Viral Disease of the Anterior Segment Anterior Segment Disease Fall 2007 Richard J.

Madonna, OD, MA, FAAO Associate Professor Office: Room 639 Phone: Ext. 4060 Resources Books 1. 2. 3. 4. 5. Atlases 1. Spalton: Atlas of Clinical Ophthalmology 2. Kratchmer: Cornea Atlas Slide Sets 1. Spalton 2. Kratchmer-also in CD-ROM 3. Catania Guides 1. Review of Optometry’s 2007 Clinical Guide to Ophthalmic Drugs Grayson’s Diseases of the Cornea The Wills Eye Manual The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology Heiberger, Madonna, and Nehmad Emergency Care in the Optometric Setting Fraunfelder and Roy: Current Ocular Therapy

PATHOLOGY OF VIRAL DISEASE 1. How a virus insures its survival: Uses host cell biochemical machinery Uses host cell genetic machinery Latency: downregulation of viral gene expression for replication (stays in the system but in inactive form) Avoids detection by host immune system Minimizes destruction of the host cell. TREATMENT OF VIRAL DISEASE OF THE ANTERIOR SEGMENT 1. Principles of Treatment Recognition of the viral agent Use of the appropriate anti-viral which kills or attenuates the virus Use of appropriate agents that modulate the inflammatory response to prevent damage, scarring and neovascularization to cornea 2. Topical anti-viral agents Trifluridine 1% solution (Viroptic) Analog of thymidine (inhibits DNA polym) Active against HSV-1 and HSV-2 Acts against virally infected AND normal cells (toxic) Heals most herpetic ulcers in 5-8 days Vidarabine 3% ointment (Vira-A) Analog of adenosine Active against HSV-1 and HSV-2 Was useful in cases of trifluridine allergy or toxicity NO LONGER ON THE MARKET
Antiviral Costs (taken from different on-line sources) Viroptic: 7.5ml bottle = $96.99 Trifluridine: 7.5ml bottle = $53.98 Acyclovir generic: 100 800mg tabs = $39.99 Zovirax: 100 400mg. tabs = $218.00 Valtrex: 21 1000mg tabs = $161.49 Famvir: 30 500mg tabs = $176.71


Systemic Anti-viral agents Acyclovir tabs (Zovirax)
Effective against HSV and HZV

Valacyclovir tabs (Valtrex)

Famciclovir tabs (Famvir)

Active against all DNA viruses in humans Used systemically in the treatment of CMV retinitis Direct action on DNA polymerase

Acts against virally infected cells ONLY (viral enzyme specific so non-toxic & well tolerated)

Poor GI absorption (need ^ dose)

Better bioavailability (lower and less frequent dosing)

Better bioavailability than acyclovir Better affinity for thymidine kinase Long intracellular t ½ Prodrug of penciclovir Not approved for topical use

Few side effects: watch renal function
Topical 3% ung not approved for ocular use in U.S. but is used dermatologically

