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?

Question

Accepted Answer

D. PCR of corneal scrapings and aqueous humour. ## 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

![Viral Keratitis diagram](https://mmcphlazjonnzmdysowq.supabase.co/storage/v1/object/public/blog-images/explanation/4021.webp)

Answer

A. Anterior segment OCT (AS-OCT) to measure stromal thickness

Answer

B. Corneal topography to detect irregular astigmatism

Answer

C. Specular microscopy to assess endothelial cell count

Explanation

Differentiation of Recurrent HSV Keratitis Subtypes

Pathophysiology of Recurrent HSV Keratitis

Investigation Comparison for Stromal vs. Immune-Mediated Disease

Why PCR (Scrapings + Aqueous) is Superior

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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