INTRODUCTION
Visceral leishmaniasis is a parasitic infection caused by protozoa of the Leishmania donovani species complex and is transmitted by sand flies. It is a disease of human beings and animals. Dogs are considered the main reservoir. The disease has a worldwide distribution. Leishmania infantum is the causative agent of the Old World canine leishmaniasis. The disease has been reported around the Mediterranean Basin, Southern Europe, West, East and North Africa, the Middle East, India and China. Leishmania chagazi, considered now as synonymous with L. infantum is responsible for the disease in the New World (South America). More and more foci are reported outside the conventional endemic areas and recently canine leishmaniasis (CanL) was identified in North America. Clinical features of the disease vary widely. It is very important for clinicians to know and recognise early ocular manifestations of leishmaniasis not only to avoid the development of irreversible lesions leading to blindness but also to initiate systemic anti-leishmanial treatment. Ocular lesions can appear independently from systemic signs, or can be combined with, before or after anti-leishmanial therapy. Any ocular tissue or adnexa can be involved, but blepharitis, conjunctivitis, keratitis and anterior uveitis are the most frequent lesions.
DIAGNOSIS
The diagnosis of ocular manifestations of CanL is based on clinical findings, parasitological techniques, serological tests and more recently using molecular methods.
Clinical signs
Eyelids
Periocular alopecia with desquamation is a characteristic feature of the disease. A differential diagnosis should be made with the same type of lesion caused by Demodex. Sometimes these two causes are seen together. Pemphigus is another cause to be considered in differential diagnosis. In rare cases, multiple granulomas can be observed on eyelids margins. These granulomas contain a great density of parasites. They are considered as typical signs of the infection and could represent the site of vector bites.
Conjunctiva, Sclera and Nictitating Membrane
Conjunctival hyperemia is a common finding in ocular leishmaniasis. Classical conjunctival alteration is chemosis. Sometimes the very prominent conjunctival thickening precedes an anterior uveitis. Deep inflammation reaches the scleral layer. Multifocal pink granulomas can appear on nictitating membrane margins or at the limbus. In these cases, a differential diagnosis with nodular episclerokeratitis, using cytology and parasite visualisation, should be considered.
Cornea
Corneal involvement is rarely seen independently. More often concurrent inflammation of the conjunctiva (kerato-conjunctivitis) or anterior uvea (kerato-uveitis) are present. Keratitis can be superficial with epithelial erosions, ulcers, neovascularisation and eventually pigmentation (not to be confused with the so called "German Shepherd chronic superficial keratitis"). Large limbal conjunctival granulomas can extend to the cornea. Interstitial keratitis is characterized by focal opacities (edema or inflammatory cells infiltrate). Deep keratitis with vessel growth and endothelial alterations is secondary to anterior uveitis.
Anterior uvea
In our series, in an endemic area, 70% of cases of anterior uveitis in dogs are caused by CanL. In a previous cytological study, we demonstrated that in most of the cases, there is a predilection for anterior segment inflammation. Granulomatous or plastic types of anterior uveitis can be seen but anterior chamber exudation is not a frequent tendency of CanL. It is in CanL that anterior uveitis is often associated with very low antibody titres and response to anti-leishmanial therapy is very poor.
Posterior segment
In our series, only 9% of CanL ocular signs involve the posterior segment. In case of anterior segment loss of transparency, Ultrasound or ERG can be useful to evaluate the posterior segment situation. Hyalitis, chorioretinitis, papillitis, small retinal haemorrhages and retinal detachment have been seen. Frequently, chorioretinal abnormalities appear to be secondary to another organ involvement (e.g., renal insufficiency).
Infrequent signs
They include: corneal dystrophies, exophthalmos, strabismus. In endemic areas, when they are observed, CanL should be considered as a possible cause. Large haemorrhages (in anterior chamber or vitreous) are not found in CanL.
Complications
The most severe complication is glaucoma secondary to anterior uveitis (the cause of 10% of the cases of blindness in our survey). At present, all treatments are ineffective. The other observed complications are KCS, corneal pigmentation, iris atrophy, cataract, retinal detachment, panophthalmitis and phthisis bulbi.
Parasitological techniques
Leishmania amastigote can be observed from lymph nodes, bone marrow smears or from ocular tissue. The sensitivity of the technique is low except for smears from granulomas which always reveal a large number of parasites. Cultures and inoculation take too long for practical purposes.
Serological tests
The Indirect Immunofluorescent Antibody Test (IFAT) and Enzyme Linked Immunosorbent Assay (ELISA) are techniques used worldwide. The Direct Agglutination Test is also a good tool under field conditions. If available, the Western Blot technique is more sensitive and suitable for diagnosis of ocular forms.
Molecular techniques
If serological techniques are able to demonstrate a previous contact with the organism, Polymerase Chain Reaction (PCR) is able to detect, by amplification, a very small quantity of leishmania DNA in tissues. In a recent comparative study we made on the results of IFAT, Western Blot and PCR it was noted that, in an endemic area, 38% of dogs with an ocular inflammation are IFAT seronegative but PCR and Western blot positive and that 68% of asymptomatic and IFAT negative dogs are Western blot positive and 59% PCR positive.
TREATMENT
As a rule, ocular inflammation must be treated aggressively to avoid complications.
Adnexal signs respond well to antileishmanial therapy. This is not always the case for deeper inflammation. Priority however should be given to control ocular inflammation. Topical and subconjunctival corticosteroids are used to treat keratoconjunctivitis but intraocular inflammation requires the use of systemic antiinflammatory drugs.
When uveitis is diagnosed, the classical treatment for anterior uveitis should be applied namely: Atropine, topical and subconjunctival corticosteroids (SAIDS). Intraocular inflammation requires the use of systemic antiinflammatory drugs. It is advisable to begin with injections of Non Steroidal Anti Inflammatory Drugs (NSAIDs). These are administered as a long term therapy. If not effective enough, a low dose corticosteroid (prednisolone: 0,16 mg/kg) is added to NSAIDS. If the uveitis is still unresponsive, a systemic cyclosporine (10-5 mg/kg) treatment should be initiated. Topical use of cyclosporine is ineffective against intraocular leishmanial inflammation. The goal is to control inflammation before synechiae occur.
Personal protocols
Leishmanial Ocular Inflammation Treatment
Ocular inflammation alone: Dog seronegative or low antibody titer:
Systemic Allopurinol
Systemic NSAIDS
Local anti inflammatory treatment
Ocular inflammation + other organs involvement: Dog seropositive
Systemic Allopurinol+ Methylglucamine
Systemic NSAIDS
Local anti inflammatory treatment
Uveitis Treatment. Personal protocol
Local treatment:
Atropine
Corticosteroids drops
Corticosteroids subconjunctival injection (watch out for post injection granulomas)
Systemic Anti inflammatory Treatment:
1 NSAIDS (see Text on "uveitis")
2 NSAIDS + SAIDS
3 Cyclosporine
CONCLUSION
Classic serology, usually useful for the diagnosis and the follow up of most cases of CanL, is often not helpful in the ocular forms of the disease. PCR test is a tool that compensates for the insufficiency of the conventional methods. Many ocular manifestations of CanL are unresponsive to antileishmanial therapy. The priority for the treatment is to control the inflammation.