This document discusses the management of herpes simplex virus (HSV) keratitis. It provides details on the diagnosis, which is primarily clinical but can be confirmed via viral culture from samples taken within days of onset. Cytopathological examination of corneal scrapings can show characteristic findings. Treatment involves antiviral agents like acyclovir administered topically or orally to eradicate the live virus. Corticosteroids are used topically to suppress inflammation and minimize scarring. Management depends on the type and severity of keratitis, with stromal keratitis generally requiring stronger treatment than epithelial keratitis.

1. MANAGEMENT OF HSV
KERATITIS
DR. POOJA SHUKLA
SRI SANKARADEVA NETHRALAYA
GUWAHATI, ASSAM, INDIA

2. DIAGNOSIS
• PRIMARILY CLINICAL
• DEFINITIVE DIAGNOSIS – VIRAL CULTURE
• EARLY CULTURING – WITHIN DAYS OF ONSET
• INCUBATION UPTO 1 WEEK
• SAMPLE SHOULD BE OBTAINED BEFORE STAINING WITH ROSE
BENGAL
• 70-80 % ULCERS (SKIN / CORNEA ) ARE CULTURE POSITIVE

3. CYTOLOGICAL EXAMINATION
• TZANCK SMEAR :
• SCRAPINGS FROM CORNEAL EPITHELIUM / CONJUNCTIVA / LIDS
• PAPANICOLAOU / GIEMSA/ GRAMS / WRIGHTS
• MULTINUCLEATED GIANT CELLS AND EOSINIPHILLIC INTRANUCLEAR INCLUSION
BODIES ( COWDRY TYPE A )

4. CELL CULTURE
• GOLD STANDARD FOR LABORATORY TESTING OF HSV
• CLINICAL SAMPLES ARE INOCULATED TO MONOLAYERS OF A549, VERO, OR
OTHER SUSCEPTIBLE CELL LINES IN GLASS TEST TUBES.
• THE MONOLAYERS ARE MONITORED EVERY OTHER DAY FOR 2–3 WEEKS
FOR THE OBSERVATION OF CHARACTERISTIC CYTOPATHIC EFFECT (CPE – CELL
ROUNDING)

5. ELVIS (ENZYME LINKED VIRUS INDUCED
SYSTEM)
• CAN PRODUCE POSITIVE RESULTS WITHIN 24 HOURS
• 0.2 ML OF CLINICAL SPECIMEN IS CENTRIFUGED ON A SPECIALLY
ENGINEERED CELL LINE THAT PRODUCES BETA-GALACTOSIDASE WHEN HSV
VIRUS IS INTRODUCED INTO THE CELL.
• AFTER THE CLINICAL SPECIMEN IS ALLOWED TO INCUBATE ON THE CELL
LINE FOR 24 HOURS, THE CELL LINE IS FIXED AND A SUBSTRATE IS ADDED TO
REACT WITH THE BETAGALACTOSIDASE TO PRODUCE A BLUE COLOR WITHIN
THE CELLS, WHICH ARE OBSERVED WITH A LIGHT MICROSCOPE UNDER 10–40×
MAGNIFICATION
• 85% SENSITIVITY

7. • DIRECT FLUORESCENT ANTIBODY :
• HIGH SENSITIVITY AND SPECIFICITY / RAPID
• EXPENSIVE / REQUIRES EXPERTISE
• ELISA :
• THE HERPCHEK,
• VIROGEN-LATEX AGGLUTINATION,
• ENZYME IMMUNOFILTRATION,
• ONE-HOUR ENZYME LINKED IMMUNOASSAY
• CAN DETECT HSV ANTIGEN IN CELL CULTURE AND DIRECT SPECIMENS WITHIN FIVE
HOURS.

