PanOph

Herpes Simplex Virus (HSV) Keratitis

Cornea

1. Virology & Epidemiology

Clinical Analogy
  • Think of HSV-1 as a 'sleeping tenant' who moves into the trigeminal ganglion for life. During stress, immunosuppression, or UV exposure, this tenant 'wakes up,' travels down the axon to the cornea, and causes damage - sometimes via direct viral cytopathic effect, sometimes by triggering the immune system to attack the host tissue. The key clinical insight is: the same virus causes different disease patterns depending on which arm of the immune response dominates.

2. Virology Essentials

Virology Essentials
Virology Essentials
FeatureHerpes simplex virus type 1 (HSV-1)Herpes simplex virus type 2 (HSV-2)
Genome• Double-stranded DNA • Approximately 152–155 kilobases • Linear• Double-stranded DNA • Approximately 152–155 kilobases • Linear
Primary site• Predominantly oral/orolabial • Primary cause of herpes simplex virus keratitis• Predominantly genital • Can cause neonatal herpes, including ocular disease
Latency site• Usually trigeminal ganglion• Usually sacral ganglia
Corneal involvement• Common • Epithelial and stromal keratitis• Uncommon in routine adult keratitis • Neonatal herpes simplex virus type 2 can cause ocular disease, including keratitis
Reactivation trigger• Reported triggers: ultraviolet or sun exposure, fever or illness, trauma or injury, immunosuppression, and menstruation• Genital infection can be transmitted from mother to infant during delivery • Can cause neonatal herpes, including ocular disease
Thymidine kinase• Initiates acyclovir activation by phosphorylation • Acyclovir resistance may result from thymidine-kinase mutations• Initiates acyclovir activation by phosphorylation • Acyclovir resistance may result from thymidine-kinase mutations, including in herpes simplex virus type 2

Epidemiology - High Yield Facts

  • Global seroprevalence of herpes simplex virus type 1 (HSV-1): 64% in people under 50 years (World Health Organization (WHO) 2020 estimate); most infections are acquired during childhood
  • Herpes simplex keratitis (HSK) is the leading infectious cause of corneal blindness in developed countries
  • Unilateral in >90% of cases; bilateral herpes simplex keratitis is associated with immunocompromise (differential diagnoses: herpes zoster ophthalmicus (HZO), Acanthamoeba keratitis (AK))
  • Annual incidence: approximately 500,000 new or recurrent episodes in the United States
  • Recurrence of any ocular herpes simplex virus disease during 12 months occurred in 32% of placebo-treated patients versus 19% of patients receiving suppressive oral acyclovir in the Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial
  • Male = Female; no racial predilection; risk increased with immunosuppression (human immunodeficiency virus (HIV), post-transplant)

Viral Lifecycle - Pathogenesis Blueprint

StageEventClinical Correlate
1. Primary infection• Herpes simplex virus binds heparan sulfate → enters epithelial cells via fusion• Primary herpes simplex keratitis / blepharoconjunctivitis
2. Retrograde transport• Herpes simplex virus travels via sensory axons → trigeminal ganglion• Primary infection is often subclinical • Retrograde transport to the trigeminal ganglion establishes lifelong latency
3. Latency• Circular episomal DNA persists • Latency-associated transcripts suppress lytic genes• Asymptomatic • Herpes simplex virus DNA may be shed in tears without lesions
4. Reactivation• Stimuli → lytic gene expression → anterograde transport → cornea• Recurrent epithelial / stromal keratitis
5. Immunopathology• CD4-positive T cells, macrophages, complement → stromal destruction• Disciform endotheliitis / necrotizing stromal keratitis

3. Classification of HSK

TypeMechanismHallmark SignCorneal SensationFluoresceinSteroids
Epithelial - DendriticDirect viral cytopathic effect (CPE)• Dendritic ulcer • Terminal bulbsDecreased; degree variablePositive staining of ulcer baseCONTRAINDICATED during active epithelial disease
Epithelial - GeographicEnlarged or coalesced dendritic lesion• Large amoeboid/geographic ulcerDecreased; degree variablePositive over epithelial ulcerCONTRAINDICATED during active epithelial disease
Epithelial - Marginal• Infectious epithelial herpes simplex virus (HSV) keratitis • Often greater inflammation near the limbus• Peripheral marginal ulcerDecreased; degree variablePositive over epithelial marginal ulcerCONTRAINDICATED during active epithelial disease
Stromal - ImmunePredominantly immune-mediated inflammation triggered by retained herpes simplex virus (HSV) antigens• Stromal inflammation • Wessely immune ring may be presentDecreased; degree variableUsually negative when the epithelium is intactYES - with antiviral cover and after active epithelial disease is excluded or controlled
Stromal - Necrotizing• Direct viral injury • Immune injury • Severe phenotype• Dense infiltrate • Necrosis • Ulceration and perforation riskMay be markedly reduced; complete absence not universalPositive when epithelial defect or ulceration is presentUse cautiously with therapeutic-dose antiviral cover and close supervision
Endotheliitis - DisciformAssociated with active herpes simplex virus (HSV) infection in the anterior chamber• Central or paracentral focal disc-shaped stromal edema • Keratic precipitates • Possible anterior uveitisMay be reduced; degree variableUsually negative when the epithelium is intactYES - with antiviral cover, generally after antiviral treatment has been initiated and with monitoring
MetaherpeticNeurotrophic - NOT active virus• Persistent oval epithelial defect • Smooth, heaped-up, or rolled edgesReduced or absentPositive over the persistent epithelial defect (PED)Generally avoid; intensive lubrication is recommended, with only carefully supervised exceptions
  • The mechanism drives the treatment.
  • Epithelial herpes simplex keratitis = antiviral therapy with or without debridement.
  • Stromal or disciform herpes simplex keratitis = corticosteroids only under antiviral cover.
  • Metaherpetic keratitis = neurotrophic, not active viral disease. Antiviral therapy has no role. Avoid corticosteroids when an epithelial defect is present; if stromal inflammation coexists, cautiously supervised diluted corticosteroids may be considered. Use intensive preservative-free lubrication; refractory or severe cases may require tarsorrhaphy.

