Organon of the Panhellenic Ophthalmological Society

Quarterly publication

FounderP.A. Konstas (Thessaloniki)

Editor in chiefN. Georgiadis (Thessaloniki)

Editorial Board

Co-Editors S. Lake (Thessaloniki) Members P. Stylianidis (Leukosia)D. Dereklis (Thessaloniki) N. Ziakas (Thessaloniki)N. Papadopoulos (Thessaloniki) N. Kozeis (Thessaloniki)A.K. Manthos (Thessaloniki) S. Gartaganis (Patra)P. Economidis (Thessaloniki) E. Kopsachilis (Thessaloniki)

A-G.P. Konstas (Thessaloniki)S. Maloutas (Thessaloniki)D. Mikropoulos (Thessaloniki)S. Baltatzis (Athens)K. Boboridis (Thessaloniki)Th. Bufidis (Thessaloniki)P. Brazitikos (Thessaloniki)A. Polychronakos (Thessaloniki)Ch. Terzidou (Athens)Ch. Kalogeropoulos (Ioannina)M. Balidis (Thessaloniki)

Ophthalmologia

International Editorial Board

Evangelos Alexandridis (Germany)Jorge Alio (Spain)

Francesco Bandello (Italy)Francesco Carones (Italy)

David Charteris (U.K.)Richard Collin (U.K.)

Ahment Cucukoglou (Turkey)Donald D’ Amico (U.S.A.)

Sheraz Daya (U.K.)Thomas Friberg (U.S.A.)

Evangelos Gragoudas (U.S.A.)Ian Grierson (U.K.)

Gabor Hollo (Hungary)Mercado Hugo-Quiroz (Mexico)

Stephen D. Klyce (U.S.A.)Marguerite B. McDonald (U.S.A.)Shlomo Melamed (Israel)Maarten Mourits (Netherlands)Murat Irkec (Turkey)Constantin Pournaras (Switzerland)Alan Robin (U.S.A.)Theo Seiler (Switzerland)William C. Stewart (U.S.A.)Miguel Teus (Spain)John Thygesen (Denmark)Petja Vassileva (Bulgaria)George Williams (U.S.A.)Leonidas Zografos (Switzerland)

Reviwers

S. AndroudiX. Kalogeropoulos

M. BalidisK. Pournaras

T. Seiler

Mailing Address

Panhellenic Ophthalmological SocietyP.O. Box 1585, 540 06 – Thessaloniki, GreeceSecretariat: Vas. Tzika, Tel.: +30 2310 994912

e-mail: info@poe.grweb-site: http://www.poe.gr

Council

President: N. PapadopoulosVice President: S. AsteriadisGen. Secretary: K. BoboridisSecretary: ¡. ∑iakasTreasurer: N. Kozeis

Publisher

University Studio PressLeonidas Michalis, 32 Armenopoulou Str.546 35 – Thessaloniki, GreeceTel. +30 2310 209637 & +30 2310 209837

OphthalmologiaVolume 22 - No 1 - 2010

Contents

Reviews 7 Age related macular degenerationA.N. Vakalis, S. Asteriades, P. Tranos

12 Is blood transfusion a risk factor for retinopathy of prematurity?I. Chatziioannidis, P. Karagianni, N. Nikolaidis

16 Hereditary retinal diseasesN. Kozeis

22 Chemical vitrectomy: a threat for vitreoretinal surgeonsor a useful tool?E. Papavasileiou, G. Morphis, D. Dereklis, I. Vasiliadis

28 Pediatric refractive surgeryN. Kozeis, N. Papadopoulou, S. Tyradelis, P. Tahiaos

32 Visual evoked potentials: contemporary diagnostic applicationsM. Parava, E. Kanonidou, A. Praidou, P. Beredimas

Clinical and 35 Management of patients with retinal tears treated with Argon-Laserlaboratory studies photocoaculation in a Greek referral center

E. Kanonidou, A. Praidou, V. Konidaris, P. Zotta, A-K.D. Alexandridis

Cases reports 38 Bilateral papilledema in Chiari I malformationA. Praidou, E. Kanonidou, V. Kanidaris, S. Maloutas,D. Paraskevopoulos, I. Magras, K. Boboridis

43 Diagnostic dilemmas in Vogt Koyanagi Harada SyndromeN. Papadopoulos, T. Empeslidis, D. Papadopoulou,G. Magioris, S. Androudi

47 Punctate inner choroidopathy – a case report and literature reviewE. Papavasileiou, G. Morphis, L. Razis, A. Gratsonidis

Cover picture: Type II choroidal neovascularization in a patient with high myopia

(P. Tranos)

Instructions for the authors

OPHTHALMOLOGIA is the official journal of the

Panhellenic Ophthalmological Society and publishes arti-

cles of every field of the ophthalmology specialty. Articles

in Greek or English language are welcome.

Depending on the type of article the publications may

be:

Editorial articleReview articles: It reflects experts’ opinion on intere-

sting topics of ophthalmology. It covers the subject in depth

with adequate literature research.

Clinical and laboratory studies: The editorial board ac-

cepts original articles of significant scientific contribution.

The structured article should be maximum 4-6 pages and

should include abstract (in Greek and English for Greek

articles) figures or graphs and references.

Interesting cases: Articles should be 2-3 pages long with

a short abstract, figures or graphs and references presen-

ting rare interesting cases or new treatment modalities.

Thesis presentations: Short reviews of recent PhD thesis

with maximum length of 5-6 pages are welcome. They sho-

uld be structured with a short introduction, materials and

methods, results, discussion, conclusions and selected

references.

General topics: In this section we welcome articles of

general interest (historic, philosophic, artistic or literature)

and scientific or professional views.

Continued medical education: Educational articles with

extensive coverage of a specific topic and literature review

are being published.

Round tables, Meetings, Conferences are being abstra-

cted in this section.

Abstracts from international literature.PostersBook reviewsNew instrumentsNews, Letters to the editorThe original articles should have not been published

previously. Their structure should be: Introduction, Ma-

terials and Methods, Results, Conclusions and References.

The first page should include the Title, authors names with

affiliations and a structured abstract as above with a ma-

ximum of 150 words. At the bottom of the page should be

the corresponding authors address and telephone numbers.

Two printed copies of the manuscript should be sub-

mitted along with an electronic form of the article and art-

work (PC formatted floppy disk or CD).

Figures should be in grayscale with a minimum of 300

dpi resolution. Color figures may be accepted with an addi-

tional charge. Graphs should be professionally reproduced

in black and white. Legends should be numbered consecu-

tively and should be typed at the end of the text.

References should be numbered consecutively in order

of appearance in the text and structured with the following

format:

Authors names (Surename and initials)

Title of article

Journal name abraviation

Issue, pages and year of publication (Fitzpatrick TB,

Zeller R, Kukita A et al. Ocular and dermal melanocytosis.

Arch. Ophthalmol. 56: 830-832, 1956.

For books: Authors names, title, editor, book title, vo-

lume, pages, issue, publisher, city, year, Whitemore PV,

Skin and Mucous Membrane Disorders. In: Th. D. Duane,

E. A. Jaeger’s (Ed): Clinical Ophthalmology, Vol 5: 27, 10-

11, Harper and Row Publishers, Philadelphia, 1985.

Editorial review follows submission of manuscript. The

editorial board reserves the right for minor alterations of

the article without authors approval. The first draft is retu-

rned to the authors for spelling and grammar corrections

only. Reprint requests are addressed to the editorial office.

Submission of manuscript is perceived as an automatic

copyright transfer to the journal OPTHALMOLOGIA. A-

ny further publication of the same material published in

this journal can only be made following written approval of

the editor.

∏ «OÊı·ÏÌoÏoÁ›·» Â›Ó·È Ùo ›ÛËÌo ÂÚÈo‰ÈÎfi Ù˘

«¶·ÓÂÏÏ‹ÓÈ·˜ OÊı·ÏÌoÏoÁÈ΋˜ ∂Ù·ÈÚ›·˜» Ì ÛÎofi ÙËÓ

ÂÓË̤ڈÛË Î·È ÂÈÌfiÚʈÛË Ùo˘ oÊı·ÏÌÈ¿ÙÚo˘. ¢ËÌoÛÈ-

‡oÓÙ·È ÚˆÙfiÙ˘Â˜ ÂÈÛÙËÌoÓÈΤ˜ ÂÚÁ·Û›Â˜ ÛÙËÓ ∂ÏÏËÓÈ-

΋ ‹ ∞ÁÁÏÈ΋ ÁÏÒÛÛ· o˘ ηχÙo˘Ó fiÏo Ùo ÂÈÛÙËÌoÓÈÎfi

Ê¿ÛÌ· Ù˘ oÊı·ÏÌoÏoÁ›·˜.

∞Ó¿ÏoÁ· Ì Ùo ›‰o˜ Î·È ÙË ÌoÚÊ‹ ÙˆÓ ¿ÚıÚˆÓ, Ùo Â-

ÚÈo‰ÈÎfi ‰ËÌoÛȇÂÈ:

™¯fiÏÈo Ùo˘ ÂΉfiÙË

∞Ó·ÛÎfiËÛË: ∞Ó·Ù‡ÛÛoÓÙ·È Û ‚¿ıo˜ ı¤Ì·Ù· ÁÂÓÈ-

Îo‡ ÂӉȷʤÚoÓÙo˜ ·fi Û˘ÁÁڷʤ· Ì ÂÍÂȉ›Î¢ÛË ÛÙo ·-

ÓÙÈΛÌÂÓo. ¶ÂÚÈÏ·Ì‚¿ÓÂÈ ÈÛÙoÚÈ΋ ·Ó·‰ÚoÌ‹, Û‡Á¯ÚoÓ˜

·fi„ÂȘ Î·È ÂÎÙÂٷ̤ÓË ‚È‚ÏÈoÁÚ·ÊÈ΋ ÙÂÎÌËÚ›ˆÛË.

∫ÏÈÓÈΤ˜ Î·È ÂÚÁ·ÛÙËÚȷΤ˜ ÌÂϤÙ˜: ∏ Û˘ÓÙ·ÎÙÈ΋ ÂÈ-

ÙÚo‹ οÓÂÈ ‰ÂÎÙ¤˜ ÚˆÙfiÙ˘Â˜ ÂÚÁ·Û›Â˜ Ì o˘ÛÈ·ÛÙÈ΋

ÚoÛÊoÚ¿ ÛÙËÓ ÂÈÛÙ‹ÌË. Δo ‰oÌË̤Óo ¿ÚıÚo Ú¤ÂÈ Ó·

Â›Ó·È ¤ˆ˜ 6 ÛÂÏ›‰Â˜ Î·È Ó· ÂÚÈÏ·Ì‚¿ÓÂÈ ÂÚ›ÏË„Ë ÛÙ·

∂ÏÏËÓÈο Î·È ∞ÁÁÏÈο ÁÈ· ÙȘ ÂÚÁ·Û›Â˜ ÛÙËÓ ÂÏÏËÓÈ΋

ÁÏÒÛÛ·, ÂÈÎfiÓ˜, ÁÚ·ÊÈο Î·È ‚È‚ÏÈoÁÚ·Ê›·.