Prodrug of acyclovir

HZV dose is always 2x more than for HSV ADENOVIRUS 1. Double-stranded DNA virus with numerous serotypes (diff. serotypes give diff. signs and symptoms) 2. Cause of a number of diseases: ocular, respiratory, GI, GU, urinary 3. Pathology *with any adenovirus, RTC 1 wk no sooner o Disrupts host cell DNA synthesis and directly toxic to host * has some latency o Causes cell lysis and virus release  responsible for signs and symptoms * Dx of an adenovirus was previously clinical, now can use a Rapid Pathogen Screening devise Adenoviral Conjunctivitis (Pink Eye) Acquired via airborne respiratory droplets or direct finger-eye transmission (ubiquitous) Incubation period of 5-12 days Acute onset of unilateral watery, red eye that involves the second eye within 1 week and subsides in 1-2 wks Clinical picture o Follicular conjunctivitis – part of lymph system, have vessels around the follicles o Hemorrhagic conjunctivitis and Photophobia o Ipsilateral lymphadenopathy- preauricular o May involve cornea: Keratitis, SEI (collection of WBC due to lymph response), SPK 2* cell lysis 5. Treatment o Rule out other causes of follicular conjunctivitis o Supportive treatment  cold compress and artificial tears o Prevent spread: viral precautions (stay home) o If unsure can use an antibiotic but do not use a steroid because can have a rebound effect after D/C (if must, use a mild one) 1. 2. 3. 4. Pharnygoconjunctival Fever 1. Adenoviral conjunctivitis with systemic signs (soar throat) and mild, transient corneal findings 2. Children: pharyngitis, follicular conjunctivitis, fever with submaxillary adenopathy 3. Supportive treatment EKC (epidemic keratoconjunctivitis) 1. Caused by adenovirus 8, 19, or 37 ( no virus isolated after 14 days) 2. Acute onset of unilateral, follicular conjunctivitis that is usually hemorrhagic and may be membranous or pseudomembranous (made of fibrin and WBCs- typically not removed). Can get a symblepharon if bad case 3. Ipsilateral lymphadenopathy (no respiratory involvement) 4. Patient is usually VERY uncomfortable (bacterial looks similar but the pt. is not as miserable) 5. Becomes bilateral (even if other eye does not have sx, do preventative tx) 6. Cornea becomes involved

o Focal epithelial opacities after about 7 days. SEI after about 14 days due to cell lysis and inflammation  epi heals w/i 1mo but SEI persistent after infection and can cause photophobia, scratchiness b/c epi does not sit well, and ↓ VA so might have to keep the pt. on steroids o 1st week incubation. 2nd week opacities. 3rd week SEI hallmark of EKC 7. Treatment o Supportive (vasoconstrictors, cold compress, viral precautiona, AT’s) o Silver nitrate 1% sol. or 5% Povidone iodine (Betadine)  drop for 1-2 min then irrigate. Kills everything it touches (toxic) but decreases viral load and duration of disease o Steroid (like Lodemax) Timing of steroid use is key to management (good for dec. SEI and inc. VA) Will make the patient feel better and see better, but may prolong the course of the disease Reserve for those who are very uncomfortable and those with reduced vision 8. Prevent spread of infection  careful patient instruction. In-office hand washing, disinfection HERPES VIRUSES 1. Cause of a number of well-known human diseases o HSV eye and genital disease o HZV: chicken pox, shingles, herpes zoster ophthalmicus o Epstein-Barr infection HSV Spread by direct contact or contaminated secretion Milder disease as compared to HZV More frequent reactivation as compared to HZV Latency in non-replicating cells Reactivation associated with trigger factors HZV Spread by aerosolization or direct contact w/ lesions More severe disease as compared to HSV Infrequent reactivation Latency in non-replicating and replicating cells No obvious trigger factors

HERPES SIMPLEX VIRUS (HSV) 1. Pathology o 90% of humans infected by age 15 (1st infection usually subclinical) o Virus latent in trigeminal and superior cervical ganglia o Reactivation triggered by factors such as stress, heat, fever, UV, trauma, hormonal changes, and other less well-known factors; genetic predisposition o Recurrent infection is diverse- virus enters latent phase in trigeminal and sup. cervical ganglia 2. Primary Infection o Children (usually less than 5yo) *sx 2-12 days after contact o Eye signs mild as compared to systemic (eye not usually 1* site of infection) o Lid vesicles, ulcerative bleph, follicular conjunctivitis, +/- cornea (corneal changes superficial) o Differential: adenovirus, chickenpox, Molluscum, Staph, vaccinia, Chlamydia o Management: eliminate virus from cornea and adjacent structures with anti-viral (Trifluridine 5x/day 3. Recurrent Infection o Latent virus activated o Cornea primary site of disease in 1st ocular recurrence (other recurrences can go further back) Epi: SPK, dendrites, geographic and amoeboid ulcers (dendridic ulcers is usually recurrent) Metaherpetic disease in V1

