Herpes Zoster Keratitis

Causative Virus

• Varicella-Zoster Virus (VZV): Human herpesvirus 3 (HHV-3); double-stranded DNA virus; member of the Alphaherpesviridae subfamily
• Primary infection — Varicella (chickenpox): Highly contagious; usually acquired in childhood via respiratory droplets or direct contact with vesicular fluid; may be subclinical
• Latency: Following primary infection, VZV travels retrograde along sensory nerve axons to establish lifelong latency in the dorsal root ganglia and cranial nerve sensory ganglia (including the trigeminal ganglion)
• Reactivation — Herpes Zoster (shingles): Occurs when cell-mediated immunity to VZV declines, most commonly with advancing age or immunosuppression; reactivation in the ophthalmic division (V1) of the trigeminal nerve results in HZO

Anatomical Basis of Ocular Involvement

• Ophthalmic division (V1): Reactivation along V1 affects the forehead, scalp, upper eyelid, and ocular surface
• Nasociliary nerve: A branch of V1 supplying the tip and side of the nose and the globe; involvement (Hutchinson's sign) strongly predicts intraocular and corneal disease
• Long ciliary nerves: Carry sensory fibres to the cornea; inflammation along these nerves leads to corneal hypoesthesia and neurotrophic keratopathy

Mechanism of Disease

1. Primary VZV infection and latency: VZV enters via the respiratory mucosa or conjunctiva → replicates locally → travels retrograde along sensory neurones to establish lifelong latency in the trigeminal ganglion (and geniculate ganglion for Ramsay Hunt syndrome)
2. Immune senescence and reactivation: Declining cell-mediated VZV-specific immunity (due to ageing, immunosuppression, or stress) allows viral reactivation within the ganglion
3. Anterograde spread: Reactivated virus travels anterograde along V1 nerve fibres → reaches periocular skin, eyelids, conjunctiva, and cornea; the dermatomal rash appears along the V1 distribution
4. Epithelial disease (direct viral cytopathic effect): VZV replication in corneal epithelial cells produces a distinctive pattern of raised mucous plaques (pseudodendrites) without the true branching ulcers or terminal end bulbs seen in HSV keratitis
5. Immune-mediated stromal disease: VZV antigens deposited in the corneal stroma trigger Type IV (delayed-type) hypersensitivity → nummular (coin-shaped) stromal infiltrates and disciform oedema; may persist or recur independently of active viral replication
6. Neurotrophic keratopathy: Viral inflammation along the long ciliary nerves causes axonal degeneration → reduced or absent corneal sensation → loss of trophic support for the corneal epithelium → persistent epithelial defects, stromal ulceration, and risk of perforation; the most significant long-term sequela of HZK

1. Epithelial Keratitis (Infectious)

• Punctate epithelial keratitis: The earliest corneal manifestation; fine superficial punctate erosions; may appear within days of the rash
• Pseudodendrites: The hallmark of VZV epithelial keratitis; raised, elevated mucous plaques with a dendritic-like branching pattern but with tapered, blunt ends — critically, no terminal end bulbs; stain with rose bengal/lissamine green; distinguished from HSV true dendrites by the absence of ulceration and terminal bulbs
• Geographic epithelial defects: Large, map-shaped epithelial erosions from coalescing pseudodendrites or secondary to neurotrophic compromise

2. Anterior Stromal Keratitis (Immune-Mediated)

• Nummular (coin-shaped) keratitis: Multiple discrete, round, anterior stromal opacities (subepithelial or anterior stromal); immune-mediated; may appear during or after the acute phase; can persist or recur for months to years
• Disciform keratitis: A central or paracentral disc of stromal oedema with associated KPs on the endothelium; similar in appearance to HSV disciform keratitis; represents an immune response to viral antigens in the stroma

3. Endotheliitis

• Keratic precipitates (KPs), corneal oedema, and raised IOP from viral antigen deposition in the trabecular meshwork (trabeculitis); may mimic acute angle-closure glaucoma

4. Mucous Plaque Keratitis

• Adherent mucous filaments or plaques on the corneal surface; may develop during or after the acute phase; can be recurrent and persist for months; associated with reduced tear function and goblet cell loss

5. Neurotrophic Keratopathy

• The most common and clinically significant long-term complication of HZK; results from damage to the long ciliary nerve supply to the cornea; characterised by reduced or absent corneal sensation, impaired epithelial healing, persistent epithelial defects (PEDs), stromal ulceration, and risk of corneal melt and perforation; classified by the Mackie staging system (Stage 1–3)