∂ӉȷʤÚoÓ ÂÚÈÛÙ·ÙÈÎfi: Δ· ¿ÚıÚ· Ú¤ÂÈ Ó· ¤¯o˘Ó

¤ÎÙ·ÛË ¤ˆ˜ 3 ÛÂÏ›‰Â˜, Ì ۇÓÙoÌË ÂÚ›ÏË„Ë ÛÙ· ∂ÏÏËÓÈο

Î·È ∞ÁÁÏÈο, ÂÈÎfiÓ˜ Î·È ‚È‚ÏÈoÁÚ·Ê›·, ·Úo˘ÛÈ¿˙oÓÙ·˜

ÂÚÈÛÙ·ÙÈο o˘ ÎÚ›ÓoÓÙ·È ÂӉȷʤÚoÓÙ· ‹ Û¿ÓÈ·, ‹ ÙËÓ

ÂÊ·ÚÌoÁ‹ οoÈ·˜ Ó¤·˜ ıÂڷ¢ÙÈ΋˜ ÌÂıfi‰o˘.

¶ÂÚ›ÏË„Ë ‰È‰·ÎÙoÚÈ΋˜ ‰È·ÙÚÈ‚‹˜: ¢ËÌoÛȇoÓÙ·È Â-

ÚÈÏËÙÈΤ˜ ·Úo˘ÛÈ¿ÛÂȘ ‰È‰·ÎÙoÚÈÎÒÓ ‰È·ÙÚÈ‚ÒÓ Ì ̤ÁÈ-

ÛÙË ¤ÎÙ·ÛË 6 ÛÂÏ›‰Â˜ Î·È ÂÚÈÏ·Ì‚¿Óo˘Ó ÂÈÛ·ÁˆÁ‹, ˘ÏÈÎfi

Î·È Ì¤ıo‰o, ·oÙÂϤÛÌ·Ù·, Û˘˙‹ÙËÛË Î·È Û˘ÌÂÚ¿ÛÌ·Ù·

Ì ·ÓÙÈÚoÛˆÂ˘ÙÈ΋ ‚È‚ÏÈoÁÚ·Ê›·.

™‡ÌÌÂÈÎÙ·: ºÈÏoÍÂÓo‡ÓÙ·È ¿ÚıÚ· ÁÂÓÈÎo‡ ÂӉȷʤÚo-

ÓÙo˜ (ÈÛÙoÚÈο, ÊÈÏoÛoÊÈο, ÏoÁoÙ¯ÓÈο Î·È ¿ÏÏ·) ‹ ı¤-

Ì·Ù· Ì ÂÈÛÙËÌoÓÈÎfi Î·È Â·ÁÁÂÏÌ·ÙÈÎfi ÂӉȷʤÚoÓ.

ªÂÙÂÎ·È‰Â˘ÙÈο ı¤Ì·Ù·™ÙÚoÁÁ˘Ï¤˜ ÙÚ¿Â˙˜, ™˘ÌfiÛÈ· Î·È ÂÚÈÏ‹„ÂȘ ÂÈ-

ÛÙËÌoÓÈÎÒÓ Û˘Ó‰ÚÈ¿ÛÂˆÓ o˘ ¤ÁÈÓ·Ó ÛÙ· Ï·›ÛÈ· ÂΉË-

ÏÒÛÂˆÓ Ù˘ ¶·ÓÂÏÏ‹ÓÈ·˜ OÊı·ÏÌoÏoÁÈ΋˜ ∂Ù·ÈÚ›·˜ ‹

¿ÏÏˆÓ ÙoÈÎÒÓ OÊı·ÏÌoÏoÁÈÎÒÓ ∂Ù·ÈÚÂÈÒÓ.

¶ÂÚÈÏ‹„ÂȘ ·fi ͤӷ ÂÚÈo‰Èο.PostersμÈ‚ÏÈoÎÚÈۛ˜¶ÏËÚoÊfiÚËÛË ÁÈ· ÂÍoÏÈÛÌfi Î·È ÂÚÁ·Ï›·.∂ȉ‹ÛÂȘ, ÁÚ¿ÌÌ·Ù· Úo˜ ÙËÓ ÂΉoÙÈ΋ ÂÈÙÚo‹.OÈ ÂÚÁ·Û›Â˜ o˘ ‰ËÌoÛȇoÓÙ·È Â›Ó·È ÚˆÙfiÙ˘Â˜ Î·È ‰ÂÓ

¤¯o˘Ó ‰ËÌoÛÈ¢ı› ·ÏÏo‡. H ‰oÌ‹ Ùo˘˜ Ú¤ÂÈ Ó· ÂÚÈÏ·Ì‚¿ÓÂÈ

Ùo ÛÎofi Ù˘ ÂÚÁ·Û›·˜, ÂÚÈÁÚ·Ê‹ Ùo˘ ˘ÏÈÎo‡ Î·È ÙˆÓ ÌÂıfi‰ˆÓ

‹ ÙËÓ ÂÚÈÁÚ·Ê‹ ÌÈ·˜ Û¿ÓÈ·˜, Ì ÂÈÛÙËÌoÓÈÎfi ÂӉȷʤÚoÓ Â-

Ú›ÙˆÛ˘, Ù· ·oÙÂϤÛÌ·Ù·, ÙË Û˘˙‹ÙËÛË Ì ٷ Û˘ÌÂÚ¿ÛÌ·Ù·,

ÙË Û¯ÂÙÈ΋ ‚È‚ÏÈoÁÚ·Ê›· o˘ ·Ú·¤ÌÂÈ Ùo ΛÌÂÓo Î·È ÂÚ›-

ÏË„Ë ÛÙËÓ ÂÏÏËÓÈ΋ ηıÒ˜ Î·È Ù›ÙÏo, oÓfiÌ·Ù· Û˘ÁÁڷʤˆÓ ηÈ

ÂÚ›ÏË„Ë Û ·ÁÁÏÈ΋ ÁÏÒÛÛ·.

T· ̄ ÂÈÚfiÁÚ·Ê· ÙˆÓ ¿ÚıÚˆÓ o˘ ηٷٛıÂÓÙ·È (ÂȘ ‰ÈÏo‡Ó)

·fi Ùo˘˜ Û˘ÁÁÚ·Ê›˜ Úo˜ ‰ËÌoÛ›Â˘ÛË ı· Ú¤ÂÈ Ó· Â›Ó·È ‰·-

ÎÙ˘ÏoÁÚ·ÊË̤ӷ Ì ‰ÈÏfi ‰È¿ÛÙËÌ· Î·È Â˘Ú¤· ÂÚÈıÒÚÈ·.

¶ÚoËÁÂ›Ù·È o Ù›ÙÏo˜ Ù˘ ÂÚÁ·Û›·˜ –o˘ Ú¤ÂÈ Ó· Â›Ó·È fiÛo Ùo

‰˘Ó·Ùfi Û˘ÓoÙÈÎfi˜–, ·ÎoÏo˘ıo‡Ó Ù· oÓfiÌ·Ù· ÙˆÓ Û˘ÁÁڷʤˆÓ

Î·È oÈ ÂÚÈÏ‹„ÂȘ. OÈ ÂÚÈÏ‹„ÂȘ ı· Ú¤ÂÈ Ó· Â›Ó·È ‚Ú·¯Â›Â˜

(150 ϤÍÂȘ ÂÚ›o˘). OÈ ÊˆÙoÁڷʛ˜ o˘ ‰ËÌoÛȇoÓÙ·È Â›Ó·È

·ÛÚfiÌ·˘Ú˜. H ‰ËÌoÛ›Â˘ÛË ÂÁ¯ÚÒÌˆÓ ÊˆÙoÁÚ·ÊÈÒÓ ‚·Ú‡ÓÂÈ

oÈÎoÓoÌÈο Ùo˘˜ Û˘ÁÁÚ·Ê›˜. OÈ Úo˜ ‰ËÌoÛ›Â˘ÛË ›Ó·Î˜ ı·

Ú¤ÂÈ Ó· Â›Ó·È ÁÚ·Ì̤ÓoÈ Â˘·Ó¿ÁÓˆÛÙ· Î·È Ù· Û¯‹Ì·Ù· Û¯Â-

‰È·Ṳ̂ӷ Ì ÛÈÓÈ΋ ÌÂÏ¿ÓË ·fi ·ÁÁÂÏÌ·Ù›· ۯ‰ȷÛÙ‹ ‹ ˙ˆ-

ÁÚ¿Êo. EÈÎfiÓ˜ Î·È ›Ó·Î˜ Ì ÙȘ ÏÂ˙¿ÓÙ˜ Ùo˘˜ ‰ÂÓ Ì·›Óo˘Ó

ÛÙo ΛÌÂÓo, ·ÚÈıÌo‡ÓÙ·È ÛÙËÓ o›ÛıÈ· fi„Ë Ùo˘˜ Î·È ·oÙÂÏo‡Ó

ÂÍ¿ÚÙËÌ· Ùo˘ ΢ڛˆ˜ ÎÂÈ̤Óo˘.

H Û˘ÁÁÚ·Ê‹ Ù˘ ‚È‚ÏÈoÁÚ·Ê›·˜ ·ÎoÏo˘ı› ·ÏÊ·‚ËÙÈ΋ ÛÂÈ-

Ú¿ ‹ ÙË ÛÂÈÚ¿ ÂÌÊ¿ÓÈÛ˘ ÛÙo ΛÌÂÓo Î·È Î¿ı ‚È‚ÏÈoÁÚ·ÊÈ΋

·Ú·oÌ‹ ÛËÌÂÈÒÓÂÙ·È ˆ˜ ÂÍ‹˜:

– OÓfiÌ·Ù· Û˘ÁÁڷʤˆÓ (ÚoËÁÂ›Ù·È Ùo ÂÒÓ˘Ìo Î·È ·Îo-

Ïo˘ı› Ùo ·ÚÈo fiÓoÌ· Û˘ÓÙÂÙÌË̤Óo).

– O Ù›ÙÏo˜ Ù˘ ‰ËÌoÛ›Â˘Û˘.

– H ›ÛËÌË Û‡ÓÙÌËÛË Ùo˘ oÓfiÌ·Ùo˜ Ùo˘ ÂÚÈo‰ÈÎo‡ fio˘ ›-

Ó·È ‰ËÌoÛÈÂ˘Ì¤ÓË.

– O ÙfiÌo˜, Ë ÚÒÙË Î·È ÙÂÏÂ˘Ù·›· ÛÂÏ›‰· Ù˘ ‰ËÌoÛ›Â˘Û˘, Ùo

¤Ùo˜, .¯. Fitzpatrick TB, Zeller R, Kukita A, et al. Ocular and

dermal melanocytosis. Arch . Ophthalmol. 56: 830-832, 1956.

– ŸÙ·Ó ÚfiÎÂÈÙ·È ÁÈ· ‚È‚Ï›o, Ù· oÓfiÌ·Ù· ÙˆÓ Û˘ÁÁڷʤˆÓ, o

Ù›ÙÏo˜ Ù˘ ÂÚÁ·Û›·˜, Ùo fiÓoÌ· Ùo˘ ÂΉfiÙË, o Ù›ÙÏo˜ Ùo˘ ‚È-

‚Ï›o˘, o ÙfiÌo˜, Ë ÚÒÙË Î·È ÙÂÏÂ˘Ù·›· ÛÂÏ›‰· Ù˘ ÂÚÁ·Û›·˜,

Ë ¤Î‰oÛË, o ÂΉoÙÈÎfi˜ o›Îo˜, Ë fiÏË, Ùo ¤Ùo˜, Whitemore PV.Skin and Mucus Membrane Disorders. In: Th. D. Duane,E.A. Jaeger’ s (Ed): Clinical Ophthalmology, Vol 5: 27, 10-11,

Harper and Row Publishers, Philadelphia, 1985.

