Review Article June 2018

Review Article

Intermediate uveitis

Anindya K Majumder, Parthopratim Dutta Majumder, Jyotirmay Biswas

Keywords: Uveitis; Intermediate uveitis; Pars planitis.

Intermediate uveitis is an intraocular inflammation involving primarily the anterior vitreous or the vitreous base, cilliary body, pars-plana and peripheral retina. Many other names have been given to the syndrome since its description by Fuchs in 1908, including peripheral uveitis, pars planitis, chronic cyclitis, peripheral uveoretinitis and vitreitis. The International Uveitis Study Group( IUSG) introduced this term Intermediate uveitis (IU) in 1987, defining the syndrome by its anatomical location1. The Standardization of Uveitis Nomenclature (SUN) Working Group defined IU as that subset of uveitis where vitreous is the major site of inflammation and the presence of peripheral vascular sheathing and macular edema should not change the classification 2. The same group defined “pars planitis” as an idiopathic subset of IU where there is snowball or snow bank formation occurring in the

absence of any systemic disease.

This condition generally affects children, young adults  as well as middle aged individuals and results in numerous sequelae, including cystoid macular edema, glaucoma, cataract formation, epiretinal membrane formation, retinal neovascularisation with or without vitreous haemorrhage, retinal detachment, rubeosisiridis, cyclitic membrane, and phthisis bulbi3,4.

Prevalence — The prevalence of intermediate uveitis has been reported to be 4 to 15% in uveitis referral practices5,6.

Aetiology:

In the cross-sectional epidemiologic studies done from the referral institutes in India, intermediate uveitis has been reported to be idiopathic in 77.5% in North East

India, 91.4% in North India, 81.6% in South India7-9. The aetiology of IU is not well known and is mostly believed to be autoimmune, although it may be associated with systemic illness such as  sarcoidosis, multiple sclerosis10-14. The presence of HLA-DR2 and specifically the HLA-DR1501 subtype in both patients with pars planitis and multiple sclerosis suggests an association between the two diseases. The fact that pars planitis increases the risk for subsequent development of multiple sclerosis, idiopathic optic neuritis, autoimmune corneal endotheliopathy, sarcoidosis, thyroid diseases and inflammatory bowel diseases14-16.

These associations suggest that an autoimmune process plays a role in pathogenesis. In addition, the presence of HLA-DR15 and HLA-A28 has also been demonstrated in patients with intermediate uveitis5.

The disease is notorious for its prolonged chronic course with exacerbations and hence the need for investigations to search for a definitive aetiology and proper management to reduce the recurrence and complications. The aetiology may be variable in different parts of the world as it could be influenced by the geographic variations and ethnicity. A number of infectious agents have been found to cause intermediate uveitis. Lyme disease caused by Borrelia burgdorferi can produce a variety of ophthalmologic changes during stages II and III of the disease. Bilateral vitritis with multiple vitreous snowballs has been reported in patients infected with the bacteria17. Toxocariasis should be considered in the differential diagnosis of intermediate uveitis especially in young patients who present with unilateral vitritis and pars plana snowbanks. Elevated levels of serum antibody are diagnostic of the condition.

1Uvea and Intraocular Inflammation services, Kamal Nayan Bajaj Sankara Nethralaya, Flat no DJ-16, Newtown action area-II, Kolkata-700156, West Bengal, India, 2Uvea and Intraocular Inflammation Services, Medical Research Foundation, Sankara Nethralaya, Old no. 18, New no. 41, College Road, Ungambakkam, Chennai-600006, Tamil Nadu, India.

Corresponding Author : Dr Anindya K Majumder, E-mail: drakm@snmail.org Received on : 22/02/2018, Revision accepted on : 17/04/2018

Conflict of Interest : None, Financial Disclosure : None

© Current Indian Eye Research.

Whipple’s disease is a multisystem disorder caused by the Whipple’s bacilli. Chronic vitritis with vitreous debris mimicking intermediate uveitis have been reported18,19.

Intermediate uveitis has also been documented with viral aetiology like Epstein-Barr virus, human T-cell lymphotropic virus type I ( HTLV –I)20-22.

