreme caution in draining a hypopyon and emphasized careful surgical techniquewhen doing so.⁴ Today, rather than trying totreat an obvious clinical sign of the condition (eg, ocular surface vascularinjection) by limiting ocular blood flow by means of therapeutic bleedingand inducing systemic hypotension with purgative balls, the veterinary ophthalmologistuses many of the same antimicrobial agents familiar to the physician, alongwith systemic and topical anti-inflammatory medications.

Wardrop was among the first to clearly differentiate in horses the primarilycorneal origin of simple inflammation from the uveal origin of the secondform of ocular inflammation that he called specific inflammation.⁴ Although the 2 forms appear superficiallysimilar, the latter has more serious consequences for vision and is the "mostdangerous disease of the Eye of the Horse." Unlike the corneal origin of simpleinflammation, he noted that the uveal origin of specific inflammation wasalso more frequent in "particular lines of blood."⁴ Thisobservation was later borne out in studies that found certain horse breedssuch as the Appaloosa to have an 8-fold increased frequency of ERU.⁵ It affected animals of all ages, all classes, andall states of condition, although horses that were "high bred" or in highcondition were believed to be more commonly affected. Dark, ill-ventilatedstables were thought to have a great influence on the incidence of the disease.⁴

Wardrop noted that specific inflammation usually develops very suddenly,that it is characterized by swelling of the eyelids and copious tearing, butthat the conjunctival injection is not as great as in simple inflammation.⁴ A key differentiating feature, however, is lack ofa "distinct speck on the cornea," and the whole anterior chamber is "dim andclouded."⁴ As in simple inflammation, thisform may exhibit varying degrees of hypopyon.⁴ Thecondition is often, at least initially, unilateral and may be quite asymmetricalin severity. He described spontaneous resolution of the inflammation overa period of a few weeks and observed that the eye may then look quite normalor may have adhesions that distorted the pupil (posterior synechia). He astutelynoted that inflammatory episodes typically recur at varying and sometimesquite distant intervals, and that ultimately the accumulated damage leadsto a cataract and visual loss.⁴ Well beforethe introduction of the ophthalmoscope in 1850,¹⁷ Wardropdescribed dissecting the eyes of these horses and finding a collection offluid "between the choroid coat and retina," condensation of the vitreal elements,and a retina that is detached and compressed "into a chord or bundle."⁴ Finally, as some of today's horse buyers can stillattest, Wardrop marveled at how astute some dealers in horses were in identifyinghorses that have had an episode of specific inflammation and how the dealerswould sell an animal (often during a period of quiescence) before the animal'svalue was lost owing to blindness.⁴

As with simple inflammation, Wardrop's description of specific inflammationis easily recognized by today's veterinary ophthalmologist. It is most commonlyknown as ERU but has also been referred to as periodic ophthalmia, recurrentiridocyclitis, relapsing uveitis, and "moon blindness." The latter term purportedlyoriginated with Vegetius in the fourth century AD, who thought that the cyclicnature of the inflammatory outbreaks was associated with changes in the phasesof the moon.¹⁸ In Wardrop's essay, he divergedfrom this traditional use of the term moon blindness andinstead used it to describe a dense white cataract that perhaps resemblesa brightly illuminated moon. Nevertheless, his description of recurring boutsof epiphora, photophobia, anterior chamber opacification, ocular vascularinjection, and the visually devastating sequelae of synechiae, cataract, andretinal detachment could be easily found in today's textbook descriptionsof horses with ERU (Figure 2 and Figure 3). With the comparatively recentadvent of tonometers such as the Mackay-Marg and Tono-Pen (Mentor Ophthalmics,Norwell, Mass) that are suitable for use in horses, glaucoma also has beenfound to be a sequelae of ERU.¹⁹ Equine recurrentuveitis is the most common cause of glaucoma in horses, although glaucomaitself is relatively uncommon in horses, perhaps because of their very largeuveoscleral outflow pathway.²⁰