™Ùo Ù¤Ïo˜ Ù˘ ‰ËÌoÛ›Â˘Û˘ ‰›ÓÂÙ·È Ë ‰È‡ı˘ÓÛË ÂÓfi˜ ·fi

Ùo˘˜ Û˘ÁÁÚ·Ê›˜ ÁÈ· ÙËÓ ·ÏÏËÏoÁÚ·Ê›·.

MÂÙ¿ ÙËÓ Î·Ù¿ıÂÛ‹ Ùo˘˜ oÈ ÂÚÁ·Û›Â˜ ÎÚ›ÓoÓÙ·È ·fi ÙË Û˘-

ÓÙ·ÎÙÈ΋ Î·È Û˘Ì‚o˘Ï¢ÙÈ΋ ÂÈÙÚo‹ Î·È ·ÎoÏo˘ı› Ë ‰È·‰Èη-

Û›· Ù˘ ÂÎÙ‡ˆÛ˘. ŸÙ·Ó ÂÙoÈÌ·ÛÙo‡Ó Ù· ‰oΛÌÈ· Ù˘ ·′‰ÈoÚıÒ-

Ûˆ˜, ·oÛÙ¤ÏÏoÓÙ·È ÛÙo˘˜ Û˘ÁÁÚ·Ê›˜ ÁÈ· ¤ÏÂÁ¯o —o˘

·ÊoÚ¿ ÌfiÓo ÙË ‰ÈfiÚıˆÛË ÙˆÓ Ï·ıÒÓ Ùo˘ Ù˘oÁÚ·Ê›o˘— ̄ ˆÚ›˜

Ó· ÂÈÙÚ¤oÓÙ·È ·ÏÏ·Á¤˜ Î·È ÚoÛı‹Î˜.

™ÙË Ê¿ÛË ·˘Ù‹ Ù˘ ÂÎÙ‡ˆÛ˘ oÈ Û˘ÁÁÚ·Ê›˜ ¤¯o˘Ó ÙË ‰˘-

Ó·ÙfiÙËÙ· Ó· ̇ ËÙ‹Ûo˘Ó ÙoÓ ·ÚÈıÌfi ÙˆÓ ·Ó·Ù‡ˆÓ o˘ ÂÈı˘Ìo‡Ó.

T· ¯ÂÈÚfiÁÚ·Ê· ÙˆÓ ÂÚÁ·ÛÈÒÓ o˘ ·oÛÙ¤ÏÏoÓÙ·È (ÂȘ ‰È-

Ïo‡Ó) Úo˜ ÙoÓ Úfi‰Úo Ù˘ Û˘ÓÙ·ÎÙÈ΋˜ ÂÈÙÚo‹˜, ·Ú·-

̤Óo˘Ó ÛÙo ·Ú¯Â›o Ùo˘ ÂÚÈo‰ÈÎo‡ Î·È ‰ÂÓ ÂÈÛÙÚ¤ÊoÓÙ·È.

OÈ ÂÚÁ·Û›Â˜ Î·È Ù· ¿ÚıÚ· o˘ ‰ËÌoÛȇoÓÙ·È ÛÙo ÂÚÈo‰È-

Îfi ·oÙÂÏo‡Ó ÓÂ˘Ì·ÙÈ΋ ȉÈoÎÙËÛ›· Ùo˘ Û˘ÁÁڷʤ· ηÈ

··ÁoÚ‡ÂÙ·È Ë ·Ó·‰ËÌoÛ›Â˘Û‹ Ùo˘˜, Ë oo›· Â›Ó·È ‰˘Ó·Ùfi Ó·

Á›ÓÂÈ ÌfiÓoÓ Î·ÙfiÈÓ ÂÁÁÚ¿Êo˘ ·‰Â›·˜.

O‰ËÁ›Â˜ ÚÔ˜ ÙÔ˘˜ Û˘ÁÁÚ·Ê›˜

Presentation

As early disease is consistent with good visual

function diagnosis is not uncommonly made on ro-

utine examination. Clinical findings in the early sta-

ges include the presence of yellow subretinal depo-

sits called drusen, and pigmentary changes in the

form of hyper or hypopigmentation. In later stages

vision may be severely affected by either the deve-

lopment of larger areas of hypopigmentation that

affect the fovea, or the development of choroidal

neovascularization and eventually scarring.

The presence of the disease is usually evident

with slit lamp examination only. However to distin-

guish between dry and wet age related macular de-

generation further testing may be necessary.

Fundus fluorescein angiography in the pre-

sence of choroidal neovascularization will reveal

the abnormal blood vessels, which will show va-

rying degrees of leakage during the late stages of

the examination.

Optical coherence tomography (OCT) has

more recently provided us with a non invasive

method of examining the macula. Several high re-

solution axial scans are taken during the exam, and

structures within the retina and the pigment epi-

thelium may be visualized with detail. Geographic

atrophy is visualized as thinning of the retina with

loss of the photoreceptor layer. Choroidal neova-

scularization can be seen as a hyperreflective stru-

cture in the area of the pigment epithelium. The

presence or absence of fluid can be seen and quan-

tified. Furthermore changes in the volume can be

detected during follow up visits with accuracy.

Therefore optical coherence tomography is a use-

ful tool in diagnosing and establishing response to

treatment for these patients.

Pathogenesis

Pathogenesis of the disease is not well under-

stood. Recently associations between age related

macular degeneration and polymorphisms in gene

encoding proteins, have shown that inheritance

plays a significant role in developing the disease.

Habitual factors such as smoking and nutrition

have also been shown to increase the risk, while

further environmental factors such as increased ex-

Ophthalmologia, 22, 1 : 7 - 11, 2010

Age related macular degeneration

A.N. Vakalis1,2, S. Asteriades1,2, P. Tranos2

1 AHEPA University Hospital, Thessaloniki, Greece2 “Retina” – Thessaloniki Retinal Consultants Thessaloniki, Greece

Age related macular degeneration, despite recent advan-ces in understanding and treating the disease, remainsthe leading cause of legal blindness for patients over 50years of age, in the western world. Several treatment mo-dalities including laser photocoagulation, photodynamictherapy, teletherapy, interleukin e.t.c. have been tried inthe past. Despite however, initially promising results, they

proved a disappointment to patients and clinicians alike.Recently the introduction of antiVegf treatments for AMDwas received with enthusiasm and appears to be a potentway for altering the natural course of the disease. Unfor-tunately it is useful to only a subgroup of patients with sig-nificant loss of vision.

Reviews∂ditor: ∞. Manthos

e-mail: amanthos@med.auth.gr

posure to sunlight may play a role and are further

investigated.

On the molecular level, exposure of the retina

to sunlight and the presence of high levels of oxy-

gen can lead to a constant oxidative stress through

the development of free radicals and may be the

initiating stimulus of the disease.

Treatment

The risk of progression to significant loss of vi-

sion varies significantly between patients. The age

related eye disease study has quantified this risk.

People with bilateral disease and small discrete

drusen had only a 0.4-3% chance of progressing

over five years. If however large drusen and pig-

mentary changes were present in both eyes, the risk

increased to 47.3%.

Loss of vision from the dry variant of the di-

sease occurs when areas of pigmentary atrophy co-

alesce and expand to involve the macula. Although

progression of this type of the disease is gradual,

the loss of vision may be as severe as in the wet

form of the disease. Attempts to prevent progressi-

on of dry AMD have focused on factors that may

reduce oxidative stress in the macula area. Quitting

smoking is highly recommended as association

with the disease is very strong. Supplementation of

nutrition with anti-oxidant vitamins, on the other

hand is more controversial. Although the age rela-

ted eye disease study found a reduced risk of pro-

8 Ophthalmologia, 22, 1 (2010)

Fig. 1, 2. Combined FFA & High Resolution OCT in a Patient with neovascular PED (fig. 1) and same patient following3 injections of Ranibizumab (Lucentis) showing partial restoration of macular anatomy with some residual PED andintraretinal fluid.

gression by up to 20% in patients receiving high

doses of vitamins C and E, beta carotene and zinc,

high doses of vitamins may be harmful and further

evidence is necessary before nutritional supple-

mentation is recommended to all AMD patients.

The development of choroidal neovasculari-

zation marks progression to the wet variant. These

patients lose vision quickly, and if left untreated,

more than half will have vision of less than 1/10, in

three years. For those patients treatment with in-

travitreal injection of an anti vascular endothelial

growth agent (anti VEGF), is the current gold

standard of care. Previous laser based treatments,

worked only for limited subgroups of wet AMD pa-

tients, and in best were able to maintain visual

aquity. In contrast to these, initial results from the

use of antivegf agents showed an increase in visual

acuity levels for a third of patients, while overall

there was an increase of 2 letter lines in 12 months.

Pegabtanib sodium (Macugen) was the first an-

tivegf agent to be licensed for use in Ophthalmology.

However this was nearly completely replaced very

early by Ranibizumab (Lucentis) that showed supe-

rior results in clinical trials. Bevacizumab (Avastin),

an antivegf agent of higher molecular weight, and the

parent molecule of lucentis, was licenced for use in

Ophthalmologia, 22, 1 (2010) 9

Fig 3, 4. Patient with wet AMD (note the hypereflective area in the retinal pigment epithelium, corresponding to the cho-roidal neovascular membrane in fig 3) and follw up san 2 months later showing complete resolution of fluid following2 Ranibizumab injections (Fig 4).

metastatic colorectal cancer, but has found wide-

spread use in Ophthalmology for financial reasons.

Following an antivegf injection, most of the

patients experience an improvement in visual acui-

ty. Optical coherence tomography shows complete

or partial absorption of fluid and restoration of

macular anatomy, although some anatomic chan-

ges always persist. Concerns about side effects, in

particular response of the eye to multiple injecti-

ons, the risk of endophthalmitis and the possibility

of systemic side effects, such as strokes, have all re-

ceded. However the need of repeated injections to

maintain a satisfactory result, paired with the fact

that a third of the patients still loose vision despite

antivegf therapy, has dampened the enthusiasm

with which the initial results were greeted.

Working out a realistic treatment regime was

also difficult for clinicians. Recommendations,

from clinical trials, for monthly injections over the

first two years were never implemented. Instead a

regime of 3 monthly injections and than follow up

on a monthly basis was preferred by most. Howe-

ver if retreatment was withheld until disease recur-

rence was evident, visual acuity was worse in 12

months compared to the group of patients that re-

ceived monthly injections. It appears that a more

aggressive treatment regime is necessary if the ini-

tial visual acuity gain is to be maintained, especially

in patients with good visual acuity and/or reduced

vision in the other eye. Attempts to reduce the ne-

ed of reinjection by means of combining antivegf

with photodynamic therapy were also unsuccessful.

When treating patients with the disease one

should bare in mind that approximately a fifth of

patients will show no significant response and tre-

atment should be discontinued. Also patients with

significant scarring or loss of foveal architecture

may not experience improvement of symptoms al-

though they may tomographically appear fluid

free. Treatment should be also discontinued in this

group of patients unless one wishes to maintain vi-

sion in the better seeing eye.