4. Clinical Features in Detail

A. Herpes Simplex Virus Epithelial Keratitis

The true dendritic ulcer, with characteristic branching morphology and terminal bulbs, is highly suggestive of herpes simplex keratitis. Understanding its morphology is exam-critical:

FeatureDendritic Ulcer (Herpes Simplex Keratitis)Pseudodendrite (Herpes Zoster Ophthalmicus)Pseudo-dendrite (Acanthamoeba)
Morphology• True branching • Linear with dichotomous branching• Raised branching “stuck-on” mucous plaques • Tapered ends• Pseudodendritiform epitheliopathy • Irregular, coarse, or gray-dirty epithelial changes
Terminal bulbs• Present • Characteristic distinguishing feature • Not strictly pathognomonic• Typically absent • Distinguishing feature• Absent
Epithelial staining• Fluorescein positive at the base • Rose bengal positive at the edges• Rose bengal positive in elevated epithelium• Fluorescein variable
Sensation• Decreased • Degree variable• May be decreased with ophthalmic-division involvement • Degree varies• May be decreased early • Preservation is not a reliable distinguishing feature
Location• Often central • May also be eccentric or paracentral• May occur with herpes zoster ophthalmicus • Associated with the ophthalmic trigeminal dermatome • Not necessarily paracentral• Early pseudodendritiform epitheliopathy • A stromal ring infiltrate may develop later
Management• Antiviral therapy • Topical or systemic• Systemic acyclovir or valacyclovir • Recommended broadly for herpes zoster ophthalmicus • Not specifically for the pseudodendritic lesion alone• Topical anti-amoebic therapy • Commonly polyhexamethylene biguanide and/or chlorhexidine • These are anti-amoebic, not antiviral, agents

B. Stromal Keratitis - Disciform

  • Wessely immune ring: Antigen-antibody precipitate at the leading edge of stromal infiltration - represents immune complex deposition, NOT active viral replication
  • Disciform edema: Central or paracentral disc of stromal edema with intact overlying epithelium
  • Keratic precipitates (KPs): Fine, stellate keratic precipitates on posterior cornea (endotheliitis component)
  • Iridocyclitis: Mild, sectoral; distinguish from pure endotheliitis
  • Intraocular pressure (IOP): May be elevated due to trabecular inflammation (trabeculitis)
  • Descemet's folds: Associated with stromal edema

C. Endotheliitis (Distinct Entity)

TypePatternKey Feature
Disciform• Central endothelial involvement• Coin-shaped corneal edema with keratic precipitates (KPs) in a disc distribution
Diffuse• Pan-endothelial involvement• Diffuse stromal edema • Keratic precipitates (KPs) throughout the entire cornea • May be associated with a retrocorneal plaque or hypopyon
Linear• Linear keratic precipitate (KP) distribution, also termed a Khodadoust line• Advances from the limbus • Separates involved edematous cornea from uninvolved clear cornea
  • Linear endotheliitis: The Khodadoust line represents an advancing front of immune reaction along the endothelium - a line of keratic precipitates separating edematous from clear cornea.
  • A Khodadoust line is characteristic of endothelial corneal graft rejection; linear keratic precipitates in herpes simplex virus (HSV) endotheliitis can resemble a Khodadoust line.

D. Neurotrophic Keratopathy (Metaherpetic)

Stage (Mackie)FeaturesManagement
Stage 1• Superficial punctate keratitis • Tear film abnormality• Lubricants • Punctal plugs
Stage 2• Persistent epithelial defect (PED) • Oval shape • Rolled edges • No stromal infiltrate• Lubricants • Bandage contact lens (BCL) • Serum eye drops
Stage 3• Stromal ulceration • Melting • Perforation• Amniotic membrane • Tarsorrhaphy • Corneal glue • Penetrating keratoplasty (PKP)
  • Neurotrophic persistent epithelial defect (PED) without evidence of active herpes simplex virus (HSV) replication: antiviral treatment does not treat the neurotrophic defect; use or continue antiviral prophylaxis when clinically indicated, and reassess for active infection if the diagnosis is uncertain.
  • In an isolated neurotrophic persistent epithelial defect (PED), avoid or minimize topical corticosteroids because they can impair epithelial recovery and may reactivate or worsen epithelial herpes simplex virus (HSV) disease; use corticosteroids only when a clear inflammatory stromal indication exists and with appropriate antiviral coverage.
  • Cenegermin (recombinant human nerve growth factor) is the first United States Food and Drug Administration-approved pharmacologic treatment for neurotrophic keratitis (Oxervate; initial United States approval in 2018).