8. PCR
• SPECIFIC AND POSSIBLY MORE SENSITIVE THAN VIRAL CULTURES
• TARGETS VIRAL DNA POLYMERASE AND THYMIDINE KINASE

9. • SEROLOGY :
• IGM – PRIMARY DISEASE / CONVERSION TO IGG TAKES 2-4 WEEKS
• CAN BE USED TO DIFFERENTIATE PRIMARY HERPETIC INFECTION FROM FIRST
OCULAR OCCURRENCE OF RECURRENT DISEASE
• USEFUL IN CHILDREN AND IN YOUNG ADULTS – POSITIVE DENOTES A PRIMARY
INFECTIVE , NEGATIVE – RULES OUT INFECTION

10. MANAGEMENT
• GOALS OF TREATMENT :
• ERADICATION OF LIVE VIRUS
• DECREASE THE CHANCE OF FUTURE RECURRENCES
• MINIMIZE SCARRING FROM INFLAMMATION

11. HERPETIC EYE DISEASE STUDY
• A SET OF MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED TRIALS
1. TOPICAL CORTICOSTEROIDS IN TREATING STROMAL KERATITIS ALREADY ON A
TOPICAL ANTIVIRAL
2. ORAL ACYCLOVIR IN TREATING STROMAL KERATITIS ALREADY ON A TOPICAL
STEROID AND ANTIVIRAL
3. ORAL ACYCLOVIR IN TREATING IRIDOCYCLITIS ALREADY ON TOPICAL STEROID
4. ORAL ACYCLOVIR IN PREVENTING RECURRENCE OF EPITHELIAL AND STROMAL KERATITIS
5. DEMOGRAPHIC AND DISEASE-SPECIFIC PREDICTORS OF RECURRENT HSV KERATITIS
6. RISKFACTORS FOR RECURRENCE OF OCULAR HSV .

12. • CORTICOSTEROIDS FOR STROMAL KERATITIS :
• ALL PATIENTS IN THE TREATMENT GROUP RECEIVED THE SAME SCHEDULE OF
TOPICAL STEROID TAPER , REGARDLESS OF CLINICAL COURSE.
• AFTER FOUR WEEKS, PREDNISOLONE PHOSPHATE 1% WAS REDUCED TO ONCE
DAILY, AFTER SEVEN WEEKS A 0.125% CONCENTRATION EYE DROP WAS
REDUCED TO ONCE DAILY, FOR A TOTAL OF 10 WEEKS

13. • FAILURE :
• NEW FOCAL STROMAL INFLAMMATION
• OR INCREASE IN THE AREA OF INFLAMED CORNEA,
• INCREASE IN THE ANTERIOR CHAMBER REACTION BEYOND A CERTAIN PROPORTION
• TIME TO FAILURE :
• TREATMENT VS CONTROL : 26 % VS 73 % AT 10 WEEKS
• 49 % VS 76 % 6 WEEKS AFTER COMPLETION OF TREATMENT

14. • EFFICACY OF ORAL ACYCLOVIR IN THE TREATMENT OF HSV –ISK ALREADY ON
TOPICAL STEROID AND ANTIVIRAL TREATMENT
• 104 PATIENTS WITH HSV –ISK WHO HAD USED TOPICAL STEROID AND WERE NOT
ELIGIBLE FOR THE AFOREMENTIONED TOPICAL STEROID FOR STROMAL
KERATITIS HEDS TRIAL WERE RANDOMIZED TO ORAL ACYCLOVIR, 400 MG FIVE
TIMES DAILY OR PLACEBO.
• DURATION – 10 WEEKS WITH AN ADDITIONAL SIX-WEEK PERIOD OF
OBSERVATION AND A SIX-MONTH EVALUATION
• MARGINALLY SIGNIFICANT TREATMENT BENEFIT ON VISION AT SIX MONTHS

15. • ORALACYCLOVIR FOR IRIDOCYCLITIS, WHILE ON TOPICAL
STEROID AND ANTIVIRAL MEDICATIONS.
• THE GOAL OF 104 PATIENTS WAS HARDLY REACHED IN THIS TRIAL; WITH ONLY
50 PATIENTS RECRUITED IN FOUR YEARS, THE DECISION WAS MADE TO
END THE STUDY AND RELEASE THE RESULTS.

