Intermediate Uveitis
Clinical Overview, Classification & Management
Examination question · ~800 words
Define intermediate uveitis. Discuss its classification, clinical features, investigations, complications, systemic associations, and management.
Try to outline your answer mentally before expanding sections below.
Intermediate uveitis (IU) is intraocular inflammation predominantly involving the vitreous, pars plana, peripheral retina, and ciliary body. It accounts for approximately 10–15% of all uveitis cases, commonly affects young adults in the 2nd–4th decades, and is often bilateral. The hallmark lesions are snowballs in the vitreous and snowbanking over the inferior pars plana. Its importance lies in a chronic smouldering course, vision-threatening complications such as cystoid macular oedema (CMO), cataract and glaucoma, and association with systemic disease, especially multiple sclerosis, sarcoidosis, tuberculosis and Lyme disease.
The SUN Working Group classifies uveitis anatomically by the primary site of inflammation. In intermediate uveitis, the primary site is the vitreous/pars plana region.
| Type | Primary Site | Includes |
|---|---|---|
| Anterior uveitis | Anterior chamber | Iritis, iridocyclitis |
| Intermediate uveitis | Vitreous / pars plana | Pars planitis, posterior cyclitis, hyalitis |
| Posterior uveitis | Retina / choroid | Retinitis, choroiditis, retinochoroiditis |
| Panuveitis | All segments | Diffuse inflammation without predominant site |
Pars Planitis vs Secondary Intermediate Uveitis
| Subtype | Definition | Systemic Association |
|---|---|---|
| Pars planitis | Idiopathic intermediate uveitis with snowballs and/or snowbanking, after excluding systemic causes | Idiopathic; multiple sclerosis may be associated |
| Secondary intermediate uveitis | Intermediate uveitis with an identifiable systemic or infectious cause | Sarcoidosis, multiple sclerosis, Lyme disease, tuberculosis, inflammatory bowel disease |
Exam point: Pars planitis is not synonymous with all intermediate uveitis. It is a diagnosis of exclusion reserved for idiopathic IU with snowballs/snowbanking.
Anatomical Basis
The pars plana begins approximately 3.5–4 mm posterior to the limbus at the pars plicata junction and extends to approximately 7–8 mm posterior to the limbus at the ora serrata. Pars plana sclerotomies are typically placed 3.5 mm from the limbus in pseudophakic/aphakic eyes and 4.0 mm in phakic eyes.
Immunopathology
- Primarily T-helper cell mediated autoimmune inflammation.
- Putative ocular autoantigens include retinal S-antigen and interphotoreceptor retinoid-binding protein (IRBP).
- The vitreous becomes a reservoir of activated T lymphocytes, macrophages and plasma cells.
- Snowballs are condensed inflammatory aggregates in the vitreous.
- Snowbanks are organised fibrovascular exudates over the inferior pars plana; neovascularisation of snowbanks may cause vitreous haemorrhage.
CMO Mechanism
Inflammatory cytokines including IL-1, IL-6, TNF-alpha and VEGF disrupt the inner blood-retinal barrier, causing fluid accumulation in the outer plexiform layer and the classic petaloid cystoid macular oedema pattern. CMO is the most common cause of visual loss in IU.
Symptoms
- Floaters are the most common presenting symptom, due to vitreous cells and debris.
- Blurred vision occurs due to CMO or vitreous haze.
- Photophobia and pain are minimal or absent, unlike acute anterior uveitis.
- Early disease may be asymptomatic and detected incidentally.
Anterior Segment Signs
- Usually quiet or mildly inflamed anterior chamber.
- Minimal keratic precipitates, trace cells or flare.
- Posterior synechiae may develop in chronic cases.
- Posterior subcapsular cataract may occur due to chronic inflammation and steroid use.
