Clinical
Leonid Skorin Jr OD, DO, FAAO, FAOCO
Herpes zoster ophthalmicus
Diagnosis and management update
erpes zoster (shingles) results from reactivation of the dormant varicella zoster virus acquired during childhood chickenpox1. The varicella zoster virus is a DNA virus, which belongs to the herpes virus family2.
Primary viral infection results in varicella (chickenpox), which is characterised by a mild yet highly contagious and disseminated vesicular eruption3. Viral latency is established during acute varicella infection. The virus takes up permanent residence in the sensory dorsal-root ganglion4. Ocular infection results when there is reactivation of the herpes zoster virus within the sensory ganglion of the trigeminal nerve, although exogenous exposure to the virus may occasionally be responsible3. Reactivation occurs during a period of decreased cell-mediated immunity to the virus5. Increasing age is the key risk factor for the development of herpes zoster1. The disease is uncommon in children, relatively constant in frequency between 20 and 50 years of age, and thereafter doubles in incidence each decade. The cumulative risk of zoster, if one lives to age 80, is about 15%6. Other risk factors include systemic corticosteroid therapy, radiation therapy, immunosuppression with cytotoxic drugs, acquired immunodeficiency syndrome (AIDS), organ transplantation, systemic disorders such as systemic lupus erythematosus, surgery, neoplastic diseases, especially lymphoproliferative cancers such as lymphoma, leukaemia and Hodgkins disease1,4-6. Younger patients are having more reactivation due to both a wider use of immunosuppressive drugs and to increasing incidence of immunosuppressive disease7. Since herpes zoster may occur in people with AIDS who are otherwise asymptomatic, testing for the syndrome may be indicated if these individuals are younger than 50 and otherwise appear healthy1.
Diagnosis
The characteristic prodromal symptoms of acute herpes zoster include two or three days of generalised malaise with fever, chills and headache3. The disease begins with a gradual onset of unilateral hyperaesthesia or paresthaesia, ranging from itching to tingling to severe pain, and these sensations are distributed along the affected dermatome (group of nerve systems)1,6. Within a few days, the skin overlying the dermatome shows signs of active
involvement. An erythematous maculopapular rash progresses to vesicles, pustules and finally crusting and scarring5 (Figure 1). The rash typically evolves over a period of four to 14 days, with completion of the vesicular phase usually within 72 hours8. The virus can be cultured from the lesions during the vesicular phase, making the patient infectious to individuals not previously exposed to the virus. Although the virus can be cultured, since it is labile, recovery is difficult1. A direct immunofluorescence assay is more sensitive than viral culture1. Cytologic examination of a smear prepared from a fresh lesion can also be done. Multinucleated giant cells with eosinophilic intranuclear inclusion bodies are characteristic of herpes infections. In most cases, testing is unnecessary, since the diagnosis can be made clinically. The skin eruption is unilateral and usually does not cross the midline. On occasion, there can be a spillover of a few lesions beyond the strict midline (Figure 2). The dermatomes most commonly affected, in order of frequency, are: thoracic (56%); cranial nerve distribution (13%); lumbar (13%); cervical (11%) and sacral (4%)9. The fifth cranial nerve (trigeminal) is divided into the ophthalmic, maxillary and mandibular divisions. The ophthalmic and maxillary are purely sensory, while the mandibular is both sensory and motor3 (Figure 3). The ophthalmic division of the fifth cranial nerve is most frequently affected6. The ophthalmic division of the fifth cranial nerve is itself divided into frontal, lacrimal and nasociliary branches. The frontal nerve is the most commonly affected nerve3. It divides into the supraorbital and supratrochler nerves, which innervate the upper eyelid, the forehead and the superior conjunctiva. The lacrimal branch innervates the lacrimal gland and the structures of the lateral canthus. The lacrimal branch is rarely affected by the herpes zoster virus. The nasociliary branch innervates the sclera, cornea, iris, ciliary body, retina and the ipsilateral tip of the nose. Vesicles on the tip of the nose indicate infection of the external nasal nerve, which is a branch of the nasociliary nerve, and are associated
Figure 1
Vesicles and pustules can be seen on an erythematous base of maculopapular lesions
Figure 2
Spillover of lesions onto left side of forehead from right-sided herpes zoster ophthalmicus
Figure 3
Maxillary division involvement of herpes zoster
34 | July 2 | 2004 OT
Clinical
Figure 5
Detrimental skin changes of the forehead and the eyelids
Figure 4