Histopathology:

Histopathology examination of ‘snowbanks’ reveals a loose fibrovascular layer containing occasional fibrocyte- like cells and scattered mononuclear inflammatory cells adjacent to the hyperplastic nonpigmented epithelium of the pars plana. An extensive fibroglial proliferation is noticed within the vitreous base, often drawing the peripheral retina anteriorly into the ‘snowbank’. Electron microscopy shows this fibroglial tissue to be composed of condensed vitreous collagen and probable fibrous astrocytes which produce larger-diameter collagen fibrils. The fibroglial proliferation also appears continuous with an ultra structurally similar pre-retinal fibroglial membrane4.

The extracellular matrix (ECM) components and resident cell populations of the ‘snowbank’ have been discussed in several research papers. The ‘snowbank’ is acellular except for cytokeratin-positive retinal pigmentepithelial cells on the uveal side. ‘Snowbank’ had a prominent dense stroma. In Immuno-histochemical studies; antibodies reacted against tenascin and the three major interstitial collagen types I, II, and III. Tenascin is a large hexameric ECM glycoprotein that is found in embryonic tissues, especially at epithelial-mesenchymal junctions and in developing brain tissue. Its expression is restricted in adult human tissues and in tumor stroma. Its re- expression occurs during wound healing, tissue remodelling. Tenascin is believed to play important roles in tissue development, wound healing and repair because it mediates several cellular activities, including cell adhesion and anti-adhesion, migration, proliferation, and differentiation4. Tenascin is highly expressed in the ‘snowbank’, with particular intense immunoreactivity on the vitreous side. In the retina, tenascin has been reported to be present in choroidal neovascular membranes23.

The function of inflammatory cells participating in chronic inflammation may be modulated through the altered organization of ECM in chronically inflamed tissues. Up- regulation of the expression of matrix metalloproteinase- 9 has been observed in human macrophages cultured on

tenascin substrate24.

The presence of tenascin in the ‘snowbank’ might promote the breakdown of the ECM and possibly modulate ECM remodelling. They are the components of a chronic inflammatory response. Tenascin also may act as an immunomodulator. Tenascin alters the adhesion properties of human monocytes, B cells, and T cells and inhibits T-lymphocyte activation.

Clinical features:

Symptoms:

Patients usually complain of blurry vision, floaters although at times they may be asymptomatic and occasionally distortion of central vision5. The vision is usually reduced sec to vitritis or cystoids macular edema.Occasionally, the patient may present with sudden loss of vision because of vitreous hemorrhage6. As the disease progresses, more profound loss of central or peripheral vision may develop from secondary glaucoma, cataract, organized anterior vitreous exudates, cystoid macular edema, vitreous haemorrhage, and retinal detachment25. The symptoms are usually gradual in onset26. Redness, pain or photophobia is not common. Approximately 70-80% of the patients present with a bilateral disease at presentation or in the follow-up5,6.

Signs:

The anterior chamber is usually quiet or there may be low grade spill over reaction. Anterior camber reaction could be moderate to severe in case of children6. There are usually no keratic precipitates but endothelial dusting and fibrin formation may be observed. Small to medium sized keratic precipitates may rarely be seen. Band shaped keratopathy may develop in children with long- standing intermediate uveitis6.

An autoimmune endotheliopathy has been described in patients with pars planitis similar to that observed in corneal allograft graft rejection15.

The iris is not typically affected in the early stages of the disease. Peripheral anterior synechiae and posterior synechiae are seen more in chronic and recurrent disease. Angle closure, papillary block and neovascularisation of iris could rarely occur.

Cataract formation is common, with posterior subcapsular opacification secondary to chronic course of the disease

and corticosteroid6. Rarely spontaneous subluxation of lens may result sec to inflammatory destruction of the zonular apparatus.

The hallmark of intermediate uveitis is the presence of vitritis. Aggregates of white or yellow exudates analogous to snowballs are classically seen in the inferior vitreous base and ora-serrata. With time, they can coalesce to form a plaque called a snow bank. The snow bank may extend circumferentially to involve the entire pars plana and anterior retina. Chronic posterior cyclitis is another subset of intermediate uveitis.