5. Investigations

Clinical Approach to Investigations

  • Herpes simplex keratitis (HSK) is largely a clinical diagnosis. Investigations are reserved for atypical presentations, treatment-resistant disease, immunocompromised patients, or pre-keratoplasty workup.
InvestigationTechnique/SampleClinical Use
Polymerase chain reaction (PCR)• Corneal scraping • Aqueous humor • Tears• Mainstay of laboratory confirmation • Atypical or clinically uncertain disease
Viral culture (laboratory gold standard)• Corneal scraping • Active lesion • Requires viable infectious material• Less used - time-consuming • Drug-sensitivity testing • Strain identification
Immunofluorescence• Corneal cells • Herpes simplex virus (HSV) antibody• Relatively rapid laboratory test • Detects herpes simplex virus (HSV) antigen
Impression cytology• Superficial corneal cells• Detect multinucleated giant cells
Confocal microscopy• In vivo imaging• Sub-basal nerve plexus changes • Stromal immune cells
Anterior segment optical coherence tomography (AS-OCT)• Non-invasive imaging• Measure stromal edema • Monitor disciform disease • Monitor endotheliitis
Aqueous humor polymerase chain reaction (PCR)• Anterior chamber paracentesis• Endotheliitis • Uveitis with herpes simplex virus (HSV), varicella-zoster virus (VZV), or cytomegalovirus (CMV) in the differential diagnosis
Specular microscopy• Endothelial cell density• Assess endothelial cell density • Monitor postoperative endothelial cell loss

Confocal Microscopy in Herpes Simplex Keratitis - Emerging Role

  • Sub-basal nerve plexus: reduced nerve density, total nerve count, and main nerve trunks correlate with reduced corneal sensation in herpes simplex keratitis
  • Dendritic inflammatory cells may be visible at the deep epithelium to sub-basal nerve plexus during active herpes simplex keratitis
  • Stroma: honeycomb-shaped hyperreflective keratocytes may suggest stromal edema
  • May aid the differential diagnosis of infectious keratitis by demonstrating Acanthamoeba cysts and fungal hyphae

Aqueous Tap Polymerase Chain Reaction (PCR) - Indications

  • Endotheliitis not responding to empirical therapy
  • Consider aqueous humor polymerase chain reaction testing when viral endotheliitis or anterior uveitis is suspected, particularly with atypical or corticosteroid-refractory disease; bilateral keratitis alone is not a specific indication
  • Differentiate herpes simplex virus, varicella-zoster virus, and cytomegalovirus because the result guides targeted antiviral therapy; cytomegalovirus disease is generally treated with ganciclovir or valganciclovir rather than relying on acyclovir
  • Pre-keratoplasty in active/suspected herpes simplex virus uveitis
  • Atypical presentation with elevated intraocular pressure and keratic precipitates (Posner–Schlossman differential diagnosis)

6. Management - Evidence-Based

The Herpetic Eye Disease Study (HEDS) Trials - Foundation of Herpes Simplex Virus (HSV) Keratitis Management

HEDS 1 Trial
HEDS 1 Trial
Herpetic Eye Disease Study (HEDS) 1 TrialInterventionKey FindingsClinical Practice
• Herpetic Eye Disease Study Stromal Keratitis, No Steroid (HEDS-SKN)• Topical prednisolone phosphate + trifluridine • Placebo + trifluridine• Steroid reduced treatment failure • Steroid shortened disease duration • Steroid reduced persistent/progressive stromal keratouveitis by 68%• Topical corticosteroid is beneficial in herpes simplex virus (HSV) stromal keratitis • Use when active epithelial herpes simplex virus (HSV) is absent • Give antiviral cover
• Herpetic Eye Disease Study Stromal Keratitis, On Steroid (HEDS-SKS)• Oral acyclovir 400 mg 5×/day × 10 weeks • Placebo • Topical steroid + trifluridine• No significant additional benefit from oral acyclovir for acute stromal keratitis• Oral acyclovir is not routinely required solely to improve acute stromal-keratitis treatment outcome
• Herpetic Eye Disease Study Iridocyclitis Trial (HEDS-IRT)• Oral acyclovir 400 mg 5×/day × 10 weeks • Placebo • Topical steroid + trifluridine• Trial was underpowered • No statistically significant benefit demonstrated • Trend suggested benefit with oral acyclovir• Do not claim oral acyclovir is proven ineffective • Evidence was inconclusive, with a trend suggesting benefit in herpes simplex virus (HSV) iridocyclitis treated with topical corticosteroid and trifluridine
Heds 2
Heds 2
Herpetic Eye Disease Study 2 TrialInterventionKey FindingsClinical Practice
Herpetic Eye Disease Study Epithelial Keratitis Trial• Topical trifluridine plus oral acyclovir versus topical trifluridine plus placebo• Oral acyclovir did not prevent subsequent stromal keratitis or iritis• Do not give oral acyclovir routinely just to prevent stromal disease after epithelial keratitis
Herpetic Eye Disease Study Prophylaxis• Oral acyclovir 400 milligrams twice daily for 12 months versus placebo• Any ocular herpes simplex virus recurrence: 19% versus 32% • In prior stromal keratitis: stromal recurrence 14% versus 28%• Long-term oral antiviral suppression is proven to reduce recurrent herpes simplex virus ocular disease, particularly in patients with previous stromal keratitis
Herpetic Eye Disease Study Recurrence-Factor Study• Psychological stress • Systemic illness • Sunlight exposure • Menstruation • Contact-lens wear • Trauma • Assessed as triggers of ocular herpes simplex virus recurrence• No significant association with psychological stress • No significant association with systemic illness • No significant association with contact-lens wear • Menstrual-period assessments had limited statistical power • Eye-injury assessments had limited statistical power • Number of previous ocular herpes simplex virus episodes was the only baseline or historical factor identified as a strong predictor of recurrence• No clear trigger was established by the Herpetic Eye Disease Study Recurrence-Factor Study • Higher numbers of previous ocular herpes simplex virus episodes indicate higher recurrence risk • Do not attribute the strong-predictor finding specifically to previous stromal keratitis in this study

