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What Is Missing From Your Presentation

1. CMV Retinitis in HIV - Missing Points

Pathogenesis / Virology

• CMV is a herpesvirus (HHV-5) causing latent infection in most healthy adults - retinitis represents reactivation of latent virus, not primary infection, in the immunocompromised host
• Mechanism: virus enters retinal cells via hematogenous spread → full-thickness retinal necrosis by direct cytopathic effect

Clinical Features - Missing Details

• Cataract as a common later-stage finding (not mentioned)
• Frosted branch angiitis (FBA): occurs in ~6% of CMV retinitis cases - marked vascular sheathing - your presentation mentions FBA separately as a standalone entity but doesn't link it to CMV
• The three distinct clinical stages from Kanski (which you have as "fulminant vs indolent" but can be expanded):
  • Early: one or two areas of dense white infiltration with flame haemorrhages starting peripherally (centrally in only 10%)
  • Established/middle: rapidly spreading full-thickness necrosis, signs of vasculitis absent or mild, perivenular translucency as it clears
  • Late: retinal atrophy, holes, arteriolar attenuation → rhegmatogenous RD

Immune Recovery Uveitis (IRU) - Needs Expansion

• IRU is thought to be a paradoxical immune reconstitution inflammatory response (IRIS) - rejuvenated immune system attacking residual CMV antigen after ART restores CD4 count
• Manifestations: anterior uveitis, vitritis, CMO, epiretinal membrane, disc oedema, vitreous haemorrhage
• Severe cases can progress to phthisis bulbi
• Treated with periocular or intravitreal steroids (oral prednisolone 0.5 mg/kg/day) + continuing ART - never stop ART
• Risk is higher in patients who had >30% retinal involvement

Systemic CMV Manifestations in AIDS (Missing entirely)

• CMV causes multi-organ disease in severely immunocompromised: colitis (most common systemic), oesophagitis, pneumonitis, encephalitis, adrenalitis
• In HIV vs transplant patients: CMV retinitis and colitis predominate in HIV/AIDS, whereas pneumonitis predominates in transplant recipients (Goldman-Cecil)
• Always screen for systemic CMV disease when retinitis is confirmed

Diagnosis - Missing Details

• Aqueous/vitreous PCR for viral DNA is the gold standard for confirmation - antibody assay (serology) is less effective because immunocompromised patients may not mount an antibody response
• Goldman-Witmer coefficient calculation from aqueous tap (mentioned briefly in your investigations slide but not explained)
• Aqueous PCR can differentiate CMV from HSV/VZV/toxoplasma in a single multiplex sample

Treatment - Missing Points

• Your flowchart is good but missing:
  • Intravitreal ganciclovir implant (Vitrasert) - sustained-release device used when systemic therapy not tolerated
  • Letermovir - newer CMV prophylactic agent in transplant recipients (not yet standard in HIV but emerging)
  • Anti-CMV prophylaxis with oral valganciclovir when CD4 <50 (some guidelines recommend)
  • Cidofovir ocular side effect: anterior uveitis with fibrinous exudate, hypotony, and decreased IOP - mentioned in Kanski; must co-administer probenecid + IV saline hydration to prevent nephrotoxicity (you mention this in the flowchart but the AAU side effect is missing)

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2. Toxoplasma Retinitis - Missing Points

Epidemiology - Missing

• Affects ~1/3 of world's population as systemic infection; ocular involvement in ~2% of seropositive individuals
• In Brazil and some tropical regions, incidence is significantly higher due to virulent local strains (Type 1 strains)
• In HIV/AIDS: CD4 count <100 - toxoplasma retinitis becomes atypical and aggressive - large bilateral confluent lesions without the classic satellite scar; can look like CMV retinitis
• Prevalence of ocular toxoplasmosis in UK/Europe ~0.5%; much higher in Brazil (~17%)

Life Cycle / Pathogenesis - Missing entirely

• Definitive host: cat (sexual cycle in feline intestine → oocysts shed in faeces)
• Intermediate hosts: mammals/humans (bradyzoite tissue cysts in muscle, brain, retina)
• Humans infected by: ingestion of oocysts (contaminated soil/water/cat faeces) OR undercooked meat (tissue cysts) OR congenital transplacental transmission
• In the retina: bradyzoites reactivate → tachyzoites multiply rapidly → direct retinal cell destruction + immune-mediated inflammation → full-thickness focal retinitis
• Adjacent to old scar because bradyzoite cysts persist at scar margins lifelong → reactivation triggered by local immune suppression, trauma, or systemic immune change

Clinical Features - Missing Details

• Size: typically 1-2 disc diameters of white fluffy retinitis
• Location: posterior pole in 75% (macular/juxtapapillary)
• Juxtapapillary toxoplasmosis (Jensen's disease): active lesion adjacent to optic disc → serious risk of optic nerve involvement → risk of permanent visual field defect even after healing
• Disc involvement: papillitis/optic nerve oedema in juxtapapillary lesions
• Anterior uveitis: granulomatous KPs (mutton-fat) in ~50% - important distinguishing feature
• Retinal vasculitis: periarteritis/periphlebitis at edges of active lesion
• Vitreous snowballs: aggregates of inflammatory cells in vitreous
• Macula involvement signs: subretinal fluid, CMO on OCT
• Self-limiting in immunocompetent: most lesions regress spontaneously in 6-8 weeks; treatment accelerates resolution and reduces risk of scar expansion

Congenital vs Acquired - Missing

• Congenital toxoplasmosis: transmitted in 1st/2nd trimester - bilateral macular scars (often bilateral, symmetrical) at birth or developing in childhood/early adulthood
• Classic triad of congenital toxo: chorioretinitis + hydrocephalus + intracranial calcifications
• Acquired (postnatal): usually unilateral; primary infection or reactivation of congenital cysts
• Primary ocular toxoplasmosis (no prior congenital infection) - becoming recognized more commonly

Diagnosis - Missing

• Serology: IgG positive in most adults (high background prevalence - not diagnostic alone); IgM positive in acute primary infection
• Aqueous PCR: gold standard when diagnosis uncertain or atypical; PCR for T. gondii DNA
• Goldman-Witmer coefficient >3 in aqueous: diagnostic (anti-toxoplasma antibodies produced intraocularly)
• OCT: shows hyper-reflective thickening of inner retina at active site; sub-retinal fluid at macula
• FFA: early hypofluorescence (blocked by dense infiltrate) → late leakage at active margins; disc leakage if juxtapapillary
• Consider HIV testing in any atypical/large/bilateral lesion

Treatment - Need to Expand

• When NOT to treat (self-limiting criteria):
  • Small peripheral lesion, >1 DD from fovea/disc, no VA drop, mild vitritis → observe only; resolves in 6-8 weeks
• Treatment indications: lesion threatening macula (<1DD from fovea), disc involvement, >2-line VA drop, large lesion >2DD, severe vitritis, immunocompromised patient
• TMP-SMX (co-trimoxazole) as first-line alternative: 160/800 mg BD × 4-6 weeks - equal efficacy to classic quadruple in multiple RCTs, cheaper, better tolerated, widely used now as first-line in many centres
• Clindamycin 300 mg QDS as monotherapy or combined with TMP-SMX
• Azithromycin 500 mg/day: alternative for sulfonamide-allergic patients
• Atovaquone 750 mg BD: alternative, active against tissue cysts (theoretically reduces recurrence)
• Intravitreal clindamycin + dexamethasone: useful when systemic therapy poorly tolerated
• Steroids: pyrimethamine/sulfadiazine regimen must be started 24-48 hours before adding prednisolone - never steroids alone (your slide has this, but the rationale should be mentioned: steroids alone can cause catastrophic expansion of active lesion by suppressing protective immunity without killing the parasite)
• Recurrence prevention: no proven prophylaxis in immunocompetent; TMP-SMX 1 DS daily for secondary prophylaxis in HIV/AIDS patients with CD4 <200

HIV/AIDS-Specific Toxoplasma Retinitis - Entirely Missing from your slides

• In AIDS (CD4 <100): lesions are atypical - no classic satellite scar, bilateral, large, multifocal, confluent
• Can mimic CMV retinitis - distinguish by: less haemorrhage than CMV; positive toxoplasma serology; response to anti-toxoplasma therapy
• Must treat aggressively and for longer - continue suppressive therapy until CD4 consistently >200 with ART
• Higher risk of concurrent CNS toxoplasmosis (ring-enhancing lesions on MRI) - always check brain imaging
• Primary prophylaxis: TMP-SMX 1 DS daily when CD4 <100

Prognosis / Complications - Missing

• Recurrence rate: 25-50% within 3 years in immunocompetent (from bradyzoite cysts persisting in scar)
• Each recurrence risks expanding the scar → cumulative visual damage
• Complications: choroidal neovascular membrane (CNVM) at old scar site (5-10%), epiretinal membrane, RD (rare), optic atrophy (juxtapapillary cases)

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3. Other General Gaps in the Presentation

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• CMV retinitis in HIV: Add slides on CMV systemic disease in AIDS, 3-stage retinitis progression (early/established/late), IRU full mechanism and management, aqueous PCR as diagnostic gold standard, and anti-CMV prophylaxis
• Toxoplasma retinitis: Needs a full expansion - life cycle, congenital vs acquired, Jensen's juxtapapillary variant, observation criteria, TMP-SMX as first-line alternative, AIDS-specific atypical presentation, recurrence rate, and prophylaxis in HIV

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LEARNING OBJECTIVES SLIDE

1. Classify retinitis and choroiditis into infectious and non-infectious categories and apply a systematic diagnostic approach
2. Identify the clinical hallmarks of CMV retinitis in HIV/AIDS patients - including the three stages of retinitis, Immune Recovery Uveitis (IRU), and the role of CD4 count in risk stratification
3. Describe the pathogenesis, clinical features, and management of toxoplasmic retinitis in both immunocompetent and immunocompromised (HIV/AIDS) patients, including congenital and acquired forms and Jensen's juxtapapillary variant
4. Differentiate CMV retinitis, ARN, and PORN based on host immune status, clinical features, speed of progression, and treatment
5. Outline first-line and alternative treatment regimens for major infectious retinitis types, including when to treat vs observe in toxoplasmosis
6. Recognise the major non-infectious retinitis and choroiditis entities (Birdshot, VKH, MEWDS, serpiginous, MFC/PIC) and apply HLA associations, multimodal imaging findings, and immunosuppression principles
7. Apply the ICG-based classification of choroiditis (choriocapillaritis vs stromal choroiditis) to guide investigation and management
8. Select appropriate investigations including aqueous PCR, Goldman-Witmer coefficient, FFA, ICGA, OCTA, FAF, and ERG for specific clinical scenarios

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REFERENCES SLIDE

Textbooks

1. Kanski JJ, Bowling B. Kanski's Clinical Ophthalmology: A Systematic Approach. 10th ed. Elsevier; 2025. [Chapters 12 - Uveitis; pp. 487-542]
2. Schachat AP, Sadda SVR, Hinton DR, et al. Ryan's Retina. 6th ed. Elsevier; 2022. [Section 4 - Inflammatory Disease/Uveitis; Chapters 75-86]
3. Goldman L, Schafer AI. Goldman-Cecil Medicine. 27th ed. Elsevier; 2024. [Chapters 347, 320, 358]
4. Rosenbaum JT (ed). Uveitis: Fundamentals and Clinical Practice. 5th ed. Elsevier; 2023.