16. CONCLUSIONS
• ORAL ANTIVIRAL PROPHYLAXIS REDUCES RECURRENCES OF EPITHELIAL AND OF
STROMAL KERATITIS ALSO HELPS IN EARLY RESOLUTION
• USE OF TOPICAL CORTICOSTEROIDS IS OF BENEFIT IN STROMAL KERATITIS –
SIGNIFICANTLY LOWER TIME TO RESOLUTION
• USE OF ORAL ACYCLOVIR MAY BE OF HELP IN IRIDOCYCLITIS ALONGSIDE
TOPICAL STEROIDS AND TFT .
• PROPHYLACTIC ORAL ACYCLOVIR HELPS PREVENT RECURRENCES OF HERPETIC
KERATITIS, PARTICULARLY STROMAL WITH A HISTORY OF RECURRENCE

17. MEDICAL MANAGEMENT
• ANTIVIRAL AGENTS – TOPICAL AND ORAL
• STEROIDS – TOPICAL AND ORAL
• INTERFERON- ALPHA 2B
• CYCLOPLEGICS
• ANTIBIOTICS – TOPICAL BROAD SPECTRUM
• LUBRICANTS
• ANTI – VEGF

18. ANTIVIRAL AGENTS
1. IDU :
• EMPLOYED AS AN ANTICANCER AGENT IN THE EARLY 1950S
• A THYMIDINE ANALOG
• INCORPORATES INTO RNA, WHICH THEN CODES FOR ABNORMAL PROTEINS
THAT IMPAIR VIRAL REPLICATION AND/OR EFFECTIVELY INHIBITS DNA
POLYMERIZATION BY BINDING TO THE RESPONSIBLE ENZYME.
• IT ALSO INCORPORATES INTO NORMAL HOST CELLS, WHICH ACCOUNTS FOR
THE TOXICITY SEEN WITH BOTH TOPICAL AND SYSTEMIC TREATMENT.

19. 2. VIDARABINE/ AR-A
• SECOND AGENT DEVELOPED FOR HUMAN USE
• INHIBITS VIRAL DNA POLYMERASE, BUT ACTS AS A DNA CHAIN TERMINATOR
AND IS INCORPORATED INTO BOTH VIRAL AND HOST DNA TO A SMALL EXTENT.
• SAFE DRUG WITH LITTLE TOXICITY, ESPECIALLY WHEN USED SYSTEMICALLY, AND
IS USED TOPICALLY IN OCULAR INFECTIONS AS WELL AS SYSTEMICALLY WHEN
ACYCLOVIR RESISTANCE IS SUSPECTED.
• ONLY AVAILABLE AS AN OINTMENT

20. 3. TRIFLURIDINE / F3T 1 %
• DEVELOPED AS AN ANTICANCER AGENT
• MECHANISM OF ACTION : SIMILAR TO IDU
• SIGNIFICANT TOXICITY : SUPERFICIAL PUNCTATE KERATITIS, LACRIMAL PUNCTAL
OCCLUSION, FOLLICULAR CONJUNCTIVITIS, AND LOCALIZED CONTACT DERMATITIS.
• STUDIES INDICATE THIS AGENT IS SUPERIOR TO IDU AND ARA-A WITH A 90–95%
EFFICACY IN ELIMINATING DENDRITIC ULCERS.
• MOREEFFECTIVE THAN IDU OR VIDARABINE IN ANTAGONIZING THE STIMULUS FOR
VIRAL REPLICATION CAUSED BY THE USE OF CORTICOSTEROIDS.
• RAPIDLY DEGRADED IN THE BLOODSTREAM AND IS NOT EFFECTIVE SYSTEMICALLY.
• DOSAGE – 1 DROP 9 TIMES DAILY UNTIL EPITHELIZATION AND THEN 5 TIMES DAILY
FOR 7 DAYS .

