19

Change and Progress in UveitisTHE cause of many forms of uveitis remains

unknown, despite better understanding of the

pathophysiology of the disease and more effectivetherapy. Some cases are the result of an infection orparasitic infestation whereas others are regularlyassociated with systemic disease, often a seronegativearthropathy. A few patients present with charac-teristic symptoms and signs and form part of a groupof conditions of unknown aetiology in which uveitis isthe prominent feature—eg, sympathetic ophthalmia,Fuchs’ heterochromic iridocyclitis, intermediateuveitis (pars planitis), and the Vogt-Koyanagi-Haradasyndrome. However, about 50 % of cases investigatedby general physicians or ophthalmologists have noobvious aetiology. 1A specific bacterium, virus, or fungus can be

implicated in perhaps 5-10% of patients. Inflam-mation may follow a penetrating injury or an area ofdeep corneal ulceration. The anterior parts of theuveal tract-the iris and the ciliary body-are mostcommonly affected and acute suppurative inflam-mation results. The eye is a richly vascular organ andis often the site of spread of organisms from other partsof the body. Candida ophthalmitis has been

increasingly recognised and has undergone importantchanges in its pattern of presentation. In 1974Edwards and his colleagues2 described 14 patients andsummarised a further 62 reports. In most instancesthere was chorioretinitis with typical white fluffyexudates on ophthalmoscopic examination.

Predisposing factors included antibiotic therapy(84%), recent surgery (65%), and steroid or otherimmunosuppressive therapy (62%). Intravenousinfusions had been given to 88 % of patients but none

1. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DCO. Acute antenor uveitisand HL-A 27 Lancet 1973, ii: 994-96

2. Edwards JE, Rods RY, Montgomerie JZ, Gaze LB. Ocular manifestations of candidasepticaemia. Review of seventy-six cases of hematogenous candida

endophthalmitis. Medicine 1974; 53: 47-75.

had a history of drug abuse. Now, 13 years later,heroin addicts are a group at special risk for systemiccandida infections.3 Dupont and Drouher4 described38 addicts, 36 of whom had cutaneous lesions ofcandidosis, 10 osteoarticular involvement, and 15metastatic ocular disease. 12 of those with ocularlesions had chorioretinitis, including 9 with hyalitis,but 3 had only an anterior uveitis. In 3 of the 15 casesthe ocular lesions were bilateral, a lower proportionthan Edwards had noted in non-addicts. All patientswith ocular disease received oral ketoconazole andsome were also given amphotericin B or flucytosine.10 had no residual ocular problems but 4 were leftwith a blind or nearly blind eye.

In some series up to 10% of cases of uveitis havebeen ascribed to toxoplasmosis. Most cases of

toxoplasma chorioretinitis in developed countries arethe result of congenital infection; in contrast, ocularinvolvement is uncommon in acquired toxoplasmosis.Focal retinitis is the rule; the parasites are thought toencyst within the retina, which they reach via thebloodstream. According to this theory inflammation,usually granulomatous, develops only if the cystsrupture. However, cyst rupture has never been seen inhistological preparations of human eyes, and theretinal damage may be a response to toxin productionby the parasite.6 6 Pathologists seldom have the

opportunity to study the human lesions of oculartoxoplasmosis and experimental models are thereforeespecially valuable.7-9

Toxocara canis is the other important parasitic causeof uveitis in the developed world.1O Over 2% of theUK population have evidence of previous toxocarainfection but most are symptom-free. Enzyme-linkedimmunosorbent assays (ELISA) have improved thesensitivity of serological testing for toxocara and mayincrease the number of cases diagnosed." Oculartoxocariasis usually presents in older children or

young adults, and can occur several years after anepisode of visceral larva migrans. This pattern ofdisease reflects the ability of toxocara larvae to remainviable for many years, to encyst in peripheral tissues,and to become reactivated much later. Using a

primate model, Watzke, Oaks, and Folk,12 have

3. Collington PJ, Sorrell TC Disseminated candidiasis: evidence of a distinctive

syndrome m heroin abusers. Br Med J 1983, 287: 861-624. Dupont B, Drouhet E. Cutaneous, ocular and osteoarticular candidiasis in heroin

addicts: new clinical and therapeutic aspects in 38 patients J Infect Dis 1985; 152:577-91.

