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
