Satisfacción de los turistas

Ronald J. Marsh, FRCS; Frederick T . F ra u n feld e r, M D ; James I. M cG ill, D Phil, FR C S

# The clinical differentiation of corneal epithelial lesions due to herpes simplex or herpes zoster may be confusing. Practical clinical tests, Including the use of topical ocular stains, are useful to differentiate corneal epithelial lesions caused by these two viruses. Two distinctive types of zoster corneal epithelial disease may be seen: an early dendritic form, and a delayed form characterized by corneal mucus plaques that may take a dendri­ form pattern. These plaques are com­ posed of mucus that Is adherent to swollen, degenerating epithelial cells. .-The clinical differentiation between these two viruses Is essential since topically . ^applied corticosteroids are contralndi- V’cated In epithelial herpes simplex and ;6ften are Indicated In the management of 'epithelial herpes zoster.

' (Arch O p h th a lm o l 94:1899-1902, 19 7 6)

rTt has recently been reported that ^ dendritic ulcers unassociated with herpes simplex infection may occur ^ith ophthalmic zoster.'=" Previously, J^hen dendritic figures were seen in I patients with ophthalmic herpes zos- a superimposed herpes simplex ^wifectlon was suspected. Since the jffpithellal diseases caused by these two .^{Viruses may appear similar blomlcro- |*copically, the clinician Is in need of

f Accepted for publication May 10, 1976. the External D iseases Clinic, M oorfields l l v * ^®sp'tal, London. Dr Frau n feld er is current- jW on sabbatical leave from the U n iv e r sity o f R A i^ n sas, Little Rock. Ark.

t V requests to External D isea ses Clinic,

' ^7® H ospiU l, C ity Road, L ondon,

England.

rapid practical differentiating pro­ cedures.

This paper describes methods to differentiate the dendritic pattern of herpes zoster from that of herpes simplex and describes two distinc­ tively different patterns of corneal epithelial disease seen In patients with ophthalmic herpes zoster.

SU B JECTS AND M ETHODS

Patients attending the E x te rn a l Dis­ eases Clinic, Moorfields Eye H ospital (C ity Road), w ith either ocular herpes simplex or zoster were examined fo r corneal epithelial lesions during the course o f th e ir disease. Approxim ately 1,100 new cases o f herpes simplex and 283 cases of herpes zoster w ith ocular involvement were seen between January 1972 and Septem ber 1974. I f comeal epithelial lesions were present, they were stained w ith solutions o f 1% rose bengal, sodium fluorescein, and, in a few cases, 1% alcian blue. In addition to a complete ocular exam ination, detailed cor­ neal drawings were made, and in selected cases, and x 10 macrocbrneal photographs were taken.* In all cases of ophthalm ic zoster, the comeal sensitivities w ere mea­ sured w ith an esthesiometer (Luneau and Coffignon).

RESULTS

Herpes zoster epithelial lesions fall into two distinct groups based on biomicroscopical appearances, tim e of onset, duration, and behavior. These lesions are best described as those of acute epithelial dendritic keratitis and delayed corneal mucus plaques. Of the 283 patients with ophthalmic zoster, 37 (13%) had acute epithelial dendritic

keratitis and 20 (7%) had delayed corneal mucus plaques.

A cu te E p ithelial K eratitis

This is characterized by small, fine, multiple dendritic or stellate lesions. Biomicroscopically, they appear slightly raised but are only intraepi­ thélial (Fig 1, B). They are located generally in the peripheral part of the cornea, and occasionally small plaques of opaque desquamated epithelium overlie them. These epithelial lesions stain moderately well with rose ben­ gal and fluorescein but only minimally with alcian blue. They are self-lim it­ ing, appearing within a few days of the onset of the rash, resolving within four to six days, and are always asso­ ciated with catarrhal conjunctivitis. These dendritic lesions may or may not be followed by an underlying superficial stromal infiltrate.