Vitreous and Posterior Segment Signs
| Finding | Description | Exam Relevance |
|---|---|---|
| Vitreous cells | Inflammatory cells graded by SUN criteria | Disease activity |
| Vitreous haze | Diffuse haziness obscuring disc and vessel details | Treatment threshold if >=2+ |
| Snowballs | White-grey opacities in inferior vitreous, often described as a string of pearls | Classic sign of IU |
| Snowbank | White fibrovascular exudate over inferior pars plana | Pathognomonic of pars planitis |
| Periphlebitis | Peripheral retinal venous sheathing | Common clue to MS-associated IU |
| Neovascularisation | Snowbank or peripheral retinal neovascularisation | Risk of vitreous haemorrhage |
| CMO | Petaloid leakage on FFA; cystic spaces on OCT | Most common cause of visual loss |
| Other signs | Disc oedema, ERM, tractional retinal detachment | Chronic or severe disease |
Vitreous haze is commonly graded using the Nussenblatt/NEI vitreous haze scale, adopted by the SUN Working Group.
| Grade | Description |
|---|---|
| 0 | No haze; clear view of disc and vessels |
| 0.5+ | Slight blurring of optic disc margins |
| 1+ | Disc and major vessels clear; minor haze |
| 2+ | Disc visible but blurred; vessels hazy |
| 3+ | Disc barely visible; diffuse haze |
| 4+ | Disc not visible; dense haze |
Ocular Investigations
| Investigation | Role in Intermediate Uveitis |
|---|---|
| Slit-lamp biomicroscopy | AC cells/flare, keratic precipitates, lens status, anterior vitreous cells |
| Indirect ophthalmoscopy with scleral depression | Detects snowballs, inferior snowbanking, periphlebitis, peripheral neovascularisation and retinal breaks |
| Fundus fluorescein angiography | Shows petaloid CMO, disc leakage, retinal vascular leakage, periphlebitis and snowbank vessel leakage |
| OCT macula | Preferred investigation for detecting and monitoring CMO, ERM and subretinal fluid |
| B-scan ultrasonography | Essential when media view is poor; detects vitreous haze, snowbank as echogenic pars plana mass, and retinal detachment |
| Fundus photography | Documentation and follow-up of disease activity |
| Visual fields | Monitoring structural/functional damage and steroid-induced glaucoma when indicated |
Systemic Workup
| Investigation | Purpose |
|---|---|
| CBC, ESR, CRP | Baseline inflammation and infection screen |
| Chest X-ray / HRCT thorax | Sarcoidosis, tuberculosis |
| ACE and serum lysozyme | Sarcoidosis support markers |
| Serum calcium / 24-hour urine calcium | Hypercalcaemia of sarcoidosis |
| MRI brain and orbit with contrast | Multiple sclerosis: periventricular demyelinating plaques, Dawson fingers |
| Lyme ELISA and Western blot | Endemic area, tick exposure or compatible systemic history |
| VDRL and FTA-ABS | Syphilis, the great masquerader |
| Mantoux / IGRA | Tuberculosis-associated uveitis |
| ANA, anti-dsDNA, ANCA | SLE or ANCA-associated vasculitis when clinically suspected |
| Toxocara ELISA | Children with unilateral IU, leukocoria or peripheral granuloma |
| HIV testing | Immunocompromised or atypical uveitis |
| HLA-B27 | If associated anterior uveitis features are present |
Investigative priority: In young patients with bilateral IU or neurological symptoms, perform MRI brain to evaluate for multiple sclerosis.