Antiviral Drugs - Mechanism & Pharmacology

DrugClassMechanismDosing (Keratitis)Notes
Acyclovir (ACV)Nucleoside analogue• Viral thymidine kinase (TK) phosphorylates acyclovir • Acyclovir triphosphate inhibits viral deoxyribonucleic acid (DNA) polymerase• Topical 3% ointment: five times daily until the corneal ulcer heals, then three times daily for 7 days • Oral: 400 mg five times daily for 5–10 days for epithelial keratitis• Established treatment for epithelial keratitis • Oral acyclovir has lower bioavailability than valacyclovir and generally requires more frequent dosing
ValacyclovirAcyclovir prodrug• L-valyl ester prodrug • Rapidly converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism• 1,000 mg twice daily for 5–10 days for epithelial keratitis • 500 mg once daily for suppression• Substantially higher oral bioavailability than acyclovir • Approximately 54.5% versus approximately 10%–20%
Ganciclovir 0.15% gelNucleoside analogue• Viral thymidine kinase (TK) activation • Ganciclovir triphosphate competitively inhibits deoxyribonucleic acid (DNA) polymerase• 1 drop five times daily until healed • Then three times daily for 7 days• May have lower toxicity potential than trifluridine (TFT) • Direct human comparative trials are limited
Trifluridine (TFT) 1%Fluorinated pyrimidine nucleoside• Antiviral mechanism not completely known• 1 drop every 2 hours while awake, maximum 9 drops/day, until re-epithelialization • Then 1 drop every 4 hours while awake for 7 days• Clinically important epithelial toxicity, particularly with prolonged or frequent use • Prolonged use may cause punctal stenosis • Avoid continuous use beyond 21 days
FoscarnetPyrophosphate analogue• Direct inhibition of viral deoxyribonucleic acid (DNA) polymerase at the pyrophosphate-binding site • Viral thymidine kinase (TK)-independent• Intravenous (IV) for acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infection in immunocompromised patients • Topical ophthalmic use is off-label and compounded• Alternative for acyclovir-resistant herpes simplex virus (HSV), including thymidine-kinase-mutant strains • Ophthalmic keratitis evidence is limited
CidofovirAcyclic nucleotide analogue of deoxycytidine monophosphate• Converted to cidofovir diphosphate by cellular kinases • Does not require viral thymidine kinase (TK) phosphorylation• Intravenous (IV) cidofovir is indicated for cytomegalovirus retinitis • Topical ophthalmic use for acyclovir-resistant herpes simplex virus (HSV) is compounded and off-label • No established subconjunctival regimen was identified• Renal toxicity is clinically important • Direct intraocular injection of commercial cidofovir is contraindicated because of ocular toxicity

Steroid Use in Herpes Simplex Virus Keratitis (HSK) - The Nuanced Approach

  • Steroids in herpes simplex virus keratitis (HSK) follow a “double-edged sword” principle: they suppress immunopathology in stromal/disciform disease but may worsen active epithelial herpes simplex virus keratitis (HSK).
  • Memorize the rule: When corticosteroids are used for herpes simplex virus stromal keratitis (HSK), use concomitant antiviral therapy.
Herpes simplex virus keratitis (HSK) typeSteroidsAntiviral cover requiredRationale
Epithelial (dendritic/geographic)AVOIDYes (treat infection)• Topical corticosteroids may worsen active epithelial herpes simplex virus keratitis (HSK). • They may promote enlargement of dendritic lesions into geographic ulcers.
Marginal ulcerCautious, low-potency steroid if significant inflammationNo antiviral if purely immune-mediated; topical/oral antiviral if epithelial herpes simplex virus (HSV) is present• Immune-mediated peripheral inflammation. • Exclude active epithelial herpes simplex virus (HSV).
Disciform / non-necrotizing stromalYES - 1st lineOral antiviral preferred - acyclovir / valacyclovir; topical antiviral may also be used• Predominantly immune-mediated inflammation/endothelial dysfunction. • Antiviral suppresses potential viral replication during steroid therapy.
Necrotizing stromalAvoid topical corticosteroids initially; introduce cautiously after initial antiviral therapySystemic/oral antiviral - strongly indicated ± topical antiviral• Both active viral replication and immune-mediated stromal destruction. • High risk of melt/perforation.
EndotheliitisYES - 1st line (topical)Oral antiviral preferred ± topical antiviral• Herpes simplex virus (HSV) endothelial dysfunction with inflammatory response. • Steroid controls inflammation while antiviral suppresses replication.
Metaherpetic (neurotrophic)Avoid routine corticosteroids; if significant inflammation requires treatment, use cautiously with close monitoringNOT required (no active virus)• Corticosteroids may delay epithelial healing. • Corticosteroids may inhibit stromal healing and increase the risk of stromal melting or perforation.

