SUN classification, grading and uveitis work-up

The Standardization of Uveitis Nomenclature (SUN) Classification

Intraocular inflammatory diseases encompass an extensive spectrum of infectious, autoimmune, and masquerade disorders. Historically, variable clinical definitions and non-standardized grading systems hampered clinical trials and cross-center comparability. In 2005, the Standardization of Uveitis Nomenclature (SUN) Working Group published international consensus guidelines establishing standardized anatomical criteria, descriptors of disease course, and quantitative biomicroscopic grading scales that remain the global benchmark for clinical practice and ophthalmic examinations.

Anatomical Classification

The SUN classification categorizes uveitis strictly according to the primary anatomical site of active inflammation, rather than secondary structural complications:

1. Anterior Uveitis: The primary site of active inflammation is the anterior chamber. Clinical subtypes include:
   • Iritis: Inflammation confined exclusively to the iris stroma and anterior chamber.
   • Iridocyclitis: Inflammation involving both the iris and the anterior portion of the ciliary body (pars plicata).
   • Anterior Cyclitis: Predominant inflammation of the ciliary body with minimal iris involvement.
   • Epidemiological context: Represents 50% to 70% of all uveitis presentations in European tertiary centers.
2. Intermediate Uveitis: The primary site of active inflammation is the vitreous cavity.
   • Encompasses vitritis, posterior cyclitis, and hyalitis.
   • Pars Planitis: Defined as a specific idiopathic subset of intermediate uveitis characterized by the presence of "snowball" vitreous opacities and/or "snowbanking" (fibrovascular or inflammatory exudate over the inferior pars plana and peripheral retina) in the complete absence of an identifiable underlying systemic infectious or autoimmune disease.
3. Posterior Uveitis: The primary site of active inflammation is the retina and/or choroid.
   • Manifests as focal, multifocal, or diffuse choroiditis, chorioretinitis (choroid primarily inflamed with secondary retinal extension), retinochoroiditis (retina primarily inflamed with secondary choroidal extension), retinitis, or neuroretinitis (retinitis accompanied by optic disc oedema and a macular star).
4. Panuveitis: Generalized intraocular inflammation with active, concurrent, and roughly equal inflammatory involvement across all three compartments—the anterior chamber, the vitreous cavity, and the retina/choroid. If inflammation predominantly resides in one anatomical zone with only spill-over cells in another, the primary site defines the disease (e.g., severe anterior uveitis with spill-over anterior vitreous cells is classified as anterior uveitis, not panuveitis).

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Descriptors of Clinical Course

The SUN Working Group established uniform criteria to define disease onset, duration, and recurrence:

• Onset: Categorized as either Sudden (acute, explosive symptomatic onset within hours to days) or Insidious (gradual, indolent, often asymptomatic presentation over weeks or months).
• Duration:
  • Limited: The inflammatory episode resolves completely within $\le 3\text{ months}$ of onset.
  • Persistent: The inflammatory process remains active for $> 3\text{ months}$.
• Clinical Course Classifications:
  • Acute Uveitis: Characterized by sudden onset and limited duration ($\le 3\text{ months}$). Example: classical acute HLA-B27-associated anterior uveitis.
  • Recurrent Uveitis: Characterized by repeated, discrete episodes of inflammation separated by untreated inactive intervals lasting at least $\ge 3\text{ months}$ off all anti-inflammatory therapy.
  • Chronic Uveitis: Persistent intraocular inflammation characterized by prompt relapse within $< 3\text{ months}$ following the discontinuation of topical or systemic therapy. Example: juvenile idiopathic arthritis (JIA)-associated uveitis.
• Remission: Defined as completely inactive disease (Grade 0 cells) maintained for $\ge 3\text{ months}$ while off all anti-inflammatory medications.

Quantitative Biomicroscopic Grading Schemes

Standardized clinical quantification of active inflammation is crucial to gauge therapeutic responsiveness and disease progression.

1. Anterior Chamber Cells (SUN Grading)

Anterior chamber cells are graded with a standard 1 × 1 mm slit beam under consistent examination conditions. SUN cell thresholds should not be conflated with a compulsory fixed magnification or every clinical severity decision.

2. Anterior Chamber Flare (SUN Grading)

Aqueous flare is optical Tyndall scattering produced by elevated protein concentrations in the aqueous humour secondary to breakdown of the blood-aqueous barrier (tight junctions of the non-pigmented ciliary epithelium and iris capillary endothelium):

Laser Flare Photometry (LFP): Uses automated helium-neon laser scatter to quantify protein leakage in photon counts per millisecond ($\text{ph/ms}$). Normal values range between 3 and 6 $\text{ph/ms}$. Particularly useful in monitoring paediatric uveitis (e.g., juvenile idiopathic arthritis) where persistent subclinical flare correlates with long-term cataract and glaucoma risk.