21. 4. ACYCLOVIR :
• MORE SPECIFIC AND THEREFORE LESS TOXIC.

22. • TOPICAL 3 % OPHTHALMIC OINTMENT - HSV KERATITIS , 5 TIMES DAILY UNTIL
REEPITHELIZATION AND THEN 3 TIMES DAILY FOR 7 DAYS
• ORAL – 400 MG
• ACTIVE DISEASE – 400 MG 5 TIMES DAILY
• PROPHYLAXIS – 400 MG 2 TIMES DAILY
• METABOLISM – KIDNEYS
• ORAL ADMINISTRATION – WITH CAUTION IN ELDERLY AND THOSE WITH IMPAIRED
RENAL FUNCTION
• CAUTION IN IMMUNOCOMPROMISED – INCREASED CHANCE OF TTP/ HEMOLYTIC
UREMIC SYNDROME

23. 5. GANCICLOVIR :
• 0.15 % GEL
• 5 TIMES DAILY UNTIL RE-EPITHELIZATION AND THEN 3 TIMES FOR 7 DAYS
• IN A STUDY COMPARING 0.15% GANCICLOVIR GEL AND 3% ACYCLOVIR
OINTMENT SIMILAR THERAPEUTIC EFFICACY SHOWN AS EPITHELIAL HEALING
RATES WAS NOTED BETWEEN EACH GROUP.

24. 6. VALACYCLOVIR :
• A PRODRUG, CONVERTS TO ACYCLOVIR
• HAS A HIGHER BIOAVAILABILITY THAN ACYCLOVIR
• 500 MG TWICE DAILY

25. Indications of oral antivirals
Treatment of
active disease
Primary HSV Immunocompromised Infants Iridocyclitis not responsive to topical
Recurrent
disease
• 2 or more episodes
of recurrent IEK
• Post PK

27. CORTICOSTEROIDS
• SUPPRESS INFLAMMATION BY INTERFERING WITH THE NORMAL IMMUNOLOGIC
RESPONSE TO VARIOUS STIMULI.
• INTERFERENCE WITH LYMPHOCYTE FUNCTION, MIGRATION, AND THE RELEASE OF
CELLULAR DIGESTIVE ENZYMES
• SUPPRESS THE LOCAL ANTIBODY-FORMING B LYMPHOCYTES OF THE CORNEA AND
UVEAL TRACT.
• SIGNIFICANT REDUCTION IN THE INFILTRATION OF PMNS AND A REDUCTION OF
STROMAL NEOVASCULARIZATION.
• EPITHELIAL DISEASE – EXACERBATED BUT CAN BE ELIMINATED WITH CONCURRENT
USE OF ANTIVIRAL THERAPY.

28. 1. Rapid and
effective relief of
inflammation
2. Reduction of
corneal scarring
and
vascularization
3. Reduction of
intraocular
sequelae such as
secondary
glaucoma /
posterior
synechiae
1. Cataract
2. Glaucoma
3. Facilitation of viral
penetration into
the cornea
4. Viral invasion of
individual
keratocytes
5. Prolonged stromal
inflammation
6. Stromal necrosis
and perforation
7. Secondary
microbial infection

29. INDICATIONS
• TOPICAL STEROIDS :
• MARGINAL KERATITIS,
• IMMUNE STROMAL KERATITIS,
• ENDOTHELIITIS,
• IRIDOCYCLITIS
• TRABECULITIS
• ORAL STEROIDS :
• SEVERE IMMUNE STROMAL
KERATITIS,
• DIFFUSE ENDOTHELITIS AND
IRITIS,
• ALL CASES OF LINEAR
ENDOTHELITIS
• PERSISTENT EPITHELIAL DEFECTS

