herpes zoster- origins Herpes Zoster “Shingles” A one sided and widespread skin disease Ganglionic latency (like HSV-1? No….) Immune Resolution Adult-Child.

herpes zoster-origins

Herpes Zoster“Shingles”

A one sided and widespread skin

disease

Ganglionic latency

(like HSV-1?No….)

Immune Resolution

Adult-Child contact

Replication in Tonsilar epith

T cell mediated Viremia to skin

Latent for decades…Then reactivation

Chickenpox

NeuronsSupport cells

Risk Factors for zosterRisk Factors for zoster Age

- most zoster occurs in those over 50

Cellular immune status – AIDS– Radiation Therapy– Cancer (esp. lymphoma)– Immunosuppresion from medical therapies

BMT & Transplants (30-55% in a year!)

Evidence suggests CD4 >> CD8 are critical to control of VZV latency

Herpes Zoster -signsHerpes Zoster -signs Pain

– Before, during and after

Vesicular skin lesions Lesions do not cross the midline of

the face -come from ganglia Many lesions over wide area-

-viral replication in the ganglia

-many neurons deliver virus to skin

Fever & Depression. Tic (“tic deleroux”)

Ocular Problems of zosterOcular Problems of zosterVZV can potentially infect every

ocular tissue !!

Punctate epithelial keratitis (PEK) Dendritic keratitis

– w/o terminal bulbi Stromal inflammation

– Harder to treat than HSV-1! Neurotrophic keratitis

– Total loss of sensation– ulceration

Rarer Findings Uveitis, retinitis, Acute retinal necrosis.

Neurotrophic KeratopathyNeurotrophic KeratopathyThe diabetic foot ulcer of the eyeThe diabetic foot ulcer of the eye

• ~ 8% of HZO patients develop total loss of corneal sensation

~ 3% of HZO patients develop neurotrophic ulceration

Iatrogenic insults are the main reason that neurotrophic corneas get into trouble.

Chronic Pain after zoster –Post Chronic Pain after zoster –Post Herpetic NeuralgiaHerpetic Neuralgia

“Constant deep burning or aching”

“Intermittent sharp,stabbing”

Allodynia-pain invoked by light or innocuous stimulation, (e.g. clothing, wind gust) -may last long after removal

-is the most distressing component of PHN-is the most common-is the most debilitating

To Brain:Conscious Perception

of Pain

Why does shingles cause pain?

Why does shingles cause pain?

SpinothalamicTract

A fibersC fibers

Spinal cord

Dorsal root ganglion

SENSORY NERVES

Latent VZV Reactivated VZV replicates in DRG…..

Ouch!!!Yeow

!!

-damages DRG, Induces Inflammation …

Brain Signals To supress Nociception- interneurons

Duh…

-damages interneuron that blocks pain-changes and C fiber physiology……

Chronic Pain!

Zoster TreatmentZoster Treatment

1. Treat the eye and active virus in skin

2. 3-5 + fold higher HSV-1 ACV dose needed for effect on VZV

3. Treat the post-herpetic pain

-Tricyclic antidepressants (gabapentin)-Amitryptilline -Corticosteroids

_Many PHN treatments don’t work -PHN is multifactorial syndrome

Topical AcyclovirOral Valacylcovir

Vaccination to prevent zoster– 10 fold higher virus than varicella vaccine

– VZV immune people get it! – Recommended to those over 60 – only human herpesvirus vaccine

– Protection Results:- not everyone……– 51% drop in zoster– 68% fall in burden of illness ( includes PHN)

Adenoviral Adenoviral InfectionsInfections

• non-enveloped virus, • 34Kbp DS-DNA, many viral proteins

• At least 51 identified Serotypes• Two major ocular diseases

• Epidemic Keratoconjunctivitis (8 and 19)• Pharyngoconjunctival fever (3,4, & 7)

EKCEKC transferred by hands, instruments, solutions. Adenovirus can survive >35 days on a

surface Epidemics arise from optometrists and

ophthalmologists offices.

Patients remain infectious for 14 days after onset of symptoms

Clinical SymptomsClinical Symptoms

Foreign Body Sensation Tearing Photophobia Sore Throat Breathing Problems Conjuntivitis NO ANTIVIRAL YET

Subeptielial inflitrates(immune mediated)may last long time -require steroids

Other Viruses causing Other Viruses causing Diseases of the EyeDiseases of the Eye

CMV (Fuchs? with HIV/AIDS Epstein Barr virus

– Both common herpesviruses affecting most people

Entero/coxsacivirus HIV (and everything resulting from it) Newcastle disease virus Vaccinia Mollocsum papilloma

Important Ophthalmic antivirals

Triflourothymidine HSV-1>> VZV

Acyclovir and valacyclovir HSV-1 and VZV

Ganciclovir and valganciclovir CMV retinitis

Foscarnet (phosphonformate) CMV (GCVr) HSV,VZV

Cidofovir CMV (GCVr)

HAART HIV/AIDs

Acyclovir, gancyclovir and Acyclovir, gancyclovir and derivativesderivatives

ACV Mechanism of Action

–HSV VZV Thymidine (nucleoside) Kinase activates it –ACV TP binds Viral DNA polymerase >>>>> cell pol–Incorporated into DNA - acts as DNA chain terminator

Valacyclovir“Valtrex”

AcyclovirLiver

The ‘new’ oral versions - “valtrex”

ACV is degraded in stomach and not good orally

“Val” forms are Ester derivatives- higher oro-bioavailability

–e.g. 63-72% stomach absorption vs 15% for ACV

drug is de-esterified by liver to give serum ACV

Allows high oral dosing (esp those needed for VZV)

liver

ACV - ResistanceACV - Resistance Readily arises in culture

– Defect /loss of TK in culture– DNA polymerase mutation altering affinity for ACV-

ppp

Rarely occurs in vivo – TK needed for reactivation and pathogensis of

HSV,VZV

– Occurs in AIDS due to long term treatments– Seems HSV VZV must make a ‘little” TK…..

Ganciclovir (Cytovene)Ganciclovir (Cytovene)

Used for hCMV only– – CMV retinitis – organ transplants

Now oral version -Val-GCV– Ester Protects in stomach

Poor retinal/brain barriers crossing

Use Ocular implants

NN

NNH

O

O

NH2

OH

OH

GCV Mechanism of action

similar to ACV- requires initial phosphorylation

DNA chain terminator

–CMV has no TK gene!!!

–CMV uses the UL97 viral protein kinase

to phosphorylate GCV!!

–Unlike ACV, GCV-PPP Inhibits both host and viral polymerase-toxic!

GCV Resistance Arises frequently (longer treatments)•10% In Retinitis and organ transplants•Change in polymerase, viral protein kinase or both

Foscarnet (phosphonoformate)Foscarnet (phosphonoformate)

Mechanism of action:– All polymerases need P-P as a cofactor– PFA is analog of P-P– binds to DNA polymerase -blocks P-P binding– Resistance? - altered DNA polymerase

Efficacy/toxicity– active on ACV GCV resistant viruses

HSV VZV and CMV– Toxic - bone, kidney, neuronal deposits

Uses:– CMV retinitis and GCVr CMV in transplants– rarely used on HSV and VZV ARN cases– Rarely used on systemic HSV and VZV

OH P P OH

OOH

OHO

OH P CH

O

OH

OH

O

PFA

P-P