A 28-year-old man with a history of recurrent corneal ulcers presents with pain, redness, and a geographic ulcer on the cornea. Slit-lamp examination shows stromal involvement with anterior chamber reaction. Which investigation is most appropriate to differentiate between recurrent epithelial HSV keratitis and necrotizing stromal keratitis?

Explanation

## Differentiation of Recurrent HSV Keratitis Subtypes **Key Point:** PCR of both corneal scrapings AND aqueous humour is essential to differentiate viral replication (epithelial/stromal keratitis) from immune-mediated stromal disease. ### Pathophysiology of Recurrent HSV Keratitis ```mermaid flowchart TD A[Recurrent HSV Keratitis]:::outcome --> B{Viral replication present?}:::decision B -->|Yes: PCR+| C[Epithelial or Stromal Keratitis]:::outcome C --> D[Treat with antivirals]:::action B -->|No: PCR−| E[Immune-mediated Stromal Keratitis]:::outcome E --> F[Treat with antivirals + topical steroids]:::action G[PCR: corneal scrapings + aqueous humour]:::action --> B ``` **High-Yield:** The presence of viral DNA in aqueous humour indicates active viral replication in stromal keratitis, whereas absence suggests immune-mediated disease (Wessely immune ring, stromal necrosis without viral replication). ### Investigation Comparison for Stromal vs. Immune-Mediated Disease | Feature | Viral Stromal Keratitis | Immune-Mediated Stromal Keratitis | |---|---|---| | **PCR (corneal scrapings)** | Positive | Negative or low-copy | | **PCR (aqueous humour)** | **Positive** | **Negative** | | **Anterior chamber reaction** | Moderate | Marked (Wessely ring) | | **Stromal infiltration** | Focal, active | Diffuse, necrotic | | **Treatment** | Antivirals ± topical steroids | Antivirals + topical steroids | | **Prognosis** | Better with antivirals | Risk of perforation if untreated | **Clinical Pearl:** Aqueous humour PCR is the **differentiator**. Viral DNA in aqueous indicates stromal involvement with active viral replication, requiring aggressive antiviral therapy. Absence of viral DNA suggests immune-mediated disease, which paradoxically requires topical steroids (in addition to antivirals) to suppress inflammation. **Warning:** Topical steroids alone in viral stromal keratitis will worsen the disease. Always confirm viral status before initiating steroids. ### Why PCR (Scrapings + Aqueous) is Superior 1. **Differentiates pathophysiology:** Viral replication vs. immune-mediated 2. **Guides therapy:** Determines need for steroids 3. **Highest specificity:** Detects viral DNA in immune-privileged aqueous compartment 4. **Prognostic value:** Aqueous PCR positivity predicts worse outcomes without appropriate antivirals