2/05■ Ocular Toxoplasmosis

uveitisJournal of the Uveitis Information Group | 2 £

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Editorial

Let me start today’s journal with some questions, dear reader:

What is the reason for most cases of posterior uveitis?In what kind of uveitis may the visual acuity already be determined before birth?Which kind of uveitis is a major problem for AIDS-patients?In what type of uveitis would treatment with corticosteroids withoutantibiotics probably be a major mistake?

The answer to all these questions is „Toxoplasmic uveitis”, caused by theparasite Toxoplasma gondii. This uveitis, known for thousands of years,is found worldwide. This is one of the reasons why today’s journal iswritten by various experts and, for the first time, including authors outside Europe (Brazil and the USA). In the following articlesthey try to describe the initiating parasite, Toxoplasma gondii, and whatrole the beloved sweet cat plays in this infection. We will hear why Toxo-plasmosis is so dangerous with possible severe consequences in preg-nancy and why it may produce massive disease in people with defectsof their immune system. Even if a few points remain controversialamongst experts, there is clear advice for a correct and successful treatment strategy for toxoplasmic uveitis, resulting in a quiet, non-inflamed eye.Unfortunately the most important problem, reducing the number ofrecurrences, remains unsolved at the moment. So, my wish for the nearfuture for patients with toxoplasmosis is to find a drug, which effec-tively can prevent new events.

All the people who participated in the preparation of this journal wishyou informative reading.

Manfred Zierhut,Professor of Ophthalmology, University Eye Clinic of Tübingen,Germany

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Patient Groups & Information . Imprint

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Patients reports - Four patients report on their experiences withuveitis caused by Toxoplasmosis Some parts of these stories are similar,some very different, illustrating the variety of toxoplasmic uveitis.

News from Science - What’s new about toxoplasmic uveitis? At the last Meeting of the Association of Research in Vision andOphthalmology in May 2005, various presentations handled new aspects ofocular Toxoplasmosis. Prof. Bahram Bodaghi reports on the most interestingfindings.

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Cover Picture - Christine Riedel, Germany gcriedel@gmx.de

P. 15 Toxoplasmosis and AIDS Problems of our immune system, especially inAIDS-patients, may result in severe ocular toxoplasmosis. Prof. CristinaMucchioli reports about this connection.

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Congenital ocular Toxoplasmosis Congenital Toxoplasmosis is the mostfrequently encountered congenital infection. Prof. Justus Garweg summarizesimportant factors which we should know about pregnancy and toxoplasmosis,and also reports on diagnostic methods we can use to detect this disease in itsearly stages.

P. 5 Portrait of Toxoplasma gondii Today´s topic will start with an introductionto the major player of this form of uveitis, the parasite Toxoplasma gondii, por-trayed by Dr. Justine Smith.

P. 36 Cultural Corner - Everything you always wanted to know aboutRennes Short portrait of this lovely city in France: come and visit!

P. 9 Ocular Toxoplasmosis This parasite is the cause of more than 50% of allcases of posterior uveitis. Prof. Carlos Pavesio describes why such an infectioncan cause uveitis in the eye, why inflammation is such an important factor forit, but also the typical signs and symptoms of ocular toxoplasmosis.

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Therapy of ocular Toxoplasmosis When and how one should treat ocu-lar toxoplasmosis will be summarized by Prof. Aniki Rothova. Fortunately,many different drugs are available and most of them are cheap. Unfortunately,the problem of recurrent uveitis is still unsolved.

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Toxoplasmosis and cats The cat is the primary host of T. gondii,contracting the disease by eating infec-ted birds and rodents whose musclesharbor tissue cysts.Fertilized eggs, or “oocytes”, measuringabout one hundredth of mm, are formedin the intestine of the cat and subse-quently shed in the feces. Oocytes areextremely hardy and may survive in theenvironment for many months. Herethey mature into an infectious form.When inhaled or ingested by anothermammal or bird, which are secondaryhosts, the oocyst passes to the intestineand hatches in the presence of digestiveenzymes. In epithelial cells that line theintestine, “tachyzoites”, the infectiousform of the organism, are generated.Tachyzoites are able to replicate by sim-ple division or so-called asexual repro-duction. The tachyzoite is crescent sha-ped and considerably smaller than theegg, measuring just one five hundredthof mm in length. After replication, asthe immune system brings the infectionunder control, tachyzoites transform

What is Toxoplasma gondii?Toxoplasma gondii (T. gondii), the causeof toxoplasmosis and a form of uveitisknown as “toxoplasmic retinochoroidi-tis”, is a parasitic microorganism thatgrows only inside the cells of humansand other mammals or the cells of birds.The genus name, Toxoplasma, derivesfrom the Greek word, toxon or “bow”,which refers to the fact that the infec-tious form of the parasite is shaped likea crescent. The species name, gondii,relates to the animal from which theparasite was first isolated, Ctenodactylusgondii, a rodent found in NorthernAfrica. T. gondii belongs to the Apicom-plexa family of microbial parasites thatalso includes Plasmodium, responsiblefor malaria, and Cryptosporidium, acause of diarrhea in humans. The para-site has a complicated life cycle thatinvolves both a primary host (in whichthe parasite reproduces sexually) andsecondary hosts (in which the parasitereproduces asexually, as describedbelow).

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Portrait of Toxoplasma gondiiToxoplasma gondii, the cause of the disease known as toxoplasmosis, is a parasitespread by cats that infects people all around the world. Justine R. Smith, MBBS PhD,who is working at the Casey Eye Institute of Oregon Health & Science University,Portland (Oregon, USA), will begin our edition on toxoplasmosis of the eye by pre-senting some interesting facts about this parasite.

into dormant tissue cysts, or “brady-zoites”, that are egg-sized or larger.However, for reasons that are not wellunderstood, these cysts may, from timeto time, convert back to tachyzoite formand a fresh cycle of infection and inflam-mation ensues. If ingested by a secon-dary host, tissue cysts will also yieldtachyzoites into the intestine.

How Toxoplasma gondiienters our livesT. gondii is a most successful parasite. Itinfects almost every mammal and bird.People become infected with T. gondii in several different ways: “eating” mate-rial that is contaminated by cat feces andcontains oocytes; consuming undercoo-ked meat that contains bradyzoites; orpassage of tachyzoites across placentafrom a pregnant woman to her unbornchild. Although we previously believedthat congenital infection was the mostcommon way to contract T. gondii,recent epidemiological studies haverevealed that infection is usually ac-quired in childhood through contactwith cats or cat-contaminated materialin the environment. Another reason thatthe parasite is so successful is its abilityto form tissue cysts. As is the case forherpes simplex virus which causes coldsores, an infected person carries T. gon-dii for the rest of his/her life. Many dif-ferent drugs have been used to treat pa-tients with toxoplasmic retinochoroiditis.However, although these may control an

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attack, none completely rid the body ofT. gondii. The pattern of infection with T. gondii in the human is illustratedin Figure 1.

Toxoplasma gondii and the eyeAfter leaving the intestine, tachyzoitesspread throughout the body primarilyvia the blood stream. During this time,the parasite may cause a mild flu-likeillness with enlargement of the lymphglands. This illness can be mistaken forglandular fever or even lymphoma.Persons with a compromised immunesystem, such as patients with AIDS, maydevelop more severe manifestations ofinfection. Once disseminated, the tachy-zoite can infect many cell types. A tachy-zoite multiples within a cell until the cellbecomes swollen and bursts; newlyreleased parasites, perhaps around 100,then infect neighboring cells. This isillustrated in Figure 2. In less than aminute the tachyzoite enters a cell, andsome cells can become infected and bekilled within the day. Depending onwhere the parasite lodges in the body,the infection has different manifestati-ons. In the eye, T. gondii may cause reti-nochoroiditis, which is described in thefollowing chapter. Parasites can producediscrete lesions in the brain, which maycause neurological symptoms depen-ding on the area of brain that is in-volved. However, most children andtheir parents are never aware that an

Figure 1Pattern of infection with T. gondii. Humans may contract toxoplasmosis by ingestingoocysts, eating poorly cooked meat containing tissue cysts, or by tachyzoite crossing the pla-centa. Once inside the human body, tachyzoites disseminate via the blood stream and mostoften cause disease in the eye and the brain.