C o rn e a l M u cu s P la q u e K eratitis

The typical lesion is a whitish-gray plaque with sharp margins that lies on the surface of the epithelium (Fig 1, C) and is linear (Fig 2) or branching (dendriform) in shape (Fig 3). These plaques are usually multiple, are vari­ able in size and shape, and may appear anywhere on the cornea. Indeed, they may change in configuration, number, and size from day to day. Fluorescein stains these lesions somewhat, while rose bengal stains the whole lesion vividly. Alcian blue stains the lesions and the associated mucus debris in the

Differenœs Between Herpes Simplex and Zoster Epithelial K

Disease • ■ Epithelium Stroma

Tear

Film - Stalnlnÿ-'Characteristic

Mechanical

DetMidement ResponseSteroid _ManlfestatlCutaneoo lerpes simplex Fine, lacy

dendrites with or without terminal end bulbs Variable Involve­ ment Usually normal Edges stain with rose - b»engal: denuded uicer base stains with fluorescein Can only be removed with epithelium May cause enlarge­ ment Current or h isto ryof cold sore lerpes zoster acute Smaller lesions, often stellate: simple raised contour; usuaiiy peripheral None Mucoid discharge Stains sparingly with rose bengal and fluorescein

Can only t>e removed with epithelium

No apparent

effect Typical zost_{rash and i} vesicles elayed (corneal mucus plaques) Coarse. elevated gray-white plaques Diffuse haze Unstable with rapid drying time Brilliant staining of wfioie lesion with rose b en g a l,. moderate with alcian blue, and sparingly with fluorescein Can t>e removed with mini­ mal damage to under­ lying epithelium No apparent

effect Typical zosi_{scarring (} same sidi

|l (Marsh, Fraunfelder, McGIII).-r-A, of Involvement In herpes simplex elial disease with epithelial edema ulceration. B, Area of Involvement in

2S zoster epithelial disease with

elial edema prior to ulceration. C, tes zoster keratitis with corneal mucus lues on surface of elevated edematous lelium, stroma edema, and keratotic

pitates.

3 b c

film. Corneal mucus plaques a r as early as seven days and as as two years a fte r the first signs jtaneous herpes zoster. The m ajor- bowever, are seen th re e to four iths a fte r the onset of the cuta- us lesions. Corneal mucus plaques ushered in by ciliary and tarsa l unctival injection, mild iritis, and refuse deposition of fine keratic ipitates. The whole of the corneal belium shows bedew ing and swel- with an unstable overlying te a r Frequently, rapid form ation of

infrequently these tak e a dendriform shape. In terestingly, resu lts of the Schirm er test are usually w ithin normal limits, but corneal sen satio n 'is always im paired. R etroillum ination and slit-lam p exam ination show fa in t superficial strom al haze over m ost of the cornea. The mucus plaque deposi­ tion tends to continue for several months, but eventually th e te a r film and epithelium stabilize, although relapses can occur a t a la te r date.

Herpes Simplex Corneal Lesions

The dendritic ulcers of herpes simplex have à ch a ra c te ristic arbores­ cent p a tte rn w ith irre g u la r b u t sh a rp ­ ly defined borders. T erm inal end bulbs are present, and th e profile on fine slit-lam p ex am in atio n dem on­ stra te s the elevated epithelial borders of the ulcer (Fig 1, A). The m argins are serrated, opaque, and m ay be asso­ ciated w ith varying am o u n ts of su p er­ ficial strom al haze. Occasionally, th ere are overlying plaques of d esquam ated epithelium. Fluorescein s ta in s the ul­ cer c ra ter intensely w here th ere is epithelial loss b u t does n o t sta in the m argin of the ulcer. In c o n tra st, rose bengal brightly s ta in s th e dam aged cells of the epithelial d efect. Alcian blue docs not, in g en eral, sta in this

Fig 2.—Corneal mucus plaques in pa with herpes zoster keratitis.