Host-Related Factors

• Age ≥60 years: The single most important risk factor; the lifetime risk of herpes zoster is approximately 30%; incidence rises sharply after age 50 as VZV-specific cell-mediated immunity declines
• Immunosuppression: HIV/AIDS, haematological malignancy (lymphoma, leukaemia), solid organ transplantation, chemotherapy, and systemic corticosteroid therapy all markedly increase risk of HZO and more severe ocular disease
• Prior varicella infection: A prerequisite for VZV latency and subsequent reactivation; unvaccinated individuals who have had chickenpox carry lifelong reactivation risk
• Female sex: Some epidemiological studies report a modestly higher incidence in women
• Psychological and physical stress: Including major illness, surgery, or emotional stress — known precipitants of VZV reactivation

Protective Factors

• VZV vaccination: Recombinant subunit vaccine (Shingrix; 2 doses) reduces risk of herpes zoster by >90% in adults ≥50 years and significantly reduces the risk and severity of PHN; live attenuated vaccine (Zostavax) less effective and not recommended in immunocompromised patients
• Childhood varicella vaccination: Universal vaccination programmes reduce the pool of latent VZV and may reduce long-term HZO incidence

Periocular and Adnexal Signs

• Dermatomal vesicular rash (V1): Unilateral erythematous vesicular eruption on the forehead, scalp, and periorbita following the V1 distribution; does not cross the midline — a key diagnostic feature
• Hutchinson's sign: Vesicles on the tip or lateral aspect of the nose (nasociliary nerve territory); present in approximately 75% of cases with ocular involvement; its absence does not exclude ocular disease
• Eyelid involvement: Vesicular rash on the upper lid (V1), lower lid if V2 involved; may cause scarring and cicatricial entropion/trichiasis
• Ptosis: From eyelid oedema, inflammation, or scarring; rarely from CN III involvement

Corneal Signs

• Pseudodendrites: The hallmark of VZV corneal disease; elevated, raised mucous plaques with a branching pattern — distinguished from HSV true dendrites by the absence of terminal end bulbs and the absence of true epithelial ulceration; stain prominently with rose bengal and lissamine green
• Punctate epithelial erosions (SPK): Fine superficial erosions; the earliest corneal manifestation; often the first sign before pseudodendrites develop
• Nummular (coin-shaped) stromal infiltrates: Multiple discrete, round anterior stromal opacities; immune-mediated; may persist for months to years and recur; do not necessarily indicate active viral infection
• Disciform stromal oedema: Central disc of stromal thickening with underlying KPs; immune-mediated; may be associated with elevated IOP
• Reduced/absent corneal sensation: A hallmark finding; assessed with cotton-wool wisp or Cochet-Bonnet aesthesiometer; may persist indefinitely after the acute episode
• Neurotrophic epithelial defects: Persistent, non-healing epithelial ulcers in a setting of reduced corneal sensation; may progress to stromal thinning and perforation

Anterior Segment Signs

• Anterior uveitis: Flare and cells in the anterior chamber; often associated with trabeculitis; may be recurrent
• Sectoral iris atrophy: A pathognomonic sign of VZV uveitis; caused by ischaemia from vasculitis of the iris vasculature; provides a clue to VZV aetiology even in the absence of a concurrent rash
• Elevated intraocular pressure: From trabeculitis; may be acutely very elevated and mimic acute angle-closure glaucoma
• Keratic precipitates (KPs): Fine to medium; distributed in a disc or diffuse pattern; associated with endotheliitis

Corneal Complications

• Neurotrophic keratopathy: The most significant long-term complication; persistent epithelial defects, stromal ulceration, and corneal melt due to absent corneal sensation and impaired epithelial trophism
• Corneal scarring and opacification: From repeated episodes of stromal keratitis or healed epithelial disease; a major cause of visual morbidity
• Corneal vascularisation: Deep stromal vessel ingrowth from chronic inflammation; increases risk of graft rejection after penetrating keratoplasty
• Persistent mucous plaque keratitis: Recurrent adherent plaques causing chronic irritation and visual disturbance
• Lipid keratopathy: Lipid deposition along corneal stromal vessels in chronic vascularised disease
• Corneal perforation: A rare but vision-threatening complication of advanced neurotrophic ulceration; requires emergency ophthalmology management

Anterior Segment Complications

• Secondary glaucoma: From repeated episodes of trabeculitis and uveitis; chronic IOP elevation can lead to glaucomatous optic neuropathy
• Cataract: Uveitis-associated, or secondary to prolonged topical steroid use
• Sectoral iris atrophy: Permanent; a pathognomonic sign of VZV uveitis from anterior segment ischaemia
• Posterior synechiae: Iris-lens adhesions from recurrent anterior uveitis; may obstruct aqueous outflow