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Figure 2T. gondii infection of human cells. (A) The T. gondii tachyzoite invades acell, (B) divides within that cell, and (C)finally causes the cell to burst with re-lease of many daughter tachyzoites thatinvade nearby cells.

infection with T. gondii has actually oc-curred. It is not until adulthood, when atissue cyst breaks down and releasestachyzoites within the eye, that toxoplas-mosis finally becomes symptomatic. We do not understand why the parasite

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TitleToxoplasmosis: a longstanding global diseaseToxoplasmosis was first described in themedical literature in the twentieth cen-tury, but it is believed to have existed forthousands of years. Throughout Wes-tern countries and in developing na-tions, toxoplasmosis is a substantialhealth problem. Toxoplasmic retino-choroiditis is the most common retinalinfection. Worldwide it is estimated thataround one billion people are infectedwith T. gondii, and as many as 1 in 5 maydevelop retinal lesions. The most com-mon time of life to contract the infectionis early childhood, but new infectionscontinue to occur through adult life.Cultures that favor eating undercookedmeat and countries with poor publichealth care, demonstrate the highestlevels of infection. Infections oftenoccur as isolated cases, but large out-breaks have been reported, such as in1995, when contamination of the localwater reservoir by feral cats resulted inthousands of human infections inVictoria, Canada.

ConclusionUnderstanding both the epidemiologyof toxoplasmosis and the basic patho-genic mechanisms of T. gondii are im-portant for development of preventivestrategies to combat the infection. Thereis no effective vaccine against T. gondii.

shows a preference to lodge in the eyeand brain in humans. One possibilityrelates to the fact that both eye and brainare specialized to develop relatively weakinflammatory responses. This is impor-tant because inflammation can causescarring that could be damaging to suchvital organs. However, at the same time,this can make it difficult for these sitesto eradicate infection. Another possibili-ty is that tachyzoites penetrate into theeye and brain more easily than otherorgans of the body. Some research fromour group suggests that the endothelialcells (cells that line blood vessels) in theretina may be particularly susceptible toinfection with tachyzoites. We comparedthe susceptibility to T. gondii infection ofretinal endothelium with endotheliumfrom other parts of the body using amethod called the [3H]-uracil incorpo-ration test. In these experiments, cellsfrom a human being are infected withtachyzoites and grown in a dish with achemical that the parasite needs (uracil).This chemical is attached to a radioactivelabel [ 3H]. The radioactivity measure-ment from any given dish indicates howwell T. gondii grew inside the cells in thedish. We observed that retinal endotheli-um yielded the highest radioactivity rea-dings of all cell types tested. Presentlywe are focusing our research on under-standing what causes this susceptibilityto infection.

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Ocular ToxoplasmosisIn people with normal immunity, the involvement of the eye is the most common reason for concern in this systemic disease. Prof. Carlos Pavesio, Consul-tant Ophthalmologist at Moorfields Eye Hospital in London, UK, describes the symptoms and signs found in ocular toxoplasmosis, which occur as a consequence of the inflammatory response triggered by the parasite which causes this disease,Toxoplasma gondii.

What is inflammation? Before going directly to the ocular di-sease, it is important to explain whatinflammation means and what it can do.Inflammation is a reaction which invol-ves activation of the immune system, inresponse to any aggression to the body,as is the case of the presence of an in-fectious agent. Our body is trying to eli-minate an aggressor. So, inflammationis an important reaction which exists toprotect the body against infections andcancer cells. But inflammation can alsocause damage, especially if very intense,because many elements of this reactioncan “attack” normal tissues which arenearby. The blood vessels become dila-ted, hence the redness seen in inflamedtissues, and allow the leakage of fluidinto the surrounding tissues, which pro-duces the swelling also present ininflammation. The vessels may be pri-marily involved in the inflammatory response, which means that the inflam-mation starts in the blood vessels them-selves, but many times they are involvedjust because they are close to a focus ofinflammation.

This attack to normal tissues producesdamage and usually results in the for-mation of scar tissue, which will havemore or less serious consequences tofunction depending on the tissue invol-ved. A small scar in the finger will haveno major consequences, but a small scarin the retina may produce significantvisual loss.

How do I get Toxoplasmosisin my eye? Until recently it was believed that mostcases of ocular disease occurred as aconsequence of congenital transmission(when the infection is acquired duringpregnancy), but the evidence availablenow shows that many cases may prob-ably result from infection acquired afterbirth. Eating undercooked meat, espe-cially pork and lamb, and contact withcats represent well known risk factorsfor acquiring the disease. More recentlyit has been found that, in rural areas, the ingestion of contaminated waterrepresents an important factor.Once the parasite is in the body it will

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reach the eye via the blood stream andwill establish itself in the retina. Thereit will form cysts, which live inside yourown cells, and do not elicit a responsefrom the immune system. This is be-cause the parasites are very smart incamouflaging themselves from yourdefences. They will only become visibleto your defences when the cysts break-down and release the parasites in theretina.

What are the symptoms? The ocular disease will present in anacute form with sudden onset of floatersand/or blurring of vision, which aresymptoms of disease occurring in theposterior part of the eye, and in somecases will also manifest symptoms ofpain, redness and light sensitivity, typi-cal of involvement of the anterior part of the eye.This is all you will feel in a case of re-activation of the eye disease, but if youhave just acquired the disease, theToxoplasma will be going everywhere inyour body and you may have variablesymptoms, ranging from a very mild fluto a more severe widespread infection.

What is actually happeninginside the eye?In ocular toxoplasmosis the primary site of inflammation is the retina, wherethe cysts, mentioned above, containingmany organisms lay dormant. It is therupture of these cysts, which produce

the inflammation called a retinitis.Depending on the location of the lesionthe symptoms will vary. A lesion whichis very close to the back of the eye (nearthe macula, which is the central area responsible for the details in your vi-sion) will produce reduction of your central vision. If the very central area is involved the vision will drop to verylow levels and this reduction of visionmay be permanent (Figure 1).A lesion which is close to the back of the eye, but not central, is likely to pro-duce blurring of vision, which will bevariable in intensity, and usually resultsin good recovery, many times to normalvalues. The reduction of vision in thesecases is because of retinal swelling pro-duced by the intense inflammationwhich is happening nearby. Once theinflammation settles down the swellingregresses and the vision improves,because the tissue was not permanentlydamaged (Figure 2 ).Lesions which involve the very peripheryof the retina will produce predominantlyfloaters, and the intensity of this willdepend, predominantly, on the size ofthe lesion. Floaters represent debrisshed into the vitreous by the inflamma-tory response, especially by leaky bloodvessels.As the inflammation settles down theamount of debris in the vitreous tends to reduce, but some degree of vitreous opacity always remains. These floatersmay be sufficiently large and numerous

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to warrant treatment. The inflammation affecting the front ofthe eye and producing the symptoms ofredness, pain and light sensitivity, is asecondary phenomenon, occurring inassociation with the primary problemaffecting the back of the eye. It willrequire specific treatment with eyedrops and it tends to get better as thedisease at the back of the eye gets undercontrol.

