The Dynamics of Varicella-Zoster Virus Epithelial Keratitis in Herpes Zoster Ophthalmicus

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1 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus The morphology of n individul VZV lesion reflects sequence of events triggered y the virus impct on cornel epithelil cells. When seen in time perspective, it ecomes evident tht the morphology of the lesions t ech moment is result of n ongoing, highly dynmic process tht involves not only the destructive ction of the virus ut lso n ction of nturl heling forces. Seril oservtions revel tht the shpes of the lesions chnge rpidly (s fst s within 24 hours). This feture is reltle to two phenomen: prtly disppernce of disesed/dmged cells in some loctions nd, s judged y the sence of ulcertions, their sustitution y fresh ones, nd prtly n ppernce of new sites of dmge in djcent res. The first phenomenon implies tht in some loctions the virus noxious ction hs cesed nd the second one tht new infections in new loctions hve occurred. In lrger lesions, this process results in their chnging shpes; in smller lesions locted t some distnce from ech other the sme is demonstrted y their coming nd going. The VZV lesions presented in this chpter hve een cptured in ptients treted with n ntivirl drug in vitro rresting the virus repliction (cyclovir, 800mg five times dy) dministered for week. It is notle tht: () new lesions continued to develop fter the tretment ws strted; these lesions were morphologiclly indistinguishle oth from those which hd developed efore tht nd from those developing fter the tretment ws stopped; nd () tht the fetures of VZV epithelil kertitis in treted ptients were indistinguishle from the nturl course of the disese oserved in ptients not treted with ntivirl drugs (cf. Chp. 3). And the sme pplied to lesions treted with topicl cyclovir (Chp. 3). In the sence of detectle effect of tretment (so clerly visile in HSV infections) in conjunction with the sence of knowledge on how rpidly invding norml (inflmmtory?) cells pper, it is possile tht in ptients susequently developing suepithelil opcities in the sme res some imges cptured oth virus-dmged nd invding cells (Cse 2, Figs nd Cse 3, Figs ). Before the surfce is restored, distinction etween the two is not possile. H. M. Tery, Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus DOI: / _2, Springer-Verlg Berlin Heidelerg 2011

2 18 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus Cse 1: Chnging Shpes of Lrge VZV Lesion Cse Report An 82-yer-old helthy mn with typicl HZO rsh in the left side of the forehed nd listers on the upper lid. The symptoms hd strted 3 dys previously. The left eye ws injected, nd the corne showed lrge VZV pseudodendrite. He ws treted with cyclovir, 800 mg five times dy, for week. The photogrphs were tken on dy 1 (t presenttion) nd on dys 4 nd 7. re of oservtion Dy 1 Fig. 2.1 Dy 1 (efore tretment). The lower prt of lrge VZV lesion (pseudodendrite, inset) consists of severl smller lesions locted close to ech other. Left: Ter fluid stined green with fluorescein sodium penetrtes into the lesions through surfce disruptions. Right: A couple of minutes lter nd fter ppliction of rose engl. With ongoing diffusion, the lesions pper lrger ut the pttern is preserved. Disesed surfce elements stin red with rose engl. (The re within frme is shown t higher mgnifiction in Fig. 2.4, overlef) Fig. 2.3 (Opposite pge) Dy 7 (6 dys of cyclovir tretment). The lesion hs chnged shpe gin (inset). Left: This photogrph tken shortly fter the ppliction of fluorescein sodium cptured the yellow (dherent) fluorescein stining of the light-reflecting plques (white rrows) present concurrently with incipient diffusion into the lesion (green stining). The dye dditionlly visulizes fine wvy lines close to the lesion (rrowhed) nd cyst (lck rrow). Right: After couple of minutes nd ppliction of rose engl. As on dys 1 nd 4, the lesion ppers lrger ecuse of the green stining. Rose engl stins the sme surfce plques s dherent fluorescein. Also in this picture, the fine wvy lines (rrowhed) re visile. For further detils see Fig. 2.7, overlef. (The mrkers re plced in corresponding loctions)

