While the diagnosis and treatment of uveitis may seem like a daunting task to the beginner, there are some tips and tricks which help to identify specific uveitides and help in appropriate treatment. If it looks like a duck, swims like a duck and quacks like a duck, chances are, it is probably a duck.

1. Infectious vs Non infectious :

It is crucial to make this differentiation as , even though certain features may be similar in both, the treatment vastly differs for these two entities. Certain clues in the history and clinical examination , in addition to the laboratory investigations will aid you in making this distinction.

A recurrent nodular scleritis in a farmer with recent history of injury with vegetative matter is most likely infective.¹

A focal necrotising retinits lesion adjacent to a chorioretinal scar with significant vitritis in a person who has close interaction with cats is ocular toxoplasmosis, the most common cause of infectious posterior uveitis.²If patient gives history of systemic infection (such as fever or urinary tract infection) followed by intense inflammation with hypopyon, diminution of vision, think of endogenous endophthalmitis as your initial differential.

It is also important to revise your diagnosis in case a patient is not responding to your initial plan of management. A repetition of the laboratory investigations or diagnostic procedures such as an aqueous or vitreous tap will help in either revising or reestablishing your diagnosis.

2. The “Uvea Panel”

Laboratory investigations in a patient presenting with uveitis should not be a ‘one size fits all’ , but rather a tailored approach depending on the most probable differential diagnoses.

A complete blood count with inflammatory markers such as ESR and CRP, along with Mantoux, HIV and treponemal and non treponemal tests (TPHA and VDRL) for syphilis (the great masquerader) are included in the initial screening. If these tests are already done before referring the patient to a uvea specialist, it will greatly enable them in narrowing down their diagnosis.

In case, the patient has specific systemic symptoms suggesting autoimmune disease, such as pain of small joints of hands (as in rheumatoid arthritis) , malar rash (as in SLE) and saddle nose, hearing loss and haemoptysis (as in Granulomatosis with polyangiitis-GPA ) further laboratory testing such as Rheumatoid factor and anti cyclic citrullinated peptide anti- CCP( in rheumatoid arthritis) ;anti double stranded DNA, anti-Smith, anti-Ro and anti-La antibodies(in case of SLE) and ANCA (in case of GPA) can be considered.³

When the clinical picture is very typical, such as a hunched back patient walking in to your OPD with a red eye, who cannot flex his neck for a slit lamp examination, with fibrinous inflammatory reaction in the anterior chamber and posterior synechiae , with a past history of recurrent similar episodes in alternating eyes, HLA B27 typing is not always necessary to establish your diagnosis. It should also be kept in mind , the chance of false positivity, due to the low specificity (38%) compared to high sensitivity (98%) in flow cytometry, which is the commonly used method for HLA B27 testing. ⁴

3. Presumed Ocular TB

India being an endemic country , many patients may have Mantoux positivity on testing (Induration more than 10 mm after 48-72 h of intradermal PPD).Therefore it is important to know the clinical phenotypes which are most suggestive of ocular TB.⁵

In anterior uveitis, a granulomatous uveitis picture , with mutton fat KPs and broad based anterior synechiae are likely to indicate a tubercular cause.

In intermediate uveitis,vitritis, inferior snowballs along with peripheral vascular sheathing, often complicated by cystoid macular edema can suggest a tubercular etiology.

Vasculitis: Tubercular vasculitis is mostly occlusive periphlebitis with retinal haemorrhages

Posterior uveitis: In posterior uveitis clinical phenotypes typical of TB are Choroidal tubercles and tuberculoma, Multifocal choroiditis and Serpiginous like choroiditis.

TB can also present as panuveitis.

Chest Xray vs CT chest: In case of high clinical suspicion of TB, it is better to do a CT chest rather than a chest Xray as an Xray might miss small mediastinal lymph nodes.⁶ Even signs of old healed TB such as calcified mediastinal lymph nodes can be considered as evidence to start ATT, if the patient has never received any anti tubercular treatment before.

ATT is given along with oral steroids for 6 to 9 months, depending upon the response to treatment, with an eye on liver function and ethambutol toxicity.

4. The Viral Realm

Clinical signs pointing towards viral anterior uveitis are granulomatous KPs, distributed in the centre of the cornea, along with Descemet’s folds, stromal haze and raised intraocular pressure. This may or may not be associated with viral keratitis. Treatment includes topical antivirals and steroids along with antiglaucoma medications and oral antivirals in case of multiple recurrences. Always do a peripheral retina examination in all viral uveitis patients.

The picture of peripheral tongue shaped retinitis lesions spreading circumferentially in an immunocompetent person is acute retinal necrosis caused by herpetic viruses ,either varicella zoster or herpes simplex or occasionally cytomegalovirus. Treatment comprises oral valacyclovir starting at 1 g tds till complete resolution of retinitis along with oral steroids +/- intravitreal ganciclovir, followed by maintenance dose of oral antivirals.⁷

PCR testing of aqueous or vitreous can help to establish a diagnosis of viral uveitis and tailor treatment such as oral Valganciclovir if the causative agent is cytomegalovirus.