30. STEROID THERAPY FOR HOW LONG
• FLARE DOSE – DOSE TAPERING BELOW WHICH INFLAMMATION FLARES UP .
• ONE SHOULD NOT TRY TO TAPER THE STEROID BELOW THIS DOSE UNTIL THE
EYE IS QUIET FOR SEVERAL MONTHS
• THE PREVENTION OF CATARACT AND STEROID-RESPONSE INCREASED
INTRAOCULAR PRESSURE IN AN EYE THAT GOES ON TO DEVELOP AN
OPAQUE CORNEA FROM CHRONIC INFLAMMATION FROM HSV SHOULD BE
CONSIDERED A TREATMENT FAILURE

31. • PATIENTS USING TOPICAL CORTICOSTEROIDS SHOULD BE ON PROPHYLACTIC
ORAL ANTIVIRALS TO REDUCE THE RISK OF RECURRENT INFECTIOUS
DISEASE.
• ACYCLOVIR 400 MG TWICE A DAY OR
• VALACYCLOVIR 500 MG ONCE A DAY

32. HSV EPITHELIAL KERATITIS

33. EPITHELIAL KERATITIS
• PHYSICAL DEBRIDEMENT
• TOPICAL ANTIVIRAL MEDICATION :
• GANCICLOVIR 0.15 % GEL
• ACYCLOVIR 3 % OINTMENT
• CYCLOPLEGICS
• BROAD SPECTRUM ANTIBIOTICS
• ORAL ANTIVIRAL AGENTS
5 times daily

34. • ANTIVIRAL THERAPY SHOULD BE CONTINUED FOR 10- 14 DAYS
• TAPERED AND CAN BE MAINTAINED ON A NIGHT TIME DOSE FOR 3 – 6 MONTHS
Ulcer fails to heal
Yes
Persistent infectious
epithelial keratitis
Neurotrophic ulcer
No
HSV epitheliopathy
? True
ulcer

35. Marginal keratitis
Topical + oral
antivirals

36. • PERSISTENT INFECTIOUS EPITHELIAL KERATITIS ANTIVIRAL RESISTANCE ?
• ACYCLOVIR RESISTANT STRAINS WILL ALSO BE RESISTANT TO GANCICLOVIR AS
THEY ARE ACTIVATED BY THE SAME THYMIDINE KINASE
• VIDARABINE MAY BE USEFUL IN SUCH CASES
• TRADE NAMES ?

37. NEUROTROPHIC KERATITIS

38. • DICONTINUATION OF ALL UNNECESSARY TOPICAL MEDICATION
• COPIOUS LUBRICATION , BROAD SPECTRUM ANTIBIOTIC
• BCL
• GENTLE DEBRIDEMENT OF MARGINS
• TARSORRHAPHY – TAPE / BOTULINUM TOXIN / SURGICAL
• AUTOLOGOUS SERUM
• AMNIOTIC MEMBRANE TRANSPLANTATION
• CONJUNCTIVAL FLAP

39. STROMAL KERATITIS
Inflammation Infection

40. Necrotizing stromal keratitis
High dose antivirals / corticosteroids

41. Immune stromal keratitis
Topical steroids / oral antivirals

42. • FIRST EPISODE
• MILD INFLAMMATION
• NO HISTORY OF PRIOR STEROID USE
• MODERATE TO SEVERE INFLAMMATION
• SIGNIFICANT VISUAL IMPAIRMENT
• PHOTOPHOBIA / DISCOMFORT
May elect not to start
steroids
Start topical steroids of
appropriate strength
and dosing

44. ENDOTHELITIS
Disciform endothelitis
Topical corticosteroids
Severe cases oral
antivirals + oral
corticosteroids

45. Diffuse endothelitis
Topical steroid plus oral
antiviral
Severe cases- oral
steroids
Linear endothelitis
Topical steroids plus oral
antivirals
+ oral corticosteroids