3 Chnging Shpes of Lrge VZV Lesion (Cse 1, cont.) Chnging Shpes of Lrge VZV Lesion (Cse 1, cont.) 19 Dy 4 Fig. 2.2 Dy 4 (3 dys of cyclovir tretment). The pseudodendrite hs chnged shpe (inset). As efore, it consists of severl djcent smller lesions nd shows the sme stining fetures (cf. Fig. 2.1). Left: Ter fluid stined green with fluorescein sodium penetrtes into the lesions; confluent surfce deris ppers s strongly light-reflecting plques (rrows). Right: A couple of minutes lter nd fter ppliction of rose engl. The lesions pper lrger, ut the pttern is preserved. Fusiform cells prllel the lesions (rrowhed). For detils, see Fig. 2.5 (rectngulr frme) nd Fig. 2.6 (ovl frme), overlef. (The rrows re plced in corresponding loctions.) Comment: In the inset is visile tht the lesion is slightly rised ove the surrounding epithelium; the green stining djcent to its lower prt is cused y pooling of green stined ter fluid in ter meniscus Dy 7

4 20 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 1, cont.) Fig. 2.4 Dy 1. Close view of the re indicted y frme in Fig. 2.1, () shortly fter the ppliction of fluorescein nd () minute or two lter. An incipient VZV lesion (white rrows) close to the min one shows swollen/rounded cells (rrowheds) nd smll cysts (lck rrows). (The mrkers re plced in corresponding loctions) Fig. 2.5 Dy 4. () This prt of the VZV lesion (indicted y rectngulr frme in Fig. 2.2) shows fluorescein diffusion into the epithelium (green) nd degenerting surfce cells/cell deris stining red with rose engl (rrowheds). () Also this re, locted distlly from the min VZV lesion, shows disesed surfce cells (rrowheds) nd fluorescein diffusion into their surroundings

5 VZV Cornel Epithelil Lesions (Cse 1, cont.) 21 VZV Cornel Epithelil Lesions (Cse 1, cont.) Fig. 2.6 Dy 4. Close view of the re indicted y ovl frme in Fig Green fluorescein stining (rrowheds) visulizes fusiform cells prlleling the lesion Fig. 2.7 Dy 7. Wvy lines (rrows) showing green stined cystic spces. Left: shortly fter the ppliction of fluorescein sodium. Right: minute or two lter; there is no fluorescein diffusion round these lines. The origin of these lines is uncertin. (The rrows re plced in corresponding loctions) Addendum Two weeks fter onset of the first (cutneous) symptoms, ll VZV lesions were gone. The corne showed fint suepithelil shdow. Four weeks fter onset, when lst seen, the corne ppered norml.

6 22 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus Cse 2: Chnging Shpes of Smller VZV Lesion Cse Report A 66-yer-old mn with left-sided hedches for week nd redness of the left eye for 3 dys. The left side of the forehed nd of the nose showed incipient vesicles. The left eye ws slightly injected, nd VZV pseudodendrite ws present in the nsl prt of the corne. Acyclovir p.o. (800 mg five times dy for week) ws strted. On the following dy, the pseudodendrite ws still present, nd new, smll one ppered in the nsl upper prt of the corne. The nterior chmer showed few cells which disppered within few dys. The photogrphs were tken on dy 1 (t presenttion), nd dys 2, 3, 4, 8, 10, 15, 24, nd fter 7 weeks. re of oservtion Dy 1 Dy 2 Dy 3 Fig. 2.8 This nd opposite pge. Dy 1 (efore tretment) dy 10. Survey t low mgnifiction of chnging shpes of pseudodendrite cptured on dys 1, 2, 3, nd (opposite pge) dys 4, 8 nd 10. The upper row shows the figure stined with fluorescein sodium, the lower row with ddition of rose engl Alredy fter 24 h, the sme lesion locted in the nsl prt of the corne is not the sme. Its shpe chnges ut, in the sence of reference points others thn the figures themselves, the exct loctions of

7 Chnging Shpes of Smller VZV Lesion (Cse 2, cont.) Fig. 2.9 (Right). Survey of chnging shpes of the sme figure t the sme occsions s in Fig. 2.8 (dys 1, 2, 3, 4, 8, nd 10), shown without stining (upper row) nd stined with rose engl only (lower row) Chnging Shpes of Smller VZV Lesion (Cse 2, cont.) 23 Dy 4 Dy 8 Dy 10 preceding nd susequent chnges cnnot e pinpointed (cf. Fig. 2.26). On dy 10, the ppernce of the lesion is still comptile with VZV infection. For some detils see Figs (Dy 1 nd dy 3, lower row, re composed photogrphs.) (Dy 1, upper row, dpted from [9], dy 1 dy 4, lower row, dpted from [7])