| Systemic Disease | Ophthalmic Clues | Key Investigation |
|---|---|---|
| Multiple sclerosis | Intermediate uveitis with prominent periphlebitis; may precede neurological symptoms | MRI brain for periventricular plaques |
| Sarcoidosis | Granulomatous uveitis, mutton-fat KPs, periphlebitis, candle-wax drippings | ACE, serum lysozyme, CXR/HRCT, serum calcium |
| Lyme disease | Tick exposure, vitritis, disc oedema or neuroretinitis | Lyme ELISA and Western blot |
| Tuberculosis | Granulomatous uveitis, exposure history, retinal vasculitis/periphlebitis | Mantoux, IGRA, CXR/HRCT |
| Inflammatory bowel disease | Crohn disease more than ulcerative colitis; periphlebitis and CMO may occur | Gastroenterology evaluation, colonoscopy when indicated |
| Whipple disease | Vitreous snowballs with systemic wasting, diarrhoea or CNS signs | PCR for Tropheryma whipplei; PAS-positive duodenal biopsy |
| Idiopathic pars planitis | Snowballs/snowbanking with negative systemic workup | Diagnosis of exclusion |
| Complication | Notes |
|---|---|
| Cystoid macular oedema | Most common cause of visual loss; seen in approximately 25–40%; monitored by OCT |
| Posterior subcapsular cataract | Due to chronic inflammation and corticosteroid exposure |
| Vitreous haemorrhage | From neovascularisation of snowbank or peripheral retina |
| Tractional or rhegmatogenous retinal detachment | Rare but vision-threatening; due to fibrovascular contraction or retinal breaks |
| Glaucoma | Most commonly steroid-induced; also due to trabeculitis or synechial angle closure |
| Epiretinal membrane | Occurs in chronic or recurrent IU; may cause metamorphopsia |
| Amblyopia | Important paediatric complication requiring aggressive visual rehabilitation |
| Band keratopathy | Calcium deposition in the horizontal interpalpebral zone from 3–9 o'clock, beginning peripherally at 3 and 9 o'clock and extending centrally; associated with chronic uveitis, hypotony or hypercalcaemia |
Treatment is indicated when there is visual or structural threat. Mild IU with good vision, minimal haze and no macular involvement may be observed.
| Indication for Treatment | Rationale |
|---|---|
| VA <=6/12 due to CMO or vitreous haze | Vision-threatening disease |
| Vitreous haze >=2+ | Clinically significant inflammatory load |
| CMO on OCT | Most common cause of visual loss |
| Neovascularisation of snowbank or retina | Risk of vitreous haemorrhage |
Step 1: Corticosteroids
| Treatment | Use | Key Points |
|---|---|---|
| Posterior sub-Tenon triamcinolone 40 mg/1 mL | Unilateral disease | Avoids systemic adverse effects; monitor IOP and cataract |
| Oral prednisolone 1 mg/kg/day | Bilateral, severe or systemic disease-associated inflammation | Taper according to response and add steroid-sparing therapy if prolonged treatment is needed |
| Intravitreal triamcinolone 4 mg/0.1 mL | Recalcitrant CMO | Risk of IOP rise and endophthalmitis |
| Dexamethasone implant 0.7 mg | CMO or active non-infectious IU, especially pseudophakic or vitrectomised eyes | Sustained release for approximately 3–6 months |
Step 2: Steroid-Sparing Immunosuppression
| Agent | Dose / Notes |
|---|---|
| Methotrexate | 7.5–25 mg weekly; monitor CBC and LFT; folate supplementation; teratogenic |
| Mycophenolate mofetil | 1–3 g/day; useful steroid-sparing option; GI adverse effects; teratogenic |
| Azathioprine | 1–2.5 mg/kg/day; useful in IBD-associated IU; check TPMT activity |
| Cyclosporine A | 2.5–5 mg/kg/day; nephrotoxicity and hypertension; monitor BP and creatinine |
| Tacrolimus | Calcineurin inhibitor alternative to cyclosporine |
Step 3: Biologics
| Biologic | Role / Notes |
|---|---|
| Adalimumab | Anti-TNF-alpha; FDA-approved for non-infectious uveitis based on VISUAL trials; screen for TB and latent infection before use |
| Infliximab | Anti-TNF-alpha IV infusion; rapid onset; used in refractory inflammatory uveitis |
| Rituximab | Anti-CD20 B-cell depletion; selected refractory cases |
| Daclizumab / basiliximab | Anti-IL-2 receptor agents; historical use |
| Secukinumab | Anti-IL-17; investigational or selected refractory contexts |
Important safety point: Anti-TNF therapy must not be started in latent TB without adequate prophylaxis. At least 4 weeks / 1 month of latent TB treatment should be completed before initiating anti-TNF therapy, with infectious disease or pulmonary input when needed.