In the inferior peripheral retina, vasculitis, obliterated venules and neovascularisation can be observed in long standing parsplana membrane which may lead to vitreous haemorrhage. Cystoid macular edema is the most common complication of intermediate uveitis resulting in decreased vision. Chronic edema can lead to degeneration, epiretinal or subretinal membranes and macular hole formation. Rarely the optic disc may present with edema, hyperaemia and neovascularisation5,6 . Rhegmatogenous retinal detachment can occur in a setting of progressive and increasing vitreoretinal contraction by the fibroglial membrane in the pars plana6.

A rare Coats’ disease–like response has also been described in patients with pars planitis. This may be the result of a shared pathogenic mechanism to the neovascularisation of the retina27.

Differential diagnosis:

The differential diagnosis for intermediate uveitis may include sarcoidosis, tuberculosis, Behcet’s disease, syphilis, Fuchs’ uveitis, Vogt-Koyanagi Harada disease, Irvine Gass syndrome, amyloidosis and large cell lymphoma5,6.

Diagnosis:

The initial screening for an intermediate uveitis patient includes several tests to exclude other diseases: complete blood count with differential; chest X-ray to rule out tuberculosis and sarcoidosis; serum angiotensin converting enzyme (ACE), serum and urinary calcium CD4/CD 8 ratio in bronchoalveolar lavage fluid and tissue biopsy to rule out sarcoidosis and antibody testing for infectious diseases, such as syphilis, toxocariasis, HTLV 1 and Lyme disease5,6.

Fluorescein angiography is a useful tool in documenting

macular and disc edema, associated retinal vasculitis, ischemia, and neovascularisation.

Optical coherence tomography (OCT) is a non-invasive technique that provides detailed information about macular edema, subretinal and epiretinal membranes and macular hole even in the presence of media haze like moderate vitreous opacities ,cataract or small pupils. Sequential OCT scans is also useful on follow-up28,29.

Ultrasound biomicroscopy is an useful tool used to assess the pars plana and cilliary body in patients with media haze, small pupil where as B ultrasonography is useful in the evaluation of retinal status, vitreous and retinal detachment. Finally, diagnostic vitreous biopsy may be necessary for definitive aetiological diagnosis and to rule out masquerades like large cell lymphoma.

Treatment:

Exclusion of underlying diseases is the first criteria for intermediate uveitis treatment. Local therapy is usually indicated when visual acuity is worse than 20/40 or in eyes with snowbanking and extensive neovascularisation or vasculitis. Treatment ranges from local ocular injections to systemic drug therapy5,6. Corticosteroids are the first line treatment option for intermediate uveitis patients. Topical steroid alone is usually ineffective.

Subtenon steroid-Most patients with intermediate uveitis and cystoids macular oedema respond to periocular injection of corticosteroid or to systemic therapy. Posterior subtenon injection of triamcinolone delivery was found to have a higher

Success rate in localization of the medication to the subtenon space overlying the macula30.

This is an important consideration when the target of the therapy is the macula, such as in patients who develop cystoids macular oedema. The injection can be repeated every 2 to 3 weeks for a total of two to three doses. Available drug in India is 0.5 to 1 ml of triamcinolone acetonide (40 mg/ml) using 26 gaze needle. The most common side effect is the rise in the intraocular pressure, especially in those who received multiple Injections31. Oral steroid-Systemic corticosteroids are first liner therapy in patients with intermediate uveitis. Previously posterior subtenon triamcinolone (PST) injections were used as first liner therapy especially in unilateral disease. But owing to the complication rates of PST, it has been reserved for nonsteroid responder intermediate uveitis

patients with macular oedema as an adjuvant to oral therapy .The usual starting dose is 1 mg/kg of body weight per day. It is tapered according to the clinical response6. Intravenous pulse methylprednisolone therapy has also produced improvement in visual acuity in a small series of patients with pars planitis32.