5. Perkins ES. Ocular toxoplasmosis. Br J Opthalmol 1973, 57: 1-17.6 Dutton GN, Hay J Toxoplasmic retinochoroiditis—current concepts in pathogenesis.

Trans Ophthal Soc UK 1983; 103: 503-07.7. Ashton N. Ocular toxoplasmosis in wallabies (Macropus rufogriseus) Am J Ophthalmol

1979; 88: 322-328. Yoshizumi MO. Experimental toxoplasma retinitis A light and electron microscopical

study Arch Pathol Lab Med 1976; 100: 487-909. Lee WR, Hay J, Hutchison WM, Dutton GN, Slim JC. A murine model of congenital

toxoplasmic retinochoroiditis. Acta Ophthalmol 1983; 61: 118-30.10 Molk R Ocular toxocariasis: A review of the literature Ann Ophthalmol 1983, 15:

216-31.

11. Ree GH, Voller A, Rowland HAK Toxocariasis in the British Isles 1982-83 Br MedJ 1984; 288: 628-29.

12. Watzke RC, Oaks JA, Folk JC. Toxocara canis infection of the eye. Correlation ofclinical observations with developing pathology in the pnmate model Arch

Ophthalmol 1984, 102: 282-91.

20

suggested that the characteristic granulomatousinflammation is due to larval excretory or secretoryproducts and is therefore seen only with viable worms.This contrasts with the traditional view that larvaldeath induces the inflammatory response. Clearly ifinflammation is due to viable larvae then this will have

important therapeutic implications since promptkilling of the larvae may be expected to shorten theclinical course.

Johnson and Wirostko13 have lately reported on themicrobiological and electron microscopic findings in11 patients with severe, apparently idiopathic, steroid-resistent uveitis (chronic idiopathic vitritis). Theycultured samples of vitreous removed duringvitrectomy on various media but obtained no growth.Similarly, no bacteria or viruses were identified byelectronmicroscopy. However, in 10 of the 14

specimens structures resembling microbial bodieswere seen in the lysosomes of polymorphonuclearleucocytes included in the sections of vitreous.

Samples of vitreous humour from 4 of these patientswere injected into the eyelids of 100 mice;14 in 15 micehistological evidence of uveitis developed and in somethe bacteria-like bodies were identified in poly-morphonuclear leucocytes. There was evidence - ofsystemic inflammation and polymorphonuclear cellsincluded in these infiltrates also contained bacteria-like bodies. If, as it seems, the inclusions are ofbacterial origin it should be possible to establishcultures and to determine antibiotic sensitivity.

Disordered immunity is often thought to be theunderlying cause of non-infectious human uveitis-clinical and experimental evidence is supported byresults of trials with immunosuppressive agents.1SUveitis occurs in association with many differentdiseases in which there is clear evidence of disordered

immunity, or at least a characteristic pattern of chronicinflammation in the affected tissue-eg, rheumatoiddisease, ankylosing spondylitis, Reiter’s disease,sarcoidosis, and Crohn’s disease. Increased levels ofimmune complexes have been reported in the serumof patients with chronic iridocyclitis, and levels ofcomplexes may be related to disease activity. 16

Antibodies develop in animals immunised withuveal extracts17 but there is seldom histologicalevidence of an associated uveitis. Similarly, in modelsof immune-complex disease in which animals aregiven repeated intravenous injections of heterologousproteins, uveitis is rare but glomerulonephritis iscommon. Essentially, the choroid is a heavily13. Johnson LA, Wirostko E Chronic idiopathic vitritis Ultrastructural properties of

bacteria-like bodies within vitreous leukocyte phagolysosomes. Am J Clin Pathol1986, 86: 19-24.

14. Wirostko E, Johnson LA, Wirostko BM. Transmission of chronic idiopathic vitritis inmice by inoculation of human vitreous containing leucocyte phagolysosomalbacteria-like bodies Lancet 1986; ii 481-83.