3. Vitreous Haze Grading (Nussenblatt 0–4+ Scale)

Vitreous haze represents proteinaceous and cellular clouding of the posterior cavity. Unlike vitreous cells (which can settle or persist indefinitely as inactive cellular debris), vitreous haze directly reflects active capillary leakage and blood-retinal barrier breakdown. It is evaluated by indirect ophthalmoscopy with a 20-dioptre condensing lens:

• Grade 0: Completely transparent vitreous; nerve fiber layer bundles, small peripapillary retinal vessels, and optic disc margins are crisply demarcated.
• Trace: Slight optical dulling of the nerve fiber layer reflex; retinal vessels remain clear.
• Grade 1+: Mild haziness; subtle blurring of the optic nerve head margin and secondary retinal vessel bifurcations.
• Grade 2+: Moderate haziness; optic nerve head and major retinal vascular arcades are clearly visible, but their fine borders and vessel walls are distinctly blurred.
• Grade 3+: Marked haziness; optic nerve head, major retinal vessels, and posterior pole landmarks are barely discernible; retinal details are severely obscured.
• Grade 4+: Severe, opaque vitritis; optic nerve head is totally invisible; red reflex is severely diminished or absent.

Granulomatous vs. Non-Granulomatous Inflammation

Differentiating granulomatous from non-granulomatous intraocular inflammation is a fundamental clinical bifurcation in the diagnostic workup:

Keratic Precipitates (KPs)

Keratic precipitates are cellular clusters adhering to the corneal endothelium, transported by convection currents within the anterior chamber (flowing downward along the cooler posterior corneal surface and upward along the warmer iris face):

1. Mutton-Fat KPs: Large, greasy, waxy, yellowish-white endothelial deposits composed microscopically of transformed macrophages, epithelioid histiocytes, and multinucleated giant cells. With chronicity, they become pigmented, crenated, and ground-glass in texture. Hallmark of granulomatous diseases: sarcoidosis, tuberculosis, syphilis, Vogt-Koyanagi-Harada (VKH) disease, and sympathetic ophthalmia.
2. Fine Non-Granulomatous KPs: Small, discrete, white, punctate endothelial deposits composed predominantly of lymphocytes, plasma cells, and polymorphonuclear neutrophils. Typical of HLA-B27 acute anterior uveitis, Behçet disease, and trauma.
3. Stellate KPs: Delicate, translucent, dendritic, star-shaped precipitates scattered uniformly across the entire corneal endothelium (violating Arlt's triangle). Characteristically characteristic for Fuchs Heterochromic Iridocyclitis (FHI / Fuchs Uveitis Syndrome) and Cytomegalovirus (CMV) anterior uveitis.
4. Endothelial Distribution (Arlt's Triangle): KPs typically settle in an inverted triangular pattern over the inferior one-third to one-half of the corneal endothelium (Arlt's triangle) due to gravity and thermal convection currents. Diffuse KPs can suggest viral disease, Fuchs uveitis or other inflammation; their distribution is supportive rather than diagnostic.

Iris Inflammatory Nodules

• Koeppe Nodules: Small, discrete, nodular inflammatory cell collections located directly at the pupillary margin, arising from the sphincter pupillae border. Can be observed in both granulomatous and severe non-granulomatous anterior uveitis; act as anchor points for posterior synechiae formation.
• Busacca Nodules: Distinct, fleshy, white-yellow cellular nodules located on the anterior iris stroma away from the pupillary border. Composed histopathologically of epithelioid cell granulomas and mononuclear aggregates. Busacca nodules are characteristic for granulomatous uveitis (principally sarcoidosis and tuberculosis) and should be interpreted with the entire phenotype.
• Berlin Nodules: Inflammatory nodular infiltrates located within the trabecular meshwork and iridocorneal angle, visualized exclusively on gonioscopy in ocular sarcoidosis.

Tailored Diagnostic Workup in Uveitis

Begin with anatomical site, unilateral/bilateral distribution, onset, recurrence, medication and immune status. Ask about pain, floaters, systemic infection exposure, travel, oral/genital ulcers, inflammatory back pain, joint disease, skin changes, respiratory symptoms, renal disease and neurological symptoms. Examine pressure, keratic precipitates, iris changes, vitreous, retina and choroid. OCT, angiography or ultrasound can resolve a specific question such as oedema, vasculitis or obscured fundus.

Syphilis can mimic many forms and warrants a low testing threshold, commonly broad adult screening with both treponemal and non-treponemal tests. Avoid asserting that every first mild episode in every adult or child requires an identical panel. Positive tests need interpretation of stage and previous treatment. IGRA supports TB exposure but cannot distinguish latent from active infection or establish ocular TB alone. Chest imaging and sarcoid tests follow phenotype and risk; ACE is affected by age, medication and other disease. HLA-B27 is useful in compatible recurrent/severe anterior disease, with assessment of spondyloarthritis symptoms. ANA identifies JIA-associated risk in the appropriate context, rather than diagnosing JIA in every child with uveitis.

Toxoplasma serology supports exposure; early disease and immunosuppression complicate interpretation. A positive IgG alone does not establish the cause of an active lesion. Aqueous/vitreous PCR can help in hypertensive anterior disease or necrotising retinitis, but sampling timing, prior treatment and assay sensitivity matter: a negative result does not always exclude infection.

Persistent atypical vitritis, sub-RPE lesions or unexplained steroid-dependent recurrence can suggest lymphoma. Coordinate sampling with pathology for cytology, flow, cytokines and molecular tests before giving steroids where clinically feasible. IL-10 or a mutation result supports but does not alone prove every diagnosis. Broad untargeted panels produce incidental positives; state how each investigation will change the differential or treatment.