Suppressive Therapy Protocol

  • Indication: Consider suppressive therapy after herpes simplex virus stromal keratitis or in patients with multiple prior ocular herpes simplex virus recurrences.
  • Regimen: Acyclovir 400 mg twice daily OR valacyclovir 500 mg once daily (equivalent efficacy in a pilot randomized trial).
  • Duration: 12 months of suppressive acyclovir was studied; individualize any longer duration according to recurrence risk and clinical context.
  • Herpetic Eye Disease Study Acyclovir Prevention Trial: 50% reduction in stromal recurrence; 45% reduction in all recurrences.
  • Resistance monitoring: Breakthrough on suppression → consider acyclovir resistance testing.
  • Post-keratoplasty: Use oral antiviral prophylaxis; at least 12 months has been studied. Individualize longer duration. Herpes simplex keratitis recurrence in the graft is associated with graft failure.

7. Surgical Management & Keratoplasty

Surgical Decision-Making Framework

  • Surgery in herpes simplex keratitis is governed by one principle: operate in quiet disease.
  • Active inflammation at the time of keratoplasty is associated with poorer graft outcomes.
  • The threshold is: at least 6 months of clinical quiescence before elective penetrating keratoplasty.
IndicationProcedureTimingSpecial Considerations
• Corneal perforation (small <2 mm)• Corneal glue (cyanoacrylate) + bandage contact lens (BCL)• Emergency• Buy time • Avoid emergency penetrating keratoplasty (PKP) in an inflamed eye
• Corneal perforation (>2 mm)• Tectonic penetrating keratoplasty (PKP) or patch graft• Emergency/urgent• High graft failure risk • Cover with systemic acyclovir
• Dense central scarring (quiet)• Penetrating keratoplasty (PKP)• Elective after a sustained period of quiescence, commonly at least 6 months• Established option for severe or full-thickness herpes simplex virus (HSV) keratitis scars • Particularly relevant when the endothelium is involved
• Scarring limited to stroma (quiet)• Deep anterior lamellar keratoplasty (DALK)• Elective• Preferred over penetrating keratoplasty (PKP) for suitable stromal scarring • Preserves the host endothelium • Reduces endothelial-graft rejection risk
• Endothelial decompensation (endotheliitis)• Descemet membrane endothelial keratoplasty (DMEK) may be considered• After active disease is controlled• Endothelial-only replacement • Possible option for persistent corneal edema after herpes simplex virus (HSV) endotheliitis • Antiviral prophylaxis is used
• Neurotrophic persistent epithelial defect (PED) (Stage 3)• Amniotic membrane transplantation (AMT)• Selected according to severity, stromal involvement, and response to medical therapy• Sutured graft or sutureless self-retaining device such as ProKera® • Therapeutic contact lens may be used when appropriate
• Lid-related exposure or inadequate closure• Lateral or central tarsorrhaphy• When clinically indicated• Reduces corneal exposure and eyelid-related friction • Protects the healing corneal epithelium • Symblepharon generally requires targeted release with a suitable barrier or graft

Deep Anterior Lamellar Keratoplasty (DALK) vs Penetrating Keratoplasty (PKP) in Herpes Simplex Keratitis - The Key Debate

ParameterDeep Anterior Lamellar Keratoplasty (DALK)Penetrating Keratoplasty (PKP)
EndotheliumHost endothelium retainedDonor endothelium
Rejection risk• No endothelial rejection • Stromal rejection is rare• Full immunological rejection possible
Herpes simplex keratitis recurrence in graft• Lower in a comparative full-bed deep lamellar keratoplasty series • Recurrence can still occur • Mechanism not established• Higher in the comparative series
Technique• Big-bubble (Anwar) technique widely used • Melles technique is an alternative • Hydrodelamination is an alternativeStandard through-and-through trephination
Failure → conversionCan convert to penetrating keratoplasty (PKP) if Descemet membrane perforation occurs intraoperativelyNot applicable
Preferred in herpes simplex keratitis?Yes - especially stromal scars with healthy endotheliumWhen endothelium is involved or deep anterior lamellar keratoplasty (DALK) is technically impossible
Suppressive antiviral• Postoperative oral antiviral prophylaxis • Commonly continued for at least 12 months • Duration individualized• Postoperative oral antiviral prophylaxis • Evidence supports 6–12 months or longer when clinically indicated • Optimal duration is not established