What is the reason for reactivation and what canbe done to prevent it ? One of the typical features of oculartoxoplasmosis is reactivation. As men-tioned above this is likely to result froma break-down of a cyst of Toxoplasmagondii and for this reason occurs com-monly near a previous scar, where cystsare more likely to be found. This lesionis referred to as a satellite lesion, and it is so typical that an ophthalmologist can make the diagnosis just by seeing it,without the need for any further tests(Figure 3).In reality the reasons for reactivation arenot clear. It is very possible that cystbreak-down represents the normal lifecycle of the cyst and the clinical manife-station will depend on the location insi-de the eye and intensity of the reactionof the organism against the parasite.There is nothing that you, as a patient,can do to change the risk of a reactiva-tion, or in other words, no change in

Figure 1: This lesion is quite central (involvingfixation) and will produce permanentvisual loss.

Figure 2: Lesion very near fixation (but not in-volving it), with significant visualsymptoms. It will result in a scar, butcentral vision may recover. The darklesion seen superiorly is just a choroidalnaevus (freckle).

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your daily routine will modify it. There is some suggestion that a more pro-longed course of treatment, given evenwithout active disease, may reduce therisk of reactivation, but the reasons forthis are also not clear and further con-firmation is necessary.

What about visual loss? When the retinal lesion involves the verycentral part of the retina (the macula),there is a good possibility that visual loss will result. Since the retinitis cau-ses necrosis (destruction of the tissue),and the retina can not repair itself, therewill be permanent loss of function. Children who acquire the disease duringpregnancy may be born with large scarsin the central retina (macula) and conse-quently with very poor vision (Figure 4 ).Unfortunately, in these cases, the di-sease usually involves both eyes. In theadult this occurrence of central lesionsinvolving both eyes is rare, but visualloss in one eye can occur.Apart from a central scar, vision may godown because of the appearance ofabnormal vessels under the retina(choroidal neovascularisation). Thesevessels may appear in association withscars of any origin and produce visualloss also by generating more scar tissue.The appearance of these vessels is notassociated with active retinal lesions,and the initial symptoms of visualdisturbance will be different from a newrecurrence of the disease. There will be

Figure 3: Typical appearance of a reactivationwith a new lesion (white) adjacent to apigmented (black), old lesion.

Figure 4: Large central scar. The retina has beentotally destroyed and the white seen isactually the sclera (outer coat of theeye).

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distortion of central vision initially, butwithout an increase in floaters. The inflammation may also involve theoptic nerve head (this is the part of theoptic nerve which is visible inside theeye and is known as optic disc). Thatmay happen when the retinal lesionoccurs very near the nerve head and willusually result in loss of visual field (thepart of your vision which is all you seearound you).Another way by which vision can beaffected is by opacification of the vitre-ous body. This is a consequence of theinflammation and may be very mild, notgenerating many symptoms, or it maybe dense enough resulting in a signifi-cant reduction in vision (Figure 5 ), whichif not resolved after medical therapy islikely to require surgery to be corrected.Another problem, which is also relatedto the changes to the vitreous induced bythe inflammation, is retinal detachment.The vitreous body is attached to the reti-na and if the vitreous becomes inflamedand contracts it may pull the retina lea-ding to a retinal detachment, which mayrequire surgery.

Can visual loss beprevented?As mentioned above, visual loss de-pends primarily on the location of thelesion in the retina, and to a certainextent on the intensity of the inflam-matory response. Once the disease be-comes active the doctor will decide if

Figure 5: Two inactive lesions (➚ ) near the opticdisc (✱ ), one of them larger with morepigmentation and the other one closerto the central retina. The vitreous bodyis not clear and is causing blurring ofvision.

treatment is necessary or not, but forthis he/she needs to see you as quicklyas possible. Some lesions will be smalland away from the centre, and for thisreason may only be observed. Some le-sions will be central and will result invision loss regardless of the doctor’s best efforts.If you have a scar very near your centralvision, the doctor will give you a grid(Amsler grid), which represents a goodway of detecting distortion induced bythe appearance of abnormal vesselsunder the retina or new macular edema(for more information see uveitis 1-05 ).The sooner they are recognised the

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better since, depending on their loca-tion, different forms of therapy may be proposed.

How to prevent acquiringthe disease?Avoiding exposure to the known risk factors is the best way of not developingthis disease. In the case of the cat it isimportant to wash your hands afterhandling the animal and especially after

cleaning the litter box. Another tip is toclean the litter box daily, since theoocysts (eliminated in the cat’s faeces)will take 48 hours to sporulate (becomeinfective) – cleaning the box everydaymeans that even if you are exposed, theToxoplasma is not ready to cause aninfection. Avoid ingestion of poorly coo-ked meat and drink bottled water inareas where you may not be certain ofthe origin of the water.

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Toxoplasmosis and AIDSWhen the immune system is not in perfect shape as in patients with AIDS, oculartoxoplasmosis may result in very severe disease. Professor Cristina Muccioli, workingat the Department of Ophthalmology at the Federal University of São Paulo, Brazil,will explain why AIDS patients have a much higher risk for such an inflammation and what is different in the therapy.

Toxoplasmosis in theimmunocompromised patient Toxoplasma gondii is an important op-portunistic pathogen among immuno-compromised patients (such as cancerpatients or organ transplant recipients)and is a particularly severe problem inHIV-infected individuals. In contrast tothe benign and self-limited course ofinfection in the general population,systemic and ocular toxoplasmosis inthe immunocompromised and in pa-tients with Acquired ImmunodeficiencySyndrome (AIDS) is an aggressive andoften fulminant disorder, causing cen-tral nervous system (CNS), visceral, andlymph node infection. Immunosuppres-sion is associated with an increased riskof life- threatening toxoplasmosis as well as increase in the severity of oculartoxoplasmosis.Toxoplasmosis is believed to be the mostcommon non-viral infection of the brainin patients with AIDS. Clinical CNStoxoplasmosis is the most frequentcause of focal brain lesions in patientswith AIDS. Toxoplasmic encephalitismay develop in 25% to 50% of AIDS

patients. Although toxoplasmic ence-phalitis is common in AIDS, ocularinvolvement, in spite of being less fre-quent, is an important entity, because it is a treatable cause of severe visual lossin some patients. Ocular lesions may bethe first manifestation of intracranialand disseminated toxoplasmosis or mayoccur without evidence of intracranialdisease.No consistently reliable and noninvasivemeans of diagnosing cerebral toxoplas-mosis has been found. Histopathologicconfirmation of the parasite in brain tis-sue obtained at biopsy yields definitivediagnosis, but false negative results havebeen reported. Serologic studies of serafrom AIDS patients typically reveal anti-toxoplasma IgG antibodies, consistentwith the high rates of seropositivityamong the general adult population.

How do we diagnose Toxo-plasmosis in AIDS patients?The diagnosis of ocular toxoplasmosis inAIDS patients can be difficult to make,

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Figure 1: Patient with AIDS and ocular toxo-plasmosis that developed (neovascula-rization ➚ ).

Figure 2: Patient with AIDS and multiple activetoxoplasmisc lesions.

because in some cases, the clinical pic-ture of ocular toxoplasmosis in AIDSmay be different and patients coulddevelop an unusual presentation such as acute anterior uveitis due to iris infec-tion with Toxoplasma gondii. Ocular toxoplasmosis is the most com-mon cause of retinal inflammation inimmunocompetent patients and one ofthe most important causes of secondaryocular infection in HIV-infected pa-tients. Ocular toxoplasmosis occurs in 1 -2% of patients with AIDS in the USand in 8% of AIDS patients in Brazil. In HIV-infected patients, ocular toxo-plasmosis can occur before the develop-ment of AIDS. The risk of life-threa-tening toxoplasmosis increases whenCD4+ T-lymphocyte counts (a subtypeof the white blood cells, which are extra-ordinary important for the control ofinfections) falls below 100/�l. Thesenumbers are not sufficient for effectivecontrol of Toxoplasma gondii. Althoughthe median CD4+ T-lymphocyte countspecifically associated with toxoplasmicretinochoroiditis is not known, thisinfection can occur at higher countsthan usually associated with cytomegalo-virus (CMV) retinitis.Although the majority of reported casesin HIV- infected patients have been uni-lateral, it is not uncommon to see bi-lateral cases. In HIV-infected patients,there can be single lesions, multifocallesions in one or both eyes, and broadareas of retinal necrosis.