Guidelines

1. Holland GN, et al. Studies of Ocular Complications of AIDS (SOCA) Research Group. Revised guidelines for management of CMV retinitis in HIV. American Journal of Ophthalmology. 1997. (Foundational classification criteria still referenced)
2. European AIDS Clinical Society (EACS) Guidelines v12.0. 2023. Available at: eacsociety.org
3. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. NIH/CDC/IDSA. Updated 2024. Available at: clinicalinfo.hiv.gov

Key Recent Papers (2022-2026)

1. Tombolini B, et al. Multiplex aqueous PCR for simultaneous detection of CMV, HSV, VZV and Toxoplasma in uveitis. Can J Ophthalmol. 2024.
2. Dominguez V, et al. JAK inhibitors (upadacitinib, baricitinib) in refractory non-infectious uveitis. Ophthalmology. 2025.
3. Accorinti M, et al. MUV Project 2025: Multimodal imaging standards for non-infectious posterior uveitis - systematic review. Am J Ophthalmol. Nov 2025. PMID: 40659111
4. Invernizzi A, et al. MUV Task Force Report 9: Minimum imaging sets for posterior uveitis. Am J Ophthalmol. Dec 2025. PMID: 40754260
5. Cicinelli MV, et al. White dot syndromes: advances in pathogenesis, imaging and treatment. Prog Retin Eye Res. Nov 2023. PMID: 37574108
6. De Simone L, et al. Resurgence of ocular syphilis: clinical features and outcomes. Br J Ophthalmol. 2025.
7. Jung HH, et al. Retinal detachment outcomes in infectious retinitis - vitrectomy with silicone oil. Korean J Ophthalmol. 2024.

Image Credits (if applicable)

• Fundus photographs and clinical images sourced from Kanski's Clinical Ophthalmology 10e (with permission) and Ryan's Retina 6e (with permission)

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• Learning Objectives → Slide 2 (immediately after title)
• References → Last slide (after Key Takeaways, Slide 53)
• You can split references into two slides if needed: "Textbooks & Guidelines" on one, "Recent Evidence" on the other - cleaner for presentation

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COMPLETE STUDY GUIDE: RETINITIS & CHOROIDITIS

Basic → Advanced | Why → How → What → Treatment

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PART 1: FOUNDATIONS

What is the Retina?

1. Internal Limiting Membrane (ILM)
2. Nerve Fiber Layer (NFL)
3. Ganglion Cell Layer (GCL)
4. Inner Plexiform Layer (IPL)
5. Inner Nuclear Layer (INL)
6. Outer Plexiform Layer (OPL)
7. Outer Nuclear Layer (ONL)
8. External Limiting Membrane (ELM)
9. Photoreceptor layer (rods + cones)
10. Retinal Pigment Epithelium (RPE)

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Why Is the Retina Vulnerable?

• Inner retina (inner 2/3): supplied by the central retinal artery (branch of ophthalmic artery) → blood-retinal barrier (BRB) provided by tight junctions of retinal vascular endothelium (inner BRB)
• Outer retina (outer 1/3 including photoreceptors): supplied by choriocapillaris via diffusion through RPE → outer BRB provided by RPE tight junctions

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General Pathogenesis of Retinitis

1. Direct Cytopathic Injury

• Viruses (CMV, HSV, VZV) and fungi replicate inside retinal cells
• Viral replication → cell lysis → full-thickness retinal necrosis
• The necrosis spreads centrifugally as the virus moves from cell to cell
• This is why viral retinitis (CMV, ARN, PORN) shows geographic white necrotic patches

2. Immune-Mediated Injury

• In parasitic infections (toxoplasma) and autoimmune disease, the damage is from the host's own immune response - T-cell mediated inflammation, cytokine storm (TNF-α, IL-6, IL-17)
• Photoreceptors die as bystanders to the battle
• This is why immunosuppression (steroids) is used alongside antiparasitics in toxoplasma

3. Ischaemic/Vascular Injury

• Vasculitis → occlusion of capillaries → capillary non-perfusion → retinal ischaemia
• Ischaemia → cotton-wool spots, NVD/NVE, vitreous haemorrhage
• Examples: Eales disease, ARN (occlusive vasculitis), syphilitic vasculitis

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PART 2: INFECTIOUS RETINITIS

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CMV RETINITIS IN HIV/AIDS

The Most Important Infectious Retinitis

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WHY Does It Happen?

The Virus

• Cytomegalovirus (CMV) = Human Herpesvirus 5 (HHV-5)
• Double-stranded DNA virus, Herpesviridae family
• Primary infection in childhood/young adulthood → usually asymptomatic or mononucleosis-like illness in healthy individuals
• After primary infection, CMV establishes lifelong latency in monocytes, macrophages, and CD34+ hematopoietic progenitor cells
• The virus is never eliminated - it is kept in check by CD4+ T-cell surveillance

The HIV Connection

• HIV destroys CD4+ T-lymphocytes progressively over years (average 8-10 years untreated)
• CD4+ count <100 cells/µL = loss of CMV-specific T-cell immune surveillance
• Latent CMV reactivates → viremia → CMV seeds the retina via the bloodstream (hematogenous spread)
• Without CD4+ T-cells to control it, CMV replicates freely in retinal cells
• CD4 <50 = highest risk (almost universal CMV disease if untreated and surviving long enough)
• Pre-cART era: ~30-40% of AIDS patients developed CMV retinitis
• Post-cART (1996 onwards): 80-90% reduction in incidence - one of the great success stories of modern medicine

Who else gets CMV retinitis?

• Solid organ transplant recipients (kidney, liver, heart) on immunosuppression
• Bone marrow / hematopoietic stem cell transplant (HSCT) recipients
• Patients on high-dose long-term corticosteroids
• Haematological malignancies (lymphoma, leukaemia)
• Important difference: In transplant patients, CMV more commonly causes pneumonitis and colitis; in HIV/AIDS, retinitis and colitis predominate - this is because the pattern of immunosuppression differs

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HOW Does It Happen? (Pathogenesis Step by Step)

1. HIV destroys CD4+ T-cells over years → immunosuppression
2. Latent CMV reactivates in circulating monocytes → CMV viremia
3. CMV-infected monocytes cross the blood-retinal barrier (already weakened by HIV vasculopathy)
4. CMV infects retinal pigment epithelium (RPE) and Müller cells first, then spreads to all retinal layers
5. Inside retinal cells, CMV replicates using the cell's own machinery → produces viral inclusion bodies (owl-eye inclusions on histology - large basophilic intranuclear inclusion surrounded by halo)
6. Cell lysis releases new viral particles → infect adjacent cells → centrifugal spread
7. The necrosis is full-thickness (all 10 layers) because CMV spreads through cell-to-cell contact without needing to cross barriers
8. The necrotic retina becomes atrophic and full of holes → predisposes to rhegmatogenous retinal detachment (RRD)
9. Minimal immune response in CD4-depleted patients → explains mild/absent vitritis (no immune cells to generate inflammation)

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WHAT Happens? (Clinical Features)

Symptoms

• Often asymptomatic initially - peripheral retinitis can progress for weeks before any visual symptoms
• When symptomatic: floaters (from mild vitritis), visual field defect (scotoma from necrotic retina), reduced central vision (macular involvement), photopsia (flashing lights)
• Pain is absent (unlike ARN or anterior uveitis)

Signs - Anterior Segment

• Anterior uveitis: usually absent or very mild (non-granulomatous)
• When present: fine stellate KPs (not mutton-fat), mild cells/flare
• Vitritis: classically MILD - this is a key distinguishing feature from ARN (which has marked vitritis)
• Cataract: develops in later stages
• Elevated IOP: possible

Signs - Fundus (Three Clinical Stages)

• One or two focal areas of dense white retinal infiltration
• Associated flame-shaped haemorrhages (the "pizza-pie" or "cottage cheese and ketchup" appearance)
• Starts peripherally in 90%, centrally in only 10%
• Extends along vascular arcades
• Peripheral lesions appear more granular with fewer haemorrhages ("indolent" pattern)

• Lesion spreads rapidly around the retina following the vasculature
• Full-thickness retinal necrosis in affected area
• Signs of vasculitis are absent or minimal (no immune cells = no vasculitis - the opposite of ARN)
• As active inflammation settles: perivenular translucency (whitish cuffing around veins that clears)
• Two clinical patterns:
  • Fulminant/Hemorrhagic: Dense white confluent necrosis + prominent haemorrhages along arcades ("pizza pie")
  • Indolent/Granular: More peripheral, granular opacification, fewer haemorrhages, slower progression over weeks

• Active retinitis settles → leaves behind retinal atrophy and scarring
• Irregular pigmentation (RPE hyperplasia) at scar margins
• Arterial attenuation as arteriolar blood supply decreases
• Retinal holes form in atrophic areas → rhegmatogenous RD in ~33-50% of eyes
• Optic atrophy from direct CMV involvement of optic nerve

Special Manifestations

• Occurs in ~6% of CMV retinitis
• Marked sheathing of retinal arteries AND veins, resembling frost on branches
• Can be confused with primary FBA (idiopathic) - CMV is the most common secondary cause

• Direct spread of CMV to the optic nerve head
• Causes disc swelling, peripapillary haemorrhages
• Risk of rapid progression to optic atrophy

Immune Recovery Uveitis (IRU)

• When ART is started → CD4+ count begins to recover over weeks-months
• The reconstituted immune system "sees" residual CMV antigen still present in the retina (even though the retinitis is controlled)
• Paradoxical inflammatory response (IRIS - Immune Reconstitution Inflammatory Syndrome) - the recovering immune system attacks the residual CMV antigen too vigorously
• This causes a new wave of intraocular inflammation despite the CMV being suppressed