Operative Pearls - HSK Keratoplasty

  • Start oral acyclovir before or just after penetrating keratoplasty; continue for at least 6–12 months; optimal dose and duration are not established.
  • Trephine a 0.25–0.5 mm oversized donor button in penetrating keratoplasty; whether this reduces peripheral limbal stress in herpes simplex virus keratitis remains uncertain.
  • Peripheral corneal neovascularization: consider preoperative fine-needle thermal cauterization combined with subconjunctival bevacizumab to regress pathological vessels before high-risk penetrating keratoplasty; controlled-trial evidence is needed.
  • High-risk vascularized beds: at least two quadrants of deep stromal vessels. Do not routinely rely on human leukocyte antigen matching to reduce rejection.
  • Postoperative corticosteroids should be tapered gradually according to graft inflammation and rejection risk, with antiviral prophylaxis continued during corticosteroid therapy; the optimal taper duration is individualized and not universally established.
  • Recurrence in the graft: determine the clinical phenotype. Treat epithelial recurrence with topical and/or systemic antiviral therapy and avoid topical corticosteroids until the epithelium has healed; treat stromal or endothelial recurrence with appropriate corticosteroid therapy under systemic antiviral cover.
  • Descemet membrane endothelial keratoplasty is a promising option for persistent corneal edema after herpes simplex virus endotheliitis in selected eyes; operate when inflammation is clinically controlled, counsel regarding recurrence, and continue perioperative antiviral management. Reported outcomes are encouraging but recurrence remains possible.

8. Management Algorithm (Flowchart)

Epithelial (Dendrite/Geographic)

  • Ganciclovir gel five times daily OR acyclovir ointment five times daily
  • NO topical corticosteroids during active epithelial herpes simplex virus keratitis
  • Trifluridine is an alternative topical antiviral treatment for epithelial herpes simplex virus keratitis
  • Epithelial debridement may be used as an adjunct to antiviral therapy in selected cases

Stromal / Disciform

  • Oral acyclovir 400 mg twice daily OR oral valacyclovir 500 mg once daily
  • Topical prednisolone 1% (slow taper)
  • Mandatory antiviral cover throughout corticosteroid therapy
  • Monitor intraocular pressure

Endotheliitis

  • Aqueous polymerase chain reaction (PCR) testing to distinguish herpes simplex virus from cytomegalovirus
  • Topical corticosteroid + systemic acyclovir (ACV)
  • Ganciclovir if cytomegalovirus is confirmed
  • Specular microscopy

Neurotrophic / Metaherpetic

  • For metaherpetic keratitis without active viral infection, antiviral therapy is not routinely required; assess for concurrent or recurrent herpetic disease.
  • Avoid or minimize corticosteroids; if clinically necessary for significant inflammation, use cautiously with appropriate herpetic disease assessment and antiviral cover when indicated.
  • Lubricants, bandage contact lens, serum drops
  • Cenegermin (Oxervate) for neurotrophic keratitis, particularly persistent epithelial defects or ulcers
  • Amniotic membrane transplantation or tarsorrhaphy as needed

After Acute Episode - Assess for Suppression

  • Suppressive therapy: consider for frequent recurrences, especially recurrent stromal keratitis, and after herpetic keratoplasty; the exact recurrence threshold should be individualized.
  • Regimen: oral acyclovir 400 mg twice daily or oral valacyclovir 500 mg once daily for 12 months; extend duration when clinically indicated, including selected high-risk post-keratoplasty cases.
  • Surgical: corneal scarring with healthy endothelium → deep anterior lamellar keratoplasty (DALK); deep scarring or endothelial compromise → penetrating keratoplasty (PKP).
  • Operate after a sustained quiescent period, commonly at least 6 months.
  • Use prolonged postoperative oral antiviral prophylaxis; duration should be individualized rather than routinely lifelong.

9. Differential Diagnosis & Special Scenarios

Differential Diagnosis

FeatureHerpes simplex keratitis (HSK)Herpes zoster ophthalmicus (HZO) keratitisAcanthamoeba keratitisCytomegalovirus (CMV) endotheliitis
• Cause• Herpes simplex virus type 1• Varicella-zoster virus• Acanthamoeba species• Cytomegalovirus
• Dendritic ulcer• TRUE dendrite • Terminal bulbs• Pseudodendrite • Mucous plaque• No true dendrite• Not applicable
• Pain• Moderate• Severe • Pre-eruptive neuralgia• EXCRUCIATING • Disproportionate to signs• Mild
• Skin lesions• Perioral cold sores • History• Dermatomal vesicles • Ophthalmic division (V1)• None• None
• Laterality• Usually unilateral• Unilateral • Dermatomal• Usually unilateral • Contact-lens wearers• Unilateral
• Contact lens• Not a risk factor• Not a risk factor• MAJOR risk factor• Not a risk factor
• Ring infiltrate• Wessely ring • Stromal• Rare• Classic Acanthamoeba ring• Not seen
• Intraocular pressure (IOP) elevation• Trabeculitis • Moderate• Common• Rare early• HALLMARK • High intraocular pressure (IOP) + keratic precipitates (KP)
• Sensation• Reduced• Markedly reduced• May be preserved early• Reduced
• Treatment• Acyclovir• Valacyclovir • Higher dose• Polyhexamethylene biguanide or chlorhexidine • Often with a diamidine• Ganciclovir or valganciclovir
• Confocal microscopy• Reduced nerve density • Dendritic cells in stroma• Similar nerve changes• Cysts • Pathognomonic• Owl's-eye endothelial cells may be visible on confocal microscopy • Endothelial changes