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Such lesions can be more severe andaggressive than the ones observed inimmunocompetent individuals. Lesionswill continue to enlarge if left untreated,which probably explains the fact thatmost reported patients have had exten-sive areas of retinal necrosis by the timediagnosis is made. In most cases of ocu-lar toxoplasmosis in immunosuppres-sed patients, there have not been pre -existing scars. Histopathologic examina-tion of eyes from immunosuppressedpatients with toxoplasmic retinochoro-iditis reveals both tachyzoites and tissuecysts in areas of retinal necrosis and within retinal pigment epithelial cells.In immunosuppressed patients, inclu-ding those with AIDS, parasites canoccasionally be found in the choroid andvitreous, and the optic nerve may beinfected (Figure 1 and 2).

How can we treat ocularToxoplasmosis in AIDS patients?The most typically used and success-ful regimen is the combination of sulfa-diazine and pyrimethamine and folinicacid. Clindamycin can be used as analternative option in patients intolerantto sulphonamide. Treatment is recom-mended for 4-6 weeks after resolutionof all signs and symptoms (sometimesfor several months or longer). Tri-methoprim/sulfamethoxazole appearsto be equivalent to sulfadiazine/pyri-methamine in HIV infected patients.

After treatment of the acute phase inAIDS patients, maintenance therapyshould be started, usually with the sameregimen that was used in the acutephase but at half the dose. Maintenancetreatment should be continued until thepatient recovers the immunity (CD4count return to more than 200 cells/�land HIV PCR viral load in the peri-pheral blood has been reasonably con-trolled for at least 6 months). Un-fortunately, treatment does not preventthe recurrence of toxoplasmosis retino-choroiditis.

ConclusionThe AIDS epidemic has stimulatedrenewed interest in the medical therapyof toxoplasmosis because toxoplasmainfection in these patients induces verysevere inflammation. A goal of ongoingre-search is to identify treatment regi-mens that will be able to kill the cysts.

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Congenital ocularToxoplasmosisCongenital toxoplasmosis (CT) is the most frequently encountered congenital in-fection. Here, Prof. Justus G. Garweg, Department of Ophthalmology, Inselspital,University of Bern, Switzerland, PD Laurent Kodjikian and Prof. Francois Peyron, atthe Departments of Parasitology and Ophthalmology, Croix-Rousse Hospital,University of Lyon I, Claude Bernard, Lyon, France report about the long-term out-come of functional and morphological manifestations with specific focus on oculardisease according to personal experience and published evidence.

Toxoplasmosis andPregnancy Toxoplasma gondii is presumably themost frequent infectious cause ofposterior uveitis (inflammation of theposterior parts of the eye, which can notbe seen from outside) throughout theworld. In the majority of cases this in-fection has been acquired long ago andthe parasites lay dormant in the healthyretinal tissue prior to inducing oculardisease. There exists evidence that 2/3 of cases are congenital in origin (whichmeans the infection has been acquiredprior to birth), and only 1/3 may be attributed to infection during life after birth. The incidence of congenital toxoplas-mosis is estimated for German spea-king countries to 0.5 – 4 infected indi-viduals per 1000 births, and in Frenchspeaking countries the incidence may be as much as 7 per 1000 births.

Approximately 40% of German womenof childbearing age have acquiredimmunity against the infection prior totheir first pregnancy, which means theyharbour antibodies against the para-sites in their sera, which protect themwidely against transmission during pre-gnancy. The remaining women have arisk of 0.5 – 1.5% of acquiring toxoplas-mosis during pregnancy. If this hap-pens, the parasite is distributed throughthe blood vessels and throughout all tissues of the body. The infection nor-mally evolves in healthy individualswithout signs of disease. For the unborn child, in contrast, thereis a significant risk of congenital in-fection and eventually severe disease.This risk at the beginning of pregnancyis pretty low, but continuously increasesto 90% at the time of delivery. Vice versa the likelihood of severe organdamage for the child decreases from

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90% at the beginning of pregnancy to less than 10% at birth (Figure 1). Iftoxoplasmosis is acquired during preg-nancy the child has an overall risk of 30– 40% of developing congenital toxo-plasmosis. The individual risk of organdamage is related to the time of fetalinfection. Very early in pregnancy it islikely to lead to death of the fetus or to produce still birth. An infection ac-quired during early pregnancy harboursa risk especially of severe neurologicaldisease. Therefore, cord blood analysis

and ultrasonography, particularly focus-sing on head and brain, should be per-formed. In contrast, ocular involvementmay occur independently of the time ofinfection with the greatest risk when theinfection is acquired around the 28thweek of pregnancy.

The outcome of disease incongenital Toxoplasmosis Information regarding the outcome ofdisease in congenital toxoplasmosis isconfusing and inconsistent. A French

Figure 1: Congenital Toxoplasmosis: Time of maternal infection and risk of transmissionto the child

organ manifestation 50%

risk of congenital infection 15%

frequent, severe frequent

rare rare, mild

Early pregnancy 3. - 6. Month Late pregnancy

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group of scientists reported a few yearsago, that, after treatment during the firstyear of life, 24% of children developed ocular lesions due to toxoplasmosis inthe later course of their lives, but in-formation regarding the visual functionis not available. Our own group hasrecently published the functional andmorphological outcomes of a great co-hort of children with congenital toxo-plasmosis who had also been treatedduring the first year of their life. After more than 6 years of follow-upafter diagnosis 71% of these childrenhad no clinical manifestation of theircongenital infection, and 5% manifestedneurological signs (i.e., hydrocephalus,cerebral calcifications and cramps), butno ocular disease. Twentyfour percent ofthe children developed ocular lesions asa consequence of their congenital dis-ease; in every fifth casetogether withother manifestations. Only 6% of chil-dren had ocular lesions at birth, theremaining ones developed these in thelater course of their life. Ocular involve-ment was observed in many cases longafter the first year, sometimes up to 10years after birth. In 66 children withocular involvement we were able to as-sess the visual function. Eighty-five per-cent of the children with chorioretinitis(Figure 2 ) had normal visual acuity,despite of their ocular lesions. In 15% of the cases visual acuity of one eye was reduced, with 12% being mild, andin only one instance there was servere

visual loss. In approximately 28% ofchildren both eyes were involved, but a moderate bilateral reduction in visualacuity was present in only 3 instances. In summary, the visual outcome of con-genital ocular toxoplasmosis seems to bemuch better for children who receivetreatment during the first year of life.

Figure 2: Congenital ocular toxoplasmosis in a27 years old healthy male individual:As is typical for congenital ocular toxo-plasmosis, there is an old chorioretinalscar (white centre and pigmented shar-ply delineated rim) which is usuallyasymptomatic. The patient visited uswith an increasing number of floaterson this eye over the last 2 weeks, butwithout any additional functionalimpairment. The view to the retinashows reactivation with a new whitishlesion and surrounding tissue swelling.

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Conclusion One might conclude that every fourthmother who acquires toxoplasmosisduring pregnancy will give birth to achild with congenital toxoplasmosis.Amongst these children with congenitaltoxoplasmosis, only one in ten will show ocular involvement at birth. Butup to the age of 10 years, 30% of chil-dren will manifest the disease in theeyes. Therefore we would suggest regu-lar eye examinations for children withcongenital toxoplasmosis. The relevanceof early diagnostics and treatment incases of suspected congenital toxoplas-mosis during pregnancy has not beenestablished and a decision is usuallymade on the individually estimated riskof complications.