48. IRIDOCYCLITIS / TRABECULITIS
Steroids topical and oral
Oral antivirals
Antiglaucoma medication

49. SURGICAL THERAPY
• TARSORRHAPHY
• AMNIOTIC MEMBRANE TRANSPLANTATION
• CYANOACRYLATE GLUING
• LAMELLAR KERATOPLASTY – HIGH INCIDENCE OF FAILURE AND REACTIVATION
OF DISEASE AT INTERFACE
• PENETRATING KERATOPLASTY

50. TRIGGERS
• SUNLIGHT
• TRAUMA (INCLUDING SURGERY),
• ABNORMAL BODY TEMPERATURE,
• MENSTRUATION,
• OTHER INFECTIOUS DISEASES, AND EMOTIONAL STRESS
• PROSTAMIDE GLAUCOMA MEDICATIONS LATANOPROST AND BIMATOPROST
• LASER PROCEDURES – LASIK , YAG LASERS , PRK/PTK

51. LATENCY ASSOCIATED TRANSCRIPTS
• HSV-1 IS MOST COMMONLY ASSOCIATED WITH INFECTION OF THE ORAL
MUCOSA, AND FOLLOWING PRODUCTIVE PRIMARY INFECTION AT THIS SITE THE
VIRUS IS ABLE TO ACCESS THE SENSORY NEURONS OF THE TRIGEMINAL GANGLIA
(TG).
• WITHIN THESE CELLS, HSV IS ABLE TO ESTABLISH A LATENT INFECTION,
CHARACTERISED BY A GLOBAL REDUCTION OF LYTIC GENE EXPRESSION AND AN
ABSENCE OF INFECTIOUS VIRUS PRODUCTION.
• DURING LATENCY, VIRAL GENE EXPRESSION IS LARGELY RESTRICTED TO THE
LATENCY-ASSOCIATED TRANSCRIPT (LAT).

53. • THE LAT IS AN 8.3KB PRIMARY TRANSCRIPT, WHICH IS SPLICED INTO STABLE 1.5
AND 2 KB MAJOR LAT INTRONS, AS WELL AS A 6.3 KB MINOR LAT EXON THAT IS
PROCESSED INTO A NUMBER OF MICRORNAS.
• LAT DO NOT ENCODE FOR ANY PROTEIN
• INVOLVED IN NEURONAL SURVIVAL , SUPPRESSION OF APOPTOSIS , INDUCTION
OF LATENCY AND REACTIVATION FROM LATENCY
• PERIODICALLY, LATENCY IS INTERRUPTED BY REACTIVATION OF VIRION
PRODUCTION FROM LATENT VIRAL DNA, ALLOWING FOR THE TRANSMISSION OF
THE VIRUS TO NEW HOSTS

54. PREVENTION
• TRIGEMINAL GANGLION LATENCY :
• LIMITED TRANSCRIPTION OF A PORTION OF VIRAL GENOME IN NUCLEUS OF
LATENTLY INFECTED NEURONAL CELLS
• LATS BLOCK EXPRESSION OF EARLY GENES AND PROTEINS THAT INITIATE VIRAL
REPLICATION

55. DISC VACCINE
• GENETICALLY ENGINEERED DEFECTIVE HSV1 WHICH CANNOT REPLICATE
BEYOND A SINGLE CYCLE IN THE HOST CELL
• TOPICAL ADMINISTRATION OF NANOPEPTIDE CARRIED DNA VACCINE EFFECTIVE
IN PREVENTING CORNEAL HSV VACCINE

56. FUTURE
• IMMUNOMODULATORS – CSA
• TOPICAL FK 506
• GENE TREATMENT
• THYMIDINE KINASE INHIBITOR
• DISC VACCINES

57. REFERENCES
1. CORNEA – FUNDAMENTALS , DIAGNOSIS AND MANAGEMENT : MARK J MANNIS,
EDWARD J HOLLAND , 4TH EDITION
2. CORNEA – 3RD EDITION
3. HERPES SIMPLEX VIRUS KERATITIS : A TREATMENT GUIDELINE , MICHAEL LEE
WHITE ,JAMES CHDOSH .

58. Thank you……