• Anterior uveitis (cells, flare, KPs) - often more severe than during the original retinitis
• Vitritis (now prominent, in contrast to the original minimal vitritis)
• Cystoid macular oedema (CMO) - major cause of visual loss
• Epiretinal membrane (ERM) formation
• Disc oedema / papillitis
• Vitreous haemorrhage
• Severe cases → phthisis bulbi (end-stage shrunken non-functional eye)

• 30% of retinal area involved by CMV retinitis

• More retinal necrosis = more residual antigen = more intense IRU
• Rapid rise in CD4 count

• Do NOT stop ART - continuing ART is essential
• Periocular steroids: sub-Tenon triamcinolone acetonide 40mg
• Intravitreal triamcinolone (IVTA) 2-4 mg for severe cases
• Oral prednisolone 0.5 mg/kg/day for moderate-severe
• Dexamethasone implant (Ozurdex) for refractory CMO
• Anti-VEGF for any associated neovascularisation

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Systemic CMV Disease in AIDS

• CMV colitis: most common systemic manifestation - bloody diarrhoea, abdominal pain, weight loss
• CMV oesophagitis: large shallow ulcers → dysphagia, odynophagia
• CMV pneumonitis: interstitial pneumonia (less common in HIV vs transplant)
• CMV encephalitis: periventricular enhancement on MRI, cognitive decline
• CMV adrenalitis: adrenal insufficiency, hypotension
• Always screen for systemic CMV when retinitis is found

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DIAGNOSIS

Clinical Diagnosis

Investigations

1. CD4+ count: cornerstone - almost all cases <100; obtain urgently if not known
2. HIV viral load: for ART optimization
3. Aqueous/vitreous PCR for CMV DNA: gold standard for confirmation, especially atypical cases
   • Sensitivity ~90-95%, specificity ~99%
   • Note: serology (CMV IgG/IgM) is unreliable in immunocompromised patients (cannot mount antibody response)
4. Multiplex PCR: single aqueous sample can simultaneously test CMV, HSV-1/2, VZV, and Toxoplasma
5. Goldman-Witmer Coefficient (GWC): ratio of intraocular CMV antibody to serum CMV antibody, corrected for total immunoglobulin
   • GWC >3 = intraocular antibody production = active intraocular CMV infection
   • Used when PCR is equivocal
6. Fundus photography + wide-field imaging (Optos): baseline documentation, monitoring progression
7. FFA: shows areas of leakage at active borders, vascular staining, optic disc leakage; areas of non-perfusion in necrotic retina
8. OCT: shows full-thickness retinal disruption at active sites, vitreous cells, epiretinal membrane, CMO (important for monitoring IRU)
9. B-scan ultrasonography: if media opacity obscures fundus view; can detect RD

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WHAT TO DO? (Treatment)

Step 1: Start ART Immediately

• ART is the mainstay of management - without CD4 recovery, no antiviral therapy is curative
• ART → CD4 rises → immune surveillance restored → CMV suppressed
• Target: CD4 consistently >100-150 cells/µL before considering stopping antivirals

Step 2: Systemic Antiviral Therapy

• Induction: 900 mg BD × 21 days (2-3 weeks)
• Maintenance: 900 mg OD (once CD4 improving)
• Valganciclovir is the oral prodrug of ganciclovir - excellent bioavailability (~60%) - absorbed in GI tract and converted to ganciclovir by intestinal/hepatic esterases
• Mechanism: ganciclovir is a nucleoside analogue - phosphorylated by CMV kinase (UL97) → incorporates into viral DNA → chain termination and DNA polymerase inhibition
• Key side effect: neutropenia (dose-limiting) - monitor FBC weekly during induction → treat with G-CSF (filgrastim) if ANC falls
• Other side effects: thrombocytopenia, anaemia, renal impairment, teratogenicity

• 5 mg/kg BD × 14 days induction → 5 mg/kg/day maintenance
• Used when oral not tolerated (vomiting, malabsorption, severe disease)
• Same mechanism and side effects as valganciclovir

• Used for ganciclovir-resistant CMV (UL97 or UL54 mutations)
• 90 mg/kg BD × 14 days induction → 90-120 mg/kg/day maintenance
• Mechanism: pyrophosphate analogue - directly inhibits CMV DNA polymerase (UL54) at the pyrophosphate binding site - does NOT require viral kinase activation (so works against UL97-mutant ganciclovir-resistant CMV)
• Key side effect: nephrotoxicity - must pre-hydrate with saline, monitor creatinine closely
• Other: electrolyte disturbance (hypomagnesaemia, hypocalcaemia, hypo/hyperkalaemia), penile ulceration, seizures
• Can be combined with ganciclovir for severe/resistant disease (synergistic)

• 5 mg/kg IV weekly × 2 doses, then 5 mg/kg every 2 weeks
• Mechanism: nucleotide analogue - does not require viral kinase phosphorylation → active against UL97-mutant ganciclovir-resistant CMV
• Must co-administer: probenecid (2g orally 3h before + 1g at 2h and 8h after) + IV saline hydration - to prevent nephrotoxicity
• Ocular side effect (important!): anterior uveitis (fibrinous, with hypopyon), ocular hypotony (IOP <6 mmHg) - can be vision-threatening; treat with topical steroids, may need dose reduction or discontinuation
• Systemic: nephrotoxicity (most serious), neutropenia

Step 3: Intravitreal Therapy (Adjunct)

• Intravitreal ganciclovir 2 mg/0.05 mL injection
• Intravitreal foscarnet 1.2-2.4 mg/0.05 mL injection
• Indications: macular/disc-threatening lesions (need immediate high local drug concentration), when systemic drugs are contraindicated, as bridge while awaiting systemic response
• Intravitreal ganciclovir implant (Vitrasert): sustained-release device surgically implanted in vitreous cavity; releases ganciclovir for ~6-8 months; excellent local control but no protection against fellow eye or systemic disease

Step 4: When to Stop Antivirals?

• When CD4 count is consistently >100-150 cells/µL for ≥3-6 months on ART
• AND retinitis is inactive (pale scar, no active white border)
• AND no evidence of systemic CMV disease
• Restart if CD4 falls <100 again

Surgical Management (Retinal Detachment)

• RD occurs in ~33-50% of eyes with CMV retinitis (higher if >25% retina involved)
• Pars plana vitrectomy (PPV) + silicone oil tamponade: ~75% anatomical success
• Silicone oil preferred over gas because RD is usually large/complex with multiple holes
• Visual outcome often limited by pre-existing macular damage from the retinitis itself
• Important: primary prophylactic laser demarcation is NOT routinely recommended (unlike ARN) because the retina is too friable

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TOXOPLASMA RETINITIS

Most Common Posterior Uveitis Worldwide

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WHY Does It Happen?

The Parasite

• Toxoplasma gondii: obligate intracellular protozoan parasite
• Definitive host: members of the cat family (Felidae) - sexual reproduction occurs only in cat intestine
• Intermediate hosts: virtually all warm-blooded mammals including humans

Life Cycle (Step by Step)

1. Cat ingests infected prey (birds, rodents containing tissue cysts)
2. Bradyzoites released in cat's intestine → invade intestinal epithelium
3. Sexual reproduction occurs in feline intestinal cells → produces oocysts
4. Oocysts shed in cat faeces (millions per day) → contaminate soil, water, vegetables
5. Oocysts sporulate within 1-5 days in the environment → become infectious

1. Humans infected by three routes:
   • Ingestion of oocysts: from contaminated soil (gardening), unwashed vegetables, water, cat litter
   • Ingestion of tissue cysts: undercooked/raw meat (especially pork, lamb, venison) containing bradyzoite cysts
   • Congenital (transplacental): tachyzoites cross placenta during maternal primary infection
2. In the human gut → oocysts/bradyzoites release tachyzoites (fast-replicating form)
3. Tachyzoites invade intestinal epithelium → enter bloodstream (tachyzoitemia)
4. Disseminate hematogenously to: brain, retina, heart, skeletal muscle
5. Inside host cells: tachyzoites replicate rapidly within a parasitophorous vacuole (membrane that protects them from lysosomal degradation)
6. Under immune pressure (IFN-γ, T-cell response) → tachyzoites convert to slow-replicating bradyzoites → form tissue cysts
7. Tissue cysts persist lifelong in the retina (and brain), walled off by a cyst wall resistant to immune attack
8. Reactivation: when local or systemic immunity wanes → bradyzoites convert back to tachyzoites → rupture cyst → new episode of active retinitis adjacent to the old scar

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HOW Does It Happen in the Retina?

1. Tachyzoites reach the retina during initial parasitemia (often in childhood for congenital, or at time of primary infection for acquired)
2. They invade retinal cells (neurons, RPE, vascular endothelium) and multiply
3. Tachyzoite replication → direct cytotoxic killing of retinal cells + host immune response (Th1-mediated: IFN-γ, TNF-α, IL-12)
4. The immune response → T-cell infiltration → intense local inflammation = the dense vitritis ("headlight in fog")
5. Eventually, bradyzoite cysts form at the periphery of the healed scar
6. Years later: local/systemic immunosuppression (pregnancy, HIV, steroids, aging) or trauma → cyst wall disrupts → bradyzoites convert to tachyzoites → reactivation at the scar margin
7. Cycle repeats: new active retinitis → new larger scar → cumulative visual damage with each recurrence

• In toxoplasma: the host's immune system is intact → vigorous Th1 response → lots of inflammatory cells pouring into vitreous → dense vitritis
• In CMV: the host's immune system is destroyed (CD4 <100) → no cells to generate vitritis → minimal/absent vitritis

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WHAT Happens? (Clinical Features)

Symptoms

• Unilateral in most cases (bilateral mainly in congenital or immunocompromised)
• Acute onset painless visual loss or blurring from macular involvement
• Floaters from vitritis (classic complaint - "dark spots floating")
• Photophobia from associated anterior uveitis
• Pain is absent (unlike corneal conditions) unless anterior uveitis is severe

Signs - Anterior Segment

• Anterior uveitis in ~50% of cases: granulomatous KPs (mutton-fat - large greasy deposits on corneal endothelium), cells and flare in anterior chamber
• Posterior synechiae (iris stuck to lens) from severe anterior inflammation
• Elevated IOP possible

Signs - Vitreous

• Dense vitritis: "headlight in fog" appearance - the active white retinal lesion visible through hazy vitreous
• Vitreous snowballs: aggregates of inflammatory cells
• The vitritis is so dense in some cases that the fundus details are obscured