| Procedure | Indications | Key Point |
|---|---|---|
| Pars plana vitrectomy | Dense vitreous haze unresponsive to medical therapy, vitreous haemorrhage, tractional RD, diagnostic biopsy | Removes inflammatory cells, cytokines and VEGF; has an anti-inflammatory effect |
| Peripheral laser photocoagulation / cryotherapy | Neovascularisation of snowbank or peripheral retina | Laser is generally preferred when view permits |
| Cataract surgery | Visually significant posterior subcapsular cataract | Operate after inflammation is controlled; perioperative immunosuppression is essential |
| Glaucoma surgery | Medically uncontrolled IOP | Prognosis guarded in active inflammation |
| Trial | Finding / Significance |
|---|---|
| VISUAL I, Jaffe GJ, Dick AD, Brezin AP et al., N Engl J Med 2016 | Adalimumab versus placebo in active non-infectious uveitis; significantly reduced treatment failure (HR 0.50, p=0.004), contributing to FDA approval for non-infectious uveitis |
| VISUAL II, Dick et al., Ophthalmology 2016 | Adalimumab reduced risk of flare in inactive non-infectious uveitis requiring systemic therapy and supported maintenance use |
| MUST Trial 2011 | Fluocinolone acetonide implant and systemic therapy had no significant VA difference at 2 years; implant caused worse ocular adverse events including IOP elevation (~60% vs ~31%), more IOP-lowering surgery and more cataract progression; systemic therapy is better for bilateral disease and has fewer ocular complications |
| POINT Trial 2019 | Compared regional corticosteroid approaches for uveitic macular oedema; intravitreal therapy was effective but IOP risk must be monitored |
| HURON Trial, Lowder C, Belfort R Jr, Lightman S et al., Arch Ophthalmol 2011 | Dexamethasone implant versus sham in non-infectious intermediate/posterior uveitis; improved vitreous haze and visual acuity |
Intermediate uveitis is one of the more common forms of paediatric uveitis and is the most common non-anterior anatomical type. Anterior uveitis remains the most common paediatric anatomical type overall.
- Often insidious and detected on school vision screening.
- Amblyopia is a major risk; refraction and occlusion therapy may be required.
- Important differential: _Toxocara canis_, presenting as unilateral IU with peripheral granuloma and leukocoria.
- CMO, band keratopathy and cataract are important causes of visual morbidity.
- Steroids require careful monitoring due to growth, cataract and glaucoma risks; steroid-sparing therapy is often needed.
- MS association is lower in children than adults; Lyme disease should be considered in endemic areas.
Trap 1 — FALSE
“Snowbank is formed in the superior pars plana.”
Snowbanking classically forms inferiorly over the pars plana, often near 6 o'clock. Superior snowbanking should prompt consideration of masquerade or unusual causes.
Trap 2 — FALSE
“Pars planitis is synonymous with intermediate uveitis.”
Pars planitis is a subset of intermediate uveitis: idiopathic IU with snowballs/snowbanking after systemic causes are excluded.
Trap 3 — FALSE
“All intermediate uveitis requires treatment.”
Mild IU with good vision, minimal haze and no CMO may be observed. Treat when VA is reduced, vitreous haze is >=2+, CMO is present, or neovascularisation develops.
Trap 4 — FALSE
“FFA is the gold standard for diagnosing and monitoring CMO in intermediate uveitis.”
FFA shows petaloid leakage and vascular activity, but OCT is preferred for diagnosis and quantitative monitoring of CMO response.
Trap 5 — FALSE
“Vitrectomy has no anti-inflammatory benefit in intermediate uveitis.”
Pars plana vitrectomy removes inflammatory cells, cytokines and VEGF from the vitreous cavity and can reduce inflammatory recurrence in selected cases.
Trap 6 — FALSE
“Sub-Tenon's triamcinolone can be given safely to all patients.”
It should be avoided or used cautiously in uncontrolled IOP, thin sclera or steroid responders; monitor for IOP rise and posterior subcapsular cataract.
Trap 7 — FALSE
“Adalimumab can be started immediately in a patient with intermediate uveitis and positive IGRA.”
Latent TB must be treated before anti-TNF therapy. At least 4 weeks / 1 month of LTBI treatment should be completed before starting anti-TNF therapy.