The role of Photodynamic Therapy

Photodynamic therapy, although a potent way

of thrombosing new vessels, was practically disconti-

nued. It appears that the transient choroidal ischae-

mia it induced, had a permanent damaging effect in

central vision. The idea of combining photodynamic

therapy with anti VEGF treatment was recently in-

troduced as a way of reducing the need for reinje-

ction. However clinical trials that were conducted

did not show benefit in VA or a reduced number of

injections in the combination group, and the idea

appears to be loosing ground. Today photodynamic

therapy may only be considered in patients comple-

tely unresponsive to anti VEGF treatment.

The role of laser photocoagulation

Laser photocoagulation produced good re-

sults in the MPS study for small extrafoveal well

delineated lesions. It is unclear whether antiVEGF

or Laser is the treatment of choice for this small

group of patients.

Ranibizumab vs Bevacizumab

Although bevacizumab remains unlicenced

for use in Ophthalmology, positive clinical experi-

ence and cost issues has resulted in the majority of

patients being treated with it in several countries.

Large scale multicenter trials comparing the two

drugs are currently ongoing, both in the UK (the

IVAN trial) and the US (the CATT study), but re-

sults will not be available until late in 2010

Research on other treatments

A small pilot study of epimacular brachythe-

rapy with Strontium 90 produced results equivalent

to Ranibizumab with out the need for retreat-ments,

and has gained much press interest. A multicenter

clinical trial (The Cabernet Study) is ongoing.

Several further agents are under investigation

including Vegf traps that appear 200 times more po-

tent than Ranibizumab, immune regulators such

complement C3 inhibitors, with very promising re-

sults. Immune modulation in particular may also be

useful in patients with the dry form of the disease,

that is completely untreatable at the moment, despite

the fact that it accounts for a significant proportion of

patients with severe loss of vision from AMD.

References

1. Chakravarthy U, et al. Age related macular degeneration

BMJ 340: c 981, 2010.

2. Smith W, Assink J, Kelien R, Mitchell P, Klaver CC, KleinBE, et al. Risk factors for age-related macular degene-

ration: pooled findings from three continents. Oph-

thalmology 108: 697-704, 2001.

3. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C,et al. Complement factor H polymorphism in age-re-

lated macular degeneration. Science 308: 385-9, 2005.

4. Owen CG, Fletcher AE, Donoghue M, Rudnicka AR. How

big is the burden of visual loss caused by age-related

macular degeneration in the United Kingdom? Br J

10 Ophthalmologia, 22, 1 (2010)

Ophthalmol 87: 312-7, 2003.

5. Woo KJ, Sanjay S, AuEong KG. The epidemiology of age-

related macular degeneration in the Indian subcon-

tinent. Acta Ophthalmol 87: 262-9, 2009.

6. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Good-ship T, Chakravarthy U. A common CFH haplotype

with deletion of CFHR1 and CFHR3 is associated

with a lower risk of age-related macular degeneration.

Nat Genet 38: 1173-7, 2006.

7. Satia JA, Littman A, Slatore CG, Galanko JA, White E.

Long term use of beta-carotene, retinol, lycopene and

lutein supplements and lung cancer risk: results from

the VITamins And Lifestyle (VITAL) study. Am J

Epidemiol 169: 815-28, 2009.

8. Beatty S, Koh HH, Henson D, Boulton M. The role of oxi-

dative stress in the pathogenesis of age-related macu-

lar degeneration. Surv Ophthalmol 45: 115-34, 2000.

9. Fletcher AE, Bentham GC, Agnew M, Young IS, Augood C,Chakravarthy U, et al. Sunlight exposure, antioxidants,

and age-related macular degeneration. Arch Ophthal-

mol 126: 1396-403, 2008.

10. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA,Shahid H, et al. Genetic factors in AMD study group.

Complement C3 variant and the risk of age-related ma-

cular degeneration. N Engl J Med 357: 553-61, 2007.

11. Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ. Comple-

ment C3 and C4 expression in C1Q sufficient and de-

ficient mice models of Alzheimers Disease J Neuro-

chem 106: 2080-92, 2008.

12. Age-Related Eye Diseases Study Group. A simplified seve-

rity scale for age-related macular degeneration. A-

REDS report 18. Arch Ophthalmol 123: 1570-74, 2005.

13. Wong TY, Chakravarthy U, Klein R, Mitchell P, Slateva G,Buggage R, et al. The natural history and prognosis of

neovascular age-related macular degeneration; a sy-

stematic review of the literature and meta analysis.

Ophthalmology 115: 116-26, 2008.

14. Age-Related Eye Disease Study Research Group. A ran-

domized, placebo-controlled, clinical trial of high-do-

se supplementation with vitamins C and E, beta caro-

tene, and zinc for age-related macular degeneration

and vision loss: AREDS report no 8. Arch Ophthal-

mol 119: 1417-36, 2001.

16. Parisi V, Tedeschi MG, Varano M, Saviano S, Piermaroc-chi S, CARMIS study group. Carotenoids and antioxi-

dants in age-related Maculopathy Italian study: ele-

ctroretinogram modifications after 1 year. Ophthal-

mology 115: 324-33, 2008.

17. Virgili G, Bini A. Laser photocoagulation for neovascu-

lar age-related macular degeneration. Cochrane Da-

tabase Syst Rev 3: CD004763, 2007.

18. Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic

therapy for neovascular age-related macular degenera-

tion. Cochrane Database Syst Rev 3: CD002030, 2007.

19. Gragoudas ES, Adamis AP, Cunningham ET Jr, FeinsodM, Guyer DR, for the VEGF Inhibition Study in OcularNeovascularization Clinical Trial Group. Peptanib for

neovascular age-related macular degeneration. N

Engl J Med 351: 2805-16, 2004.

20. Rich RM, Rosenfeld PJ, Puliafito CA, Dubovy SR, Davis JL,Flynn HW Jr, et al. Short-term safety and efficacy of in-

travitreal bevacizumab (Avastin) for neovascular age-

related macular degeneration. Retina 26: 495-511, 2006.

21. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, for theMARINA Study Group. Ranibizumab for neovascular

age related macular degeneration. N Engl J Med 355:

1419-31, 2006.

22. Brown DM, Kaiser PK, Michels M et al; ANCHOR StudyGroup. Ranibizumab versus verteporfin for neovascu-

lar age-related macular degeneration. N Engl J Med

355: 1432-4412, 2006.

23. Fung AE, Rosenfeld PJ, Reichel E. The international in-

travitreal bevacizumab safety survey: using the inter-

net to assess drug safety worldwide. Br J Ophthalmol

90: 1344-9, 2006.

24. Chakravarthy U, Lim JI. New treatments for acute neo-

vascular macular degeneration. BMJ 10: 269-70, 2007.

25. Eldem B. Visual acuity response profiles of patients with

neovascular AMD treated with quarterly dosing of ra-

nibizumab in the EXCITE study. Retina Congress

Scientific Abstracts, 2009.

28. Witkin AJ, Vuong LN, Srinivasan VJ, Gorczynska I, Re-ichel E, Baumal CR, et al. High-speed ultrahigh reso-

lution optical coherence tomography before and after

ranibizumab for age-related macular degeneration.

Ophthalmology 116: 956-63, 2009.

29. Nguyen QD, Shah SM, Browning DJ, Hudson H, SonkinP, Hariprasad SM, et al. A phase 1 study of intravitre-

al vascular endothelial growth factor trap-eye in pa-

tients with neovascular age-related macular degenera-

tion. Ophthalmology 116: 2141-8, 2009.

30. Schmidt Erfurth U. Verteporfin Photodynamic therapy

and ranibizumab combination for subfoveal CNV se-

condary to AMD. 12 month efficacy. Results of the

Mont Blanc Study. Retina Congress Scientific Ab-

stracts, 2009.

31. Avila MP, Farah ME, Santos A, Karpran Z, Duprat JP,Woodward BW, et al. Twelve month safety and visual

acuity results from a feasibility study of intraocular epi

retinal radiation therapy for the treatment of subfove-

al CNV secondary to AMD. Retina 29: 157-69, 2009.

32. Emerich DF, Thanos CG. NT 501: an ophthalmic implant

of polymer-encapsulated ciliary neurotrophic factor-

producing cells. Curr Opin Mol Ther 10: 506-15, 2008.

33. Holers VM. The spectrum of complement alternative

pathway-mediated diseases. Imuunol Rev 223: 300-16,

2008.

34. Schnatbaum K, Locardi E, Scharn D, Richter U, HawlischH, Knolle J, et al. Peptidomimentic C5a receptor anta-

gonists with hydrophobic substitutions at the C termi-

nus: increased receptor specificity and in vivo activity.

Bioorg Med Chem Lett 16: 5088-92, 2006.

35. Landa G, Butovsky O, Shoshani J, Schwartz M, Pollac A.Weekly vaccination with Copaxone (glatiramer aceta-

te) as a potential therapy for dry age-related macular

degeneration. Curr Eye Res 33: 1011-3, 2008.

Ophthalmologia, 22, 1 (2010) 11

Retinopathy of prematurity (ROP) affects ma-

inly neonates of extremely low birth weight (ELBW)

<1000 g. It was originally described in 19421. It is

characterized by neovascular membranes and vascu-

lar shunts in retina’s peripheral avascular zone, un-

dergoing contraction and, finally, detachment at the

final stage of the illness2. The pathogenesis of ROP

is mostly explained by vasoconstriction and/or by

the impact of free oxygen radicals to the vessels of

the retina3,4.

Due to the fact that more and more ELBW

neonates survive and that ROP is the main reason

of blindness to neonates, it seems that the determi-

nation of risk factors is of great importance. Initial-

ly, there were mentioned certain risk factors like the

administration of oxygen and prematurity, resulting

in restriction of oxygen administration5-7. Oxygen

has been referred as a risk factor since 19501.

The fact that more premature neonates mana-

ge to survive, has led to increase of ROP incidence.

Neonates of BW <800 g and GA <28 weeks appe-

ar with increased ROP (especially of its serious

form) incidence, while neonates of BW >1000 g

and GA >31 weeks ROP is relatively rare, due to

the development of protective mechanisms against

oxygen toxicity8. Oxygen is not the only risk factor

for ROP, since it has not been observed in neo-

nates with persisting hyperoxemia or its presence

in neonates where it was not administerred9,10. O-

ther factors are sepsis, apnea, hypoxia, patent du-ctus arteriosus, the administration of indome-thacin, intraventricular bleeding11. In 1950 it was

the first time when Mallek and Spohn referred to

the relationship between blood transfusions [repla-

cement blood transfusions (RBT) and exchange

transfusion (ET)] and ROP1, even though its pa-

thophysiology has not been clarified12-15. Anemiahas also been referred in certain studies as a risk

factor for ROP, due to tissue hypoxia and as a con-

sequence neovascularization of the retina16.

The role of blood transfusion to ROP patho-

genesis is a very important matter, since in a po-

pulation of high-risk neonates every day clinical

practice transfusion guidelines usually are not be-

Ophthalmologia, 22, 1 : 12 - 15, 2010

Is blood transfusion a risk factor for retinopathy of prematurity?