Signs - Fundus

• Focal, raised, fluffy white retinal lesion (typically 1-2 disc diameters in size)
• Full-thickness retinal whitening with indistinct margins
• Located at the border of an old pigmented chorioretinal scar (the "satellite lesion" sign) - pathognomonic
• Posterior pole in 75% (macular area most common)
• Disc involvement (juxtapapillary) in 15-20%: papillitis, disc oedema → Jensen's disease (see below)
• Retinal vasculitis: periarteritis and periphlebitis at the edges of active lesion (sheathing of vessels)
• After treatment/spontaneous resolution → lesion atrophies centrally → leaves pigmented chorioretinal scar

• Well-demarcated chorioretinal atrophy with hyperpigmented borders (RPE hyperplasia at margins)
• Punched-out appearance
• Choroidal vessels visible through the atrophic RPE
• Scar grows with each recurrence

Jensen's Juxtapapillary Choroiditis (Named Entity - Exam Important)

• Active toxoplasma lesion adjacent to the optic disc (within 1 DD of disc margin)
• Causes: papillitis (optic disc swelling), peripapillary haemorrhages, visual field defects (arcuate scotoma, enlarged blind spot)
• Serious because even a small scar adjacent to the disc can cause permanent significant visual field loss
• Always treat regardless of lesion size when juxtapapillary location confirmed

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Congenital vs Acquired Toxoplasmosis

Congenital Toxoplasmosis

• Mother acquires primary T. gondii infection during pregnancy (previously seronegative)
• Tachyzoites cross the placenta to infect the fetus
• Risk of transmission increases with gestational age (1st trimester ~15%, 3rd trimester ~70%)
• BUT severity of fetal damage is inversely related: 1st trimester infection = most severe damage

1. Bilateral macular chorioretinal scars (often symmetric, at the macula)
2. Hydrocephalus (tachyzoites infect ependymal cells → obstruct CSF drainage)
3. Intracranial calcifications (periventricular on CT/MRI)

• Bilateral macular scars at birth or developing in childhood/early adulthood
• The child may appear normal at birth → present with squint or poor vision in first decade
• Scars can reactivate in adolescence/adulthood → accounts for many "primary acquired" presentations
• Associated microphthalmia, nystagmus if severe

Acquired (Postnatal) Toxoplasmosis

• Usually unilateral
• Most cases in adults represent reactivation of congenital cysts (patient doesn't recall being sick)
• True primary acquired infection can cause retinitis (outbreaks reported from contaminated water supplies in Brazil)
• Brazilian type I strains: particularly virulent → larger, more aggressive lesions

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Toxoplasma in HIV/AIDS

Why is it different?

• CD4 <100 → cell-mediated immunity destroyed → bradyzoite cysts reactivate unchecked
• Without T-cell control: tachyzoites spread uncontrolled across the retina

How it looks different (Atypical features):

• No classic satellite scar sign: no old scar to reactivate next to (or scar not visible due to overwhelming necrosis)
• Bilateral lesions: multiple simultaneous reactivations
• Large, confluent, multifocal: unlike the focal 1-2DD lesion of immunocompetent
• Minimal vitritis: similar to CMV (no immune cells) - the classic "headlight in fog" may be absent
• Less haemorrhage than CMV retinitis (key distinguishing feature)
• Can look nearly identical to CMV retinitis → aqueous PCR + toxoplasma serology needed

Concurrent CNS toxoplasmosis:

• Always request brain MRI in HIV patient with toxoplasma retinitis
• CNS toxoplasmosis: ring-enhancing lesions at cortico-medullary junction on contrast MRI
• Concurrent in 25-40% of AIDS patients with ocular toxo

Management in AIDS:

• Treat more aggressively and for longer than immunocompetent
• Continue suppressive therapy until CD4 consistently >200 with ART
• Secondary prophylaxis: TMP-SMX 1 DS (160/800 mg) once daily indefinitely until CD4 >200 sustained
• Primary prophylaxis: TMP-SMX 1 DS daily when CD4 <100 (protects against both PCP and toxoplasma encephalitis/retinitis)

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DIAGNOSIS of Toxoplasma Retinitis

Clinical Diagnosis

• Classic presentation (active white lesion + satellite scar + vitritis + posterior uveitis) in young immunocompetent patient = clinical diagnosis, no further testing needed
• Atypical cases (no scar, immunocompromised, bilateral) require investigation

Investigations

1. Toxoplasma serology (IgG + IgM):
   • IgG positive = previous exposure (doesn't mean active disease - ~30-40% of adults worldwide are IgG positive)
   • IgM positive = acute/recent primary infection
   • IgG negative in typical presentation = reconsider diagnosis (not toxoplasma)
   • Note: IgG can be negative in AIDS patients despite active infection (immunosuppressed can't make antibodies)
2. Aqueous PCR for T. gondii DNA:
   • Gold standard for atypical/uncertain cases
   • Anterior chamber tap (0.1-0.2 mL) under sterile conditions
   • High specificity; sensitivity lower than PCR for CMV/HSV
   • Multiplex PCR covers CMV, HSV, VZV, and toxoplasma simultaneously
3. Goldman-Witmer Coefficient (GWC):
   • Compares intraocular toxoplasma IgG production to serum IgG (corrected for total immunoglobulin)
   • Formula: (aqueous anti-toxo IgG / total aqueous IgG) ÷ (serum anti-toxo IgG / total serum IgG)
   • GWC >3 = significant intraocular antibody production = active intraocular toxoplasmosis
   • Highly specific when positive
4. OCT:
   • Active lesion: hyper-reflective thickening of inner retinal layers; subretinal fluid at macula
   • Old scar: full-thickness atrophy, RPE loss, choroidal thinning
5. FFA (Fundus Fluorescein Angiography):
   • Active lesion: early hypofluorescence (blocked by dense infiltrate) → late hyperfluorescence (leakage at active margins + surrounding vessels)
   • Disc leakage in juxtapapillary disease
   • Vasculitis: perivenous leakage
6. HIV test: mandatory in any atypical, bilateral, or large lesion
7. Brain MRI with contrast: if HIV positive or CNS symptoms

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WHEN TO TREAT vs OBSERVE

• Small peripheral lesion (<1 DD from fovea/disc)
• Not threatening macula or optic disc
• No significant VA drop (<2 lines)
• Mild vitritis
• Immunocompetent patient
• Self-limiting in 6-8 weeks

• Lesion within 1 DD of fovea (macular threat)
• Lesion within 1 DD of optic disc (disc threat / Jensen's disease)
• VA drop of ≥2 lines
• Large lesion (>2 DD)
• Severe vitritis obscuring fundus
• Immunocompromised patient (always treat)
• Congenital active disease
• Patient's only eye

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WHAT TO DO? (Treatment)

Classic Quadruple Therapy (Traditional First-Line)

1. Pyrimethamine: loading dose 200 mg (day 1), then 25 mg/day
   • Mechanism: DHFR inhibitor (dihydrofolate reductase inhibitor) → blocks folate synthesis in T. gondii
   • Acts against tachyzoites (active form) - does NOT eliminate bradyzoite cysts
   • Side effects: bone marrow suppression (leucopenia, thrombocytopenia, megaloblastic anaemia)
2. Sulfadiazine: loading dose 2g, then 1g QDS (4g/day)
   • Mechanism: sulfonamide - inhibits DHPS (dihydropteroate synthase) - blocks earlier step in folate synthesis
   • Acts synergistically with pyrimethamine (sequential blockade of folate synthesis)
   • Side effects: crystalluria/nephrolith (drink plenty of water), hypersensitivity rash, Stevens-Johnson syndrome
3. Folinic acid (leucovorin): 10 mg every other day (some give daily)
   • NOT folic acid - a common and dangerous exam error
   • Why folinic acid? Pyrimethamine blocks DHFR → folic acid cannot be converted → pyrimethamine would harm the patient's bone marrow
   • Folinic acid bypasses DHFR → supplements human marrow → protects patient
   • T. gondii cannot use exogenous folinic acid (lacks the transport mechanism) → does NOT interfere with antiparasitic effect
   • Folic acid requires DHFR to be activated → would be blocked by pyrimethamine → useless and misleading
4. Prednisolone: 0.5-1 mg/kg/day orally
   • Start 24-48 hours AFTER starting antiparasitic therapy
   • Never give steroids alone without antiparasitic cover - this can cause catastrophic expansion of active lesion (steroids suppress the host's protective immune response → unchecked tachyzoite proliferation)
   • Purpose: reduces inflammatory damage from host immune response (vitritis, CMO, optic neuritis)
   • Taper over 4-6 weeks alongside antiparasitic therapy

Modern First-Line Alternative: TMP-SMX

• Trimethoprim-sulfamethoxazole (Co-trimoxazole): 1 double-strength (DS) tablet (160/800 mg) BD × 4-6 weeks
• Multiple RCTs show equivalent efficacy to classic quadruple regimen
• Advantages: much cheaper, better tolerated, single tablet, widely available
• Used as first-line in many centres now
• Can add clindamycin for severe cases

Other Alternatives

• Clindamycin 300 mg QDS ± TMP-SMX: good alternative, especially sulfonamide-allergic patients
• Azithromycin 500 mg/day: macrolide, for sulfonamide + clindamycin intolerance
• Atovaquone 750 mg BD: hydroxynaphthoquinone; theoretically active against both tachyzoites and bradyzoites (the only drug that may reduce the cyst burden → potentially reduce recurrence risk); used in refractory/intolerant cases
• Spiramycin: used specifically in pregnant women in first trimester (crosses placenta less; does not treat fetal infection but reduces transmission risk)
• Pyrimethamine + azithromycin or pyrimethamine + atovaquone: alternative combinations

Intravitreal Therapy

• Intravitreal clindamycin 1 mg/0.1 mL + intravitreal dexamethasone 0.4 mg:
  • Used when systemic therapy not tolerated or contraindicated (e.g. pregnancy)
  • Provides local therapy directly

Treatment in HIV/AIDS

• Same regimens as above BUT:
  • Continue suppressive dose (half of treatment dose) after acute treatment until CD4 >200
  • TMP-SMX 1 DS daily for secondary prophylaxis (also provides PCP prophylaxis)
  • Start ART early to restore CD4

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Prognosis & Complications

• Immunocompetent: generally good; lesion heals in 6-8 weeks; most retain useful vision unless macular/juxtapapillary
• Recurrence rate: 25-50% within 3 years; each recurrence → larger scar → cumulative vision loss
• Complications:
  • Choroidal neovascular membrane (CNVM) at scar site: ~5-10%, treat with anti-VEGF
  • Epiretinal membrane
  • CMO from chronic inflammation
  • RD (uncommon, unlike CMV/ARN)
  • Optic atrophy (juxtapapillary)
  • Glaucoma from chronic anterior uveitis
• Immunocompromised (AIDS): poor without treatment; can be bilateral, blinding, and life-threatening (concurrent CNS toxo)

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ACUTE RETINAL NECROSIS (ARN)

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WHY / HOW?