5. Intermediate uveitis

The chronic and relapsing nature of intermediate uveitis (IU) makes it a challenging task to pin on the diagnosis and treatment. Some of the common etiologies for IU include infections like tuberculosis, syphilis, toxoplasmosis, toxocariasis and Lyme's disease. Non infectious causes include sarcoidosis, multiple sclerosis, amyloidosis, masquerade and idiopathic. The recent SUN classification (2021) divides IU into pars planitis (associated with snowballs, snowbanking and peripheral vascular sheathing ) and Non-pars planitis type .

• Complete blood count, Mantoux testing, Serological tests ( HIV ,TPHA and VDRL), CT chest and ultrasound abdomen are done to rule out infective causes.
• Multimodal imaging helps in assessing the severity of inflammation .

Optical Coherence Tomography (OCT) helps in detecting inflammatory cells in the posterior vitreous phase ,cystoid macular edema and is also useful to assess the disease progression.⁸ Fundus Fluorescein Angiography (FFA) is useful in diagnosing vascular leak, capillary non perfusion areas, neovascularization, optic disc leak and cystoid macular edema. B scan ultrasonography is helpful in cases where the there is complete obscuration of media due to vitritis .

• In case of inconclusive results in other tests, vitreous biopsy with PCR testing or histopathological examination of the sample is preferred. It is an invasive diagnostic procedure which is used to identify the pathogen in cases of suspected infectious uveitis or to look for malignant cells in case of intraocular lymphoma.
• Infectious etiologies must be treated with their concerned antimicrobial regimen. For treating non infectious uveitis, Kaplan's 4 step approach is no longer preferred ,especially with the advent of immunosuppressants and newer biologicals. Cryotherapy has become obsolete. Posterior subtenon's injection of triamcinolone acetonide or intravitreal corticosteroids like ozurdex implant, along with systemic corticosteroids are the initial line of management. Recurrent and refractory cases require the use of Immunosuppressants (like methotrexate, Mycophenolate mofetil, Azathioprine) and newer biologicals like (TNF alpha inhibitors, JAK kinase inhibitors , monoclonal antibody , Interleukin inhibitors and interferons).
• Therapeutic pars plana vitrectomy is indicated in cases of dense vitreous opacification, vitreous haemorrhage, retinal detachment and epiretinal membrane. It is also helpful in manually clearing the proinflammatory cells from the vitreous.

6. Uveitis in the little humans

Paediatric uveitis remains a major cause of concern ,as children might present to the OPD very late, only after visually disabling complications have set in. 70 % cases are non infectious.⁹ This requires early diagnosis and aggressive management including immunosuppressant medications, in order to prevent blinding sequelae and the deleterious effects of prolonged use of oral steroids. Long term management is done best, in concurrence with a paediatric rheumatologist.

Common causes of paediatric infectious uveitis include tuberculosis, viral and toxoplasmosis.

Previously , children with Juvenile Idiopathic Arthritis who developed complicated cataract were left aphakic post surgery due to poor visual outcome with primary IOL implantation. Recent long term studies have shown favourable results with primary IOL implantation, provided there is adequate inflammatory control.¹⁰

7.Endogenous endophthalmitis (EE)

EE accounts for 2-15% of endophthalmitis cases. Some of the high risk factors include uncontrolled diabetes, long term hospitalization, organ transplantation, liver disease, malignancy, indwelling catheters, intravenous drug abuse (IVDA), alcohol abuse, HIV infection, blood dyscrasias, middle aged women with history of recurrent urinary tract infection.¹⁰ Ophthalmologists must be alarmed when they come across patients with the following signs.

• Sudden and rapid deterioration of vision with severe ocular inflammation with lid edema ,chemosis, corneal edema ,hypopyon and fibrin in the anterior chamber.

• Localized foci of infection like iris nodules ,subretinal abscess, whitish plaques in the retina/

Aqueous or vitreous tap for microbiological examination for smear and culture is crucial in identifying the pathogen and is usually combined with intravitreal injection of Vancomycin, Voriconazole and Ceftazidime.This should be followed by appropriate systemic antimicrobial therapy depending on the sensitivity of the organism. Empirical treatment with topical and systemic antibiotics while waiting for the culture report is also helpful. In severe and delayed presentation, immediate pars plana vitrectomy with silicon oil injection with or without lensectomy could help in saving vision.

8. Masquerade Syndrome

Uveitis Masquerade syndrome are a group of non inflammatory diseases secondary to intraocular malignancies or ocular metastasis and often resemble our usual uveitic manifestations. Some of the common masqueraders include primary vitreoretinal lymphoma, uveal melanoma, metastatic carcinoma of breast ,lung , skin, leukemia and systemic amyloidosis.