Diagnostics in congenitalToxoplasmosis If a congenital toxoplasmosis is suspec-ted, it is strongly recommended toobtain not only mother blood but alsoumbilical vein blood from the child inorder to have baseline values for thedevelopment of immunity of the childagainst the parasite. After birth, a de-tailed clinical examination of the pos-terior parts of the eye and a skull x-ray or ultrasonography is performed depen-ding on the clinical findings at birth.Blood examinations are performed tofollow the development of Toxoplasmaantibodies during the first year of life.

The therapy of congenitalToxoplasmosis Until now there is no evidence that early (i.e. during pregnancy) therapy isable to reduce the risk of congenitalinfection or to prevent severe organmanifestations. However, therapy ofchildren with congenital infection during the first year of their lives hasgenerally been found to be beneficialand therefore has been widely accepted.

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Therapy of ocular ToxoplasmosisTreatment of ocular toxoplasmosis is not always necessary, but when indicated several good drugs are available. Prof. Dr. Aniki Rothova from the Uveitis Center atthe FC Donders Institute of Ophthalmology, University Medical Center Utrecht, theNetherlands, describes the rules for treatment and possible drugs.

Who needs treatment ofocular Toxoplasmosis? Not everybody who has ocular toxoplas-mosis (OT) needs treatment. An episodeof active OT usually quietens downspontaneously within several weeks.Moreover, the drugs used for toxoplas-mosis may cause adverse effects. Inaddition, the treatment has limitedeffect: it only stops the multiplication ofparasites during the active attack, butdoes not destroy the silent “sleepingform” of the parasite, the bradyzoite.The bradyzoite remains in the retinathroughout the patient’s life and maycause flare-ups. Unfortunately, the cur-rently available drugs do not eliminatethis silent form of Toxoplasma from theeye and therefore treatment does notprotect patients against possible futureattacks. The most important complica-tion of OT is a permanent loss of visualacuity through the formation of scars inthe central part of the retina (macula).During an active attack of OT, the inflammation causes a cloudy visionand patients might see moving blackshadows, but these problems usually

disappear during several weeks. What is more, during the attacks the scars inthe retina are formed, but fortunatelynot all patients develop scars in the cen-tral part of the retina. If the scar is situ-ated in the peripheral (not seeing) partof the retina, the visual prognosis isexcellent. However, if the lesion is situ-ated in the centre of the retina (macula)or near the optic nerve, permanent loss of central visual acuity may occurand these patients require aggressivetreatment (Figure 1).

Antibiotics are important The standard treatment includes a com-bination of diverse anti-parasitic drugs,of which the most powerful is pyrime-thamine (Daraprim). The treatment isusually given for four to six weeksduring an active attack, but may be lon-ger; the duration of treatment differswith the individual and (largely)depends on the severity of the attack.Additional drugs, such as sulfonamidesor various antibiotics (clindamycin or

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azithromycin) improve the effectivenessof the treatment. Sulfonamides add tothe anti-parasitic effect of pyrimetha-mine, but frequently cause allergic reac-tions, such as severe skin rash. More-over, pyrimethamine and sulfonamidesmay also severely reduce the growth of blood cells in the bone marrow andmay cause a temporary drop in whiteblood cells and platelets. Therefore,regular control of blood counts is neces-sary. Toxoplasma parasites and youngblood cells need folic acid for their growth. Pyrimethamine and sulfonami-des prevent the formation of folic acid in the human body. However, contraryto Toxoplasma, human cells in bonemarrow can use folinic acid given intablets (folinic acid works like folic acidin human body). Therefore folinic acid(Ledervorin) is usually added to the treatment to prevent side effects of pyrimethamine and sulfonamides. Folicacid should not be used during the treat-ment, since it makes the treatment inef-fective. The antibiotics clindamycin andazithromycin have a weaker effect onToxoplasma than pyrimethamine, butluckily both have relatively few sideeffects. In laboratory experiments theexpensive drug atovaquone was alsoeffective on the latent forms of parasiteand a hope has arisen that atovaquonecould destroy all the parasites in humanbody. Unfortunately, the eradication andthe cure with atovaquone do not occur in humans and even despite this treat-

ment, the recurrent form of the diseasedevelops frequently. Treatment withsteroid eye drops may further reduce the inflammation. Additional eye dropsmay be needed to reduce elevated intra-ocular pressure.

Should Corticosteroids bepart of the medication? Corticosteroids are drugs, which canstrongly reduce the eye inflammation,but unfortunately they might also stimu-late Toxoplasma growth. It is sometimesnecessary to use prednisone with thepurpose to reduce inflammation duringthe course of OT. However, it is essen-tial never to use corticostroids alone, butalways together with anti -parasiticdrugs. Typically corticosteroids areadded to treatment 1 - 3 days after com-mencement of the antiparasitic drugs.

Figure 1: Toxoplasmic lesion in the retina beforethe treatment

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Problem: the pregnant women andocular Toxoplasmosis Pregnant women who have a flare -up of OT are normally not treated unlessthey have dangerous or severe symp-toms. This is because the medicationsmight be of considerable risk to thefetus, especially in the early stages of thepregnancy. The cooperation of gynecolo-gist and ophthalmologist is required inthese cases. The antibiotic spiramycin isgiven to pregnant women with systemictoxoplasmosis to prevent the infection ofthe fetus; this drug is in high concen-tration in the placenta and can form abarrier between infected mother and not (yet) infected child. Spiramycin doesnot penetrate into the eye and is notused for ocular disease.

Treatment of patients withlow immunity (AIDS patients, patients on anti- cancertreatments and patients following organtransplantations):In general, the same drugs are used foras in patients with full immunity; how-ever, continued treatment with at leastone anti-parasitic drug is necessary tomaintain disease quiescence (see alsopage 17).

Prevention of future attacks The eye problems in OT are likely torecur and it takes constant watchfulness

to notice new flare -ups early and to pre-vent deterioration of eyesight. Reliablemedical prevention of future attacks isnot yet possible. Prolonged treatmentwith at least one of the anti -parasiticdrugs minimizes the frequency of recur-rences, but the experiences with thislong-term treatment are not abundantand the optimal regimens for continuedtreatment are not yet established. Never-theless, for patients at risk of losing visual acuity in their better eye, contin-ued treatment with anti -toxoplasmicdrugs might be the only option.

Congenital disease Pregnant woman with systemic toxo-plasmosis should always be evaluated byan experienced gynecologist. The treat-ment possibilities depend on the stageof the pregnancy and on evidence of in-fection of the fetus. Newborns infectedby Toxoplasma should be evaluated andtreated by an experienced pediatricianeventually together with an ophthalmo-logist and if necessary, a neurologist.Infected newborns are usually treatedwith a combination of pyrimethamineand sulfonamides during one year (see also page 21).

Prevention of ToxoplasmosisSince a vaccine is not yet available, it isimportant to prevent toxoplasmosis inpregnant women and people with de-creased immunity. The crucial factor isadequate information how to avoid

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infection (e.g. cook meat until it is welldone and do not taste on beforehand,wash fruit and vegetables, wear gloveswhen working in the garden and avoidcat litter). There are several examples inEurope, France and Austria in particu-lar, where Toxoplasma infection is as-sessed in the course of general pro-grams for all women at childbearingage. At present, a special EuropeanToxoplasmosis Working Group of ex-perts investigates the efficacy of thesestrategies and evaluates the best regi-mens for prevention and treatment possibilities for pregnant women andtheir newborn children infected withtoxoplasmosis.