• Causative agents: HSV-1 (adults >50), HSV-2 (young adults, neonates), VZV (commonest overall in some series, especially elderly); rarely EBV/CMV
• Occurs in immunocompetent patients - this is critical (vs PORN which is immunocompromised)
• Pathogenesis: virus reaches the retina via retrograde axonal transport along optic nerve from primary CNS infection (hence posterior uveitis can follow encephalitis) OR hematogenously
• Once in the retina: direct viral cytopathic necrosis of full-thickness retina + occlusive vasculitis (immune-mediated) → ischaemic and necrotic retina

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WHAT? (American Uveitis Society Diagnostic Criteria - all 5 required)

1. Peripheral, circumferential necrosis of retina - sharp demarcated borders
2. Rapid circumferential spread without treatment
3. Occlusive vasculitis (arterial > venous) - white sheathing of arterioles
4. Marked vitritis and anterior uveitis (granulomatous KPs, hypopyon possible)
5. No evidence of immunocompromise

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WHAT TO DO?

Urgency

Treatment

1. IV Aciclovir 10-15 mg/kg Q8h (TDS) × 10-14 days: first-line; blocks HSV/VZV DNA polymerase
2. Step down: oral Valaciclovir 2g TDS (or Famciclovir 500mg TDS) × 6-12 weeks (long prophylactic course to prevent second-eye involvement)
3. Adjunct intravitreal foscarnet or ganciclovir: if severe, or if systemic therapy delayed
4. Aspirin 300-600 mg/day: to reduce vasculitis-mediated occlusion and second-eye risk (anti-platelet + anti-inflammatory effect)
5. Prophylactic laser demarcation: laser applied to posterior border of necrosis zone → creates a scar barrier → reduces RD risk
6. Vitrectomy: for RD or dense vitreous opacity
7. Long-term oral antiviral prophylaxis: at least 12 weeks, some extend to 6-12 months

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PROGRESSIVE OUTER RETINAL NECROSIS (PORN)

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WHY/HOW?

• VZV predominantly (rarely other herpesviruses)
• Exclusively in severely immunocompromised: AIDS with CD4 <50, organ transplant, lymphoma
• KEY DIFFERENCE from ARN: in PORN, the immune system is destroyed → the virus causes pure cytopathic necrosis with no inflammatory response → absent vitritis and anterior uveitis
• Starts in outer retinal layers (photoreceptors, RPE) → rapidly progresses to full-thickness necrosis
• Multifocal, starts at posterior pole (opposite to ARN which starts peripherally)

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WHAT?

• Multifocal deep yellow-white infiltrates, posterior pole + optic nerve
• No vitritis, no anterior uveitis (the immune system is silent) - this is the single most important distinguishing feature
• Confluent, rapidly coalescing lesions → "cracked mud" or "jigsaw" appearance in later stages
• Bilateral in ~70%
• Full-thickness necrosis within DAYS (extremely rapid)
• RD in >80%, almost universal
• Prognosis: no light perception in >50% of affected eyes; devastating

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WHAT TO DO?

• IV Ganciclovir + IV Foscarnet combined (both drugs simultaneously): combination is superior to monotherapy
• Intravitreal ganciclovir + foscarnet: also given
• Start ART immediately: the only disease modifier; immune reconstitution slows progression
• Vitrectomy + silicone oil for RD
• Overall prognosis remains terrible despite treatment

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COMPARISON TABLE: CMV vs ARN vs PORN

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SYPHILITIC RETINITIS

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WHY/HOW?

• Treponema pallidum (spirochaete) - sexually transmitted; also congenital
• The "Great Imitator" - can mimic virtually any retinal or uveal condition
• Incidence is globally resurgent (2020s) - often associated with HIV co-infection
• Ocular syphilis occurs in secondary (hematogenous dissemination, weeks after primary chancre) and tertiary stages
• Pathogenesis: T. pallidum crosses BRB hematogenously → directly infects retinal/uveal tissue + triggers intense immune response (Th1 + immune complex deposition)

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WHAT?

• Anterior uveitis: granulomatous or non-granulomatous, dilated episcleral vessels
• Intermediate uveitis: vitritis, snowbank
• Posterior uveitis: focal or multifocal chorioretinitis, retinitis, vasculitis
• Neuroretinitis: disc oedema + macular star (hard exudate deposits in Henle's layer)
• Acute Syphilitic Posterior Placoid Chorioretinitis (ASPPC): large yellow placoid macular lesion - characteristic FA shows early block (hypofluorescence), late stain (hyperfluorescence)
• Optic neuritis: papillitis, can cause acute severe visual loss
• Exudative RD: from intense choroidal inflammation

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DIAGNOSIS

1. RPR/VDRL: non-treponemal tests - positive in active disease; titre correlates with disease activity; can be false-positive
2. TP-PA or FTA-ABS: treponemal tests - highly specific; remain positive lifelong after infection (cannot use to monitor treatment response)
3. Both tests needed: RPR for activity + TP-PA for confirmation
4. Aqueous PCR: if seronegative (rare) or atypical
5. CSF analysis: if neurological symptoms (neurosyphilis must be excluded)

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WHAT TO DO?

• All ocular syphilis = neurosyphilis protocol (regardless of neurological symptoms):
  • IV Penicillin G 18-24 million units/day (3-4 MU Q4h or continuous infusion) × 10-14 days
  • Alternative: IV Ceftriaxone 2g/day × 14 days (if penicillin allergy non-anaphylactic)
  • Penicillin allergy (non-pregnant): Doxycycline 100mg BD × 28 days (less reliable for CNS)
  • Penicillin allergy + pregnant: desensitise to penicillin and treat with penicillin G
• Topical/oral steroids for severe uveitis after antibiotic initiation
• Follow-up RPR titre at 3, 6, 12 months: fourfold fall = adequate response
• Excellent prognosis with early IV penicillin; irreversible damage if treatment delayed >2 weeks

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CANDIDA RETINITIS/ENDOPHTHALMITIS

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WHY/HOW?

• Candida albicans (most common), C. glabrata, C. tropicalis
• Route: hematogenous - candidaemia seeds the choroid/retina
• Risk factors: IV drug use, central venous lines (TPN patients), ICU patients, immunocompromised, broad-spectrum antibiotics (destroy gut flora → Candida overgrowth → gut translocation → candidaemia)
• Retina infected secondary to chorioretinitis (choroid first, then retina)

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WHAT?

• White fluffy "cotton ball" colonies in retina/vitreous
• Multiple, bilateral, no/minimal vitritis initially

• "String of pearls" - colonies extend into vitreous on a string-like stalk
• Vitreous abscess = full fungal endophthalmitis
• Dense vitritis, hypopyon possible

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WHAT TO DO?

• Blood cultures: positive in ~50% with ocular candida; draw multiple sets
• Aqueous/vitreous culture: if endophthalmitis suspected
• Ophthalmology review is mandatory in all patients with candidaemia (screening fundus exam)

• Chorioretinitis without vitritis: Fluconazole IV/PO (excellent ocular penetration)
• Chorioretinitis with vitritis: Voriconazole (better CNS/ocular penetration) or Liposomal Amphotericin B
• Intravitreal voriconazole 100 µg/0.1 mL or Intravitreal amphotericin B 5-10 µg/0.1 mL: for endophthalmitis
• PPV (vitrectomy): for vitreous abscess, removes fungal load, improves drug penetration
• Treat candidaemia systemically (remove lines, antifungal systemic therapy ×4-6 weeks minimum)
• Echinocandins (caspofungin, micafungin): poor ocular penetration - NOT used for ocular disease

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TUBERCULOSIS OCULAR DISEASE

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WHY/HOW?

• Mycobacterium tuberculosis - reaches uvea/choroid hematogenously during primary or reactivation TB
• Choroid has the richest blood supply of any tissue per gram → highly susceptible to haematogenous seeding
• Two mechanisms:
  1. Direct infection: mycobacteria seed the choroid → choroidal granuloma
  2. Hypersensitivity reaction: immune response to mycobacterial antigens → serpigenous-like choroiditis (TB-serpiginous or "serpiginoid")

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WHAT?

• Choroidal granulomas: solitary or multiple, yellow-white lesions; hallmark of TB choroiditis
• Serpiginous-like choroiditis (TB-serpiginous): responds to anti-TB therapy (key distinguishing point - true serpiginous does not)
• Retinal vasculitis: periphlebitis (Eales-like)
• Neuroretinitis: optic disc oedema + macular star
• Subretinal abscess: rare but serious
• Anterior uveitis: granulomatous, mutton-fat KPs

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DIAGNOSIS

• Mantoux (PPD) test and/or QuantiFERON-TB Gold (IGRA): positive = previous exposure (not active disease alone)
• CXR/CT chest: look for active/previous TB
• Aqueous PCR for M. tuberculosis DNA: useful but low sensitivity
• Choroidal biopsy: rarely needed; demonstrates caseating granuloma with Langhans giant cells on histology (Ziehl-Neelsen stain for AFB)

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WHAT TO DO?

• Standard 4-drug ATT: HRZE (Isoniazid + Rifampicin + Pyrazinamide + Ethambutol) × 2 months, then HR × 4 months = 6 months total
• Steroids: add after 2 weeks of ATT (to avoid unmasking TB) for severe vitritis, CMO, optic neuritis
• TB-serpiginous: ATT + prednisolone; anti-VEGF for any MNV
• Important: Ethambutol itself causes optic neuropathy (colour vision loss, centrocaecal scotoma) - monitor Ishihara/colour vision monthly

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NON-INFECTIOUS RETINITIS & CHOROIDITIS

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BIRDSHOT RETINOCHOROIDOPATHY

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WHY?

• Autoimmune: T-cell mediated attack on choroidal melanocytes and retinal antigens
• HLA-A29 association in >95-96% of patients - most specific HLA-disease association in all of uveitis (background prevalence of HLA-A29 in general population = ~7%)
• HLA-A29 presents self-peptides to CD8+ T-cells → breakdown of self-tolerance → immune attack on uveal/retinal tissue

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WHO?

• Middle-aged, predominantly Caucasian women
• Bilateral, chronic, slowly progressive

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WHAT?