Trap 8 — FALSE
“Band keratopathy in uveitis is an inferior 5–6 o'clock calcium deposit.”
Band keratopathy is calcium deposition in the horizontal interpalpebral zone from 3–9 o'clock, beginning near 3 and 9 o'clock and extending centrally.
Trap 9 — FALSE
“The pars plana lies 2–4 mm behind the limbus.”
The pars plana begins about 3.5–4 mm posterior to the limbus and extends to about 7–8 mm posteriorly; 2 mm is within pars plicata/ciliary process territory.
Q: What is the most common presenting symptom of intermediate uveitis?
A: Floaters, due to vitreous cells and inflammatory debris.
Q: What is the hallmark sign of pars planitis?
A: Inferior pars plana snowbanking with vitreous snowballs, after excluding systemic causes.
Q: What is the most common cause of visual loss in intermediate uveitis?
A: Cystoid macular oedema.
Q: Peripheral retinal periphlebitis, intermediate uveitis and abnormal MRI brain suggest what diagnosis?
A: Multiple sclerosis until proven otherwise.
Q: Candle-wax drippings, bilateral hilar lymphadenopathy and hypercalcaemia suggest what diagnosis?
A: Sarcoidosis.
Q: Unilateral intermediate uveitis in a child with leukocoria and peripheral granuloma suggests what diagnosis?
A: _Toxocara canis_; confirm with Toxocara ELISA and exclude retinoblastoma clinically.
Q: Which imaging test is preferred for monitoring CMO response?
A: OCT macula because it is non-invasive and quantitative.
Q: When should MRI brain be considered in intermediate uveitis?
A: Young patients with bilateral IU, periphlebitis or neurological symptoms should be evaluated for multiple sclerosis.
A 28-year-old woman has bilateral intermediate uveitis with snowballs, 2+ vitreous haze and CMO OU. MRI brain shows two periventricular T2 hyperintense lesions but she has no neurological symptoms, consistent with clinically isolated syndrome. What are the implications of adalimumab in this context, and how would you optimise management?
Answer
This is a conflict between uveitis control and neurological safety. Anti-TNF-alpha agents such as adalimumab and infliximab are contraindicated or avoided in demyelinating disease, including multiple sclerosis and clinically isolated syndrome, because they may precipitate or worsen demyelination.; In a 28-year-old woman, pregnancy planning matters: methotrexate and mycophenolate are teratogenic; azathioprine is relatively safer when systemic immunosuppression is needed.
References
- VISUAL I, Jaffe GJ, Dick AD, Brezin AP et al., N Engl J Med 2016. Adalimumab versus placebo in active non-infectious uveitis; significantly reduced treatment failure (HR 0.50, p=0.004), contributing to
- FDA approval for non-infectious uveitis
- VISUAL II, Dick et al., Ophthalmology 2016. Adalimumab reduced risk of flare in inactive non-infectious uveitis requiring systemic therapy and supported maintenance use
- MUST Trial 2011. Fluocinolone acetonide implant and systemic therapy had no significant VA difference at 2 years; implant caused worse ocular adverse events including IOP elevation (~60% vs ~31%), more IOP-lowering surgery and more cataract progression; systemic therapy is better for bilateral disease and has fewer ocular complications
- HURON Trial, Lowder C, Belfort R Jr, Lightman S et al., Arch Ophthalmol 2011. Dexamethasone implant versus sham in non-infectious intermediate/posterior uveitis; improved vitreous haze and visual acuity
- Internal ledger cross-check: IU-061 correctly cites Jaffe GJ et al., N Engl J Med 2016;375(10):932-943. VISUAL I is a landmark NEJM publication, not Ophthalmology. Author surname 'Jabobiec' does not match any known VISUAL I investigator.
- MUST Trial primary findings are well established: the implant caused substantially more IOP elevation and cataract compared to systemic therapy. The claim as written inverts the IOP finding, which is a dangerous factual error for exam and clinical practice.
- Nussenblatt RB et al. established this scale; adopted by SUN Working Group 2005. 'BSRS' is not a recognized standard abbreviation in international ophthalmology literature.