Granulomatous and non granulomatous uveitis

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Granulomatous vs. Non-Granulomatous Uveitis

Definition and Overview

Uveitis is inflammation of the uveal tract (iris, ciliary body, choroid). It is classified anatomically (anterior, intermediate, posterior, panuveitis) and by histological/clinical pattern - granulomatous or non-granulomatous - based on slit-lamp findings, predominantly the character of keratic precipitates (KP) and iris nodules.

Key Distinguishing Features

Feature	Non-Granulomatous	Granulomatous
Onset	Usually acute	Usually chronic/insidious
Course	Acute, often recurrent	Chronic, persistent
Laterality	Typically unilateral	Often bilateral
Keratic precipitates (KP)	Small, white, fine ("dust-like")	Large, greasy - "mutton fat" KP; may become pigmented or "ground glass"
KP distribution	Inferior triangle (Arlt's triangle)	Arlt's triangle or diffuse (Fuchs exception)
Iris nodules	Less common; Koeppe nodules (pupillary margin) may be seen	Busacca nodules (iris stroma) - pathognomonic; Koeppe nodules (pupillary margin)
Hypopyon	Common in HLA-B27-related AAU (fibrinous, immobile)	Less common
Aqueous flare	Present	Present
Posterior synechiae	Common	Common
Systemic workup	Often not needed for single, mild, unilateral episode	Always investigate

Kanski's Clinical Ophthalmology, 10th ed., p. 445-447

Non-Granulomatous Uveitis

Characteristics

Small KP - composed mainly of lymphocytes and neutrophils. The SUN (Standardized Uveitis Nomenclature) Working Group grading for AC cells uses a 1 mm x 1 mm slit beam field. Longstanding non-granulomatous KP may become pigmented but remain small.

Causes (Table 12.1, Kanski)

Idiopathic (~30-50%) - no identifiable systemic association

HLA-B27-associated (most common identifiable cause, ~20% of AAU):

Ankylosing spondylitis
Reactive arthritis (Reiter syndrome)
Psoriatic arthritis
Inflammatory bowel disease
Classically: bilateral acute recurrent alternating anterior uveitis (characteristic pattern)

Infectious:

Varicella zoster (current/past ophthalmic shingles)
Lyme disease
Miscellaneous viral infections

Non-infectious:

Juvenile idiopathic arthritis (JIA) - chronic anterior uveitis, typically non-granulomatous
Behcet disease - acute bilateral shifting hypopyon iritis, retinal vasculitis; hypopyon has minimal fibrin so it shifts with head position (unlike HLA-B27)
Multiple sclerosis
SLE
Drug-induced
Tubulointerstitial nephritis and uveitis (TINU) syndrome

Clinical pattern

Acute onset, unilateral pain, redness, photophobia, watery discharge, miosis. Fibrinous exudate in AC is common in severe AAU, especially HLA-B27-related.

Granulomatous Uveitis

Characteristics

Large "mutton fat" KP - composed of epithelioid cells and multinucleated giant cells (same cells as in systemic granulomas). KP can become pigmented over time or assume a "ground glass" appearance. Busacca nodules (stroma) and Koeppe nodules (pupillary margin) are characteristic. More commonly chronic and bilateral.

Important caveat: Granulomatous conditions (e.g., sarcoidosis) can sometimes present with non-granulomatous AAU. - Kanski, p. 465

Causes

Sarcoidosis (most common granulomatous uveitis):

Mutton-fat KP in Arlt's triangle
Busacca + Koeppe iris nodules
Berlin nodules (anterior chamber angle)
Snowball vitreous opacities
Nodular trabecular meshwork involvement
Bilateral hilar lymphadenopathy on CXR (90% abnormal)
Elevated serum ACE and lysozyme
Negative tuberculin test in BCG-vaccinated patients
Kanski, p. 472; [Rheumatology 2-Volume Set, Elsevier 2022]

Tuberculosis (TB):

Chronic granulomatous uveitis; may mimic sarcoidosis
Positive tuberculin / IGRA

Syphilis:

Chronic granulomatous or non-granulomatous; yellowish roseolae (iris nodules from dilated vessels)
Can affect any segment; "great masquerader"

Toxoplasma (anterior component):

Granulomatous unilateral anterior uveitis with mutton-fat KP in Arlt's triangle; occurs only with concurrent toxoplasmic retinitis (white "satellite" lesion adjacent to old chorioretinal scar)