Stromal disease: necrotizing and non-necrotizing *all of these produce Endothelial disease massive discomfort o May also affect TM, uvea o If have a HSV, there is always a potential of getting an ocular breakout, but there is a genetic component involved in the likelihood of the breakout 4. Treatment of HSV Keratitis. o Recognize tissue layers involved o Recognize infectious and immune components o Use appropriate anti-viral and anti-inflammatory meds. o Goals Eradicate live virus ID  Eradicate  Modulate immune syst. Promote healing ^ ocular recurrence  ^ risk of VA loss Minimize scarring Decrease risk of recurrence HSV Epithelial Keratitis (Dendritic Keratitis) 1. Clinical Picture o Unilateral, follicular conjunctivitis. Ipsilateral lymphadenopathy. Discomfort and variable amounts of pain (1st have pain, then as have recurrences, nerve cells get damaged and pain sensation dec.) 2. Cornea o Dendrite is classic, but not always the presentation * may be central or peripheral A true ulcer (loss of epi): base stains brightly with fluorescein, edges with rose True terminal end bulbs (heaping up of tissue at ends) o May present as SPK or large amoeboid or geographic ulcers (more severe in immunocompromised or steroid fed) o Will lead to corneal scarring, especially with recurrences: ground glass appearance – as get deeper into tissue, can scar and appear as a whitish haze in the cornea 3. Treatment o Although epithelial disease is self-limiting, treatment is indicated to reduce corneal damage and reduce immune response to infection (on average dendrites heal in 6 days) o 1% trifluridine sol. Q2h for first few days, taper as dendrites regress; no more than 9x/day (toxic) o Supplement with tears and cycloplege for comfort o No need for ointment at bedtime (Vira-A no longer available anyway) o Debridement useful, particularly if large amounts of dead tissue o NO TOPICAL STEROIDS IN ISOLATED HSV EPITHELIAL KERATITIS – since epi. keratitis is infectious, the steroid feeds it. o Oral agents are useful but not the current standard in U.S.; use when trifluridine toxic, when epithelium in very bad shape, or in immunocompromised o One week treatment with orals: Acyclovir 400 mg five times per day or Valacyclovir 500 mg three times per day or Famciclovir 250 mg three times per day 4. Recurrence o 25% recurrence risk over two years after first episode of epithelial keratitis

o 43% risk after second recurrence o Greater number of recurrences lead to: scarring and vascularization, increased risk of recurrence, increased risk of stromal disease o Even though disease is self limiting, tx dec. risk of damage and recurrence o Complications  Neurotrophic ulcer and SPK due to antiviral med. toxicity Neurotropic Keratitis (Metaherpetic Ulcer) 1. 2. 3. 4. 5. 6. Epithelial defect due to loss of corneal innervation, BM damage and poor tear film (ie: stroke of CN V…) Red eye, FBS, swollen lid - but not infectious Range from SPK to full-blown ulcer – typically round or oval, not dendridic BEWARE of secondary bacterial infection De-epithelialization – need CN V to maintain connections b/w epi and BM so very easy to rub off epi Treatment o Mild: tears, erythromycin ung, bandage CL or patch o Increasing Severity: treat as bacterial ulcer; consider tarsorraphy (sew lids together) HSV Stromal Disease 1. Inflammatory reaction to viral antigens. Not an active replication–may occur during or w/o epi disease 2. Inflammation deeper within the eye: stroma, endothelium, TM, uvea involved 3. Usually occurs after previous bouts of epithelial disease, but NOT always. 4. Clinical Presentation o Uncomfortable eye (variable pain) with degreased vision o Terminology variable o Non-necrotizing and necrotizing  non-necrotizing  interstitial keratitis – stromal inflammation w/ intact epithelium. Nonnecrotizing is often in the form of disciform keratitis (disk of edema with intact epithelium and increased IOP)  necrotizing usually involves neovascularization o Also: interstitial keratitis, keratouveitis, iridocyclitis 5. Treatment o Aggressive inflammation management with antiviral cover: frequent use of steroid with slow taper + Viroptic QID and taper with steroid 4 days QID  Steroids can activate HSV (trigger replication) so do not use steroids 3 days TID for an active HSV infection (eipithelial) but for a stromal HSV (not 2 days BID actively replicating) use a steroid Q2H and cover with an antiviral QID 1 day QD o Manage IOP o Cycloplegia for comfort 6. Recurrence o 11%/year risk of developing stromal keratitis with or without treatment following epithelial keratitis o HEDS II tells us that we can reduce the risk of recurrence of herpetic disease with long-term use of oral acyclovir - 400mg Acyclovir BID for 1 year decreases the recurrence rate of any HSV by 30 and stromal disease by 50% in those at risk for stromal disease