8 24 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 2, cont.) Dy 1 Fig Dy 1, efore tretment. () Individul swollen/rounded cells (rrowheds) present close to the left upper prt of the lesion (rrow). () Surfce elevtions (drk, owed rrows) in pposition to the lesion (stright rrow) stining yellow with fluorescein

9 VZV Cornel Epithelil Lesions (Cse 2, cont.) 25 VZV Cornel Epithelil Lesions (Cse 2, cont.) Dy 4 c d Fig Dy 4, 3 dys of cyclovir tretment. () shows light-reflecting surfce plques (rrows) efore stining, () n erly stining with fluorescein sodium reveling n dditionl, incipient lesion (short white rrow); (c) swollen/rounded cells (rrowheds) nd surfce elevtion (owed rrow) in pposition to the lesion (protruding in the green stined ter film refreshed fter link), nd (d) rose engl stining of surfce plques; in the lower prt is visile n dditionl green fluorescein stining connecting the lesions (lck rrow). (The long white rrows re plced in corresponding loctions; (c) composed photogrph)

10 26 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 2, cont.) Dy 8 c Fig Dy 8, (fter 7 dys of cyclovir tretment). In () re visile foci of dmge, prtly s light-reflecting surfce plques (long rrows) nd prtly s dmged surfce cells (short rrow); in plces re visile lightreflecting dots (rrowhed). () shows yellow (dherent) stining with fluorescein sodium of surfce plques (long rrows) nd disesed cells (short rrow), nd epithelil cysts (lck rrows). Also this photogrph shows lightreflecting dots (white rrowhed). (c) With rose engl, the surfce plques (long rrows) nd disesed surfce cells (short rrow) stin red. The lesions show limited diffusion of fluorescein (green). In the surroundings re visile light-reflecting dots (white rrowhed). (The rrows re plced in corresponding loctions; (c) is composed photogrph) Comment Whether, t this stge, the light-reflecting dots represent virus-infected cells or norml (inflmmtory?) ones, or oth, cnnot e decided. Cf. Figs nd Figs

11 VZV Cornel Epithelil Lesions (Cse 2, cont.) 27 VZV Cornel Epithelil Lesions (Cse 2, cont.) Dy 10 Fig This figure, cptured on dy 10 (3 dys fter the tretment ws stopped), is still comptile with result of VZV infection () Before stining re visile mny light-reflecting dots, gglomerted or individul (rrowheds) () Fluorescein sodium visulizes disesed surfce cells nd cell deris (yellow stining) nd smll cystic spces (rrow) c (c) Disesed surfce cells nd cell deris re clerly visile fter the ppliction of rose engl. The stining is in plces confluent, nd there is still limited diffusion of green stined ter fluid (white rrow). Also this photogrph cptured lightreflecting not-stinle dots outside the figure (rrowheds). (The lck rrow points to the sme cyst s in [])

12 28 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus Suepithelil Opcities: A Sequel of VZV Epithelil Kertitis (Cse 2, cont.) Dy 15 Dy 24 7 weeks Fig All surfce chnges hve disppered. Anorml cells situted out the level of the sement memrne (present on dy 15, 24, nd 7 weeks fter onset in the re previously showing VZV epithelil lesions) pper s fine dots (shown t higher mgnifiction in Figs nd 2.16) Dy 24 Fig Anorml cells (rrowheds), individul or grouped, on dy 24

13 Suepithelil Opcities: A Sequel of VZV Epithelil Kertitis (Cse 2, cont.) 29 Suepithelil Opcities: A Sequel of VZV Epithelil Kertitis (Cse 2, cont.) 7 weeks Fig Anorml cells (rrowheds) 7 weeks fter onset. In () is visile their light-reflecting property (not exctly the sme res) Addendum The skin lesions disppered within week leving no scrs. Three months fter onset, the ptient hd no complints, nd the corne showed no sequele.