Special Scenarios

Herpes simplex keratitis in immunocompromised patients

  • Higher risk of bilateral disease, more aggressive course, or atypical presentation
  • Acyclovir-resistant herpes simplex keratitis is more common; consider foscarnet and resistance testing when feasible
  • Consider aqueous polymerase chain reaction for cytomegalovirus and herpes simplex virus when the presentation is atypical, refractory, or suggests viral endotheliitis or anterior uveitis
  • Use valacyclovir or another anti-herpes antiviral for selected high-risk patients with human immunodeficiency virus infection or transplantation according to immune status, transplant phase, rejection treatment, and ocular disease; prophylaxis is not universally indefinite

Herpes simplex keratitis (HSK) in Pregnancy

  • Acyclovir and valacyclovir are considered low risk in pregnancy.
  • Available human data have not shown an increased risk of major birth defects, although data remain limited and treatment should be clinically indicated.
  • Topical or oral antiviral therapy may be used for epithelial herpes simplex keratitis; no evidence establishes topical therapy as universally preferred during the first trimester.
  • Active genital herpes simplex virus infection or viral shedding at delivery carries a risk of neonatal herpes; risk is highest when genital infection is newly acquired near term.
  • For recurrent genital herpes, suppressive treatment beginning at 36 weeks may be prescribed with oral acyclovir 400 milligrams (mg) three times daily or oral valacyclovir 500 milligrams (mg) twice daily.
  • Suppressive treatment reduces recurrences at term but does not eliminate neonatal transmission risk.

Herpes Simplex Virus Keratitis and Refractive Surgery (Laser-Assisted In Situ Keratomileusis/Photorefractive Keratectomy)

  • History of herpes simplex virus keratitis: relative contraindication to laser-assisted in situ keratomileusis; consider only if disease has been quiescent for at least 1 year and there is no prior stromal disease
  • Photorefractive keratectomy does not eliminate herpes simplex virus reactivation risk; both photorefractive keratectomy and laser-assisted in situ keratomileusis can trigger reactivation
  • Consider perioperative systemic antiviral prophylaxis when performing refractive surgery in a patient with a history of herpes simplex virus keratitis
  • After laser-assisted in situ keratomileusis, distinguish herpes simplex virus keratitis reactivation from diffuse lamellar keratitis

Acyclovir-Resistant Herpes Simplex Virus Keratitis (HSK)

  • Suspect if lesions show no signs of resolution within 7–10 days despite adequate acyclovir therapy, especially in an immunocompromised patient
  • Mechanism: thymidine kinase (TK) gene mutation is most common
  • Deoxyribonucleic acid (DNA) polymerase gene mutations are less common
  • Confirm with viral culture
  • Perform antiviral susceptibility testing when virus is isolated
  • Treatment option: foscarnet, administered intravenously or topically; it does not require activation by viral thymidine kinase
  • Topical foscarnet evidence is limited mainly to small reports and case series
  • Alternative treatment: cidofovir, used off-label or as a compounded preparation; clinical evidence is limited
  • Trifluridine does not require prior activation by viral thymidine kinase and may retain activity against thymidine-kinase-deficient strains

10. Emerging Concepts & Future Directions

  • Herpes simplex virus vaccine programs: No licensed vaccine exists for either herpes simplex virus type. GEN-003 was an investigational therapeutic subunit vaccine for recurrent genital herpes simplex virus type 2 infection; it was not an ophthalmic herpes simplex keratitis vaccine.
  • Gene editing using clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9 (CRISPR-Cas9): Experimental approaches target herpes simplex virus genomes, including latent reservoirs in trigeminal ganglia, to reduce reactivation; published herpes simplex keratitis studies remain preclinical, including mouse models.
  • Small interfering ribonucleic acid antivirals: Small interfering ribonucleic acid (siRNA) targeting infected-cell polypeptide 4 (ICP4), an early transcriptional activator required for productive herpes simplex virus type 1 (HSV-1) replication, has shown antiviral activity in preclinical ocular models; topical ocular delivery remains under development.
  • Topical ciclosporin A 0.05%: Its adjunctive use with antiviral therapy and topical corticosteroid therapy for herpetic stromal keratitis has limited clinical evidence and remains investigational. Systemic ciclosporin was not detected after topical ocular administration of the 0.05% emulsion.
  • Corneal confocal microscopy as a biomarker: Sub-basal nerve plexus density is an emerging research measure associated with herpes simplex virus keratitis severity and nerve regeneration; its use as a validated treatment-response biomarker or clinical-trial endpoint remains unestablished.
  • Descemet membrane endothelial keratoplasty for herpes simplex virus endotheliitis: Selected case reports and a retrospective case series describe favorable graft clarity and visual outcomes for irreversible or recurrent endothelial decompensation, generally with perioperative oral antiviral therapy; evidence remains limited and recurrence can occur.
  • Brincidofovir (lipid-conjugated cidofovir): Oral bioavailability and a favorable renal-safety profile compared with intravenous cidofovir have been demonstrated in clinical studies; use for acyclovir-resistant herpes simplex keratitis remains investigational and is not an established ophthalmic treatment.