Nasociliary involvement (Hutchinsons sign) with lesions on the ipsilateral side of the nose with a higher incidence of ocular involvement. This is known as Hutchinsons sign, and if it is present, warrants a thorough ophthalmic evaluation4 (Figure 4). The absence of this sign is no guarantee that the virus is not present in the ocular nerves and therefore the eye may still be involved7. blunt-ended and more superficial. They are usually located peripherally and stain minimally with rose bengal and fluorescein13. On occasion, mucous plaques can be found incorporated with the dendritic lesions. Late corneal damage results from neurotrophic keratitis, which is often associated with exposure keratitis and occurs in approximately 25% of these patients14. The loss of corneal sensation initially may be localised to a small area of the cornea and eventually leads to epithelial breakdown, which forms a horizontally oval pattern. Anterior uveitis is seen in at least 40% of patients with herpes zoster ophthalmicus15. When the cornea and the sclera are inflamed, uveitis is almost always present. Patients with anterior uveitis will complain of ocular pain, red eye, photophobia, epiphora and blurred vision. Examination will reveal the presence of extravasated white blood cells along with protein and fibrin (flare) in the aqueous humour, keratic precipitates (clumps of white blood cells on the corneal endothelium) and conjunctival injection resulting from either a more diffuse hyperaemia or a more specific circumciliary flush where the eye exhibits a reddened, violaceous hue immediately adjacent to the cornea and over the location of the ciliary body16. Hyphaema and hypopyon may develop when the disease is especially severe. The onset may be delayed for months after disappearance of the rash. Always warn any patient to return for re-evaluation if they develop any signs or symptoms of iritis so that treatment can be initiated promptly. Chronic uveitis may result in glaucoma, cataract, iris atrophy or residual pupillary changes16. Most of the complications which involve the retina and the optic nerve have an ischaemic origin. They include central retinal artery occlusion, central retinal vein occlusion, delayed thrombophlebitis, ischaemic retinitis and ischaemic optic neuropathy. Untreated patients have an extremely poor outcome, and retinal
Ocular involvement
Patients with ocular involvement of the herpes zoster virus have the condition known as herpes zoster ophthalmicus. These patients may present with a wide range of problems10. These include conjunctivitis, scleritis, keratitis, anaesthetic cornea, iridocyclitis, retinitis, choroiditis, optic neuritis and atrophy, retrobulbar neuritis, Argyll-Robertson pupil, exophthalmos, partial or complete third, fourth or sixth nerve palsy, isolated pupillary paralysis, acute retinal necrosis, acute or chronic glaucoma, cicatricial lid retraction, persistent eyelid ptosis and sympathetic ophthalmia. Ocular damage occurs in nearly 50% of such patients, especially if the nasociliary nerve is involved11. Ocular involvement can develop as soon as several days, or as late as years, after the formation of vesicles12. The varicella zoster virus infects the deeper layers of the dermis, which can lead to permanent changes to the delicate skin of the eyelids and the forehead. These changes result from pitting, scarring, pigmentation, ulceration and ischaemic vasculitis, which can result in extensive sloughing of the eyelid tissue (Figure 5). Ulceration and extensive scarring may lead to cicatricial ectropion, trichiasis and lid retraction. The cornea can be involved early or late in herpes zoster ophthalmicus. The most common corneal lesions are coarse punctate epithelial keratitis and pseudodendritic keratitis3. Unlike in herpes simplex, these pseudodendrites are
detachment resulting from retinal holes may subsequently develop. Some patients may develop acute retinal necrosis, which is characterised by multiple white opaque patches of thickened retina, sharp demarcation lines between normal and abnormal retina, vasculitis affecting both arteries and veins, peripheral intraretinal haemorrhage, optic neuritis, retinal neovascularisation, vitreo-retinal traction and vitritis17. About 63% of patients with acute retinal necrosis become legally blind6. Infection with herpes zoster virus is the second most common cause of facial nerve paralysis18. Incomplete blinking and lagophthalmos, which usually accompanies facial nerve paralysis, can put the patients cornea in even more danger of damage, especially if it is already neurotrophic. Facial paralysis may be part of the Ramsay Hunt syndrome. This syndrome is believed to result from a herpetic inflammation of the geniculate ganglion, the somatic sensory locus of the seventh or facial cranial nerve6. Besides a severe form of facial paralysis, the patient will also have partial or total hearing impairment, a herpetic rash along and on the ear and within the ear canal, tinnitus, vertigo, nausea, dizziness and unsteadiness of gait5,6. Management is aimed at protecting the eye and preventing complete denervation which should be undertaken in conjunction with otolaryngologic consultation.
Post-herpetic neuralgia
The most longstanding and common complication of shingles is post-herpetic neuralgia (PHN). Its incidence is actually increased in patients with ophthalmic zoster and lasts longer when the trigeminal nerve is affected19. The most common definition of PHN is the presence of pain more than a month after the onset of acute zoster infection when the skin lesions have healed20. Most patients report a deep aching or burning pain, throbbing, shooting pain like electric shocks, unbearable itching and allodynia (pain produced by normally non-noxious stimuli such as very light stroking of the skin). Because of this chronic pain, patients with PHN often exhibit symptoms of insomnia, anorexia, fatigue, constipation, decreased libido, and depression19. In most patients, PHN resolves within one year, but in extreme cases may persist for 15 to 20 years.