I. Chatziioannidis, P. Karagianni, N. Nikolaidis

B′ Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, General Hospital “Papageorgiou”, Thessaloniki, Greece

Retinopathy of prematurity (ROP) occurs mainly in pre-mature neonates of extremely low birth weight. It is a veryimportant illness, since it may have serious complications(partial or total blindness). Its pathogenesis is explainedmostly through vessel spam and the effect of oxygen freeradicals to the vessels of the retina. Some of the most se-rious factors for ROP are, the administration of oxygen,sepsis, apnea episodes and the patent ductus arteriosus.Blood transfusions are essential for hemodynamic stabili-zation and the support of a neonate with lung disease. Theeffect of blood transfusion in the pathogenesis of ROP is amatter of dispute. Some of the main pathophysiology me-chanisms are displacement of the oxyhemoglobin disso-

ciation curve and iron overload. Iron overload releases hy-droxyl and superoxide radicals. Despite the fact that therole of iron in causing ROP has been questioned, it hasbeen proved that it causes cellular damage, since it actslike a catalyst to the reactions that prooduce superoxideradicals and leads to lipid peroxidation. It becomes ob-vious, to a certain point, that the need to administrate oxy-gen to neonates submitted to transfusion transforms thetransfusion correlation of blood and ROP to a correlation ofadministerred oxygen and ROP. Taking stricter transfusioncriteria and the use of erythropoietin, in order to restrict thenumber of transfusions especially in high-risk neonates,could help reduce the risk for ROP.

ing uniformely followed17,18. ELBW neonates of

<1000 g are transfused, at a percentage of 90%,

those of 1000 g – 1500 g in a percentage of 40% and

those of >1500 g rarely if they are clinically stable.

Neonates develop anemia due to their rapid

growth, insufficient erythropoiesis and frequent

blood sampling19. The majority of blood transfusi-

ons are given during the first 3-4 weeks of the neo-

nate’s life and they are considered to be necessary

for the hemodynamic stabilization and the support

of the neonate’s lung disease20. The pathophysiolo-

gical mechanisms that contribute to the develop-

ment of ROP due to transfusions using adult red

blood cells, are the following:

1) The transposition of the oxy-hemoglobindissociation curve21,22 to the right results in incre-

ase of the amount of oxygen delivery to the tissues

and subsequent toxicity to the vessels of the reti-

na22. Fetal hemoglobin (HbF) is reduced to a per-

centage of <2% at the end of the first semester of

its extra-uterine life, while hemoglobin A (HbA)

increases, which easily allows and consequently in-

creases the oxygen delivery to the retina. Since he-

moglobin of red blood cells is the “vehicle” that

transmits oxygen but at the same time it causes o-

xidative stress to tissues and, consequently, to the

retina, the administration of adult blood is reaso-

nably correlated to ROP23.

2) Iron overload and the release of hydroxylradicals from superoxide and hydrogen peroxide

(Haber – Weiss reaction)24-26. Transfused red

blood cells are considered to have a shorter life-

span in comparison to the adults27, “burden” their

organism with 0,5 mg iron/ml of the administrated

blood20. Ceruloplasmin and transferrin provide

protection, but in premature neonates of GA<33

weeks their levels are low and soon transferrin is

saturated28. In premature neonates, after they have

been transfused, in comparison to term delivery

neonates, there has been observed an increase in

the amount of ferrous iron (Fe++), due to the fact

that ferroxidase and ascorbic acid have been redu-

ced19. Ferrous iron acts as a catalyst to reactions

producing hydroxyl radicals (for a short period of

time) and generate lipid peroxidation with conse-

quent cellular damage25. Moreover, considering

the immaturity of the antioxidant defensive mecha-

nisms in premature neonates, the increase of hy-

droxyl radicals may lead to ROP, as well as chronic

lung disease29,30, necrotizing enterocolitis and in-

tracranial hemorrhage31-35. Finally, the inability in

associating exchange transfusions and ROP (in op-

position to blood transfusions) could be explained

by the increase of iron load (Fe+2) and not by the

transposition of the oxyhemoglobin dissociation

curve19,36.

Hesse et.al. have recently studied the relation

between blood transfusions, iron load of and ROP

at neonates <1500 g2. After taking under conside-

ration gestational age at birth, duration of oxygen

administration (FiO2 >30%) and duration of me-

chanical ventilation, it was found that the risk for

the appearance of ROP was significantly increased,

depending on the volume of blood, which was tran-

sfused (Relative Risk 6,4 and 12,3 for transfusions

at 16-45 mk/kg and 45 ml/kg respectively) but not

with iron (Fe) metabolism. Consequently, it was

not confirmed that blood transfusion through the

increase of iron load, predisposes to ROP2.

A retrospective study of a group of neonates

<1000 g who received supplemental oxygen, sho-

wed that there was an increase in ROP incidence of

those neonates that were transfused. These find-

ings were in agreement with other studies37. The

initial studies that correlated blood transfusions

and ROP did not take under consideration the du-

ration and fragment of inspired oxygen38. Oxygen

is considered to be one of the most often admini-

strated “drug” to high risk neonates that are under

treatment in NICU, e.g. for Respiratory Distress

Syndrome, septicemia, bronchopulmonary dyspla-

sia, etc. Providing supplemental oxygen to these

neonates renders the need for blood transfusions.

Subsequently, any correlation between blood tran-

sfusion and ROP could be transformed into a cor-

relation between oxygen and ROP1.

Since blood transfusions with adult hemoglo-

bin,, are considered responsible for ROP, we wo-

uld expect that ROP would be of higher incidence

in infants receiving intrauterine transfusion, a phe-

nomenon that has been reported38. The amount of

oxygen that is transferred to tissues is not deter-

mined only by the oxyhemoglobin dissociation

curve but also by microcirculation and hemodyna-

mic factors37. Brooks et.al in a prospective rando-

mized study of administrating blood transfusion in

neonates <1250 g in order to conserve the Hct

>40%, from the 29th – 71rst day of their life found

no correlation with ROP16. The time period for the

enrollment into the study was chosen due to pra-

ctical weaknesses, to apply the transfusion proto-

cols in unstable high risk neonates during the first

Ophthalmologia, 22, 1 (2010) 13

14 Ophthalmologia, 22, 1 (2010)

period of their life, but also due to the fact that

ROP appears and develops within the 29th – 34th

weeks postconceptional or during the first 8-10

weeks of their life. For this particular study serious

reservations were expressed some in respect to the

accuracy of the methodology (sample) and also for

the statistical analysis39,40. The relation between

blood transfusions and ROP has been confirmed15,

20,25,37, regardless of the opposite conclusions made

by some studies, especially since it has been con-

firmed that an increase in iron load and hydroxyl ra-

dicals take place after blood transfusion.

Limiting oxidative stress, especially in prema-

ture high risk neonates for developing ROP, can be

achieved either through limiting the number of

blood transfusions, or applying stricter criteria for

blood transfusions and amount of blood collected

or with the administration of erythropoietin. In the

future, the administration of blood that would con-

tain antioxidants, or the direct administration of

antioxidants to premature neonates, would bring

under control the risk for ROP appearance. Fur-

ther laboratory and clinical studies will help to-

wards this direction.

Preferences

1. Sacks LM, Schaffer DB, Anday EK, Peckham GJ, Delivo-ria-Papadopoulos M. Retrolental fibroplasia and

blood transfusion in very-low birth weight infants. Pe-

diatrics 68(6): 770-4, 1981.

2. Hesse L, Eberl W, Schlaud M,Poets CF. Blood transfusion.

Iron load and retinopathy of prematurity. Eur J Pe-

diatr 156: 465-470, 1997.

3. Ashton N, Cook C. Direct observation of the effect of oxy-

gen on developing vessels: preliminary report. Br J

Opthalmol 38: 433-440, 1954.

4. Chan-Ling T, Gock B, Stone J. The effect of oxygen on va-

soformation cell division: Evidence that the “physio-

logical hypoxia” is the stimulus for normal retinal vas-

culogenesis. Invest Ophtalmol Vis Sci 36: 1201-1214,

1995.

5. Ashton N, Ward B, SerpelL G. Role of oxygen in the gene-

sis of retrolental fibroplasias. BrJ Ophtalmol 37: 513-

20, 1973.

6. Patz A, Hoeck LE, De La Cruz E. Srudies on the effect of

high oxygen administration in retrolental fibroplasias.

I. Nursery observations. Am J Opthalmol 35: 1248-52,

1952.

7. Kinsey V, Hemphill FM. Preliminary report of a coopera-

tive study of retrolental fibroplasias. Am J Opthalmol

40: 166-74, 1955.

8. Good, WV, Hardy, RJ, Dobson, V, et al. The incidence and

course of retinopathy of prematurity: findings from

the early treatment for retinopathy of prematurity

study. Pediatrics 116: 15k 2005.

9. Aranda JV, Sweet AY. Sustained hyperoxemia without ci-

catricial retrolental fibroplasia. Pediatrics 54: 434-37,

1974.

10. Adamkin DH, Shott RJ, Cook LN, Andrews BF. Nonhy-

peroxic retrolental fibroplasias. Pediatrics 60: 828-30,

1977.

11. Al-Amro SA, Al-Kharfi TM, Thabit AA, Al-Mofada SM.

Risk factors for acute retinopathy of prematurity.

Compr Ther 33(2): 73-7, 2007.

12. Cooke RWI, Clark D, Hickey-Dwyer M, Weindling AM.

The apparent role of blood transfusions in the deve-

lopment of retinopathy of prematurity. Eur J Pediatr

152: 833-36, 1993.

13. Hesse L, Ebert W, Schlaud M, Poets CT. Blood transfu-

sion: iron load and retinopathy of prematurity. Eur J

Pediatr 56: 465-70, 1997.

14. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA.

High iron status in very low birth weight infants is as-

sociated with an increased risk of retinopathy of pre-

maturity. J Pediatr 131: 541-44, 1997.

15. Shohat M, Reisner SH, Krikler R, Nissenkorn I, Yassur Y,Ben-Sira I. Retinopathy of prematurity : incidence and

risk factors. Pediatrics 72: 159-63, 1983.

16. Brooks S, Marcus DM, Gillis D, Pirie E, et al. The effect

of blood transfusion protocol on retinopathy of pre-

maturity: a prospective, randomized study. Pediatrics

104(3): 514-18, 1999.

17. Bifano FM, Curran TM. Minimizing donor blood expo-

sure in the neonatal intensive care unit current trends

and future prospects. Clin Perinatol 22: 657-69, 1995.

18. Levy GJ, Strauss RG, Hume H, et al. National survey of

neonatal transfusion practices. Red blood cell the-

rapy. Pediatrics 91: 523-29, 1993.

19. Hirano K, Morinobu T, Kim H, Hiroi M, et al. Blood tran-

sfusion increases radical promoting non-transferrin

bound iron in preterm infants. Arch Dis Child Fetal

Neonatal Ed 84: F 188-F193, 2001.

20. Turker G, Sarper N, Gokalp AS, Usluer H. The effect of

early recombinant erythropoietin and enteral iron

supplementation on blood transfusion in preterm in-

fants. Am J Perinatol 22(8): 449-55, 2005.

21. Drack AV. Preventing blindness in premature infants. N

Engl J Med 338: 1620-21, 1998.

22. James L, Greenough A, Naik S. The effect of blood tran-

sfusion on oxygenation in premature ventilated neo-

nates. Eur J Pediatr 156: 139-41, 1997.