C ytology

Ballooned epithelial cells, syncytial multinucleated giant cells, occasional epithelial cells with intranuclear eosino­ philic inclusions: mononuclear leukocytes may be present

Ballooned epithelial cells, multinucleated giant cells, margination of chromatin and glassy basophil, intranuclear Inclusion bodies

Mucus adherent to ballooned epithelial cells with occasional multinucleated giant cells

Fig 3.-D e n d rifo rm corneal mucus plaque seen in patient with herpes zoster kerati­ tis.

considerable amount of mucus in the ^car film. The lesions frequently start ^ plaques of opaque cells on the epithelial surface. They may appear in a coarse, punctate, stellate, or dendrit- *c pattern, and within a few days the center of the plaque desquamates to form a linear or arborescent ulcer. Wild iritis with keratitic precipitates and a ciliary injection may occur with

^^ch O p h th a lm o l-V o l 94, Nov 1976

symptoms often disproportionate to the clinical findings.

DIFFERENTIATION

Methods to differentiate corneal epithelial herpes simplex from herpes zoster include the following.

B io m ic ro sc o p y

While the previously described epi­ thelial lesions caused by herpes sim ­ plex and zoster differ as to size, shape, distribution, and appearance (Fig 1), it is difficult with many lesions to make a clinical diagnosis by biomi­ croscopical examination alone.

S ta in in g D iffe re n c e s

Rose bengal brilliantly stains the entire corneal mucus plaque and the margins of herpes simplex dendritic ulcers, but it stains only moderately well the small acute dendritic zoster lesions. Fluorescein stains the ulcer bed of herpes simplex dendritic ulcers intensely; however, the delayed cor­ neal mucus plaques and the acute dendritic zoster lesions are only mod­ erately well stained. Alcian blue stains the corneal mucus plaques well, but the lesions of the acute herpetic zoster and simplex are stained poorly.

M e ch a n ica l D e b rid e m e n t

The dendritic lesions due to herpes simplex and zoster can be removed only if the corneal epithelium is removed. Since the corneal mucus plaques are on the surface of the epithelium, they can be removed easily by gentle scraping with mini­ mal damage to the underlying epithe­ lium.

R e s p o n s e to C o rtic o s te ro id s

Topical corticosteroids applied to the acute lesions of herpes zoster do not appear to be detrimental, since the lesions disappear within about the same length of time as those that do not receive this medication. Cortico­ steroids do not have a notable effect on corneal mucus plaques, since they vary in size, number, appearance, and frequency regardless of whether or not this medication is used. Topically applied corticosteroids seem to pro­ vide most patients increased ocular comfort and are necessary in some

cases for the accompanying i Corticosteroids must be used caution in cases of herpes zoster loss of corneal sensation and ne paralytic ulceration because of danger of perforation. Topically! ministered corticosteroids can often do appreciably increase i width of individual branches as we the overall size of dendritic les/ caused by epithelial herpes simph

A s s o c ia te d C u ta n e o u s L eslom

Patients with acute herpetic zos will have the typical acute skin lesil of herpes zoster; the corneal mu| plaques generally appearing later the course of the disease will be a; dated with old typical zoster scarr^ on the same side of the face. Of coui herpes simplex can also be associai with vesicles around the lids and the lips.

C ytology

Scrapings from the margins herpes simplex and the acute zost lesions show degenerating cells

al

Virology

Herpes simplex virus can be read il] isolated from the edges of its ulcer In ten cases, we have failed to isolât] varicella zoster virus from the delayel zoster corneal mucus plaques.

COMMENT

There are specific zoster corneal epithelial lesions that can be distinl guished from those of herpes simplex) These lesions can be differentiated or the bases of biomicroscopical af pearance, staining characteristics, fa^ cility of debridement, cytology, an( virus isolation techniques. In addition, herpes zoster keratitis can be differ­ entiated into two groups: acute-j dendritic lesions, and delayed-corneall

mucus plaques. The acute epithelial lesions were described by Pavan- Langston and McCulley,* who ob­ tained varicella zoster virus from three cases within the first four days of the disease. The delayed lesions described here seem to be the sam e as those reported by P iebenga and Laib- son,- who did not succeed in culturing a virus in 11 cases.

Our figure o f 13% acute zoster- induced dendritic keratitis is probably low, since most cases w ere not seen within the first three to four days of onset and the cutaneous involvem ent was so severe in others that the cornea could not be adequately exam ined at an early stage in the disease.