Neurological Complications

• Post-herpetic neuralgia (PHN): Neuropathic pain persisting beyond 90 days after rash onset; the most common and debilitating complication of herpes zoster overall; incidence 10–15% overall, rising to 25–40% in patients over 60 years; severe PHN significantly impairs quality of life
• Cranial nerve palsies: CN III (oculomotor), IV (trochlear), or VI (abducens) involvement from vasculitis or direct nerve infiltration; causes diplopia and ptosis
• VZV vasculopathy: Rare but recognised; cerebral vasculitis causing contralateral hemiplegia; may occur weeks to months after HZO; refer urgently to neurology

Associated Systemic Conditions

• HIV/AIDS: HZO in a young patient (<50 years) without other risk factors should prompt HIV testing; HIV-positive patients have a higher risk of HZO, more severe disease, bilateral involvement, and VZV treatment resistance; immune reconstitution inflammatory syndrome (IRIS) may worsen ocular disease after antiretroviral therapy initiation
• Haematological malignancy: Lymphoma (particularly Hodgkin's lymphoma) and leukaemia are strongly associated with increased HZO incidence; HZO may be a sentinel presentation of undiagnosed haematological disease — investigate if no clear immunosuppressive history
• Organ transplantation: Both solid organ and haematopoietic stem cell transplant recipients are at high risk; HZO may be more severe and difficult to treat in this group
• Post-herpetic neuralgia: Requires multidisciplinary management; first-line agents include gabapentin, pregabalin, tricyclic antidepressants (amitriptyline), and topical lidocaine or capsaicin patches; refer to a pain specialist or neurologist for refractory cases
• Ramsay Hunt syndrome (HZV geniculate ganglion reactivation): Facial nerve palsy, auricular vesicles, and sensorineural hearing loss; may co-occur with HZO; refer urgently to ENT/neurology
• VZV vasculopathy: Rare cerebral arteritis causing stroke (typically contralateral hemiplegia to the affected eye); may occur weeks to months after HZO; requires urgent neuroimaging and neurology referral
• Disseminated zoster: In severely immunocompromised patients; widespread cutaneous and potentially visceral involvement (pneumonitis, hepatitis, encephalitis); requires intravenous acyclovir and urgent medical care

Clinical Diagnosis

HZK is primarily a clinical diagnosis based on the history and examination findings. Laboratory investigations are used for confirmation in atypical cases.

• History: Age ≥50, immunosuppression, typical prodromal burning/pain, prior chickenpox or shingles episodes
• Dermatomal rash assessment: Confirm unilateral V1 distribution; confirm absence of midline crossing; assess for Hutchinson's sign (vesicles on nasal tip/side)
• Slit-lamp examination: Essential; assess for pseudodendrites, nummular infiltrates, KPs, AC reaction, corneal sensation, and IOP

Hutchinson's Sign

Staining Techniques

• Rose bengal or lissamine green: Stains pseudodendrites (devitalised mucous plaques) prominently; better for delineating VZV epithelial lesions than fluorescein
• Fluorescein sodium: Stains true epithelial defects (ulcers); pooling in stromal oedema; useful for identifying neurotrophic defects

Corneal Sensation Testing

• Cotton-wool wisp test: Bedside assessment; compare both eyes and all quadrants; reduced sensation indicates neural compromise
• Cochet-Bonnet aesthesiometer: Quantitative; gold standard for monitoring neurotrophic keratopathy progression

Laboratory and Ancillary Investigations

• PCR (polymerase chain reaction): From tears, conjunctival swab, or corneal scraping; the gold standard for distinguishing VZV from HSV in atypical or rash-negative cases; highly sensitive and specific
• VZV IgM serology: Useful for serological confirmation in atypical presentations; less practical for acute clinical decision-making
• Intraocular pressure measurement: Essential when trabeculitis or endotheliitis is suspected; acute IOP elevation with corneal oedema requires urgent assessment
• Anterior segment OCT (AS-OCT): Useful for quantifying stromal oedema, corneal thinning in neurotrophic disease, and detecting subtle epithelial and endothelial pathology
• In vivo confocal microscopy (IVCM): Detects corneal nerve fibre loss and inflammatory cell infiltrates; useful for monitoring neurotrophic keratopathy and evaluating corneal nerve density