Immunosuppressive agents

When periocular injection or systemic corticosteroids results in minimal or no improvement and recurrence or if corticosteroids result in significant side effects, such as  a persistent increase in intraocular pressure, other immunosuppressive agents may be used. A number of such agents have been used, including methotrexate, azathioprine, cyclophosphamide, cyclosporine A33-36 .

Methotrexate is the molecule of choice in the paediatric age group due to its lower side effects. Azathioprine is the most widely used broad spectrum molecule for recurrent disease and maintenance therapy in case of adults. Cyclophosphamide is a reserved molecule used for recalcitrant cases but serious systemic toxicity limits its use. Mycophenolate mofetyl has been used successfully in all age group owing its lower spectrum of side effects.

LASER photocoagulation

Laser photocoagulation of peripheral retina was found to be efficacious in the treatment of neovascularisation of the vitreous base in patients with pars planitis37,38. Laser photocoagulation of peripheral retina combined with pars plana vitrectomy could be option for recalcitrant cases not responding to any other therapy5.

Cryotherapy

Cryotherapy for snowbanking is indicated after periocular or systemic corticosteroid therapy failure where the parsplana membrane is very anterior in location (difficult for the laser to reach) and showing proliferative changes. Destruction and elimination of the neovascularisation and ischemic tissue seems to be the mechanism behind the success of this treatment 39. The prognosis after cryotherapy is better if the snowbank extends less than 600 of the periphery5.

Possible complications of cryotherapy are transitory worsening of vitritis, cataract development , hyphema, macular oedema, retinoschisis and rhegmatogenous or tractional retinal detachment 40.

Surgical Therapy

  1. Pars plana vitrectomy

Pars plana vitrectomy may be performed inpatients that have chronic and significant inflammation and cystoid macular oedema not responding adequately to medical therapy and in non clearing vitreous haemorrhage41-43.

  • Cataract surgery

Cataract formation is an important cause of visual loss in patients with intermediate uveitis. It is a common complication occurring in approximately 9 to 57% of the patients. Surgery is preferably indicated when the inflammation is controlled for at least 8-12 weeks period. Systemic corticosteroids should be started 4 to 7 days before the surgery44. Non-dilating pupil, secondary angle closure ,inadequate capsular support are a few complications faced during surgery . Proper care must be taken to prevent postoperative inflammatory macular oedema.

Management approach  described  by Kaplan- Management of intermediate uveitis can be done by a modified five step approach (Modified Kaplan’s method).

1st step: Posterior subtenon injection of Triamcinolone acetonide (Depot steroid)

2ndstep: Oral steroid (Prednisolone acetate 1 -1.5mg/ kg body weight)

3rd step: Addition of Immuno suppressive agents

4th step: Biological agents (e.g. TNF alpha blockers) 5th step: Vitrectomy /Laser.

The use of posterior subtenon triamcinolone actonide injection is reserved due to its side effects (IOP rise, cataract formation). It could be useful in pseudophakic inflammatory cystoids macular oedema, preoperatively in uveitic cataract extraction and in patients where systemic therapy is contraindicated (e.g. pregnancy) and there was no history of steroid response previously.

Summary

The diagnosis of Intermediate uveitis includes detailed clinical examination and tailored laboratory investigations to exclude possible etiologies. The diagnosis of uveitis is always evolving as the disease process continues; it gives more clinical clues to a clinician. The clinical examination is challenging in cases of children and etiological diagnosis is tricky in cases of elderly population

considering masquerades. A clinician must be very thorough in detailed examination of the anatomical extent of uveitis and order investigations accordingly. Ultrasound biomicrosopy can be considered where the clinical examination of pars plana is difficult. Vitreous biopsy is to be considered when blood investigations are inconclusive and patient not responding adequately to  an anti-inflammatory therapy. Immunosuppresive agents are to be considered early in cases of recurrent and relentless disease and in children. Posterior subtenon triamcinolone injection is to be used judiciously after exclusion of steroid response in a patient. Patients of Intermediate uveitis should be counseled about the chronicity of the disease and complication of it and need for long term systemic therapy. Early diagnosis and timely treatment can prevent serious complications of the disease.

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