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.
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: email@example.com 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 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
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.
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.
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.
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.
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.
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.
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 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 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.
- 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.
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.
- Bloch ME,Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol 1987;103:234–5.
- Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 140:509–16.
- Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmol 1993;100:818–25.
- Abu El-Asrar AM, GeboesK. An immune- histochemical study of the ‘snowbank’ in a case of pars planitis. Ocular Immunology and Inflammation 2002;10:117–23
- Lemos SR, Orefice F. Uveiteintermediaria. In Or´efice, F. Uve´ýtes— Cl´ýnica e Cir ´urgica Rio de Janeiro( CulturaM´edica) 2000;843–59.
- Lai WW, Pulido JS. Intermediate uveitis. Ophthalmol ClinNor Amer. 2002; 15:309–17.
- Das D, Bhattacharjee H, Bhattacharya PK. Patterns of uveitis in North East India: a tertiary care center study. Indian J Ophthalmol 2009;57:144–6.
- Singh R, Gupta V, Gupta A . Pattern of uveitis in a referral eye clinic in North India. Indian J Ophthalmol 52:121–5.
- Rathinam SR, Namperumalsamy P. Global variations and pattern changes in epidemiology of uveitis. Indian J Ophthalmol 55:173–83.
- Zierhut M, Foster CS. Multiple sclerosis, sarcoidosis and other diseases in patients with pars planitis. Dev Ophthalmol 23:41–7.
- Donaldson MJ, Pulido JS, Herman DC, Diehl N, Hodge D. Pars planitis: a 20-year study of incidence, clinical features, and outcomes. Am J Ophthalmol 144:812–7.
- Biswas J, Sudharshan S. Intermediate uveitis. In: Gupta A, Gupta V, Herbort CP, Khairallah M (eds) Uveitis text and imaging. 2009,Jaypee Brothers Medical Publishers, New Delhi
- Lam S, Tessler HH. Intermediate uveitis. In Tasman W, Jaeger EA. JB Lippincott 1987;Philadelphia:pp.1– 15.
- Milanowski SM, Pulido JS, Goeken NE, Brown CK,Folk JC. The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis. Ophthalmology 1993; 100:1199–205.
- Khodadoust AA, Karnama Y, Stoessel KM et al. Pars planitis and autoimmune endotheliopathy. Am J Ophthalmol 1986;102:633–9.
- Breeveld J, Rothova A, Kuiper H. Systemic diseases associated with intermediate uveitis. Cleve Clin J Med 1993;60:460–5.
- Winward KE, Smith JL, Culbertson WW et al. Ocular Lyme borreliosis. Am J Ophthalmol 1989;108: 651– 7.
- Avila MP, Jalkh AE, Feldman E et al. Manifestations of Whipple’s disease in the posterior segment of the eye. Arch Ophthalmol 1984;102:384– 90.
- Font RL, Rao NA, Issarescu S et al. Ocular involvement in Whipple’s disease. Arch Ophthalmol 1978;96:1431–6.
- Boskovich SA, Lowder CY, Meisler DM et al. Systemic diseases associated with intermediate uveitis. Cleve Clin J Med 1993;60:460–5.
- Mochizuki M, Watanabe T, Yamaguchi K et al. Uveitis associated with human T-cell lymphotropic virus type I and in HIV-infected patients. Am J Ophthalmol 1992;114:123– 9.
- Mwanza JC, Kayembe DL. Uveitis in HIV-infected patients. Eur J Ophthalmol 2001;11:53– 6.
- Nicolo M, Piccolino FC, ZardiL,Giovannini A, Mariotti
C. Detection of tenascin-C in surgically excised choroidalneovascular membranes. Graefe’s Arch Clin Exp Ophthalmol. 2000;238:107–11.
- Wallner K, Li C, Shah PK, Fishbien MC, Forrester JS, Kaul S, Sharifi BG. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation 1999;99:1284–9.
- Capone Jr. A, Aaberg TM. Intermediate uveitis. In:Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology, WB Saunders. 1994;Philadelphia:pp.423–42.
- Lam S, Tessler HH. Intermediate uveitis. In: TasmanW, Jaeger EA, editors. Duane’s clinical ophthalmology, JB Lippincott. 1987;Philadelphia(4)
- Suh DW, Pulido JS, Jampol LE, et al. Coats’-like response in pars planitis. Retina 1999;19:79–80.
- Schuman JS, Puliafito CA, Fujimoto JG. Optical Coherence Tomography of Ocular Diseases. Slack Incorporated. 2004; New Jersey (2nd).
- Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F, Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthalmol 2004;49:470–90.
- Freeman WM, Green RL, Smith RE. Echographic localization of corticosteroids after periocular injection. Am J Ophthalmol 1987;103:281–8.
- Helm CJ, Holland GN. The effects of posterior subtenon injection of triamcinolone acetonide in patients with intermediate uveitis. Am J Ophthalmol 1995;120:55– 64.
- Wakefield D, Jennings A, McCluskey PJ. Intravenous pulse methyl prednisolone in the treatment of uveitis associated with multiple sclerosis. Clin Exp Ophthalmology 2000;28:103–26.
- Lazar M, Weiner MJ, Leopold IH. Treatment of uveitis with methotrexate. Am J Ophthalmol 1969; 67:383– 7.
- Charamis I, Skouras I. Treatment with azathioprine of peripheral chronic cyclitis with cystoid edema of the macula. KlinMonatsblAugenheilkd 1977; 170:362–5.
- Gills JP, Buckley CE. Oral cyclophosphamide in the treatment of uveitis. Trans Am Acad Ophthalmol Otolaryngol 1970;74:505–8.
- Nussenblatt RB, Palestine AG, Chan CC. Cyclosporine therapy for uveitis: long-term follow-up. J Ocul Pharmacol 1985;1:369– 82.
- Park SE, Mieler WF, Pulido JS. Peripheral scatter photocoagulation for neovascularization associated with pars planitis. Arch Ophthalmol 1995;113: 1277– 80.
- Pulido JS, Mieler WF, Walton D, et al. Results of peripheral laser photocoagulation in pars planitis. Trans Am Ophthalmol Soc. 1998;96:127– 37.
- Aaberg TM. The enigma of pars planitis. Am J Ophthalmol 1987;103:828–30.
- Wolf MD, Mieler WF, Chou F. Retinal detachment after cryotherapy and vitrectomy for peripheral uveitis. Presented at the American Academy of Ophthalmology Annual Meeting. Dalas, Nov, 1992.
- Kaplan HJ. Surgical treatment of intermediate uveitis. Dev Ophthalmol 1992; 23:185–9.
- Dugel PU, Rao NA, Ozler S et al. Pars plana Vitrectomy for intraocular inflammation related to cystoid macular edema unresponsive to corticosteroids: a preliminary study. Ophthalmology 1992;99:1535–41.
- Smiddy WE, Isernhagen RD, Michels RG, et al. Vitrectomy for nondiabetic vitreous hemorrhage. Retina 1988;8:88–95.
- M´eier FM, Tuft SJ, Pavesio CE. Cataract surgery in uveitis. Ophthalmol Clin Nor Amer. 2002;15:365–73.