14 30 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus Cse 3: Appernce nd Disppernce of VZV Cornel Epithelil Lesions Cse Report A 70-yer-old helthy womn hd hd left-sided hedches nd irrittion in her left eye for 3 dys. The eye ws injected, the nsl prt of the corne showed few smll VZV epithelil lesions nd the nsl prt of the upper lid group of smll listers. She ws treted with cyclovir p.o., 800 mg five times dy for week. While on tretment, she developed typicl HZO rsh. New cornel epithelil lesions continued to pper t (or close to) the originl site, nd in other loctions (sucentrlly, in the prepupillry re, nd close to the upper limus). Ten dys fter onset (dy 7 fter presenttion), the eye showed mild nterior uveitis treted with topicl cortisone. This tretment ws slowly tpered. The photogrphs were tken on dy 1 (t presenttion), nd dys 3, 5, 7, 9, 11, 14, nd 16. The lst VZV comptile epithelil lesion ws oserved on dy 22 (not photogrphed). The following series of photogrphs shows follow-up of the development of VZV epithelil lesions in the nsl prt of the corne, cptured on dys 1 nd 3, nd (opposite pge) on dys 5, 7, 9 nd 11. The drwings, composed from severl photogrphs, comprise lso chnges not stining with rose engl. In the sence of reference points, they show the positions of the lesions in reltion to their ckground, i.e., n iris structure visile in the photogrphs; its outlines re indicted in the drwings y the dotted ornge lines. Becuse not exct, the drwings serve only orienttion purposes; chnges of individul structures cnnot e pinpointed. Figs show some detils cptured t these occsions. Dy 1 Dy 3

15 Appernce nd Disppernce of VZV Cornel Epithelil Lesions (Cse 3, cont.) 31 Appernce nd Disppernce of VZV Cornel Epithelil Lesions (Cse 3, cont.) Dy 5 Dy 7 Dy 9 Dy 11

16 32 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 3, cont.) re of oservtion Dy 1 In frme: the re shown elow (-d) c d Fig d Before tretment. Two smll VZV lesions (rrows) close to ech other, one strongly light-reflecting nd one less so. Arrowheds indicte swollen/rounded cells (visile in d). In (c) is visile limited fluorescein diffusion nd in (c d) rose engl stining of dmged surfce cells/cell deris. (The mrkers re plced in corresponding loctions)

17 VZV Cornel Epithelil Lesions (Cse 3, cont.) 33 VZV Cornel Epithelil Lesions (Cse 3, cont.) re of oservtion Dy 3 In frme: the re shown elow (-) c d Fig After 2 dys of cyclovir tretment. () The light-reflecting lesions (rrows) stin () green with fluorescein sodium. There is no diffusion into the surroundings. (The rrows re plced in corresponding loctions.) (c) A rounded lesion (long rrow) present sucentrlly stins green with fluorescein sodium nd, in the center, red with rose engl. Close to it is visile n incipient lesion (short rrow) tht does not stin. (d) shows light-reflecting lesion (white rrow) nd cornel nerve (lck rrow)

18 34 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 3, cont.) re of oservtion Dy 5 In frme: the re shown elow in (-) c d Fig After 4 dys of cyclovir tretment. () Adjcent incipient lesions (rrows) contining swollen/rounded cells (rrowheds); () the left lesion shows fluorescein diffusion nd red stining of surfce cells/cell deris. (The rrows re plced in corresponding loctions.) (c d) shows incipient lesions (rrows) tht developed in new (sucentrl) loction; they show the sme stining s in ( ). In (d) re visile swollen/rounded cells (rrowhed, cf. lso inset). (The rrows re plced in corresponding loctions)

19 VZV Cornel Epithelil Lesions (Cse 3, cont.) 35 VZV Cornel Epithelil Lesions (Cse 3, cont.) re of oservtion Dy 7 In frme: the re shown elow (-d). The long white rrow indictes the sme loction in ll photogrphs c d Fig After 6 dys of cyclovir tretment. The lower prt of the lesion shown ove shows VZV typicl mixture of fetures: () light-reflecting surfce plques (long white rrow) pper () right in the ter film stined green with fluorescein, nd (c d) stin red with rose engl. Fluorescein visulizes protruding swollen/rounded cells (, rrowhed), surfce elevtions ( nd c, owed rrows), nd diffusion into the tissues (c, short white rrow). In (d) re dditionlly visile swollen/rounded cells (rrowhed). (Adpted from [7])

20 36 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 3, cont.) re of oservtion Dy 9 In frme: the re shown elow in (). The lck rrowheds re plced in the sme loction in ll photogrphs. c d e Fig () shows red stining of dmged cells (lck rrowheds), surfce plques (long white rrows), nd penetrtion of green stined ter fluid into the epithelium (short white rrow; composed photogrph). In the pir of photogrphs ( nd c) re visile swollen/rounded cells (white rrowheds) present in res stining green in () nd lrger rounded structures (lck rrow), proly cysts. (d nd e) This pir of photogrphs shows n re to the left from the min lesion; it contins heped-up norml cells (white rrowhed) ut it does not stin. Cf. Fig nd Figs (overlef) Comment Similrly to Cse 2 (Fig ), it is impossile, t this stge, to differentite virus-infected cells from norml (inflmmtory?) ones.