o Recommendation: use long-term acyclovir (or other oral) in patients at greatest risk of recurrence or vision loss (does not treat, only decreases recurrence) HERPES ZOSTER VIRUS (HZV) 1. Varicella-Zoster Virus (VZV) o Humans are the only natural host. Causes two diseases: chickenpox (1*) and shingle (2*) o If V1 affected get herpes zoster ophthalmicus (HZO) 2. Varicella Infection o >90% of the population infected by adolescence o Highly contagious via aerosol route and secretions through conjunctiva and respiratory mucosa o Seasonal outbreaks: late Winter and early Spring o 14 day incubation period o Contagious 2 days before rash and until all lesions crusted over o Latency in dorsal root ganglia o Generally lifelong protection against future infection o May have ocular manifestations: vesicles, follicular conjunctivitis, keratitis, other o Treatment is supportive. Varivax vaccine available to reduce risk of developing chicken pox o REACTIVATION: vesicular eruptions limited to single sensory or cranial nerve 3. HZV Infection o Reactivation influenced by advanced age and immunodeficiency o Now available: Zostavax vaccine to reduce the risk of developing recurrent infection (shingles) o No seasonal, sexual, or racial predilection o 20% of those with chickenpox will get HZV o Lower thoracic and upper lumbar affected 50% of the time; cranial nerves 13-20% o Clinical Manifestations Prodrome: fever, hyperesthesia, pain, and burning along affected dermatome; lasts 2-3 days before macules appear May have systemic manifestations of respiratory tract, GI, CNS Herpes Zoster Ophthalmicus (HZO) 1. 1st division of trigeminal nerve and its brances (even if eye itself is not involved) Ophthalmic and frontal most common 50% develop ocular complications: if tip of the nose involved Hutchinson’s sign (nasocilliary n.) there is a 76% risk of ocular involvement vs. 34% if sign is missing 2. Widespread and diverse ocular signs – remember that direct occurs due to direct viral invasion, secondary inflammation, vasculitis, nerve damage, and scarring 3. Clinical manifestations o Lids: pitting, pigmentation, exposure, ectropion, entropion, dermal scarring (looks like a burn scar) o Conjunctiva: follicular conjunctivitis, symblepharon and associated problems o Cornea • Early: SPK, SEI, keratouveitis, pseudodendrites (swollen epi that stains poorly, not a true ulcer) • Delayed: serpiginous ulcers, mucous plaques, disciform keratitis • Chronic: bullous keratopathy, neurotrophic keratopathy (round/oval, stains) o Episcleritis and scleritis -HSV usually o Uveitis, usually associated with corneal involvement involves o Elevated IOP: trabeculitis, uveitic, synechia cornea/stroma. -HZV has the potential to involve the entire eye