15 Nussenblatt RB, Palestine AG, Chan CC Cyclosporin A therapy in the treatment ofintra ocular inflammatory disease resistant to systemic corticosteroids and cy totoxicagents Am J Ophthalmol 1983; 96: 275-82

16 Char DH, Stem P, Masi R, Christensen M. Immune complexes in uveitis. Am JOphthalmol 1979, 87: 678-81.

17. Aronson SB. Expenmental allergic uveitis Uveitis following immunization tohomologous and heterologous uveal and retinovitreous preparations Arch

Ophthalmol 1968; 80: 235-42.

pigmented vascular bed, and pigment itself is onlyweakly antigenic. In a series of reports over the past 20years Wacker and his colleaguesl8 have focusedattention on the role of retinal, rather than uveal,proteins in the induction of uveitis. They havecharacterised a soluble glycoprotein, molecular weight55 000, associated with the plasma membrane ofphotoreceptor cells,19 now generally known as retinalS (for soluble) antigen. In some species a singleinjection of less than 5 J.1g, emulsified in Freund’s

complete adjuvant, induces uveitis. Ultrastructuralstudies have confirmed that the rod outer segment ofthe photoreceptor layer is the initial target for theinflammatory reaction.2o There is evidence of bothhumorap1 and cell-mediated 22 immune reactions toretinal antigens in patients with uveitis, suggestingthat immunological abnormalities may eithercontribute to, or result from, the retinal damageassociated with uveitis.

Experimentally the density and histological patternof the reaction is very much a function of the amountof retinal antigen administered—eg, in guineapigs 50J.1g induces a massive panophthalmitis in which theinflammatory infiltrates are a mixture of poly-morphonuclear leucocytes, eosinophils, and somemacrophages. In contrast, lower doses of antigenproduce a posterior chronic inflammatory uveitis. Atsome dosage levels the histological features are veryreminiscent of human sympathetic ophthalmitis.These different histological patterns suggest thatmore than one type of immunological mechanism isinvolved in induction of uveitis. The acute inflam-

matory reaction associated with the higher doses ofantigen can be suppressed, or eliminated, if animalsare first depleted of complement.24 Moreover, someforms of experimental disease can be prevented by thesimultaneous administration of cyclosporin, 25 whichis predominantly an inhibitor of T cells. As a result,cyclosporin has been used in a small number ofpatients with severe uveitis in whom corticosteroid orcytotoxic therapy has been unsuccessful or associatedwith unacceptable side-effects." 5 of 16 patients withsevere uveitis treated at the National Institutes ofHealth showed a good clinical response. However, themost recent report from this group emphasises thatnephrotoxicity is common and "decisions to use

18 Wacker WB, Lipton MM. Experimental allergic uveitis homologous retina as

uveitogenic antigen. Nature 1965, 206: 253-54.19. Wacker WB, Donoso LA, Kalsow CM, Yankeelov JA Jr, Organisciak DT

Experimental allergic uveitis. Isolation, characterization, and localization of asoluble uvenitopathogenic antigen from bovine retina. J Immunol 1977; 119:

1949-58.

20 Forrester JV, Borthwick GM, McMenamin PG Ultrastructural pathology ofS-antigen uveoretinitis. Invest Ophthalmol Vis Sci 1985; 26: 1281-92.

21. Gregerson DS, Abrahams IW, Thiokill CE. Serum antibody levels of uveitis patientsto bovine retinal antigens. Invest Ophthalmol Vis Sci 1981; 21: 669-80.

22 Nussenblatt RB, Gery I, Ballintine EJ, Wacker WB. Cellular immune responsivenessof uveitis patients to retinal S-antigen. Am J Ophthalmol 1980; 89: 173-79.

23. Rao NA, Wacker WB, Marak GE Experimental allergic uveitis Clinicopathologicfeatures associated with varying doses of S-antigen. Arch Ophthalmol 1979, 97:1954-58

24. Marak GE, Wacker WB, Rao NA, Ward PA. The effects of complement depletion onexperimental allergic uveitis. Ophthalmol Res 1979; 11: 97-107.