1. Systemic Antivirals — The Critical 72-Hour Window

• Valacyclovir 1000 mg three times daily × 7–10 days — preferred first-line agent; superior oral bioavailability compared to acyclovir; simpler dosing
• Famciclovir 500 mg three times daily × 7–10 days — alternative with equivalent efficacy to valacyclovir
• Acyclovir 800 mg five times daily × 7–10 days — effective but less convenient dosing; use if valacyclovir/famciclovir unavailable
• Intravenous acyclovir 10 mg/kg every 8 hours: For immunocompromised patients, disseminated zoster, or involvement of the CNS; requires hospital admission

2. Epithelial Keratitis (Pseudodendrites)

• No topical antivirals: Topical acyclovir and ganciclovir are not effective against VZV; do not prescribe topical antivirals for HZK epithelial disease
• Preservative-free lubricating eye drops: Frequent instillation for symptomatic relief and epithelial support
• Mechanical débridement of mucous plaques: Removal of adherent pseudodendrites with a cotton-tipped applicator or spatula; reduces antigen load and improves patient comfort
• Avoid topical steroids during active epithelial disease

3. Anterior Stromal / Immune Keratitis

• Topical corticosteroids: Prednisolone acetate 1% or equivalent; for immune-mediated nummular keratitis and disciform keratitis; dose and taper based on response
• Systemic antiviral cover: Continue or initiate oral valacyclovir during steroid treatment to prevent rebound viral replication
• IOP monitoring: Regular assessment; consider topical IOP-lowering agents if steroid-induced rise occurs

4. Neurotrophic Keratopathy

• Intensive preservative-free lubricants: Hourly or more frequently as required; viscous drops or gels preferred for persistent defects
• Bandage soft contact lens: Protects the epithelium and reduces mechanical trauma; monitor closely for secondary infection
• Autologous serum eye drops: Contains epithelial growth factors and neurotrophins; effective for persistent epithelial defects unresponsive to standard lubrication
• Cenegermin 0.002% (recombinant human nerve growth factor): Approved for moderate-to-severe neurotrophic keratitis; promotes epithelial healing and corneal nerve recovery; 8 times daily × 8 weeks
• Tarsorrhaphy: Lateral or medial tarsorrhaphy to reduce corneal exposure and facilitate healing in refractory cases; temporary or permanent
• Amniotic membrane transplant: For persistent epithelial defects and stromal ulcers; promotes healing and reduces inflammation
• Refer to ophthalmology for all but the mildest cases

5. IOP and Uveitis Management

• Topical beta-blockers or carbonic anhydrase inhibitors for trabeculitis-associated IOP elevation
• Avoid prostaglandin analogues in active anterior segment inflammation (risk of worsening cystoid macular oedema and uveitis)
• Cycloplegia (cyclopentolate 1% or homatropine 2%) for associated uveitis and pain relief from ciliary spasm
• Long-term IOP monitoring for secondary glaucoma in patients with recurrent trabeculitis or uveitis

6. Prevention — VZV Vaccination

• Shingrix (recombinant subunit vaccine, RZV): Two doses intramuscularly 2–6 months apart; >90% effective in adults ≥50 years for preventing herpes zoster and PHN; recommended over Zostavax; suitable for immunocompromised patients (though immunogenicity may be reduced)
• Early systemic antiviral treatment (within 72 hours) reduces the duration and severity of PHN
• PHN pharmacotherapy: Gabapentin, pregabalin, tricyclic antidepressants, topical lidocaine patches, capsaicin 8% patch; refer to pain specialist or neurologist for refractory PHN

Treatment Summary Table

Visual Prognosis by Disease Type

• Epithelial keratitis (pseudodendrites): Generally self-limiting; resolves within 2–3 weeks with systemic antivirals and lubricants; minimal or no permanent corneal changes
• Nummular stromal keratitis: Good if treated early; nummular opacities may persist but rarely cause significant visual loss; recurrences possible over months to years
• Disciform keratitis: Good with appropriate steroid therapy; may recur; risk of cumulative corneal scarring with multiple episodes
• Neurotrophic keratopathy: Variable to poor; the leading cause of severe visual loss in HZK; depends on the degree of corneal sensation loss and adherence to intensive lubrication; advanced cases require surgical intervention (tarsorrhaphy, corneal transplantation)
• Endotheliitis and trabeculitis: Generally good with treatment; chronic or recurrent disease can lead to secondary glaucoma and endothelial cell loss

Post-Herpetic Neuralgia (PHN)

• Incidence: 10–15% overall; up to 25–40% in patients aged >60 years
• Severity and duration increase with age; PHN can persist for years and cause significant disability
• Early antiviral treatment within 72 hours reduces PHN risk; Shingrix vaccination reduces PHN by >90% in vaccinated individuals

Prognostic Factors