Today ERU is regarded as an umbrella term for a diverse set of diseasescharacterized by episodes of active uveitis alternating with varying intervalsof clinical quiescence.⁹ It undoubtedly remainsone of the leading causes of blindness in horses worldwide.^5-8 Thetypical initial episode consists of severe anterior uveitis, but subsequentepisodes are less severe and more chronic in nature. Ultimately, the accumulatedeffects of the inflammation lead to progressively more destructive pathologicchanges and visual loss. Causes believed to be important today include thespirochetes Leptospira interrogans and Borrelia burgdorferi; other bacterial infections that include brucellosis,salmonellosis, streptococcus hypersensitivity, Escherichiacoli, and Rhodococcus equi; the parasites Onchocerca cervicalis, Toxoplasma gondii, and various other intestinal parasites; and viral agents that includeequine influenza virus, equine herpesvirus 4, equine arteritis virus, andpossibly equine anemia virus.^9,21 Inaddition, blunt or penetrating trauma may play an inciting role by breakingdown the relatively labile equine blood-aqueous barrier. Wardrop's admonitionto consider the environment proved to be prescient, since it is clear thatmany of the infectious causes of ERU in horses are acquired through less-than-optimalhusbandry practices.⁹ Again, the striking similaritiesbetween the recognized causes of ERU in horses and the causes of uveitis inhumans speaks to Wardrop's insight into comparative ophthalmology.

The pathophysiology of ERU is unclear, but the disease undoubtedly hasan immune-mediated basis.⁹ It has been speculatedthat a common theme of all of these inciting causes is that they disrupt therelatively unstable blood-aqueous barrier of the equine eye and allow immunologicallyreactive components to enter the eye. Hypersensitivity to L interrogans serovars (especially pomona)is commonly implicated as a cause, and the equine cornea and lens have beenshown to share antigenic properties with this organism.²² Althoughanti-Leptospira antibodies are found in the serum,tears, and aqueous humor of horses infected with Leptospira, living organisms are not necessary for ERU to occur.^23,24 Frequently,uveitis may not be seen until 15 months after systemic infection with Leptospira,²⁵ and the factthat it can resolve with only anti-inflammatory drugs again suggests thatit is primarily immune-mediated in nature.

Although horses that are seropositive for antibodies to L interrogans serovar pomona are 13.2 timesmore likely to have uveitis than seronegative horses,⁵ notall seropositive horses will develop uveitis.^26,27 thisfinding, in conjunction with the recognized heritable nature of ERU, has ledsome to suggest that ERU in horses occurs in a manner analogous to that inhumanswho posses the tissue marker HLA-B27 and develop uveitis in assiciationwith Klebsiella species.^28,29 Thatis, uveitis develops only if the horse possesses an as yet undefined specifictissue antigen and is also exposed to L interrogans. Nevertheless,a significant number of horses with uveitis are seronegative to all serovarsof L interrogans, indicating that this organism aloneis not the sole cause of ERU in horses.

The histopathological changes in ERU have built on Wardrop's descriptions,and today ERU is characterized as a uveal lymphoplasmacytic inflammatory infiltratethat most commonly affects the nonpigmented ciliary epithelium of the ciliaryprocesses^7,30-33 (Figure 4). Other histologically identifiablelesions involving the nonpigmented ciliary epithelium include linear eosinophilicintracytoplasmic inclusions that may be located within mitochondria and thickacellular hyaline membranes closely adherent to the inner aspect of the nonpigmentedciliary epithelium³¹ (Figure 5). In patients with chronic ERU undergoing an acute episode,a perivascular lymphoplasmacytic inflammatory infiltrate within the choroid,retina, optic nerve, and anterior uveal tract is often identifiable.³³ An exudative retinal detachment may result from thechorioretinitis. These retinal detachments may focally reattach because offibrous organization or may progress to total separation.³³ Vitreousopacities, chorioretinitis, retinal detachment, and optic nerve atrophy arefrequently observed in chronic ERU (Figure6).