Conclusion There are multiple drugs available forthe reduction of inflammation in oculartoxoplasmosis. Unfortunately none ofthese drugs seems to reduce the rate ofrecurrences. So, the future research hasto concentrate on this issue.

Figure 2: Same lesion, 3 weeks after the onset oftreatment

Figure 3: Same lesion, 6 weeks after the onset oftreatment

Patient Report from France

Narrative from a motherconfronted with congenitalToxoplasmosis.

I was 26 years old when pregnant withmy first child. At the first consultationthe gynecological examination revealedno antibodies to toxoplasmosis. The gynecologist warned me of the risks ofcontracting toxoplasmosis during preg-nancy and gave me dietary and hygieneadvices to prevent contracting the dis-ease. I followed this advice avoiding ea-ting red meat and cooking vegetablesand fruits, except for those with rind. Inspite of this, at the monthly serologicaltesting in my 6th month of pregnancy,the gynecologist told me I had just sero-converted. My antibodies were positive;I had caught toxoplasmosis. I was extre-mely anxious, knowing the risks of fetalinfection and did not understand, how Ipossibly had acquired it, since I hadadhered rigorously to the diet and hadhad no contact with cats. I later learnedthat other means of contamination hadbeen discovered: tap water or by brea-thing in contaminated dust. I was im-mediately treated with the antibiotic

Rovamycin while awaiting sampling ofamniotic fluid to know if the baby wascontaminated. The day of the scheduledsampling, the gynecologist could notperform the puncture due to the stage of pregnancy; the baby took up too much space, so there was not enoughfluid accessible. Since sampling was too risky, they decided to treat me as ifthe baby was contaminated. I thereforetook two antibiotics, Adiazine and Malo-cide, until the end of my pregnancy.I delivered early, at the 36th week ofpregnancy. The baby was hospitalizedfor cord blood sampling and serology for antibodies, a cerebral echography, aspinal tap, an ophthalmological exami-nation and an overall biological workup.I was at his side throughout the tests. I was worried, imagining that he mightbe contaminated and have ocular andcerebral complications.Happily, he was in good health. How-ever, he was contaminated and thepediatrician recommended a one -yeartreatment with antibiotics (Adiazine andAmlocide in alternation with Rova-mycine) and cortisone. It was very hardto have him take the medicine. Indeed,these antibiotics do not exist in pediatric

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Patient

Toxoplasmosis in Uveitis

formulas. Therefore we had to use pillsdestined for adults, to adapt the doses to his weight, crush the pills and makehim swallow them mixed with milk. Hethen associated milk with medication,which had to be taken absolutely. Hedeveloped anorexia and was very diffi-cult to feed. He also had to undergo ablood test once a month to keep track of his antibodies and secondary effectsof the treatment. This was a particularlydifficult period for both him and us.The ophthalmological examinationswere normal and the infant developednormally, save for his nutritional dis-orders, which persisted until he was 6 years old.I thought I could relax, but when he was 11 years old, his school called us. My son complained of a black spot infront of his right eye. I urgently consul-ted an ophthalmologist and the doctorconfirmed the presence of a burst ofocular toxoplasmosis centered besidethe optic nerve and a large black spot inthe visual field linked to the focus. Myson was hospitalized for 3 days in apediatric unit to be treated with anti-biotics, as usual Adiazine and Malocide,and cortisone perfusions. After 3 weeks,there was a cutaneous allergic reactionto Adiazine, which was replaced withZithromax. But this treatment was effec-tive and the focus rapidly healed andeach day my son could see a reduction of his black spot until it disappearedcompletely.

Today, my son is 13 years old. He is very well. However, I know that a re-lapse can occur in 50% of the cases within 3 years. I have therefore warnedhim and asked him to alert me to anyocular anomalies. I am also well awarethat there is no definitive cure. For him, it is a source of anxiety and he con-stantly asks me questions about toxo-plasmosis. If he has another recurrence,he knows he will have to be treatedagain. There is a maintenance therapy,which greatly reduces the frequency ofrecurrences. One only has to take aBactrim pill once every three days for atleast 2 years. This only applies to multi-relapse cases. Since my son had an allergic reaction to Adiazine, he cannottake advantage of this treatment, whichis otherwise efficacious.We must live with the risk of a recur-rence and remain vigilant withoutworrying too much. My son has askedall the questions and all the answers provided have been frank. This has fi-nally allowed us to reassure him. I hopethat this narrative will be useful to oth-er women confronted with the problemof congenital toxoplasmosis. I confess I initially felt very guilty because I pas-sed on this disease to my son. But inretrospect, I realize that I did what wasnecessary to avoid contracting toxo-plasmosis. Fate did the rest.

C. V.

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Patient

Ocular Toxoplasmosis in aGerman Patient

With the exception of wearing glasses,which is usually quite normal as onegrows older, I have never had any eyeproblems. Therefore it was very frigh-tening to experience what became a ma-jor problem with my left eye, almost overnight. I remember quite well that my eye felt strange. It was like suddenlyhaving the sensation of something beingin it. Furthermore an opaque coating hadformed over the eye. There was no painand I felt perfectly fine otherwise.As it is often the case, this happened at aweekend. By Monday I was very muchaware that something was wrong, as thesymptoms had not disappeared. I im-mediately went to my eye doctor, whowas most concerned, as the pressure inmy eye was very high. Consequently Iwas given a tablet to relieve this. My doctor admitted that he was not entirelysure what was wrong, however he had a feeling that it may be uveitis caused by toxoplasmosis. He recommended thatI go to my doctor to have blood tests doneand that I should see an eye specialist assoon as possible. The situation was veryworrying and all I could think about wasthat I may be going blind.After initial visits to the local hospital myhusband and I decided to seek specialistadvice. Having seen the specialist it wasthen confirmed that I did indeed havetoxoplasmosis induced uveitis. When the

treatment began, it was at the time agreat relief as finally a name had been put to the problem and it was now beingtreated. Treatment consisted of a barrage of pillsincluding antibiotics and cortisone inhigh doses. This did not help my self-confidence, as I gained weight with thecortisone and had to counter act otherunwanted side affects which could haveaffected other parts of my body.I learned that the kidneys needed help so I had to take medicine for that. Alsobone problems can arise in the long termhence more pills to counteract this, not tomention the numerous eye drops whichhave to be fitted in between. Suffice it tosay I had to make a daily plan of what andwhen to take. However at the time Iwould have taken anything, if it wouldhave helped to solve the problem.After many visits to the specialist it see-med that things were improving. Un-fortunately, it was not to be and aftercomplications it became necessary tohave a delicate surgery (vitreous mem-brane had formed in front of the macula)which was also done successfully.Gradually, after more than two years,things have stabilised and although thesight in my left eye will never be as it was due to macular atrophy, I‘m thankfulthat at least the inflammation seems tobe quiet.

S. S.

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nosis. While the cloudiness and flashesof light are gone, I can still see debriswhen I’m in bright rooms or looking at white surfaces and it will likely be awhile before that debris absorbs into mybody. I am grateful, however, to havebeen in such good hands throughoutthis experience.