11. Viva Pearls & Emerging Concepts

  1. Terminal bulbs are characteristic of a herpes simplex virus dendrite; their absence does not exclude herpes simplex virus keratitis.
  2. Wessely immune ring = noninfectious stromal immune infiltrate associated with antigen–antibody complexes; it does not by itself establish active viral replication or viral clearance.
  3. Assess corneal sensation in suspected herpes simplex virus keratitis; a cotton-wisp comparison with the fellow eye is a practical bedside test, and hypoesthesia is a useful clinical clue.
  4. Herpetic Eye Disease Study prevention trial: oral acyclovir 400 mg twice daily for 12 months reduced recurrence from 28% to 14% in patients with prior stromal disease, supporting suppressive therapy during treatment.
  5. Rose Bengal stains devitalized epithelium at dendrite edges; fluorescein stains the ulcer base - both useful, different information.
  6. Metaherpetic ulcer (neurotrophic) = persistent epithelial defect with reduced corneal sensation; manage with neurotrophic support. Antivirals are not indicated when there is no active viral infection.
  7. Cytomegalovirus endotheliitis clue: coin-shaped keratic precipitates with corneal edema and raised intraocular pressure in an immunocompetent patient; confirm the viral cause and treat cytomegalovirus disease with ganciclovir-based therapy plus appropriate anti-inflammatory treatment.
  8. Deep anterior lamellar keratoplasty preferred over penetrating keratoplasty in herpes simplex virus keratitis with healthy endothelium - eliminates endothelial rejection and reduces graft recurrence.
  9. Aqueous humor polymerase chain reaction can help differentiate herpes simplex virus, varicella-zoster virus, and cytomegalovirus endotheliitis and guide targeted antiviral treatment when the diagnosis is uncertain.
  10. Acyclovir is phosphorylated by viral thymidine kinase to acyclovir triphosphate, which inhibits herpes simplex virus deoxyribonucleic acid polymerase; resistance most commonly involves thymidine kinase mutations but may also involve deoxyribonucleic acid polymerase mutations.
  11. Bilateral herpes simplex virus keratitis should prompt assessment for immunosuppression and relevant systemic risk factors; consider human immunodeficiency virus testing and further immune evaluation when clinically indicated.
  12. After penetrating keratoplasty for herpes simplex virus keratitis, long-term oral antiviral prophylaxis is generally recommended, commonly for at least 1 year; longer or indefinite treatment should be individualized according to recurrence risk and tolerance.
  13. Cenegermin (Oxervate® 0.002%) - authorized in the European Union in 2017 and approved by the United States Food and Drug Administration in 2018 for neurotrophic keratitis; the European indication is moderate or severe disease corresponding broadly to stages 2 and 3.
  14. Ganciclovir 0.15% gel is indicated for acute dendritic herpetic keratitis in adults and pediatric patients aged 2 years and older; contact lenses should not be worn during treatment. Trifluridine should not be continued beyond 21 days because of potential ocular toxicity.
  15. In herpes simplex virus keratitis with raised intraocular pressure, use appropriate pressure-lowering therapy. Prostaglandin analogues may be avoided when clinically feasible because reactivation has been reported, but the association remains uncertain and controversial.

12. Consultant-Level MCQ Traps & Viva Pearls

MCQ

Q1. MCQ TRAP: A 34-year-old patient with HSK presents with a dendritic ulcer. The resident prescribes topical prednisolone 1% along with acyclovir ointment. What is the expected outcome?

MCQ

Q2. A patient with known HSK and previous PKP presents with a recurrence of HSK in the graft. The best immediate management is:

MCQ

Q3. The Khodadoust line in HSV endotheliitis represents:

MCQ

Q4. MCQ TRAP: A 28-year-old CL wearer presents with a ring infiltrate. Confocal microscopy shows double-walled cysts in the stroma. What is the diagnosis and how does the dendrite differ from HSK?

MCQ

Q5. Cenegermin (Oxervate®) is used in which type of HSK-related condition?

13. Advanced Consultant-Level Question

Consultant-level oral-exam question

A 45-year-old immunocompetent patient presents with recurrent bilateral stromal HSK - fourth episode in 3 years, now on acyclovir 400mg BD as suppressive therapy. Examination reveals a large central corneal scar in the right eye and an active disciform keratitis in the left with 4 quadrants of superficial neovascularization. The patient is keen on bilateral corneal grafting. Questions to consider:

  1. What is your pre-operative workup and optimisation strategy for the vascularised left eye?
  2. What surgical technique is preferred and why, given the clinical findings?
  3. How do you manage the apparent suppression failure on acyclovir 400mg BD?
  4. What HLA-matching strategy would you employ and what is the evidence base?
  5. What is the long-term immunosuppression protocol post-bilaterally and how do you balance systemic side effects with graft survival?
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