21 VZV Cornel Epithelil Lesions (Cse 3, cont.) 37 VZV Cornel Epithelil Lesions (Cse 3, cont.) Dy 11 re of oservtion In frme: the re shown elow in (-d). The white rrow indictes the sme loction in ll photogrphs. c d Fig These lesions () contin light-reflecting dots (rrowhed), () show rose engl stining nd limited green fluorescein stining, nd (c) seem composed of heped-up rounded cells (rrowhed); lso the surroundings show mny rounded cells ( nd d, rrowheds) in res tht do not stin. Cf. Figs nd (overlef). At the sme occsion (dy 11), new incipient lesions were cptured in different re (Fig. 2.28)

22 38 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VV Cornel Epithelil Lesions (Cse 3, cont.) Dy 14 Dy 16 A few ptches of surfce deris stining red with rose engl re still present In frme: the re shown in Fig. 2.23, elow In this re, rose engl surfce stining hs disppered In frme: the re shown in Fig. 2.24, elow Fig () In this re, surfce chnges hve disppered. The rounded cells (rrowhed) proly represent norml cells situted out the level of the sement memrne. () For comprison, inflmmtory cells (rrowhed) ttched to the endothelium during nterior uveitis (cptured on dy 7) Fig Anorml cells (rrowhed) situted out the level of the sement memrne re of oservtion Fig (right) At the sme occsion (dy 16), the upper prt of the corne showed new VZV lesions

23 Development of VZV Cornel Epithelil Lesions in the Sme Loction (Cse 3, cont.) 39 Development of VZV Cornel Epithelil Lesions in the Sme Loction (Cse 3, cont.) Dy 7 Dy 9 Dy 11 Fig Dys 7, 9, nd 11. The three pirs of photogrphs cptured rre occsion. By coincidence, VZV lesions developed centrlly, in loction tht showed gryish lines due to epithelil sement memrne dystrophy (rrows). The chnging pttern within 48 h, cused y disppernce of some lesions, or their prts, concurrently with the ppernce of new ones is well visile in reltion to the dystrophy. The rrows re plced in corresponding loctions, oth efore (upper row) nd fter stining with fluorescein sodium nd rose engl (lower row)

24 40 Chpter 2 The Dynmics of Vricell-Zoster Virus Epithelil Kertitis in Herpes Zoster Ophthlmicus VZV Cornel Epithelil Lesions (Cse 3, cont.) Fig Dy 7, fter 6 dys of cyclovir tretment. () This lesion (rrow) locted sucentrlly shows swollen/rounded cells t the edges (rrowhed); similr cells re visile in the upper right corner (rrowhed). () shows the light-reflecting property of the sme lesion. (The rrows re plced in corresponding loctions.) Four dys lter, lesions with similr fetures were cptured in different re (cf. Fig. 2.28, opposite pge)

25 VZV Cornel Epithelil Lesions (Cse 3, cont.) 41 VZV Cornel Epithelil Lesions (Cse 3, cont.) Fig Dy 11, 3 dys fter cyclovir tretment ws stopped. This sucentrl re shows () n incipient lesion (owed rrow), more dvnced one (long rrow), nd swollen/rounded cells (rrowheds); the gry rrow points to smll cyst. In (), fluorescein hs disppered from the ter film: The incipient lesion (owed rrow) does not stin; the more dvnced lesion (long rrow) shows limited green fluorescein stining, nd rose engl stining; to the right re visile swollen/ rounded cells (rrowhed) nd smll cyst (gry rrow). (The rrows re plced in corresponding loctions) Addendum Three months fter onset, when lst seen, the ptient ws symptom-free. The corne showed no sequele of the infection; the only finding ws epithelil sement memrne dystrophy.

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