23. Sullivan JL. Iron plasma antioxidants, and the oxygen

radical disease or prematurity. Am J Dis Child 142:

1341-44, 1988.

24. Gutteridge JM. Fate of oxygen free radicals in extracel-

lular fluids. Biochem Soc Trans 10: 72-3, 1982.

25. Wardle SP, Drury J, Garr R, Weindling AM. Effect of

blood transfusion on lipid peroxidation in preterm in-

Ophthalmologia, 22, 1 (2010) 15

fants. Arch Dis Child Fetal Neonatal Ed 86: F46-F48,

2002.

26. Pollak A, Hayde M, Hayn M, et al. Effect of intravenous i-

ron supplementation on erythropoiesis in erythropoie-

tin-treated premature infants. Pediatrics 107: 78-85,

2001.

27. Bard H, Widness JA. The life span of erythrocytes tran-

sfused to preterm infants. Pediatr Res 42: 9-11, 1997.

28. Lackmann GM, Schnieder C, Bohner J. Gestational age-

dependent reference values for iron and selected pro-

teins of iron metabolism in serum premature human

neonates. Biol Neonate 74: 208-213, 1998.

29. Cooke RWI, Drury JA, Yoxall CW, et al. Blood transfu-

sion and chronic lung disease in preterm infants. Eur

J Pediatr 156: 47-50, 1997.

30. Silvers KM, Gibson AT, Russell JM, et al. Antioxidant a-

ctivity, packed cell transfusions, and outcome in pre-

mature infants. Arch Dis Child Fetal Neonatal Ed 78:

F 214-19, 1998.

31. Ogihara T, Kitagawa M, Miki M, et al. Susceptibility of

neonatal lipoproteins to oxidative stress. Pediatr Res

29: 39-45, 1991.

32. Gopinathan V, Milller NJ, Milner AD, et al. Bilirubin and

ascorbate antioxidant activity in neonatal plasma.

FEBS Lett 349: 197-200, 1994.

33. Saugstad OD. Oxygen toxicity in the neonatal period.

Acts Paediatr Scand 79: 881-92, 1990.

34. Ogihara T, Okamoto R, Kim HS, et al. New evidence for

the involvement of oxygen radicals in triggering neona-

tal chronic lung disease. Pediatr Res 39: 117-19, 1996.

35. Ogihara T, Hirano K, Morinobu T, et al. Raised concen-

trations of aldehyde lipid peroxidation products in

premature infants with chronic lung disease. Arch Dis

Child Fetal Neonatal Ed 80: F21-5, 1999.

36. Sullivan JL. Iron, plasma antioxidants, and the ‘oxygen

radical disease of prematurity’. Am J Dis Child 142:

1341-1344, 1988.

37. Clark C, Gibbs JH, Maniello R, Outebridge EW, ArandaJ. Blood transfusion: a possible risk factor in retrolen-

tal fibroplasias. Acta Paediatr Scand 70: 535-39, 1981.

38. Gunn TR, Easdown J, Outerbridge EW, et al. Risk factors

in retrolental fibroplasias. Pediatrics 65: 1096, 1980.

39. Saunders RA, Purohit D, Hulsey TC. The effects of blood

transfusion protocol on retinopathy of prematurity. Pe-

diatrics 106 (2 Pt 1): 378-9; author reply 379-80, 2000.

40. Dani C, Rubaltelli FF. The effects of blood transfusion

protocol on retinopathy of prematurity. Pediatrics 106

(2 Pt 1): 379, 2000.

Introduction

This article briefly reviews the most recent lit-

erature on advances in hereditary retinal diseases.

Retinitis pigmentosa, Leber’s congenital amau-

rosis, X-linked retinoschisis, Best’s disease, Star-

gardt’s disease and congenital stationary night

blindness are reviewed (Fig. 1).

Retinitis pigmentosa is a progressive rod-cone

dystrophy. Nyctalopia, progressive visual field loss

and decline of visual acuity are the most common

manifestations. The clinical features include gra-

dual increased bone spiculed pigmentation, atte-

nuation of retinal vasculature and waxy disc pallor.

Three modes of Mendelian inheritance occur,

with autosomal dominant inheritance (adRP) be-

ing the most common. adRP leads to a great loss of

foveal cones shown by ocular coherence tomogra-

phy (OCT), visual field defects and visual acuity

changes.1 Early outer nuclear layer thinning with

inner nuclear layer thickening in patients with X-

linked retinitis pigmentosa2 and thinning of the re-

tinal nerve fiber layer in patients with pallor of the

optic disc.3 Other mutations on the affected gene

(RHO gene – I179F and PRP) have variable ex-

pressivity in members of the same family, someti-

mes ranging from classic retinitis pigmentosa to

pattern dystrophy and Stargardt’s disease.4,5 Rese-

archers continue to identify new mutations that

cause retinitis pigmentosa4,7-15.

Examination of family members in these cases

is useful. Electroretinogram is useful in these pa-

tients. The findings in patients with retinitis pig-

mentosa are classically described as ‘extinguished’

and the rate of decline is similar among patients, re-

gardless of inheritance pattern or degree of vision

loss. Treatment with vitamin A causes a slightly slo-

wer rate of decline. Most patients retain useful visi-

on into old age.6 The search for a treatment for reti-

nitis pigmentosa is mainly focused on genetic stu-

dies. These can be divided into two categories: pre-

vention of retinal degeneration and restoration of

degenerated retina. The first involves defining mu-

tation effects at the molecular level and seeking

ways to restore genetic function or supplement de-

ficiencies before retinal degeneration occurs. It was

found that PRPF31 gene mutations actually inhibit

the expression of other genes- photoreceptor spe-

cific.16 Subretinal injection of an adeno-associated

viral vector (AAVV) in mice has been used to si-

multaneously prevent expression of nonfunctional

mutant rhodopsin and produce wild-type functional

rhodopsin, leading to improvement in electroretino-

gram responses.17 Studies to restore function in de-

generated retina have focused on the use of retinal

stem cells in the hope of creating new functional

photoreceptors. A recent study found that intravi-

treal and subretinal injection of stem cells into re-

tinitis pigmentosa mice was not effective in creating

photoreceptor cells.18 Other researchers, by inje-

cting intravitreal AAVV in a rat model of arRP,

Ophthalmologia, 22, 1 : 16 - 21, 2010

Hereditary retinal diseases: Review

N. Kozeis

Paediatric Ophthalmology Unit, Eye department Hippokration hospital of Thessaloniki, Greece

In this article the recent advances in diagnosis, geneticsand treatment of hereditary retinal diseases, are reported.The recent literature on retinitis pigmentosa, Leber’s con-genital amaurosis, X-linked retinoschisis, Best’s disease,Stargardt’s disease and congenital stationary night blind-

ness, is reviewed. Extensive investigation and advancesin technology are leading to genetic testing that aids cli-nicians in the diagnosis of these diseases. Genetic, labo-ratory and human clinical trials may lead to future treat-ment of these disorders.

tried to photosensitize other cells in the retina, pri-

marily the retinal ganglion cells and the electro-

retinogram responses were improved.19

Leber’s congenital amaurosis

Leber’s congenital amaurosis (LCA) is descri-

bed as a stationary severe cone–rod dystrophy. It is

characterized by a normal appearing fundus at

birth, early development of nystagmus and ‘eye-

poking’ by the child. LCA can be a difficult diag-

nosis to make with certainty. Electroretinogram is

usually helpful, since it is flat from birth.

Some variants of LCA overlap with early-on--

set retinitis pigmentosa.20 Bone spicule pigmen-

tation and maculopathy could occur after the age

of 6 years. In these patients may be attributed the

diagnosis of early-onset retinitis pigmentosa, LCA

type II, or childhood retinal dystrophy. OCT sho-

wed that LCA patients with RPE65 mutations ma-

intain a normal retinal architecture, being possibly

more responsive to treatment compared with

RDH12 and CRB1 mutations.21,22

Approximately 70% of LCA mutations have

been identified. However, new mutations are being

discovered.23,24 LCA is mainly an autosomal reces-

sive disease, but a few cases of autosomal dominant

LCA were found.25

LCA has been successfully treated via genetic

transplantation in RPE65-deficient Briard dogs.

This procedure was shown clinically to improve rod

and cone responses by electroretinogram.26 Human

patients with RPGRIP1 mutations may demonstrate

treatment potential because of their maintenance of

retinal structures well into the course of the disea-

se.27 Current human clinical trials evaluate the safety

and efficacy of subretinal AAVV gene replacement

in LCA patients with RPE65 mutations.28,29

X-linked retinoschisis

X-linked retinoschisis (XLRS) is the most com-

mon cause of macular degeneration in young males.

Females are the carriers of the disease and males

manifest the disease. Clinically, these patients have

foveal schisis that often extends into the periphery.

On fluorescein angiogram hyperfluorescent foveal

cystic changes are seen without leakage. Electrore-

tinogram reveals decreased b-wave amplitudes.

Atypical cases like white dots in the macula at

the level of the retinal pigment epithelium and re-

duced visual acuity, macular dragging, bilateral exu-

dative retinal detachments, macular pigmentary

changes, and macular holes.30-32 In cases of atypical

and severe retinal pathology, electroretinogram can

show decreased A and B wave forms. OCT seems to

be more useful in making the diagnosis in these cas-

es. The severity of disease seems to correlate with

the type of mutation, with more severe pathology

caused by upstream mutations in exons 1-3.33

Multifocal electroretinogram reveals areas of

retinal dysfunction in some carriers.34,35

Twelve novel mutations were recently repor-

ted: three on exon 4.30,31,36,37

The mutations associated with XLRS inhibit

the production of retinoschisin- a protein.38 Re-

search into the treatment of XLRS has focused on

replacing the production pathway for this protein.

Early intravitreal injection of AAVV genes in ani-

mals has shown promise in structural and functio-

nal rescue.39 These results would probably apply to

young patients whose retinal architecture has not

undergone permanent changes (Fig. 2).40

Best’s disease is an autosomal dominant vitel-

liform dystrophy. It is characterized by lipofuscin ac-

cumulation in the retinal pigment epithelium, nor-

mal appearing retina, a round slightly elevated ma-

cular vitelliform lesion ultimately leading to scar for-

mation. Electroretinogram is normal, whereas the

electro-oculogram is subnormal.41 OCT has docu-

mented the transition from stage III to stage IV le-

sions, showing the presence of lipofuscin in the su-

bretinal pigment epithelium cystic space.42,43

A functional analysis of the bestrophin gene

found that in normal patients the protein is expres-

sed in greater quantities outside the macular a-

Ophthalmologia, 22, 1 (2010) 17

Fig. 1. Retinitis pigmentosa.

rea.44 It was concluded that with a loss of bestro-

phin function, the macula is more susceptible to

lipofuscin accumulation than the peripheral retina.

New mutations of Best’s disease continue to

be found. At least 10 new mutations in have re-

cently been reported.41,45,46 Researchers are also

looking for a genetic cause of adult vitelliform

macular dystrophy.47

There are no recent advances in the genetic

treatment of Best’s disease (Fig. 3).

Stargardt’s disease is an autosomal recessive

disease. It is characterized as an atrophic macular

dystrophy. Visual loss usually precedes macular

changes (a ‘beaten bronze’ appearance with occa-

sional flecks and a ‘dark choroid’ on fluorescein

angiogram).