S. F.

Patient Report from the USA

I feel extremely lucky to have been bornwith very good (20/15) vision, so it wasquite the shock when I woke up one daywith cloudy vision in my left eye. It wasvery subtle the first day and part of mewondered if I was just imagining it.Fortunately I happen to work in an ophthalmology clinic, so the next day adoctor looked at my eye. He saw swel-ling on the cornea and white blood cells accumulating in the front of myeye. I was diagnosed with iritis. I beganusing steroid drops four times a day and followed up with my doctor threedays later. He told me that my eye loo-ked much better, which I didn’t under-stand because my vision was gettingworse. The cloudiness increased signifi-cantly, to the point that everyone andeverything looked as if it were a“Glamour Shot” photo. I was seeingdebris in the form of little specks andlines, as well as experiencing occasionalflashes of light. I was also having a lot of difficulty driving at night, because the cloudiness made headlight glare sobad. My doctor referred me to an uveitisspecialist, who diagnosed me with toxo-plasmosis. I was happy to taper off thesteroid drops, but I had to start takinglarge antibiotic pills for six weeks. Forthe first few weeks I saw no improve-ment in my vision, and when it did start improving, it was a slow process. It is now three months since my diag-

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Patient Report from Brazil

I am a 24 year old lady from Brazil.When I first woke up with one of myeyes completely blurred, not seeing anything, I started to feel desperate.I went to a hospital to be examined by a doctor that referred me to a uveitis specialist. I talked to some friends andmade a web search to try to identify aspecialist and I found the one who real-ly took good care of my eyes and me.She (the uveitis specialist) examined myeyes and answered all my questionsregarding what uveitis and toxoplasmicuveitis are and how my treatment willbe. After a while I was a little calmer but I felt very anxious and very scaredabout what could happen to my vision.I started my treatment with the combi-ned specific therapy comprised of sul-phadiazine, pyrimethamine and folinicacid as well as with oral corticosteroidsand topical eye drops.After 2 weeks my vision was not goodenough and my doctor requested ano-ther ophthalmological examination (cal-led OCT) that revealed macular edemaas a complication. I started to feel veryscared with the possibility of having myvision decreased or with the possibilityof losing my vision. My doctor again wasvery professional and asked me to main-tain the treatment and to stay calm wai-ting for the improvement in my vision.According to my doctor, my vision has agood chance to recover because the toxo-

plasmic lesion was not in a very impor-tant location at the retina.After 6 weeks of therapy I recovered,reaching my previous visual acuity andstarted taper the drugs.After this period, I stopped all medicati-ons and I am having now regular eyeexaminations every 6 months. So far, Ihave not developed any new ocular le-sions, which I know may happen.What I want to say in my report is thatduring the period that I developed blur-red vision, I could not stop thinking onhow important vision is, especially forsomeone like me who is still doing aUniversity course and working in a labo-ratory where I must have very good vi-sion to perform my work. I do realizehow important it was to be helped andexamined by a good specialist that wasable to offer me good ocular treatmentas well as a good psychological support.

CFM

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slight inflammatory reaction, thoseinjected with 10,000 tachyzoites andexamined at day 6 after injection dis-played severe retinochoroiditis, vitritis,destruction of retinal architecture andretinal detachment. High numbers ofparasites could be detected in all layersof the retina as well as the optic nerve.This murine model will allow the au-thors to address different issues such ashow ocular immune responses areactivated and which parasite proteins are important for the development ofocular lesions.

Analysis of immunomodulatory Genesof human Müller Cells infected withToxoplasma gondii. Knight et al., Rayne Institute, London,United Kingdom

Human Müller cells, one of the retinalcomponents, have been used to studymolecular interactions with the parasite(two different strains of T. gondii ). Nu-cleic acids and supernatants were collec-ted from infected and non-infected

Experimental models

Development of an acute ocularToxoplasmosis Model in Mice. I.Blader, E.Charles. Microbiology and Immunology,University of Oklahoma Health SciencesCenter, Oklahoma City, OK., USA

The pathogenesis of ocular toxoplasmo-sis needs to be better defined. It is stillimportant to develop different experi-mental models in order to understandthe pathophysiology of toxoplasmic reti-nochoroiditis but also to develop diag-nostic tools and to evaluate different the-rapeutic strategies before clinical trials.Interestingly, a new model of acute ocular toxoplasmosis in mice was pre-sented by Blader and Charles from theUniversity of Oklahoma. Different con-centrations of Toxoplasma gondii wereinjected into the vitreous of C57BL/6mice and inflammation was assessed at 2, 4 and 6 days after injection. In the comparison with eyes injected with1,000 tachyzoites, which showed very

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News from ScienceIn each edition “uveitis” will present a service for ophthalmologists informing aboutaspects from pathogenesis, diagnostics and therapy of uveitis. This time ProfessorBahram Bodaghi, University of Paris VI, Paris, France, reports from the Meeting ofthe ARVO (Association for Research in Vision and Ophthalmology) which took placein May 2005 in Fort Lauderdale, USA, when 10 presentations were dedicated to toxo-plasmic retinochoroiditis.

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cells at different time intervals and compared using DNA microarray tech-nology. This method allowed the au-thors to evaluate upregulation of diffe-rent pro-inflammatory proteins such asMCP-1, IL-6 and IL-8 after infection.Interestingly, upregulation of thesemolecules plays an important role inrecruiting inflammatory cells to clearinfection. The cytokines IL-4 and IL-6may play a role in the promotion andmaintenance of parasite encystment.

Interaction between Toxoplasma gondiiTachyzoites and retinal microvascularEndothelium. Chipps et al., Casey Eye Institute,Oregon Health & Science University,Portland, OR, USA

Endothelial cells are another major celltype for parasitic replication and animportant target for the pathogenesis ofthis agent. Susceptibility to ocular toxo-plasmosis may be related to preferentialbinding between tachyzoite and endo-thelial cells. By using a recombinant yel-low fluorescent protein-expressing RHstrain T. gondii tachyzoites to infect sec-tions of unfixed human retina, Chipps etal. quantified the number of parasitesoverlying endothelium compared withnon-endothelial retina. The distributionof binding was different for endothelialand non-endothelial regions in twoindependent donors. Obviously, the abi-lity of tachyzoites to bind to retinal endo-

thelium is an important factor influen-cing susceptibility to parasitic infection.This interaction may be a critical factorfor infection and disease progression.

Epidemiology

Epidemiology of secondary Uveitis inGermany. Leuchtenberger et al., InterdisciplinaryUveitis Center, University of Heidelberg,Heidelberg, Germany

In order to evaluate distribution of thedisease and determine the efficacy ofantiparasitic strategies epidemiologicaldata on ocular toxoplasmosis are stilllacking in the general population butalso during immunodeficiency. Data on secondary uveitis in Germanyhave been reported by Leuchtenberger etal. 1022 patients were included in thisretrospective study, performed between2001 and 2004. More than 58% of pa-tients presented with a secondary uvei-tis. An infectious condition was deter-mined in 18% of patients, the most fre-quent types being herpetic infections(37%) followed by toxoplasmosis (34%).In AIDS patients, the prevalence of toxo-plasmic retinochoroiditis seems to chan-ge since the introduction of highly activeantiretroviral therapy. Cytomegalovirusretinitis remains the major vision-threa-tening condition even though its inci-dence has significantly decreased.

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Prevalence of Posterior OphthalmicDisease in Patients seen in a collaborative Infectious Disease/Ophthalmology Clinic Setting. Gill et al., Ophthalmology, Mount SinaiMedical Center, New York, NY, USA

Ophthalmic Manifestations in HIV positive Patients: Evaluation of 286consecutive Patients in one Year.Modorati et al., Departement ofOphthalmology, University Hospital San Raffaele, Milan, Italy.

Two studies, one from the USA and onefrom Italy have determined the inci-dence of ocular complications in HIV-patients followed between 2002 and2004 or 2003 and 2004, respectively.Interestingly, results seem to be similarin both series. Toxoplasmosis was iden-tified in nearly 6% of patients in NewYork (USA). Frequency of toxoplasmo-sis, syphilis, candidiasis and tuberculo-sis was 12.2% in Milan (Italy).

Diagnosis

Recurrent ocular ToxoplasmosisEvaluation: Findings from FluoresceinAngiography and Indocyanine GreenAngiography. M.H. Amaro andC.Muccioli, Ophthamology, FederalUniversity of São Paulo, São Paulo,Brazil.