• Cream/salmon/white ovoid patches at posterior pole and mid-periphery, scattered in a "birdshot/buckshot scatter" pattern radiating from the disc
• Vitritis always present (mild to moderate)
• Retinal vasculitis: periphlebitis
• CMO: major cause of visual loss
• ERG abnormalities: rod and cone dysfunction - appear early, before clinical worsening → essential monitoring tool
• Disc oedema, optic atrophy in severe cases
• ~33% eventually achieve <6/60 visual acuity

Investigations

• HLA-A29: >95% positive - the key diagnostic test
• FFA: vascular leakage, disc staining, foveal sparing (early)
• ICGA: hypofluorescent lesions - more numerous than visible on fundoscopy; persist into late phases
• FAF: hypo-AF lesions more numerous than visible
• OCTA: flow voids in choroidal stroma; choriocapillaris affected late
• ERG: rod and cone amplitude reduction - monitor every 6 months

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WHAT TO DO?

• Oral prednisolone: initial control, but long-term steroids cause side effects → must add steroid-sparing
• MMF (Mycophenolate mofetil) 2-3g/day: first-choice steroid-sparing; inhibits de novo guanosine synthesis → suppresses T and B-cell proliferation
• Cyclosporin 2.5-5 mg/kg/day: second-line or combination; inhibits calcineurin → blocks IL-2 → T-cell suppression
• Azathioprine: alternative steroid-sparing
• Anti-TNF biologics (Adalimumab, Infliximab): refractory cases; Level-1 evidence from VISUAL I & II trials (adalimumab)
• JAK inhibitors (upadacitinib, baricitinib): emerging for refractory disease (2025)
• CMO management: Ozurdex (dexamethasone implant), IVTA
• Duration: minimum 2 years immunosuppression before considering cautious withdrawal

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VKH (VOGT-KOYANAGI-HARADA)

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WHY?

• Autoimmune granulomatous panuveitis targeting melanocytes (choroidal, leptomeningeal, skin, inner ear)
• HLA-DR4/DRw53: genetic susceptibility (Asian, Hispanic, Middle Eastern, Native American)
• T-cell mediated immune attack on melanocyte antigens (tyrosinase-related proteins) triggered by viral infection or other stimulus

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WHO?

• Asian, Hispanic, Middle Eastern predominance; young to middle-aged adults; female slight preponderance

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FOUR PHASES:

1. Prodromal (1-2 weeks): meningism, headache, fever, neck stiffness, dysacusis (tinnitus, hearing loss), dysacusis, CSF pleocytosis, tinnitus → mimics viral meningitis
2. Acute uveitic (weeks): bilateral exudative RD (bullous, shifting SRF), disc oedema, mutton-fat KPs; panuveitis; multiple SRF pockets on OCT
3. Convalescent phase (months): sunset glow fundus (diffuse RPE/choroidal depigmentation - orange-red fundus), Dalen-Fuchs nodules (collections of epithelioid cells beneath RPE at periphery)
4. Chronic recurrent phase: episodic granulomatous anterior uveitis; subretinal neovascular membranes; posterior synechiae

• Poliosis (white hair/eyebrows/eyelashes)
• Vitiligo (skin depigmentation)
• Alopecia (hair loss)

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DIAGNOSIS (American Uveitis Society Criteria)

1. Bilateral chronic iridocyclitis
2. Posterior uveitis (exudative RD, disc hyperaemia, sunset glow)
3. Neurological signs (tinnitus, meningismus, CSF pleocytosis)
4. Cutaneous findings (poliosis, vitiligo, alopecia)

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WHAT TO DO?

• Acute phase: IV methylprednisolone 1g/day × 3 days (pulse) → oral prednisolone 1-1.5 mg/kg/day with slow taper over 6-12 months
• Steroid-sparing: MMF, azathioprine, cyclosporin - add from 3-6 months
• Biologics: adalimumab for refractory disease
• Early aggressive treatment reduces risk of chronic phase complications (sunset glow, subretinal fibrosis, cataracts, glaucoma)

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SERPIGINOUS CHOROIDOPATHY

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WHY/HOW?

• Idiopathic - thought to be an immune-mediated attack on the choriocapillaris
• Mechanism: lobular choriocapillaris ischaemia → RPE + outer retinal atrophy → spreads in characteristic pattern
• HLA-B7 association
• TB must be excluded (TB-serpiginous looks identical but responds to ATT)

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WHAT?

• Bilateral chronic recurrent; male predominance; middle-aged
• Starts peripapillary (adjacent to optic disc) → extends centrifugally in a "snake-like" (serpiginous) pattern over years
• 5% start at macula (macular serpiginous - worse prognosis)
• Active edge: grey-white, ill-defined, slightly elevated
• Inactive centre: scalloped chorioretinal atrophy with RPE loss
• FFA: early hypofluorescence (ischaemia) → late hyperfluorescence at active edge (staining)
• ICGA: persistent late hypofluorescence (choriocapillaris dropout)
• FAF: active edge = hyper-AF border; inactive area = hypo-AF (atrophy)
• Choroidal neovascular membrane (MNV) in 15-35%

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WHAT TO DO?

• Exclude TB (IGRA, Mantoux, CXR, CT chest) - if TB positive = TB-serpiginous → treat with ATT + steroids
• Oral prednisolone + steroid-sparing (MMF/cyclosporin/azathioprine) for maintenance
• Anti-VEGF (bevacizumab/ranibizumab) for MNV
• No proven treatment to prevent recurrence (chronic, relapsing course)

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MEWDS, APMPPE, MFC/PIC (White Dot Syndromes) - Summary

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EALES DISEASE

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WHY?

• Idiopathic occlusive periphlebitis - inflammation of peripheral retinal veins of unknown cause
• TB hypersensitivity has been proposed but is controversial (not proven)
• Affects young South Asian males predominantly (20-30 years)
• Three overlapping stages: Inflammatory → Occlusive → Neovascular

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WHAT?

• Bilateral but asymmetric periphlebitis: venous sheathing, haemorrhages along veins
• Peripheral capillary non-perfusion → neovascularisation (NVE/NVD)
• Recurrent vitreous haemorrhage (1/3 of eyes) - the presenting complaint in most
• Traction retinal detachment in end-stage

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WHAT TO DO?

• Inflammatory stage: periocular/systemic/intravitreal steroids; consider anti-TB therapy if strong TB evidence (Mantoux strongly positive, CXR changes)
• Photocoagulation (scatter PRP) to non-perfused peripheral retina → prevents NV
• Anti-VEGF for active NVE/NVD
• PPV (vitrectomy) for non-clearing vitreous haemorrhage or TRD

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DRUG-INDUCED RETINOPATHY (Brief)

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NEURORETINITIS

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• Combination: optic disc swelling + macular star (star-shaped hard exudate in Henle's fibre layer around fovea)
• Cause: Bartonella henselae (60%) - cat scratch disease; syphilis; Lyme; TB; idiopathic (~25%)
• Macular star forms as disc swelling resolves (lipid leaks from disc along Henle's layer)
• Bartonella serology: IgG/IgM; treat with Doxycycline 100mg BD + Rifampicin × 2-4 weeks
• Idiopathic (Leber's stellate neuroretinitis): good prognosis, often self-limiting

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INVESTIGATIONS - MASTER TABLE

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FINAL MNEMONICS

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GENERAL PATHOGENESIS OF RETINITIS & CHOROIDITIS

From First Principles — Complete Deep Dive

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STEP 1: UNDERSTAND THE NORMAL RETINA AND ITS DEFENCES

The Retinal Layers (Why Each One Matters)

VITREOUS
    ↓
1. Internal Limiting Membrane (ILM) — basement membrane of Müller cells; boundary with vitreous
2. Nerve Fibre Layer (NFL) — axons of ganglion cells heading to optic disc
3. Ganglion Cell Layer (GCL) — cell bodies of ganglion cells (1 million)
4. Inner Plexiform Layer (IPL) — synapses between ganglion cells & bipolar cells
5. Inner Nuclear Layer (INL) — bipolar, amacrine, horizontal, Müller cell nuclei
6. Outer Plexiform Layer (OPL) — synapses between bipolar & photoreceptors
7. Outer Nuclear Layer (ONL) — cell bodies of rods and cones (photoreceptors)
8. External Limiting Membrane (ELM) — junctional complex of Müller cells
9. Photoreceptor Layer — inner and outer segments of rods (120 million) and cones (6 million)
10. Retinal Pigment Epithelium (RPE) — single layer of pigmented epithelial cells
    ↓
Bruch's Membrane — thin ECM layer
    ↓
Choriocapillaris — fenestrated capillary network
    ↓
Choroidal Stroma — larger vessels (Sattler's and Haller's layers)
    ↓
Suprachoroidal Space
    ↓
Sclera

• CMV destroys all 10 layers (full-thickness necrosis) → permanent vision loss even if scarred
• PORN starts in layers 7-10 (outer retina - photoreceptors and RPE) → hence "outer" retinal necrosis
• Toxoplasma causes full-thickness focal necrosis in a limited zone + surrounding inflammation
• White dot syndromes (MEWDS, APMPPE, serpiginous) primarily affect choriocapillaris + RPE → outer retina is the main casualty

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The Blood-Retinal Barrier (BRB) — The First Line of Defence

Inner BRB

• Formed by tight junctions (zonula occludens) between retinal vascular endothelial cells
• Specifically: the claudin-5, occludin, and ZO-1 proteins form the tight junctional complexes
• Also: pericytes wrap around capillaries and secrete factors that maintain endothelial tight junctions
• Glial support: Müller cells and astrocytes send endfeet onto capillary walls and secrete factors (VEGF, angiopoietin) that maintain barrier integrity
• Blocks: immune cells, large molecules, pathogens from entering the retina from capillaries

Outer BRB

• Formed by tight junctions between RPE cells
• The RPE acts as the gatekeeper between the choriocapillaris (fenestrated, leaky) and the outer retina (photoreceptors)
• The choriocapillaris has fenestrations (large pores) → freely leaks plasma proteins → the RPE tight junctions are the actual barrier
• Blocks: pathogens and immune cells from entering outer retina from the choroid

Why the BRB exists:

• The retina is metabolically one of the most active tissues in the body (especially photoreceptors - they burn glucose and oxygen at very high rates to maintain their dark current)
• Photoreceptors are irreplaceable once lost
• The BRB creates a controlled microenvironment with precise ion concentrations (K⁺, Ca²⁺) essential for phototransduction
• Even mild oedema (fluid accumulation) physically separates photoreceptors from the RPE and choriocapillaris → disrupts the oxygen and nutrient supply → rapid photoreceptor death