• Few clinical signs mimicking uveitis include severe anterior uveitis with exudates associated with hypopyon or hyphema , retinal pigment epithelial mottling ,sub-retinal deposits, serous retinal detachment ,optic disc edema, choroidal mass and retinal haemorrhages like roth spots . Retinoblastoma is another important masquerader in paediatric population presenting as anterior uveitis associated with pseudohypopyon and anterior chamber seeding.¹¹
• Certain special characteristics in multimodal imaging are extremely useful in identifying the etiology. Typical ‘Leopard skin appearance ‘ on FFA and sub-RPE infiltrates on OCT are features favouring lymphoma. Choroidal metastasis on OCT has a ‘lumpy bumpy’ appearance over the surface of the lesion. Ultrasound biomicroscopy (UBM) will be helpful in cases with anterior segment involvement with iris or trabecular meshwork infiltration.
• In cases of suspected vitre-retinal lymphoma ,MRI brain is also advised to rule out CNS lymphoma. Apart from systemic imaging like PET scan to identify the location of the primary ,histopathology and cytology of ocular tissue like aqueous or vitreous is done to look for malignant cells ,MYD88 gene mutation and Interleukin ratio (IL10 :IL 6 >1) in case of primary vitreoretinal lymphoma.

These patients should be managed using a multidisciplinary and a collaborative approach involving ophthalmologists, oncologists, surgeons and radiologists. Even in the absence of risk factors favouring malignancy, any individual with suspicious and atypical clinical features should undergo a thorough systemic evaluation.

9. Scleritis

Treating scleritis is a great challenge, as the patients often present with severe intolerable pain. Clinching on the right diagnosis (infective or non-infective) plays an important role in deciding on the management. Scleritis is classified into anterior ,diffuse , nodular,posterior and necrotizing scleritis.

• Eliciting good history is the first and foremost task of identifying the etiology. Some of the points favouring infective scleritis include trauma history, farmer by occupation, nodule associated with pus pointing, multiple foci of abscess ,associated keratitis and hypopyon.¹²Ultrasound biomicroscopy is done to assess the extent of infection and to rule out any scleral breach. Pseudomonas aeruginosa, tuberculosis and nocardia are some of the commonest bacteria isolated. Incision and drainage with smear and culture of pus sample or scleral tissue biopsy is required to identify the microorganism. Herpetic family like herpes simplex and varicella zoster viirus are also recognized causes of scleritis and can present with associated vesicular rash distributed along ophthalmic nerve. As the scleral inflammation is also partially immune mediated, along with the specific antimicrobial regimen, low dose oral corticosteroids is also advised is some cases to avoid structural damage and to relieve pain.
• Non infective scleritis is usually associated with autoimmune diseases like Rheumatoid arthiritis , Granulomatosis with Polyangiitis (necrotizing scleritis), Takayasu's arteritis, Relapsing polychondritis and Polyarteritis nodosa. Ocular inflammation usually resolves when the systemic disease is under control. Lab investigations like Complete blood count ,ESR,CRP,ANCA,ANA,Rheumatoid factor are useful. Ultrasound is done to measure the retinochoroidal thickness in order to rule out posterior scleritis .Topical and oral corticosteroids along with systemic immunosuppressants are used to treat non infective scleritis.
• Certain drugs like bisphosphonates , pamidronate ,topiramate and covid vaccines have also been reported to cause scleritis .Surgically induced necrotizing scleritis is another small set of entity which could occur following pterygium, cataract, strabismus or glaucoma surgery. Any patient with prior history of scleritis are more prone for developing a recurrent episode post cataract surgery. Clear corneal incisions are preferred in such cases ,especially those cases with severe scleral thinning .

10. Dealing with the aftermath

Inflammation itself or the treatment modalities used to control inflammation can lead to ocular and systemic complications.

Ocular complications include complicated cataract , secondary glaucoma, cystoid macular edema and band shaped keratopathy( BSK). Cataract surgery in complicated cataract requires a minimum three month duration of no inflammatory activity with/ without treatment, prior to surgery. Glaucoma management includes medical as well as surgical management ,including laser iridotomy and filtering surgeries. BSK involving the visual axis will need chelation therapy. Cystoid macular edema can be managed by topical steroids, NSAIDs (and even topical interferons), posterior subtenon or intravitreal injections of triamcinolone or occasionally even intravitreal steroid depots . Newer agents like intravitreal tocilizumab (IL-6 inhibitor) are being evaluated for treatment of refractory uveitic macular edema. Therapeutic PPV even without any macular interventions, can lead to improvement in macular edema.¹³

Systemic complications might be part of the disease spectrum ,such as CNS involvement in a sarcoidosis patient, or haemoptysis due to pulmonary involvement in a patient with Granulomatosis with polyangitis scleritis, or secondary to treatment such as steroid induced raised blood sugar or pressure or long term effects such as reduced bone density and pathological fractures.

Patients on immunosuppressant medication need to undergo periodic monitoring of blood cell counts and liver function tests to look for toxic side effects such as cytopenia and hepatotoxicity.

References

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