Although Wardrop viewed specific inflammation as usually incurable,he thought there was some benefit from bleeding (≤2.9-4.8 L from the jugularvein closest to the affected eye), administering purgative balls, feedinga "cooling diet" (less high-energy feedstuffs such as grain), and improvingthe ventilation of the stable.⁴ Given thatERU frequently resolves spontaneously (at least initially), and that chronicforms may require slitlamp biomicroscopy to identify that they are active,it is highly likely that many treatment strategies—perhaps even thoseused today—are erroneously believed to be effective. He also applieda "vinous tincture of opium" with a brushlike camel's-hair pencil to the globe2 to 3 times daily, meaning he applied medicine that stained the eye, usinga whiskerlike instrument for its application. He believed that this procedurewas helpful in some cases,⁴ although the realvalue of this therapy may simply have been to provide some degree of painrelief.

Of interest is Wardrop's observation that, as in humans, ERU is ofteninitially unilateral. He questioned whether destroying the first eye wouldarrest the progress of the disease in the fellow eye, and so he treated avaluable race horse with unilateral disease by incising the cornea and expressingthe lens, vitreous, and other intraocular contents. He reported that the animaldid not experience an episode in the opposite eye for up to 6 years later.He noted that others before him used less refined techniques for destroyingthe diseased eye such as putting quicklime between the eyelids or by thrustinga nail into the eye in hopes of preventing the disease in the opposite eye.⁴ Obviously, such therapy would be considered crueltoday.

Although there is some suggestion that severe ERU might allow the exposureof immunologically isolated antigenic constituents such as interphotoreceptorretinoid-binding protein or retinal S antigen³⁴ and,hence, could result in disease in the contralateral eye, to date no studyhas demonstrated a benefit to destroying the affected eye; in addition, thehistological changes seen in ERU are not consistent with sympathetic ophthalmia.Currently, ERU is not regarded as a variant of sympathetic ophthalmia butinstead as a disease that often affects both eyes asymmetrically. The slitlampbiomicroscope, a tool not available to Wardrop, has allowed the detectionof low-grade inflammation in the fellow eye of a substantial number of horsesthat have what appears to the naked eye to be unilateral disease.

Today's veterinary ophthalmologist uses many of the same medicationsthat the physician uses to treat humans with recurrent uveitis. Because itmay be difficult to safely approach the eye of a very large animal that hasconsiderable ocular pain, a subpalpebral lavage system is occasionally placedto facilitate treatment of fractious animals. This system consists of a tubethat is placed into the dorsal or ventral conjunctival fornix and out throughthe skin of the upper or lower lid, respectively. This tube connects witha port that is secured near or through the mane of the horse and allows medicationto reach the corneal surface safely through the opening in the fornix. Thetreatment of ERU is also complicated by the fact that even topical atropinesulfate can induce gastrointestinal tract stasis and colic (which can be fatalto large herbivores), and that systemic corticosteroid therapy may resultin the keratinized hoof separating from the underlying bone (laminitis), therebypotentially permanently crippling the animal.³⁵ Recentlytopical and intravitreal cyclosporine (administered as a sustained-releaseintravitreal implant) has shown promise in reducing the severity of the diseaseand the frequency of attacks.³⁶ Although parsplana vitrectomy has been suggested as another avenue to prevent recurrentepisodes,³⁷ this approach requires longer-termfollow-up and replication at other centers before it can be widely advocated.

As evident, our understanding of ERU has come a long way since JamesWardrop differentiated between the various forms of ocular inflammation inthe horse. Nevertheless, ERU remains the most common cause of blindness inhorses, and much more needs to be done if we are to address the economicallyimportant and aesthetically disfiguring condition effectively. Unfortunately,despite potent modern immunosuppressive drugs and broad-spectrum antibiotics,today's veterinary ophthalmologist would have to agree with Wardrop's observationin 1819 that "however beneficial these remedies may be in diminishing theseverity of the symptoms, yet they never prevent the repetition of attacks,and the ultimate destruction of the organ."⁴

Correspondence: Paul E. Miller, DVM, Department of Surgical Sciences,School of Veterinary Medicine, University of Wisconsin–Madison, 2015Linden Dr, Madison, WI 53706-1102 (millerp@svm.vetmed.wisc.edu).

Submitted for publication July 1, 2003; final revision received October26, 2003; accepted December 11, 2003.