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Ocular Immune Privilege — Why the Eye Suppresses Inflammation

Mechanisms of Ocular Immune Privilege:

• Prevent immune cells from entering
• Block complement activation
• Prevent antigen presentation to systemic lymphocytes

• The aqueous humour and vitreous contain:
  • TGF-β2 (transforming growth factor-β2): inhibits T-cell activation, NK cell activity, and macrophage activation
  • α-MSH (α-melanocyte-stimulating hormone): induces regulatory T-cells (Tregs)
  • VIP (vasoactive intestinal peptide): suppresses Th1 responses
  • CGRP (calcitonin gene-related peptide): inhibits macrophage activation
  • Soluble FasL (CD95L): induces apoptosis of invading T-cells (T-cells that enter the eye are killed)
• The RPE itself secretes TGF-β and thrombospondin → suppresses microglial and macrophage activation

• The eye has no conventional lymphatics → antigens cannot easily reach regional lymph nodes
• Antigens from the anterior chamber drain to the spleen via blood → induce systemic tolerance (ACAID = Anterior Chamber-Associated Immune Deviation)

• Corneal endothelium, lens epithelium, and retinal cells express very low levels of MHC II → cannot efficiently present antigens to CD4+ T-cells → prevents activation of adaptive immunity

• CD46, CD55, CD59 expressed on ocular cells → prevent complement-mediated damage

WHY Privilege Matters for Retinitis:

• Pathogens enter → antigen is presented locally
• Immune privilege is overwhelmed
• A large inflammatory response ensues
• The collateral damage from inflammation (cytokines, reactive oxygen species, complement) ADDS to the damage from the pathogen itself
• In some diseases (autoimmune choroiditis, birdshot, VKH), the inflammation IS the disease - there is no pathogen, just a misdirected immune attack

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STEP 2: HOW PATHOGENS ENTER THE EYE

1. Hematogenous Spread (Most Common Route)

• Pathogen travels in bloodstream → reaches the highly vascular choroid (richest blood supply in the body per gram)
• The choriocapillaris is fenestrated → pathogens easily leak into choroidal stroma
• From choroid → RPE barrier must be crossed to enter retina
• Examples: CMV (from viremia), Candida (from candidaemia), T. gondii (from initial tachyzoitemia), Mycobacterium tuberculosis (from bacteraemia), Treponema pallidum (secondary syphilis bacteraemia), toxocara larvae

2. Retrograde Axonal Transport

• Virus travels backward along the axons of the retinogeniculate pathway (optic nerve → optic chiasm → lateral geniculate → optic radiation)
• HSV and VZV use this route - they reactivate in the trigeminal/geniculate ganglion → travel anterograde along corneal nerves OR retrograde along optic pathways to the retina
• This explains why ARN can follow herpes encephalitis or zoster ophthalmicus

3. Direct Contiguous Spread

• From a nearby infected structure into the eye
• Example: CMV spreading from optic nerve directly into the retina; or corneal ulcer spreading into the anterior segment

4. Reactivation from Latency Within the Eye

• The most important mechanism for toxoplasma: bradyzoite cysts already present within retinal tissue → reactivate locally
• CMV: latent in circulating monocytes → reactivation during viraemia → seeds retina afresh (not true in-eye latency, but endogenous reactivation)

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STEP 3: THE THREE FUNDAMENTAL MECHANISMS OF RETINAL DAMAGE

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MECHANISM 1: DIRECT CYTOPATHIC INJURY

Who uses this mechanism?

• CMV, HSV, VZV, PORN (pure cytopathic)

What happens, step by step?

• CMV enters via endocytosis after binding to heparan sulphate proteoglycans on the cell surface, then uses CD46, EGFR, and integrins as co-receptors
• Viral envelope fuses with cell membrane → nucleocapsid delivered to cytoplasm → transported to nucleus
• HSV/VZV similarly enter via glycoprotein binding to nectin/HVEM receptors

• Viral genome enters the nucleus → hijacks the host cell's transcriptional machinery
• Viral DNA polymerase (UL54 for CMV) replicates viral DNA exponentially
• Immediate early (IE) genes are expressed first: these suppress host cell's antiviral defences
• Then early (E) genes: encode viral replication enzymes (including UL97 kinase for CMV)
• Then late (L) genes: encode structural proteins (capsid, tegument, envelope)
• New viral particles assembled in the nucleus → acquire envelope from nuclear membrane → exported via vesicular transport

• Hundreds to thousands of viral particles assembled → cell membrane ruptures → virions released
• Released virions immediately infect adjacent cells → centrifugal spread through retinal tissue
• The dead cell leaves a zone of necrosis

• "Owl-eye" (CMV) intranuclear inclusions: the enlarged nucleus packed with viral particles surrounded by a clear halo (like an owl's eye) - classic on histopathology
• Retinal cell bodies are destroyed → full-thickness coagulative necrosis of all 10 layers
• The necrotic retina appears white because: (a) loss of normal RPE pigment absorption, (b) oedema and debris filling the retinal layers, (c) opacification of necrotic cells

• Necrotic retinal tissue is gradually resorbed by macrophages and microglial cells
• Replaced by a thin, atrophic, gliotic scar (reactive gliosis from remaining Müller cells and astrocytes)
• The atrophic retina has:
  • Multiple retinal holes (from ischaemia and mechanical stress)
  • Loss of photoreceptors → scotoma in that area
  • Holes + vitreous traction → rhegmatogenous RD

• CMV has receptors on multiple retinal cell types (RPE, Müller cells, endothelial cells, neurons) → infects all layers simultaneously
• VZV in PORN preferentially targets outer retinal cells first (photoreceptors, RPE) because of specific receptor distribution → "outer" necrosis initially → but progresses to full-thickness rapidly

• CMV in AIDS: CD4+ T-cells are nearly absent → no lymphocytes to infiltrate the vitreous → minimal/absent vitritis despite devastating retinal necrosis
• ARN (immunocompetent): intact immune system → massive T-cell and macrophage infiltration into vitreous → marked vitritis and panuveitis
• This is one of the most important concepts in infectious retinitis

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MECHANISM 2: IMMUNE-MEDIATED INJURY (Adaptive Immune Inflammation)

Who uses this mechanism?

• Toxoplasma retinitis (mixed: direct + immune-mediated)
• All autoimmune choroiditides: Birdshot, VKH, serpiginous, MEWDS, APMPPE
• Syphilitic retinitis (immune complex + T-cell)
• ARN (immune-mediated vasculitis on top of viral necrosis)

The Cellular Cascade - Step by Step:

• Pathogen (or self-antigen in autoimmune disease) is processed by:
  • Resident ocular macrophages (perivascular macrophages in choroid)
  • Retinal microglia (resident CNS macrophages of the retina)
  • Dendritic cells in the uveal tract
• These Antigen Presenting Cells (APCs) display peptide fragments on:
  • MHC Class II → presents to CD4+ T-helper cells (adaptive immune response)
  • MHC Class I → presents to CD8+ cytotoxic T-cells (direct killing)
• APCs also produce IL-12 → this drives naive T-cells toward Th1 differentiation

• Naive CD4+ T-cells in regional lymphoid tissue (or in the eye during immune breakdown) become activated when they recognise antigen on MHC II
• They differentiate under cytokine influence:

• Primary Th1 cytokine
• Activates macrophages → upregulates MHC II (more antigen presentation → amplification loop)
• Induces nitric oxide (NO) production → direct microbicidal activity → also kills nearby bystander cells
• Induces iNOS (inducible nitric oxide synthase) in retinal cells → NO radicals → oxidative damage

• Produced by activated macrophages and Th1 cells
• Dual role: kills pathogens (upregulates phagocytosis) + causes tissue damage
• TNF-α binds TNFR1 on retinal neurons and RPE → activates caspase-8 → apoptosis
• TNF-α also disrupts tight junctions of BRB (via NF-κB pathway) → increases vascular permeability → macular oedema
• TNF-α from sympathetic ophthalmia has been shown to cause mitochondrial oxidative stress in the outer retina → photoreceptor apoptosis (research from Ryan's Retina)
• This is why anti-TNF agents (adalimumab, infliximab) are effective in autoimmune uveitis

• Amplifier cytokine: drives Th17 differentiation, stimulates B-cells to produce antibodies
• Promotes VEGF production → vascular leakage → macular oedema, CMO
• Elevated IL-6 in vitreous correlates with CMO severity in birdshot and VKH

• Th17-derived
• Recruits neutrophils (PMNs) to the site → neutrophils release elastase, MPO, ROS → tissue destruction
• Important in Behcet's disease (occlusive vasculitis) and ARN

• Fever, pain, local oedema
• Activates endothelium → upregulates ICAM-1 and VCAM-1 → allows lymphocyte rolling, adhesion, and transmigration across the BRB

• Released by ischaemic retinal cells, activated Müller cells, macrophages
• Disrupts VE-cadherin at endothelial junctions → BRB breakdown → vascular leakage → retinal oedema
• Drives neovascularisation (new vessel formation) → neovascular vessels are leaky, fragile → vitreous haemorrhage
• Also promotes MNV (myopic neovascularisation in choroid) in conditions like MFC, PIC, serpiginous

• Activated macrophages (M1 phenotype) engulf pathogens and apoptotic debris
• They also produce:
  • Matrix metalloproteinases (MMPs) → break down extracellular matrix → facilitate immune cell trafficking but also destroy Bruch's membrane → allows subretinal neovascularisation (CNVM)
  • Reactive Oxygen Species (ROS): H₂O₂, superoxide, OH radical → lipid peroxidation of photoreceptor outer segments → photoreceptor apoptosis
  • Nitric oxide (NO): through iNOS → peroxynitrite formation → DNA damage and protein nitration
  • Complement activation: C3a, C5a (anaphylatoxins) → mast cell degranulation → further vascular permeability + PMN recruitment; C5b-9 (membrane attack complex) → direct cell lysis

• Macrophages persistently activated → recruit more T-cells → granuloma forms
• Structure of granuloma:
  • Centre: the antigen (organism, debris) + activated macrophages fusing into epithelioid cells
  • Middle layer: Langhans giant cells (multinucleated giant cells formed by macrophage fusion)
  • Outer layer: CD4+ T-lymphocytes (Th1), fibroblasts → wall it off
• In the eye: this appears as mutton-fat KPs (epithelioid macrophage aggregates on corneal endothelium), choroidal granulomas (Dalen-Fuchs nodules in VKH and sympathetic ophthalmia), vitreous snowballs
• Granulomas contain the organism but also cause ischaemia to surrounding tissue by blocking blood flow (choriocapillaris) → outer retinal atrophy adjacent to granulomas

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MECHANISM 3: ISCHAEMIC/VASCULAR INJURY

Who uses this mechanism?