Unlike some retinal dystrophies, the clinical

picture for Stargardt’s disease is highly variable.

The involved gene, ABCA4, has been associated

with pattern dystrophy, Stargardt’s disease and re-

tinitis pigmentosa. Patients with ABCA4 mutations

with Stargardt’s-like disease may progress in later

years to a severe retinitis pigmentosa-like pictu-

re.48-50 Mutations in the peripherin/RDS gene can

also have a Stargardt’s appearance but they usually

lead to autosomal dominant disease ranging from

no clinical abnormalities to pattern dystrophy sim-

ulating fundus flavimaculatus. These patients gen-

erally have a later onset of disease and a better vi-

sual prognosis.51

Three novel mutations in the ABCA4 gene we-

re recently associated with Stargardt’s disease.48,52,53

Other studies showed that ABCA4 may act as a

modifier gene in other retinal dystrophies.49,54,55

The ABCA4 mutations causing recessive Star-

gardt’s disease and ELOVL4 mutations causing

autosomal dominant Stargardt’s disease are still

not well understood. Recent studies demonstrate

that mutations do not affect retinal development

but may affect production of phosphatidylcholines

that are specific to the retina.56,57

Congenital stationary night blindness

Congenital stationary night blindness (CSNB)

is a nonprogressive retinal disorder. It is characte-

rized by poor night vision, maintenance of photo-

pic vision and varied ocular symptoms like myopia,

nystagmus and decreased visual acuity. There are

different inheriting forms of CSNB (X-linked re-

cessive being most common). The fundus is normal

in most and the electroretinogram ‘negative’.58

Electroretinogram is vital in distinguishing

CSNB from other types of retinal disease. Although

electroretinogram patterns have been extensively

correlated with the type of CSNB, it is possible for

novel mutations to cause similar findings. Two au-

tosomal recessive CABP4 mutations were found to

cause CSNB, with electroretinogram findings re-

sembling the X-linked recessive form normally ca-

used by a CACNA1F mutation.59,60 Novel muta-

tions continue to be associated with CSNB.59,61-63

Oscillatory potentials and immunohistochemi-

stry suggest a reorganization of inner retinal layers

with ectopic synaptic contacts between retinal cells

as a result of the mutation.64-66

How to test for hereditary retinal diseases

Although genetic testing has traditionally be-

en limited by availability, cost, and time require-

18 Ophthalmologia, 22, 1 (2010)

Fig. 2. Best’s disease. Fig. 3. Stargardt’s disease.

ments, there are several advances and resources

that facilitate genetic testing for clinicians today.

Two technological advancements in genetic

testing of retinal diseases are rapidly changing the

efficiency of testing. The microarray ‘gene chip’ is

revolutionizing the screening process for genetic dis-

ease. It allows the clinicians to test for hundreds of

known mutations on multiple genes in one test.67

(Commercially available: Asper Biotech - Tartu, E-

stonia; http://www.asperbio.com). These tests are an

excellent and economic first screening tool for iden-

tifying the most common mutations associated with

inherited retinal diseases.68-70

The second technique involves ‘high-through-

put resequencing techniques’ by single nucleotide

polymorphism genotyping. By choosing four single

nucleotide polymorphism markers for each candi-

date gene, uninvolved genes can be rapidly dismis-

sed and involved genes discovered. This technique

allows researchers to identify new pathologic mu-

tations in a highly efficient manner.71

Conclusion

Till now, hereditary retinal diseases were one

of the most difficult cases to treat. The recent re-

search identifies and highlights the pathophysiolo-

gical mechanisms and gives hope that advances in

genetic therapies will be made. Human clinical tri-

als are already taking place for LCA, with results

which are expected.

References

1. Sandberg MA, Rosner B, Weigel-DiFranco C, et al. Disease

course of patients with X-linked retinitis pigmentosa

due to RPGR gene mutations. Invest Ophthalmol Vis

Sci 48: 1298-304, 2007.

2. Aleman TS, Cideciyan AV, Sumaroka A, et al. Inner reti-

nal abnormalities in X-linked retinitis pigmentosa

with RPGR mutations. Invest Ophthalmol Vis Sci 48:

4759-65, 2007.

3. Walia S, Fishman GA, Edward DP, Lindeman M. Retinal

nerve fiber layer defects in RP patients. Invest Oph-

thalmol Vis Sci 48: 4748-52, 2007.

4. Grondahl J, Riise R, Heiberg A, et al. Autosomal dominant

retinitis pigmentosa in Norway: a 20-year clinical fol-

low-up study with molecular genetic analysis: two no-

vel rhodopsin mutations: 1003delG and I179F. Acta

Ophthalmol Scand 85: 287-97, 2007.

5. Leroy BP, Kailasanathan A, De Laey J-J, et al. Intrafami-

lial phenotypic variability in families with RDS muta-

tions: exclusion of ROM1 as a genetic modifier for

those with retinitis pigmentosa. Br J Ophthalmol 91:

89-93, 2007.

6. Berson EL. Long-term visual prognoses in patients with

retinitis pigmentosa: the Ludwig von Sallmann lectu-

re. Exp Eye Res 85: 7-14, 2007.

7. Gamundi MJ, Herman I, Muntanyola M, et al. High preva-

lence of mutations in peripherin/RDS in autosomal

dominant macular dystrophies in a Spanish popula-

tion. Mol Vis 13: 1031-7, 2007.

8. Waseem NH, Vaclavik V, Webster A, et al. Mutations in the

gene coding for the premRNA splicing factor, PR PF31,

in patients with autosomal dominant retinitis pig-

mentosa. Invest Ophthalmol Vis Sci 48: 1330-4, 2007.

9 Ghazawy S, Springell K, Gauba V, et al. Dominant retinitis

pigmentosa phenotype associated with a new muta-

tion in the splicing factor PRPF31. Br J Ophthalmol

91: 1411-4, 2007.

10. Chakarova CE, Papaioannou MG, Khanna H, et al. Mu-

tations in TOPORS cause autosomal dominant retinitis

pigmentosa with perivascular retinal pigment epithe-

lium atrophy. Am J Hum Genet 8: 1098-103, 2007.

11. Zhang Q, Zulfiqar F, Xiao X, et al. Severe retinitis pig-

mentosa mapped to 4p15 and associated with a novel

mutation in the PROM1 gene. Hum Genet 122: 293-

9, 2007.

12. Chang W, Ding Q, Tang Z, et al. A novel de novo frame-

shift mutation of RPGR ORF15 is associated with X-

linked retinitis pigmentosa in a Chinese family. Mol

Vis 13: 1548-54, 2007.

13. Jin ZB, Gu F, Ma X, Nao-I N. Identification of a novel

RPGR exon ORF15 mutation in a family with X-lin-

ked retinits pigmentosa. Arch Ophthalmol 125:1407-

12, 2007.

14. Barragan I, Borrego S, Abd El-Aziz MM, et al. Genetic

analysis of FAM46A in Spanish families with auto-

somal recessive retinitis pigmentosa: characterization

of novel VNTRs. Ann Hum Genet 72: 26-34, 2007.

15. Guyon R, Pearce-Kelling SE, Zeiss CJ, et al. Analysis of six

candidate genes as potential modifiers of disease ex-

pression in canine XLPRA1, a model for human X-lin-

ked retinitis pigmentosa 3. Mol Vis 13: 1094-105, 2007.

16. Mordes D, Yuan L, Xu L, et al. Identification of photore-

ceptor genes affected by PRPF31 mutations associa-

ted with autosomal dominant retinitis pigmentosa.

Neurobiol Dis 26: 291-300, 2007.

17. O’Reilly M, Palfi A, Chadderton N, et al. RNA interferen-

ce-mediated suppression and replacement of human

rhodopsin in vivo. Am J Hum Genet 81: 127-35, 2007.

18. Canola K, Angenieux B, Tekaya M, et al. Retinal stem

cells transplanted into models of late stages of retini-

tis pigmentosa preferentially adopt a glial or a retinal

ganglion cell fate. Invest Ophthalmol Vis Sci 48: 446-

54, 2007.

19. Tomita H, Sugano E, Yawo H, et al. Restoration of visu-

Ophthalmologia, 22, 1 (2010) 19

20 Ophthalmologia, 22, 1 (2010)

al response in aged dystrophic RCS rats using AAV-

mediated channelopsin-2 gene transfer. Invest Oph-

thalmol Vis Sci 48: 3821-6, 2007.

20. Schuster A, Janecke AR, Wilke R, et al. The phenotype of

early-onset retinal degeneration in persons with RDH

12 mutations. Invest Ophthalmol Vis Sci 48: 1824-31,

2007.

21. Jacobson SG, Cideciyan AV, Aleman TS, et al. RDH12

and RPE65, visual cycle genes causing Leber congeni-

tal amaurosis, differ in disease expression. Invest

Ophthalmol Vis Sci 48: 332-8, 2007.

22. Simonelli F, Ziviello C, Testa F, et al. Clinical and mole-

cular genetics of Leber’s congenital amaurosis: a mul-

ticenter study of Italian patients. Invest Ophthalmol

Vis Sci 48: 4284-90, 2007.

23 Sun W, Gerth C, Maeda A, et al. Novel RDH12 mutations

associated with Leber congenital amaurosis and cone-

rod dystrophy: biochemical and clinical evaluations.

Vis Res 47: 2055-66, 2007.

24. Perrault I, Delphin N, Hanein S, et al. Spectrum of

NPHP6/CEP290 mutations in Leber congenital amau-

rosis and delineation of the associated phenotype.

Hum Mut 28: 416, 2007.

25. Wang P, Guo X, Zhang Q. Further evidence of autoso-

mal-dominant Leber congenital amaurosis caused by

heterozygous CRX mutation. Graefes Arch Clin Exp

Ophthalmol 245: 1401-2, 2007.

26. Le Meur C, Stieger K, Smith AJ, et al. Restoration of vi-

sion in RPE65-deficient Briard dogs using an AAV

serotype 4 vector that specifically targets the retinal

pigmented epithelium. Gene Ther 14: 292-303, 2007.

27. Jacobson SG, Cideciyan AV, Aleman TS, et al. Leber

congenital amaurosis caused by an RPGRIP1 mutati-

on shows treatment potential. Ophthalmology 114:

895-8, 2007.

28. University College London: First clinical trial of gene

therapy for childhood blindness; 1 May 2007. London,

UK: University College London; 2007. http://www.ucl.

ac.uk/media/library/genetherapy [Accessed 27 Fe-

bruary 2008].

29. USNational Institute of Health: Phase I trial of gene vector

to patients with retinal disease due to RPE65 mutations.

Rockville, Maryland, USA: US National Institute of

Health; 2008. http://clinicaltrials.gov/ct/show/NCT

00481546;jsessionid=1D885B29C723E42F77EC598CF

48FF90?order=2 [Accessed 27 February 2008].

30. Tsang SH, Vaclavik V, Bird AC, et al. Novel phenotypic

and genotypic findings in X-linked retinoschisis. Arch

Ophthalmol 125: 259-67, 2007.

31. Shukla D, Rajendran A, Gibbs D, et al. Unusual manife-

stations of X-linked retinoschisis: clinical profile and

diagnostic evaluation. Am J Ophthalmol 144: 419-23,

2007.