25. Nussenblatt RB, Rodrigues MM, Wacker WB, Cevano SJ, Salinas-Carmona MC,Gery I. Cyclosporin A inhibition of experimental autoimmune uveitis in Lewisrats. J Clin Invest 1981, 67: 1228-31.

21

cyclosporin in non-fatal autoimmune disease involve abalance between toxicity and efficacy",26

Lens-induced ophthalmitis is another poorlyunderstood form of uveitis which may have an

immunological basis. One of the most puzzlingclinical features is the extreme variation in responsefollowing either traumatic or surgical damage to thelens capsule. In many instances there is little or noreaction, but capsular damage may be followed bysevere granulomatous inflammation which progressesto endophthalmitis. The potential antigenicity of lensproteins was first documented at the turn of the

century and modem ELISA techniques have shownthat over 50% of normal individuals have serumantibodies to whole lens homogenates. 27 However,uveitis following lens extraction or trauma is onlyslightly more common in patients with antibodies.Protein makes up 35 % of the mass of the human lens,probably a higher concentration than in any othertissue. Many distinct antigenic components have beenidentified within the lens and some of these are also

expressed in extraocular tissue and in the lens of aremarkable range of lower vertebrates.28 Rahi, Misra,and Morgan29 have succeeded in raising antibodies toautologous lens protein in rabbits but this is associatedwith only a mild uveitis. As yet there is no entirelysatisfactory model of lens-induced (phacoallergic orphacoanaphylactic) endophthalmitis. 30

MAN, DOGS, AND HYDATID DISEASE

Jenner was one of the first scientists to draw attention tothe dangers of keeping pets when he wrote: "The deviationof man from the state in which he was placed by natureseems to have proven to him a prolific source of diseases ...The wolf disarmed of his ferocity is now pillowed in theLady’s lap".1 Why dogs were first domesticated is unclear,but it was probably due to a combination of factors such astheir value in hunting, transportation, defence, herding,scavenging, and fighting and their usefulness as food,bedwarmers, and pets.2 Whatever the reason, the

relationship between man and dog facilitates thetransmission of about fifty diseases.3 One of the most

important of these, although not the most prevalent, is

hydatid disease, caused by the small canine taeniidEchinococcus granulosus.

26 Palestine AG, Austin HA, Balow JE, et al. Renal histopathologic alterations in patientstreated with cyclosporine for uveitis. N Engl J Med 1986; 314: 1293-95.

27. Nissen SH, Andersan P, Andersen HMK. Antibodies to lens antigens in cataract andafter cataract surgery. Br J Ophthalmol 1981; 65: 63-66.

28 Naisel H, Goodman M The ontogeny and specificity of human lens proteins. InvestOphthalmol 1965; 4: 129-37

28 Naisel H, Goodman M The ontogeny and specificity of human lens proteins. InvestOphthalmol 1965; 4: 129-37

29. Rahi AHS, Misra RN, Morgan G Immunopathology of the lens III Humoral andcellular immune responses to autologous lens antigens and their roles in ocularinflammation. Br J Ophthalmol 1977; 61: 371-79.

30. Marak GE, Rao NA, Antonakou G, Shwinski A. Experimental lens induced

granulomatous endophthalmitis in common laboratory animals Ophthalmic Res1982; 14: 292-97.

1. Jenner E. An enquiry into the causes and effects of the veriolae vaccinae, a diseasediscov ered in some of the western counties of England, particularly Gloucestershireand known by name of cow pox London: Sampson Low, 1798.

2 Manw ell C, Ann Baker CM. Domestication of the dog: hunter, food, bed-warmer, oremotional object? Z Tierzuchtg Zuchtgsbiol 1984, 101: 241-56.