Fluorescein and indocyanine greenangiography (ICG) are two diagnosticmethods used for the management ofposterior uveitis. Fluorescein angiogra-phic patterns have been previously well-described, showing the presence of anecrotic lesion within the retina.Angiographic findings observed in 23cases with recurrent toxoplasmosis havebeen reported. Toxoplasmic regions dis-play initial hypofluorescence in the cen-tre of the active recurrent lesion andhyperfluorescence in the margin in thelater phases in all cases. ICG showedinitial hypofluorescence in the activerecurrent lesions, but also multiplehypofluorescent spots surrounding theactive lesion in more than 2/3 of cases,multiple hypofluorescent spots far awayfrom the active lesion in normal areas in the funduscopy and fluoresceinangiography (25% of cases) and finallyhyperfluorescent spots in the region of active lesion in less than 10% of cases. ICG gave evidence of more wide-spread disease or adjacent inflammatoryeffects due to the infectious agent.

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Interestingly, these results show that the disease may involve more areas than what was expected.

Immunoblot and Witmer's CoefficientComparison in ocular ToxoplasmosisGalland et al., Ophtalmologie, CHU Timone, Marseille, France.

Role of PCR in Diagnosis andManagement of infectious Uveitis.Vasseneix et al., Ophthalmology, La PitiéSalpêtrière Hospital, Paris, France

Diagnostic management of infectiousuveitis remains a major challenge forophthalmologists. PCR and serologicanalysis of ocular fluids may be propo-sed in atypical forms of severe, chronicand sight-threatening uveitis, in order to avoid the use of aggressive or nonconventional immunosuppressants andto propose a specific therapeutic stra-tegy. The diagnosis of ocular toxoplas-mosis is based on clinical examination,especially funduscopy. However, in aty-pical cases, analysis of ocular fluids(aqueous humor or vitreous) is manda-tory in order to confirm a parasitic infec-tion. Three different presentations werededicated to the molecular diagnosis ofinfectious uveitis, including toxoplasmicretinochoroiditis. T. gondii proteins (immunoblot) andspecific anti-parasite antibody produc-tion may be identified in the aqueoushumor. In a retrospective study perfor-

med between 2001 and 2004, results of anterior chamber tap performed in 40 cases of putative and severe toxoplas-mic retinochoroiditis were reported.Sensitivity of the immunoblot techniquewas 63.6% and that of the Witmer co-efficient 45.5%. Combined sensitivity ofboth techniques together was 77.3%. For the authors, this type of examinationappears to be indicated in atypical casesof ocular toxoplasmosis when diagnosisis not made after two weeks of evolution.

Vasseneix et al. have reported the serolo-gical and molecular analysis of aqueoushumor in patients referred for an infec-tious condition with an atypical clinicalpresentation. Among 671 patients ma-naged during 2001, an infectious condi-tion was identified in 188 cases (28%).Toxoplasmosis was the most frequentetiology (67 cases) followed by herpeticinfections (51 cases), bacterial infections(53 cases) and candidiasis (6 cases).Analysis of ocular fluids was contribu-tory in 87% of parasitic uveitis, 45% ofviral anterior uveitis and 83% of viralretinal necrosis. PCR seemed to be moreinformative in patients with viral infec-tion, whereas evaluation of specificintraocular antibody production wasmore sensitive in patients with toxo-plasmosis.

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Therapeutic options

Verteporfin Photodynamic Therapy(PDT) of CNV Associated WithToxoplasma Retinochoroiditis. Leys et al., Ophthalmology, University Hospitals Leuven, Leuven, Belgium

Conventional treatment of ocular toxo-plasmosis is based on antiparasiticdrugs. Different molecules are nowavailable and different associations may be used in order to control para-site replication. Choroidal neovasculari-zation remains one of the complica-tions of toxoplasmic lesions. Secondaryhemorrhage may induce severe visualloss. As for age-related macular degene-ration, photodynamic therapy with ver-teporfin may be proposed in compli-cated lesions of ocular toxoplasmosis.Leys et al. report a series of 8 patients,treated for choroidal neovascularization.Mean visual acuity increased from20/225 to 20/123 during a mean follow-up of 2 years. Persistent closureof neovascular lesions was achieved in 7 out of 8 patients with a mean num-ber of 1.8 treatments and without anysignificant adverse event. However, alonger follow-up is recommended be-fore further conclusions.

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Cultural Corner

You will be able to walk at leisure in theold districts. Around the Cathedral, cen-tury-old streets remain in spite of theterrible fires of December 29, 1720during which 33 streets and 900 houseswere burnt to the ground. Explore thelovely narrow streets of “Saint-Sauveur”,“de la Psalette”, “du Chapitre”, “Saint-Yves” and “Saint-Michel”, with colour-ful wooden houses dating back to theXVth century.

The city hall was built in the XVIIth century by Gabriel. It looks upon theNational Theatre of Brittany by thearchitects Joly and Carly. The square isexceptionally pretty. Nearby the Parlia-ment of Brittany, designed by Salomonde Brousse in the XVIIth century de-serves your admiration.

On Saturday mornings you can discoverthe public market on the Place des Lices,whose name comes from the tourna-ments of the Middle Ages. This marketis one of the best-known and richest in France.

Rennes is the capital of Brittany. It isconnected to Paris by train (2 hours 15with the TGV). The names “Rennes”stems from “Riedones”, a tribe that in-habited this part of Gaul in the 2nd century BC. The Romans named it“Condate”. Attacked in 275 AD, the cityis later fortified, and the wall reinfor-ced still during the XIVth and XVth centuries.

King Charles VIII’s engagement cere-mony to the duchess Anne de Bretagnewas held in the Notre Dame de BonneNouvelle chapel in 1491. Brittany thenbelonged to France, as ascertained in1532 by the Union treaty.

Today there are more than 200,000inhabitants in Rennes. The city buzzeswith activity in fields such as teaching(60,000 students), research (3,500 re-searchers), and music (in particular the renowned “Transmusicales”).

Public transportation allow blind or handicapped to discover the city.

Everything You AlwaysWanted to Know AboutRennes

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A few miles away are famous placesfrom ancient legends such as the “Valsans retour” (Vale whence none iscoming back), the fountain of Barentonor Merlin’s tomb. A bit further away areSaint-Malo, Dinard, Lorient, Quiberonand Belle-Île en Mer.

Enjoy your stay!

Marie-Jo Ménager-Joulain

Image:Porte Mordelaise

uveitis

Patient Groups & Information

Uveitis Information GroupA patient led information and support group.

Activities- Provision of information and support by letter, phone and email. - Public meetings around the UK.- Web site

To Contact:POST: UIG, South House, Sweening. Vidlin, Shetland Isles, ZE2 9QEEMAIL: info@uveitis.netWEBSITE: www.uveitis.net

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uveitis appears twice a year – in German, French and English languageFree for members of the national uveitis patient interest groups

Circulation: 8500 copies for the English edition (in total 24.000 copies)

Editor for the English version: Uveitis Information Group

Contact: Phil Hibbert, South House, Sweening. Vidlin, Shetland Isles, ZE2 9QE

Phone: +44 (01806) 577310 Email: info@uveitis.net Website: www.uveitis.net

Overall Editor: Manfred Zierhut

Editorial Office: Bahram Bodaghi, Andrew Dick, Jutta Grimm, Phil Hibbert, Matthias Nahm, Chris Parkin, Lancelot Pecquet, Chris Rodgers, Aniki Rothova, Manfred Zierhut

Design: ©Norbert Falk . Reutlingen, Germany

Cheques may be payable to Uveitis Information Group.Outside the UK, please contact the UIG.

Articles in this journal reflect the opinions of the authors and not necessarily of the editorial office.

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