Sympathetic ophthalmia:

Bilateral diffuse granulomatous panuveitis after penetrating trauma or surgery to one eye
Delayed hypersensitivity to sequestered retinal antigens
Can occur from 2 weeks to many years after injury
Treated with systemic immunosuppressants
Robbins & Kumar Basic Pathology, p. 2418

Vogt-Koyanagi-Harada (VKH) disease:

Bilateral granulomatous uveitis; associated with vitiligo, poliosis, dysacusis, meningism
Acute VKH: bilateral serous retinal detachment + anterior uveitis
Chronic VKH: "sunset glow" fundus

Lens-induced (phacoanaphylactic) uveitis:

Granulomatous response to lens protein after capsule rupture

Leprosy (lepromatous):

"Iris pearls" (CAU); granulomatous infiltration

Iris Nodule Summary

Nodule	Location	Associated with
Koeppe	Pupillary margin	Both granulomatous AND non-granulomatous
Busacca	Iris stroma	Granulomatous uveitis only
Berlin	Anterior chamber angle	Sarcoidosis
Roseolae	Iris (dilated vessels)	Syphilis
Iris pearls	Iris	Lepromatous CAU

Investigations

Single mild unilateral non-granulomatous AAU with no systemic features - no investigation required.

Investigate when:

Recurrent, severe, or bilateral AAU
Chronic or treatment-resistant uveitis
Granulomatous signs present
Intermediate or posterior uveitis coexists
Systemic features suggest a specific diagnosis

Key tests:

HLA-B27 - for seronegative spondyloarthropathy-associated uveitis
Serum ACE + lysozyme + CXR - sarcoidosis
Mantoux/IGRA (Quantiferon-TB gold) - tuberculosis
FTA-ABS / VDRL / TPHA - syphilis
ANA - JIA-associated uveitis
Toxoplasma IgG/IgM serology - toxoplasmosis
Aqueous PCR - herpes viruses (HSV, VZV, CMV), especially in hypertensive or steroid-unresponsive uveitis
Chest CT - if CXR negative but sarcoid suspected
Conjunctival or transbronchial biopsy - histological confirmation of sarcoidosis

Management

Topical Corticosteroids

First-line for anterior uveitis. A typical AAU tapering schedule (Kanski):

Every hour for 3 days
Every 2 hours for 3 days
QID x 1 week → TID x 1 week → BD x 1 week → OD x 1 week, then stop (typically 5-6 weeks total)

For chronic anterior uveitis (CAU): aim for complete suppression (zero AC cells AND no flare); even low-grade activity is associated with more complications.

Cycloplegic/Mydriatic Agents

Used to:

Prevent posterior synechiae (PS) formation
Break down recently formed PS
Relieve ciliary spasm (pain/photophobia)

Agent	Duration
Cyclopentolate	12-24 hours
Homatropine	~3 days
Atropine	7-10 days

Phenylephrine 2.5% or 10% is added to break established PS. Mydricaine No. 2 (adrenaline + atropine + procaine) can be used subconjunctivally when drops fail.

Systemic Treatment (for severe/chronic/posterior/granulomatous uveitis)

Oral prednisolone - for severe bilateral or posterior uveitis
Steroid-sparing agents - methotrexate, mycophenolate mofetil, azathioprine for JIA-associated CAU or sarcoid
Biologics - anti-TNF agents (adalimumab) for non-infectious uveitis refractory to conventional immunosuppression
Periocular/intravitreal steroids - for posterior uveitis or CMO

Treat the Underlying Cause

TB uveitis: anti-tubercular therapy
Syphilitic uveitis: penicillin
Toxoplasma: pyrimethamine + sulfadiazine + folinic acid (for vision-threatening lesions)
Sympathetic ophthalmia: high-dose systemic corticosteroids ± steroid-sparing agents

Complications (Both Types)

Cataract, glaucoma (trabecular damage, steroid-induced, or synechial angle closure), posterior synechiae, band keratopathy, cystoid macular edema (CMO), epiretinal membrane, vitreous haemorrhage, retinal detachment, phthisis bulbi.

Sources: Kanski's Clinical Ophthalmology: A Systematic Approach, 10th ed. | Robbins & Kumar Basic Pathology | The Wills Eye Manual | Rheumatology 2-Volume Set (Elsevier, 2022)

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