3 Baxter DN. Leck I The deleterious effects of dogs on human health: 2. Caninezoonoses. Comm Med 1984, 6: 185-97.

Awareness that hydatid disease is a global problem isincreasing and today there are few countries where thedisease has not been recorded. The prevalence of the diseasein man is determined to a great extent by his behaviour.Several studies have shown that occupational, sociocultural,religious, and behavioural factors usually account for

regionally high incidences of the disease. For example, thehighest incidence of hydatidosis in the world is found amongthe Turkana people living in Kenya, and even here there areregional differences. The annual incidence of the disease inthe north of Turkana district (220/100 000/year) is ten timesgreater than in the south.4 In Turkana, conditions for thetransmission of the parasite between the definitive and theintermediate hosts are ideal. All slaughtering is done at

home, and any hydatid cysts found are fed to dogs, whichmakes for a high prevalence of Egranulosus in the large dogpopulation.5 The higher incidence of hydatidosis in thenorth is due to the more intimate contact that the peoplehave with their dogs-which spend much time in the huts,are allowed to clean children of vomitus or faeces, scavengefrom cooking utensils which are left on the ground, andoften defaecate near the houses. Such practices create anextraordinarily high infection pressure on the people whichdoes not seem to exist to such an extent in the rest of theworld.

Diagnosis of hydatid disease has been improved bycombining ultrasound and computed tomographic scanswith new developments in the serological detection of bothEchinococcus antigens and antibodies with enzyme-linkedimmunosorbent assays.6 Such tests are also proving to be ofvalue in trials of albendazole.’ Until lately surgery was themainstay of treatment but this has its own inherent dangers,including inoperable postoperative recurrence despite theuse of scolecidal adjuncts such as 0-5 % silver nitrate or 0- 1 %cetrimide. The introduction of mebendazole held out some

promise of a realistic alternative to surgery, but results wereinconsistent and the drug was largely discontinued.8Albendazole sulphoxide destroys protoscoleces in vitro9 andin vivo in sheepl° and achieves much higher cyst and serumconcentrations than does mebendazole.1O Perioperativealbendazole therapy may help in reducing secondaryhydatidosis.11 Side-effects with this drug have been mildand always reversible.’ Other drugs, such as praziquantel,are also being investigated. Further work is required with allthese parasiticides before they can be applied to the routinetreatment of hydatidosis.The first programme for controlling hydatidosis was

started over 120 years ago in Iceland, where an estimated 1in every 6 people had the disease; 12 today the disease has not

4 French CM, Nelson GS. Hydatid disease in the Turkana District of Kenya. II a studyin medical geography Ann Trop Med Parasitol 1982, 76: 439-57.

5. Macpherson CNL, French CM, Stevenson P, Karstad L, Arundel JH. Hydatiddisease m the Turkana district of Kenya, IV The prevalence of Echinococcusgranulosus infections m dogs, and observations on the role of the dog in the lifestyleof the Turkana Ann Trop Med Parasitol 1985, 79: 51-61

6 Craig PS, Zeyhle E, Romig T. Hydatid disease. Research and control in Turkana II.

The role of immunological techniques for the diagnosis of hydatid disease. TransRoy Soc Trop Med Hyg 1986; 80: 183-92

7. Morris DL, Dykes PW, Marriner S, et al. Albendazole. objective evidence of responsein human hydatid disease. JAMA 1985; 252: 2053-57

8. Schantz PM, Van den Bossche H, Eckert J Chemotherapy for larv al echinococcosis inanimals and humans: Report of a workshop Z Parasitenkund 1982, 67: 5-26

9 Chinnery J, Morris DL Effect of albendazole sulphoxide on viability of hydatidprotoscoleces Trans Roy Soc Trop Med Hyg (in press)

10 Morris DL, Clarkson MJ, Stallbaumer MF, Pritchard S, Jones PS, Chinnery JB.Albendazole treatment of pulmonary hydatid cysts in naturally infected sheepstudy with relevance to man Thorax 1985; 40: 453-58

11. Morris DL, Chinnery JB, Hardcastle JD Can albendazole reduce the risk of

implantation of spilled scoleces? An animal study. Trans Roy Soc Trop Med Hyg1986; 80: 481-84.

12 Schwabe CW Veterinary medicine and human health. 3rd ed London: Williams &

Wilkins, 1984