The differentiating featu res o f ocu­ lar herpes sim plex and zoster ep ith e­ lial disease are reviewed in the Table. An important differentiation is be­ tween the herpes sim plex and the zoster-induced corneal mucus plaques, both of which may take a dendritic pattern. Prior to reports o f pure zoster-induced dendritic epithelial le­ sions, there have been several cases of herpes simplex epithelial disease re­ ported occurring in eyes o f p atien ts who have suffered from zoster (w ith­ out viral cultures).-"' A recent article reported three cases of cutaneous periocular herpes sim plex that m im ­ icked herpes zoster." A review o f 500 cases of ocular zoster seen in this institution during a five-year period showed only two cases o f clinical ophthalmic zoster w ith virologically proved herpes sim plex keratitis. The two diseases affecting the sam e eye were separated by eig h t years in one patient and by tw o w eeks in the other. The herpes sim plex keratitis su­ perseded the herpes zoster in both instances. We, therefore, conclude that coincident corneal epithelial in­ fection with the tw o viruses is an extremely rare event, and th at herpet­ ic epithelial keratitis w ith cutaneous periocular zoster and dendriform le­ sions on the involved side are caused by zoster until proved otherw ise. Rose bcngal stain is a particularly impor­ tant test to differentiate these two conditions, and mechanical debride­

m ent is a very helpful additional factor.

The appearance o f the corneal mucus plaques associated w ith zoster keratitis in a dendritic pattern is almost characteristic enough that one can identify them as such even in the absence of a recent history or mild initial attack of zoster. The diagnosis would be reinforced by finding typical zoster skin scarring, iris atrophy," and scleral atrophy.'" Corneal mucus plaques, however, are also found in other conditions, especially w ith kera­ titis sicca; thus far in sicca they have not been seen in a dendriform pattern."

The cause of herpes sim plex and acute zoster dendrites is clearly due to viral invasion and replication in the corneal epithelial cells.' It is inter­ estin g that a recent paper describes typical virus-like particles in the epithelium of the cornea in a case o f chickenpox with com plicating con­ junctivitis." The cause o f the corneal mucus plaques is more difficult to explain. As yet, no virus has been grown from these lesions by ourselves or by others,-' but cytologic study shows the epithelial cells underlying the plaques to be swollen w ith large multinucleated cells. In k eratitis sicca, these plaques tend to form in areas of extrem e drying, such as in corneal areas where the tear film is the m ost unstable. Possibly if the corneal tear film break-up takes a dendriform shape, these areas m ay allow mucus plaque to adhere in a dendritic pattern. Fluorescent antibody sta in ­ ing of cells under a probable plaque in one case has shown featu res su g g e s­ tive of viral infection.'^ On the other hand, the clinical findings, such as preceding disciform keratitis w ith immune rings, accom panying iritis, and episcleritis, may su g g e st that s o m e . form o f im m unologic m echa­ nism is involved.

Perhaps the m ost im portant value of differentiating these lesions is in the m anagem ent o f the disease. Topi­ cal ocular corticosteroids are contrain­ dicated in epithelial herpes sim plex lesions; however, they are o f value

with corneal mucus plaque keratitis of zoster, mainly for treating,the cor^pli- cating episcleritis and iritis that so often occur. Corneal mucus plaques have been decreased by topical ocular acetylcysteine application." Further­ more, in our experience, idoxuridine preparations, although invaluable in herpes simplex keratitis, adversely affect the already compromised cor­ neal epithelium in the delayed zoster lesions.

Research to Prevent Blindness Inc provided assistance in the preparation of the illustra­ tions.

Jane Field provided secretarial assistance. Prof Barrie Jones provided suggestions and advice during the preparation o f this communica­ tion. Cytologic studies were performed in the Cytology Department, St Mary’s Hospital, Lon­ don, England.

Nonproprietary Names and Trademarks of Drugs Id o x u rid in e -Z )e n d rid , H erplex, Stoxil. A c e tylcystein e-M tico m yst, N ac.

References

1. Pavan-Langston D, McCulley JP: Herpes zoster dendritic keratitis. Arch Ophthalmol