• ARN (occlusive vasculitis)
• Eales disease (periphlebitis → non-perfusion → NV)
• Syphilitic vasculitis
• Behcet's disease (occlusive venous and arterial disease)
• Radiation retinopathy
• CMV retinitis (areas of retinal non-perfusion adjacent to necrosis)

Step by Step:

• Inflammatory mediators (TNF-α, IL-1β, IFN-γ) act on vascular endothelium
• Endothelial cells upregulate:
  • ICAM-1 (intercellular adhesion molecule 1)
  • VCAM-1 (vascular cell adhesion molecule 1)
  • E-selectin, P-selectin
• These adhesion molecules allow circulating leukocytes to:
  • Roll along the endothelium (selectins)
  • Adhere firmly (integrins binding ICAM-1/VCAM-1)
  • Transmigrate through the vessel wall (diapedesis)

• Leukocytes accumulate in the periadventitial space around retinal vessels
• This is seen clinically as:
  • Venous sheathing (white cuffing around veins) = lymphocytic periphlebitis → in Eales disease, birdshot, sarcoid
  • Arterial sheathing = arteritis → in ARN (occlusive arteriolar vasculitis)
• Leukocytes release elastase and proteases → degrade the vessel wall
• Immune complex deposition (in syphilis) → complement activation → further vessel wall damage

• Damaged endothelium + inflammatory infiltration → thrombosis in the vessel lumen
• In ARN: the arterioles become occluded → complete cessation of blood flow to inner retina
• This is why ARN lesions extend along the vascular territories - ischaemia follows the distribution of occluded vessels

• Inner retinal layers (ganglion cells, NFL, inner nuclear layer) are supplied by the central retinal artery branches → these die first in ischaemia
• Cotton-wool spots = microinfarcts of the nerve fibre layer → accumulation of axoplasmic debris at the infarct border (visible as white fluffy spots on fundoscopy)
• Complete ischaemia → pan-retinal necrosis in the affected territory
• Adjacent retina develops capillary non-perfusion (seen on FFA as dark areas with no dye leakage)

• Ischaemic retinal cells and Müller cells release VEGF proportional to the degree of ischaemia
• VEGF diffuses to the retinal surface and vitreous → stimulates endothelial cell proliferation and migration → new vessel formation (neovascularisation)
• New vessels (NVD = at disc, NVE = elsewhere) are:
  • Fragile (immature, lack tight junctions) → bleed easily → vitreous haemorrhage
  • Grow into the vitreous gel → fibrotic contraction of vitreous → tractional retinal detachment (TRD)
• This neovascular phase is why Eales disease and advanced CMV/ARN cases can present with vitreous haemorrhage

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STEP 4: HOW THE SPECIFIC LOCATION OF INFLAMMATION DETERMINES THE CLINICAL APPEARANCE

The Choroid vs The Retina - Why It Matters

• The lesion is deep (posterior to RPE)
• Appears as deep yellow/white spots on fundoscopy (subretinal, behind the retinal vessels)
• FFA: lesion is blocked early (deep tissue blocks dye) → stains late as the inflammation causes RPE breakdown
• ICGA: the gold standard for choroidal disease because ICG dye is taken up by the choroid → hypofluorescent dots = areas where choroidal perfusion is lost
• OCT: RPE irregularity, sub-RPE material, choroidal thickening (oedema during active phase)
• Vitritis may be mild or absent in early pure choroiditis (the inflammation hasn't broken through to the vitreous yet)

• Lesion appears white and fluffy (retinal oedema, necrosis)
• Vitritis becomes prominent (cells in vitreous)
• FFA: early hypofluorescence (blocked by necrosis/infiltrate) → late hyperfluorescence (leakage from damaged vessels at active margins)
• OCT: hyper-reflective thickening of inner retinal layers → then full-thickness necrosis → then atrophy

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STEP 5: THE FINAL COMMON PATHWAY — HOW VISION IS LOST

Pathogen/Autoimmune trigger
        ↓
BRB breakdown
        ↓
Inflammatory cells enter retina
        ↓
Cytokines (TNF-α, IFN-γ, IL-6, VEGF, NO, ROS)
        ↓
        ┌──────────────────────────────────────┐
        │                                        │
  Direct cell killing                  Vascular damage
  (necrosis/apoptosis)                (ischaemia, non-perfusion)
        │                                        │
  Photoreceptor death            Capillary dropout → VEGF
        │                                        │
   Scotoma/Blind area            Neovascularisation
        │                              ↓
   Macular oedema              Vitreous haemorrhage
   (CMO via VEGF/IL-6)         Tractional RD
        │                              │
        └──────────┬───────────────────┘
                   ↓
          PERMANENT VISION LOSS

1. Photoreceptor loss → absolute scotoma (irrecoverable)
2. Macular oedema (CMO) → distortion and VA reduction (recoverable if treated early)
3. Retinal detachment → sudden visual field loss (recoverable if repaired promptly)
4. Optic atrophy → permanent visual field defect (irrecoverable)

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STEP 6: THE IMMUNE PRIVILEGE PARADOX — WHY BREAKING PRIVILEGE MAKES THINGS WORSE

• You need enough immune response to kill the pathogen (or stop the autoimmune attack)
• But too much immune response kills the photoreceptors you're trying to save

• Steroids suppress the Th1 response (IFN-γ production drops)
• Without IFN-γ, macrophages can't kill tachyzoites
• Tachyzoites proliferate unchecked
• Active retinitis expands catastrophically

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STEP 7: MOLECULAR MIMICRY — THE CAUSE OF AUTOIMMUNE CHOROIDITIS

• A pathogen (usually viral) has a protein sequence that is structurally similar to a self-protein in the eye (choroidal melanocyte antigens, RPE proteins, photoreceptor proteins)
• The immune system generates T-cells and antibodies against the pathogen
• After infection clears, these T-cells and antibodies cross-react with the self-protein in the eye
• The retina/choroid becomes the target of an immune attack meant for the pathogen

• A viral trigger (unknown, possibly Epstein-Barr or HHV-6 based on epidemiological data) in a genetically susceptible individual (HLA-DR4)
• The virus has a peptide resembling tyrosinase (an enzyme in melanocytes)
• Anti-viral CD4+ T-cells → cross-react with choroidal melanocyte tyrosinase → attack melanocytes
• Melanocytes are destroyed in: choroid, skin (vitiligo), hair (poliosis), inner ear (dysacusis), leptomeninges (meningism)
• This explains why VKH affects ALL melanocyte-rich tissues simultaneously

• Trauma to one eye exposes previously hidden retinal antigens (S-antigen/arrestin, IRBP) to the systemic immune system
• These antigens are in an immune-privileged site, so the immune system has never developed tolerance to them
• T-cells are generated against retinal S-antigen → traffic to the OTHER eye → attack its retina → bilateral granulomatous uveitis

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STEP 8: THE CHOROIDITIS-SPECIFIC ICG-BASED PATHOGENESIS

Type 1: Choriocapillaritis (Primary Inflammatory Target = Choriocapillaris)

• The choriocapillaris (fenestrated capillary network at the inner face of the choroid) is the primary target
• Inflammatory cells → choriocapillaris endothelial dysfunction → lobular ischaemia (each lobule of choriocapillaris is an end-artery territory)
• When a lobule is ischaemic: the overlying RPE is deprived of oxygen and nutrients → RPE dysfunction → photoreceptors die in that zone
• On ICGA: hypofluorescent spots = lobules with reduced/absent flow
• On OCTA: choriocapillaris flow deficits map exactly to clinical lesions

Type 2: Stromal Choroiditis (Primary Inflammatory Target = Choroidal Stroma)

• The inflammatory cells (lymphocytes, plasma cells, granulomas) fill the choroidal stroma (the connective tissue layer containing Sattler's and Haller's vessel layers)
• The choriocapillaris is often preserved early (because the inflammation is deeper)
• Granulomas compress the choriocapillaris from below → secondary ischaemia → RPE atrophy
• Dalen-Fuchs nodules (VKH/sympathetic ophthalmia): collections of depigmented RPE cells + epithelioid macrophages between Bruch's membrane and RPE

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SUMMARY DIAGRAM — ALL PATHOGENESIS IN ONE FLOW

CAUSATIVE AGENT
      │
      ├── Pathogen enters via hematogenous spread / axonal transport / reactivation
      │         └── Route to retina or choroid
      │
      ├── DIRECT CYTOPATHIC (CMV, HSV/VZV in ARN/PORN)
      │         ├── Viral entry → replication → cell lysis → necrosis spreads
      │         ├── Full-thickness retinal necrosis
      │         ├── No vitritis if immunocompromised (no immune cells)
      │         ├── Atrophic holes → Rhegmatogenous RD
      │         └── Vision loss: scotoma + RD
      │
      ├── IMMUNE-MEDIATED (Toxoplasma, VKH, Birdshot, Sarcoid, Syphilis)
      │         ├── Antigen presented on MHC II → CD4+ T-cell activation
      │         ├── Th1 → IFN-γ → macrophage activation → granuloma / intracellular killing
      │         ├── Th17 → IL-17 → neutrophil recruitment → vasculitis
      │         ├── TNF-α, IL-6, ROS, NO → BRB breakdown → oedema → CMO
      │         ├── Dense vitritis (cells in vitreous from intact immune system)
      │         ├── Granuloma → Dalen-Fuchs nodules / choroidal granulomas
      │         └── Vision loss: CMO + photoreceptor apoptosis + disc oedema
      │
      └── ISCHAEMIC/VASCULAR (Eales, ARN vasculitis, Behcet, Radiation)
                ├── TNF-α → endothelial ICAM/VCAM upregulation → leukostasis
                ├── Leukocyte transmigration → periadventitial inflammation
                ├── Arterial/venous occlusion → non-perfusion
                ├── Ischaemia → Cotton-wool spots → pan-retinal necrosis
                ├── VEGF release → NVD/NVE → vitreous haemorrhage
                ├── Fibrosis → Tractional RD
                └── Vision loss: ischaemic scotoma + vitreous haemorrhage + TRD

ALL THREE CONVERGE ON:
      Photoreceptor death → Permanent vision loss
      CMO → Reversible VA loss (if treated)
      RD → Emergency surgery needed
      Optic atrophy → Permanent field loss

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