o Neuro-ophthalmic: tonic pupil, optic neuropathy, ophthalmoplegia o Retina: vascular occlusion, retinitis, choroiditis, ARN, PORN 4. Neuralgia o Acute: with rash o Postherpetic Neuralgia: persistant pain that can be severe o Immunocompromised have a 3-4x higher risk of neuralgia 5. Treatment o Treat skin with wet dressings o Systemic: best if utilized within 72 hours of onset to reduce pain and decrease severity of postherpetic neuralgia (dec. duration and severity) Acyclovir 800 mg five times/day x 7-10 days Use one of the Valacyclovir 1000 mg TID x 7 days three, not all Famciclovir 500 mg TID x 7 days o Ocular Surface disease: tears and antibiotic Deeper: steroids, cycloplegia, antibiotic coverage Neurotrophic: as HSV Scleritis: in consultation, treatment usually systemic o Neuralgia Acute: use antiviral to decrease severity and duration and analgesic Post-herpetic: creams, H-2 blockers, TCA, ganglionblock (cut nerve) CHLAMYDIAL INFECTION 1. Chlamydia are obligate intracellular parasites 2. Cause of three ocular diseases: trachoma, adult inclusion conjunctivitis, neonatal conjunctivitis 3. Chlamydia is most common cause of chronic (> 6 weeks) conjunctivitis. Adenovirus causes acute conj’itis Trachoma 1. Overview o Leading cause of preventable blindness worldwide (poor, arid regions) o Repeated reinfection by Chlamydia trachomatis – especially in kids (peak prevalence in 3-6yo) o Transmission: ocular secretions hand to eye o Possible role of flies, bacterial conjunctivitis, HLA type 2. Clinical Features o Limbal follicles (Herbert’s Pits) and Follicular conjunctivitis (in kids the follicular conjunctivitis is greater at the lower lid and in adults in the upper lid) o Papillary reaction that may be significant o Repeated infection leads to scarring: lids, conjunctiva (Arlt’s Line – horizontal line on upper palpebral conj), cornea: entropion, trichiasis, corneal opacification o Chronic follicular conjunctivitis  scarring of conjunctiva  lid and lash distortion (entropion and trichiasis)  corneal abrasion  scarring of cornea  blindness o Usually a clinical diagnosis (no diagnostic tests) 4. Treatment o World Health Organization SAFE strategy (Surgery for trichiasis, Antibiotics, Face washing, Environmental improvements) o Antibiotics Tetracycline ung

Zithromax (azithromycin) 20 mg/kg in kids or 1 g in adults single dose o Handwashing: shown to be the single best way to reduce incidence Adult Inclusion Conjunctivitis 1. Overview o STD: C. trachomatis (same bug that causes Trachoma) o Oculogenital disorder: about 1% of infected develop AIC but 54% of men and 74% of women with AIC have a positive genital culture YOU HAVE A PUBLIC HEALTH ROLE o Transmission is finger-eye 2. Clinical Features o Inferior follicular conjunctivitis o Non-tender node (preauricular) o Lids stuck upon awakening o Heals without scarring (self limiting) o Chronic: common cause of chronic conjunctivitis 3. Diagnosis o Conjunctival scrapings, Culture, ELISA, PCR 4. Treatment is SYSTEMIC o Tetracyclines: tetracycline 250 mg x 21 days or doxycycline 100 mg BID x 21 days or azithromycin 1 g single dose o MUST TREAT SEXUAL PARTNERS Neonatal Inclusion Conjunctivitis 1. Overview o 1.6 – 12% of newborns o Chlamydia more common than gonorrhea in industrialized nations o Acquired from mother during delivery o Associated with nasopharyngeal infection, other 2. Clinical Features o About 5th day after birth o Lid edema, conjunctival hyperemia, papillary hypertrophy (why no follicles?), mucopurulent discharge, corneal infiltrates, can lead to scarring 3. Diagnosis o MUST R/O N. gonorrhea o Rule out other possible causes o Crede’s prophylaxis also cause of conjunctivitis 4. Treatment o Prophylactic erythromycin to babies born to infected mothers MISCELLANEOUS VIRAL CONDITIONS OF ANTERIOR SEGMENT Thygeson’s SPK

1. 2. 3. 4. 5.

Possible viral etiology Chronic condition with exacerbations and remissions Uncomfortable eye during exacerbations “White eye” (actually a little red) with bilateral, intraepithelial punctate opacities that stain Treatment: tears, ung, mild steroid, mast cell stabilizers, bandage CL, antivirals, cyclosporine have been utilized Molluscum contagiosum

1. 2. 3. 4.

Viral wart: single or multiple nodules with “cheesy” core May cause keratoconjunctivitis Associated with immunocompromised Treat by opening with needle and squeezing out discharge