Treatment
The skin of patients with herpes zoster is highly inflamed, tender and responsive to the slightest touch. In the acute phase of illness, measures to relieve those sensations and provide local comfort will soothe the rash of zoster. Wet dressings or compresses with aluminum acetate, or Burows solution, calamine-containing lotions and creams, 10% trolamine
35 | July 2 | 2004 OT
Clinical
Leonid Skorin Jr OD, DO, FAAO, FAOCO
salicylate (Aspercreme) and silver sulfadiazine (Silvadene Cream) can help protect sensitive skin and keep clothes from rubbing against skin lesions21. None of these products should be used on the eyelids or periocular surfaces. In patients with corneal disciform immune oedema or iritis, the standard topical steroids (prednisolone acetate 1%) and cycloplegics (homatropine 5%) should be used to minimise inflammation-induced damage. A topical antibiotic agent for additional coverage may be used. Unless a concomitant herpes simplex keratitis is suspected, topical antiviral agents such as trifluridine 1% (Viroptic) are not indicated. Therapeutic high water soft bandage contact lenses can help when the epithelium is ulcerated, but should not be used if the epithelium is only roughened since the lenses themselves may induce an epithelial break7. Bandage contact lenses increase the risk of infectious corneal ulceration, and therefore topical antibiotics should always be used whenever such contact lenses are worn. Scarred corneas may necessitate corneal transplantation. Incomplete eyelid closure can be treated with artificial tears, eyelid taping at bedtime or tarsorrhaphy (sewing the lateral aspect of the upper and lower eyelids together). The mainstay of herpes zoster therapy is the systemic antiviral drugs. These are acyclovir (Zovirax), valacyclovir (Valtrex) and famciclovir (Famvir) (Table 1). All three medications shorten the duration of viral shedding, halt the formation of new lesions more quickly, accelerate the rate of healing and reduce the severity and duration of pain1. Therapy is most
effective if started within 72 hours of the diseases onset21. Unfortunately, antiviral drugs do not reliably prevent post-herpetic neuralgia22. The anti-ulcer drug cimetidine (Tagamet) reduces pain and pruritis in acute zoster, presumably by blocking histamines in the periocular tissues7. In immunocompetent patients, oral corticostersoids can be considered in combination with the standard oral antiviral therapy. Acute pain is relieved more quickly and skin lesions heal more rapidly but more importantly, patients have an improved quality of life as measured by reductions in the use of analgesics, the time to uninterrupted sleep, the time to resumption of usual activities, if this combination therapy is used1,21. Corticosteroids beneficial effect on the incidence, configuration, or severity of PHN remains unproven1,21. Once the patient has developed PHN, a wide variety of topical and systemic treatment modalities can be tried to bring the patient some relief from the pain19,20. Topical anaesthetics, such as lidocaine and prilocaine cream, or the pain transmission inhibiting capsaicin cream, can be used once the skin lesions have healed. The tricyclic anti-depressants, which block the re-uptake of norepinephrine and serotonin, and relieve pain by increasing the inhibition of spinal neurons involved in pain perception, have long been used successfully to treat PHN. Anticonvulsants, such as gabapentin (Neurontin), carbamazepine (Tegretol) and phenytoin (Dilantin), have also been found to be effective in treating PHN. Narcotic analgesics, such as oxycodone, can help since they work within the spinal
cord, the brain and even the peripheral nervous system. Neural blockade with stellate ganglion blocks are most effective for relieving acute pain, but may prevent PHN if given early in the course of the disease and repeated. Non-pharmacologic, non-invasive and non-traditional therapies, such as transcutaneous electrical nerve stimulation (TENS), hypnosis, biofeedback, acupuncture and other cognitive and behavioural techniques, complement the traditional medical treatment of PHN. For the patient with severe and nonresponsive pain, referral to a pain management clinic would be appropriate.
Herpes zoster prevention
The best method to prevent the infection and PHN sequelae may be to vaccinate children for the varicella infection. A live Oka-strain vaccine (Varivax) is currently available in the US and has been recommended for universal childhood vaccination1. The long-term effects of varicella vaccine in childhood on the development of herpes zoster in the adult years are not known. It will take decades to know how durable the immune response to the vaccine is and whether the rates of subsequent exogenous reinfection or viral reactivation remain low throughout life23. As humoural and cellular responses to varicella zoster virus wane with age, vaccination may reinvigorate these responses20. Whether vaccine-induced immune enhancement will reduce the incidence or severity of herpes zoster in older adults is being investigated.
About the author
Dr Leonid Skorin is a US ophthalmologist practising in the Albert Lea Eye Clinic, Mayo Health System, Minnesota. Therefore, please note that this article is written from a US ophthalmological perspective.
Table 1 Oral antiviral therapy for herpes zoster
MEDICATION Acyclovir (Zovirax) Valacyclovir (Valtrex) Famciclovir (Famvir) DOSAGE 800mg five times a day 1000mg three times a day 500mg three times a day DURATION Seven to 10 days Seven days Seven days
References
For a full set of references, email [email protected].
36 | July 2 | 2004 OT
