A 28-year-old man presents with a 3-week history of right eye pain, photophobia, and progressive vision loss. He had a dendritic ulcer 2 months ago treated with topical acyclovir. On examination, visual acuity is 6/18. Slit-lamp biomicroscopy shows a dense, white, granular infiltrate in the corneal stroma with intact epithelium and anterior chamber reaction (3+ cells). Corneal sensation is normal. What is the most likely diagnosis and the appropriate next step in management?

Question

Accepted Answer

A. HSV stromal keratitis; start topical prednisolone 1% 4 times daily plus oral acyclovir 400 mg 5 times daily. ## Clinical Diagnosis: HSV Stromal Keratitis

**Key Point:** The history of prior dendritic ulcer, recurrent HSV infection, and **stromal infiltration with intact epithelium** indicates **HSV stromal keratitis (HSK)** — a delayed hypersensitivity immune response to viral antigen in the stroma, not active viral replication.

## Pathophysiology of HSV Stromal Keratitis

```mermaid
flowchart TD
  A[Primary HSV Epithelial Infection]:::outcome --> B[Viral Antigen in Corneal Stroma]:::outcome
  B --> C{Immune Response Type}:::decision
  C -->|Acute: 2-4 weeks| D[Type III/IV Hypersensitivity]:::action
  C -->|Chronic: Months-Years| E[Immune Complex Deposition]:::action
  D --> F[Stromal Inflammation + Neovascularization]:::action
  E --> F
  F --> G[Dense Stromal Infiltrates + Scarring]:::outcome
  G --> H[Vision Loss + Potential Perforation]:::urgent
```

## Differential Diagnosis: Epithelial vs. Stromal HSV Keratitis

| Feature | Epithelial HSV | Stromal HSV (HSK) |
|---------|---|---|
| **Onset** | Acute (days) | Subacute to chronic (weeks–months) |
| **Ulcer Pattern** | Dendritic or geographic | Intact epithelium |
| **Stromal Involvement** | Minimal | Dense infiltrates, neovascularization |
| **Corneal Sensation** | Reduced | Normal or near-normal |
| **AC Reaction** | Mild (0–1+) | Moderate to severe (2–4+) |
| **Pathology** | Active viral replication | Immune-mediated (Type III/IV hypersensitivity) |
| **Treatment** | Antivirals alone (acyclovir) | **Antivirals + Topical Steroids** |
| **Prognosis** | Good; heals in 7–10 days | Variable; risk of scarring & vision loss |

**High-Yield:** HSV stromal keratitis is an **immune-mediated disease**, not active viral infection. Therefore, steroids are NOT contraindicated — they are ESSENTIAL to suppress the inflammatory response. However, steroids MUST be combined with systemic antivirals to prevent epithelial reactivation.

## Management of HSV Stromal Keratitis

### Step 1: Confirm Diagnosis
- History of prior HSV epithelial disease
- Stromal infiltration with intact epithelium
- Normal or near-normal corneal sensation (rules out active epithelial disease)
- Anterior chamber reaction (immune response)

### Step 2: Initiate Dual Therapy

**Topical Prednisolone 1%:**
- Frequency: 4–6 times daily initially, taper over 4–6 weeks
- Mechanism: Suppresses Type III/IV hypersensitivity and inflammatory cytokines
- Efficacy: Reduces stromal edema and neovascularization

**Oral Acyclovir 400 mg:**
- Frequency: 5 times daily for 10–14 days, then consider long-term prophylaxis (400 mg 2–3 times daily)
- Mechanism: Prevents epithelial reactivation and viral shedding
- Rationale: Steroids alone risk epithelial breakdown and geographic ulceration

**Clinical Pearl:** The combination of topical steroid + systemic antiviral is the cornerstone of HSK management. Steroids without antivirals lead to epithelial disease; antivirals without steroids fail to resolve stromal inflammation.

### Step 3: Monitoring
- Slit-lamp examination every 1–2 weeks
- Monitor for epithelial breakdown (indicates need to reduce steroid dose)
- Assess for stromal clearing and reduction in AC reaction
- Long-term: Watch for corneal scarring and neovascularization

## Why This Is NOT the Other Diagnoses

**Bacterial Keratitis:**
- Bacterial keratitis presents with **epithelial defect** and **suppurative infiltrate** (not granular)
- Rapid onset (24–48 hours) with severe pain
- Corneal scraping would show bacteria on Gram stain
- This patient has intact epithelium and prior HSV history — bacterial infection is unlikely

**Fungal Keratitis:**
- Fungal keratitis is rare in immunocompetent hosts without risk factors (contact lens trauma, topical steroid abuse)
- Presents with **feathery infiltrate** and **satellite lesions**
- Slow progression over weeks to months
- KOH mount would be negative in HSK
- No mention of risk factors in this case

**Acyclovir-Resistant HSV:**
- Rare in immunocompetent patients (<1% incidence)
- Typically presents with **recurrent epithelial disease**, not stromal infiltration
- Stromal disease in HSV is immune-mediated, not due to viral resistance
- Switching to ganciclovir without steroids would fail to address the underlying immune pathology

## Long-Term Management

**Key Point:** HSV stromal keratitis has a chronic course with risk of recurrence (up to 50% over 5 years). Long-term prophylaxis with oral acyclovir 400 mg 2–3 times daily reduces recurrence risk by ~50%.

**Mnemonic: STEROID-ANTIVIRAL (S-A) Rule for HSK**
- **S** = Steroids (topical, tapered over weeks)
- **A** = Antivirals (systemic, long-term prophylaxis)
- Together they prevent both immune-mediated stromal damage and viral reactivation

**Warning:** Do NOT use steroids without antivirals in HSV disease — risk of epithelial breakdown and geographic ulceration. Do NOT use antivirals alone in HSK — stromal inflammation will persist.

![Viral Keratitis diagram](https://mmcphlazjonnzmdysowq.supabase.co/storage/v1/object/public/blog-images/explanation/3941.webp)

Answer

B. Bacterial keratitis; perform corneal scraping and culture, then start topical fortified antibiotics

Answer

C. Fungal keratitis; perform KOH mount and start topical natamycin 5%

Answer

D. Acyclovir-resistant HSV keratitis; switch to topical ganciclovir 0.15% 5 times daily

Explanation

Clinical Diagnosis: HSV Stromal Keratitis

Pathophysiology of HSV Stromal Keratitis

Differential Diagnosis: Epithelial vs. Stromal HSV Keratitis

Management of HSV Stromal Keratitis

Step 1: Confirm Diagnosis

Step 2: Initiate Dual Therapy

Step 3: Monitoring

Why This Is NOT the Other Diagnoses

Long-Term Management

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Feature	Epithelial HSV	Stromal HSV (HSK)
Onset	Acute (days)	Subacute to chronic (weeks–months)
Ulcer Pattern	Dendritic or geographic	Intact epithelium
Stromal Involvement	Minimal	Dense infiltrates, neovascularization
Corneal Sensation	Reduced	Normal or near-normal
AC Reaction	Mild (0–1+)	Moderate to severe (2–4+)
Pathology	Active viral replication	Immune-mediated (Type III/IV hypersensitivity)
Treatment	Antivirals alone (acyclovir)	Antivirals + Topical Steroids
Prognosis	Good; heals in 7–10 days	Variable; risk of scarring & vision loss