32. Suganthalakshmi B, Skukla D, Rajendran A, et al. Gene-

tic variations in the hotspot region of RS1 gene in In-

dian patients with juvenile X-linked retinoschisis. Mol

Vis 13: 611-7, 2007.

33. Li X, Ma X, Tao Y. Clinical features of X linked juvenile

retinoschisis in Chinese families associated with novel

mutations in the RS1 gene. Mol Vis 13: 804-12, 2007.

34. Kim LS, Fishman GA, Szlyk JP. Multifocal ERG fin-

dings in carriers of X-linked retinoschisis. Doc Oph-

thalmol 114: 21-6, 2007.

35. SaldanaM, Thompson J, Monk E, et al. X-linked retino-

schisis in a female with a heterozygous RS1 missense

mutation. Am J Med Genet A 143: 608-9, 2007.

36. Jin Z, Nao-I N. A novel truncating Rs1 mutation asso-

ciated with X-linked juvenile retinoschisis. Jpn J Oph-

thalmol 51: 71-3, 2007.

37. Zeng M, Yi C, Guo X, et al. Identification of novel muta-

tions in the XLRS1 gene in Chinese patients with X-

linked juvenile retinoschisis. Curr Eye Res 32: 685-91,

2007.

38. Vijayasarathy C, Takada Y, Zeng Y, et al. Retinoschisin is

a peripheral membrane protein with affinity for anio-

nic phospholipids and affected by divalent cations. In-

vest Ophthalmol Vis Sci 48:991–1000, 2007.

39. Kjellstrom S, Bush RA, Zeng Y, et al. Retinoschisis gene

therapy and natural history in the Rs1h-KO mouse:

long-term rescue from retinal degeneration. Invest

Ophthalmol Vis Sci 48: 3837-45, 2007.

40. Sikkink SK, Biswas S, Parry NRA, et al. X-linked retino-

schisis: an update. J Med Genet 44: 225-32, 2007.

41. Wabbels B, Preising MN, Kretschmann U, et al. Genotype-

phenotype correlation and longitudinal course in ten

families with Best vitelliform macular dystrophy. Gra-

efes Arch Clin Exp Ophthalmol 244: 1453-66, 2006.

42. Vedantham V, Ramasamy K. Optical coherence tomo-

graphy in Best’s disease: an observational case report.

Am J Ophthalmol 139: 351-3, 2005.

43. Arora R, Das S, Shroff D, et al. In vivo microscopy of

Best’s vitelliform macular dystrophy: optical coheren-

ce tomography study of combined stage III and IV le-

sions. Clin Experiment Ophthalmol 35: 287-91, 2007.

44. Mullins RF, Kuehn MH, Faidley EA, et al. Differential

macular and peripheral expression of bestrophin in

human eyes and its implication for Best disease. Invest

Ophthalmol Vis Sci 48: 3372-80, 2007.

45. Merchant D, Yu K, Bigot K, et al. New VMD2 gene muta-

tions identified in patients affected by Best vitelliform

macular dystrophy. J Med Genet 44:e70, 2007.

46. Sodi A, Passerini I, Simonelli F, et al. A novel mutation

in the VMD2 gene in an Italian family with Best mac-

ulopathy. J Fr Ophthalmol 30: 616-20, 2007.

47. Zhuk SA, Edwards AO. Peripherin/RDS VMD2 muta-

tions in macular dystrophies with adult-onset vitelli-

form lesion. Mol Vis 12: 811-5, 2006.

48. Beit-Ya’acov A, Mizrabi-Meissonnier L, Obolensky A, etal. Homozygosity for a novel ABCA4 founder splicing

mutation is associated with progressive and severe

Stargardt-like disease. Invest Ophthalmol Vis Sci 48:

4308-14, 2007.

49. Valverde D, Riviero-Alvarez R, Aguirre-Lamban J, et al.

Ophthalmologia, 22, 1 (2010) 21

Spectrum of the ABCA4 gene mutations implicated in

severe retinopathies in Spanish patients. Invest Oph-

thalmol Vis Sci -48: 985-90, 2007.

50. Rosenberg T, Klie F, Garred P, Schwartz M. N965S is a

common ABCA4 variant in Stargardt-related retino-

pathies in the Danish population. Mol Vis 13: 1962-9,

2007.

51. Boon CJF, vann Schooneveld MJ, den Hollander AI, et al.Mutations in the peripherin/RDS gene are an impor-

tant cause of multifocal pattern dystrophy simulating

STGD1/fundus flavimaculatus. Br J Ophthalmol 91:

1504-11, 2007.

52. Yzer S, van den Born LI, Zonneveld MN, et al. Molecular

and phenotypic analysis of a family with autosomal re-

cessive cone-rod dystrophy and Stargardt disease. Mol

Vis 13: 1568-72, 2007.

53. Riveiro-Alvarez R, Valverde D, Lorda-Sanchez I, et al.Partial paternal uniparental disomy (UPD) of chro-

mosome 1 in a patient with Stargardt disease. Mol Vis

13: 96-101, 2007.

54. Michaelides M, Chen LL, Brantley MA Jr, et al. ABCA4

mutations and discordant ABCA4 alleles in patients

and siblings with bull’s-eye maculopathy. Br J Oph-

thalmol 1: 1650-5, 2007.

55. Stenirri S, Battistella S, Soriani N, et al. Molecular scan-

ning of the ABCA4 gene in Spanish patients with reti-

nitis pigmentosa and Stargardt disease: identification

of novel mutations. Eur J Ophthalmol 17: 749-54, 2007.

56. McMahon A, Jackson SN, Woods AS, Kedzierski W. A

Stargardt disease-3 mutation in the mouse Elovl4 ge-

ne causes retinal deficiency of C32-C36 acyl phospha-

tidylcholines. FEBS Lett 581: 5459-63, 2007.

57. Li W, Chen Y, Cameron DJ, et al. Elovl4 haploinsuffi-

cency does not induce early onset retinal degeneration

in mice. Vision Res 47: 714-22, 2007.

58. Vedantham V, Jethani J, Vijayalakshmi P. Electroretino-

graphic assessment and diagnostic reappraisal of

children with visual dysfunction: a prospective study.

Indian J Ophthalmol 55: 113-6, 2007.

59. Zeitz C, Kloeckener-Gruissem B, Forster U, et al. Mutati-

ons in CABP4, the gene encoding the CA2Ò - binding

protein 4, cause autosomal recessive night blindness.

Am J Hum Genet 79: 657-67, 2006.

60. Jalkanen R, Bech-Hansen NT, Tobias R, et al. A novel

CACNA1F gene mutation causes Aland island eye di-

sease. Invest Ophthalmol Vis Sci 48: 2498-502, 2007.

61. Szabo V, Kreienkamp HJ, Rosenberg T, Gal A. p.Gln200

Glu, a putative constitutively active mutant of rod a-

transducin (GNAT1) in autosomal dominant congeni-

tal stationary night blindness. Hum Mutat 2007; 28:

741-2, 2007.

62. Hayashi T, Gekka T, Takeuchi T, et al. A novel homozy-

gous GRK1 mutation (P391H) in 2 siblings with Ogu-

chi disease with markedly reduced cone responses.

Ophthalmology 114: 134-41, 2007.

63. Peloquin JB, Rehak R, Doering CJ, McRory JE. Functio-

nal analysis of congenital stationary night blindness

type-2 CACNA1F mutations F742C, G1007R, and

R1049W. Neuroscience 150: 335-45, 2007.

64. Yu M, Peachey NS. Attenuation of oscillatory potentials

in nob2 mice. Doc Ophthalmol 115: 173-86, 2007.

65. Bayley PR, Morgans CW. Rod bipolar cells and horizon-

tal cells form displaced synaptic contacts with rods in

the outer nuclear layer of the nob2 retina. J Comp

Neurol 500: 286-98, 2007.

66. Gregg RG, Kamermans M, Klooster J, et al. Nyctalopin

expression in retinal bipolar cells restores visual fun-

ction in a mouse model of complete X-linked conge-

nital stationary night blindness. J Neurophysiol 98:

3023-33, 2007.

67. Koenekoop RK, Lopez I, den Hollander AI, et al. Genet-

ic testing for retinal dystrophies and dysfunctions:

benefits, dilemmas and solutions. Clin Experiment

Ophthalmol 35: 473-85, 2007.

68. National Eye Institute: National Ophthalmic Disease

Genotyping Network (eyeGENE). Rockville, Mary-

land, USA: National Eye Institute; 2008.

69. University of Iowa: The John and Marcia Carver Non-

profit Genetic Testing Laboratory. Iowa City, Iowa,

USA: University of Iowa; 2008.

70. University of Michigan Kellogg Eye Center: Ophthalmic

Molecular Diagnostic Laboratory. Ann Arbor, Mi-

chigan, USA: Kellogg Eye Center; 2008.

71. Pomares E, Marfany G, Jose Brion M, et al. Novel high-

throughput SNP genotyping cosegregation analysis

for genetic diagnosis of autosomal recessive retinitis

pigmentosa and Leber congenital amaurosis. Hum

Mutat 28: 511-6, 2007.

A 55 year old woman presented with meta-

morphopsia and decreased visual acuity in the

right eye for two months. She was asymptomatic in

the left eye. The visual acuity in the right eye was

6/60 and in the left eye 6/6. She underwent colour

fundus photography and OCT wich revealed in right

eye Stage II macular hole. She had focal vitreo-

macular adhesion surrounded by elevation of the

posterior vitreous cortex. (Fig. 1.) She was offered

the option of having microplasmin intravitreal in-

jection in the right eye and she accepted that.

She underwent i.v. injection of …mg micro-

plasmin and she had an OCT scan one month after

the injection. The OCT revealed no vitreomacular

traction and closure of the macular hole. The vi-

sual acuity improved from 6/60 to 3/6 and she had

no metamorphopsia.

The purpose of the trial ‘Microplasmin Intra-vitreal Injection for Non-Surgical Treatment ofFocal Vitreomacular Traction’ is to evaluate the

safety and efficacy of microplasmin, administered

as an intravitreal injection, in subjects with focal

vitreomacular adhesion. In previously performed

clinical trials, some patients treated with intravi-

treal microplasmin have had resolution of their un-

derlying condition, including macular hole closure,

without need for vitrectomy. It is believed that the

potential benefits outweigh the potential risks.

Vitreous biochemistry

That vitreous is now considered an important

ocular structure with respect to both normal phy-

siology and several important pathologic conditi-

ons of the posterior segment is due in no small part

to a better understanding of the biochemical com-

position and organization of vitreous. Vitreous bio-

chemistry has been extensively reviewed elsewhere.

The features of vitreous biochemistry that are most

relevant to this thesis concern the macromolecules

hyaluronan and collagen, because these are the ma-

jor constituents of vitreous along with water.

AGE-related vitreous degeneration

During aging, substantial alterations take pla-

ce in the vitreous body. Beginning after the fourth

decade of life, there is a significant decrease in the

gel volume and an increase in the liquid volume of

human vitreous. Postmortem studies led to the

concept that derangement of the normal hyaluro-

nan/collagen association results in the simulta-ne-

ous formation of liquid vitreous and aggregation of

collagen fibrils into bundles of parallel fibrils seen

macroscopically as large fibers. In the posterior vit-

reous, such age-related changes form large pockets

of liquid vitreous, recognized clinically as “lacu-

nae”. By the ages of 80 to 90 years, more than half

the vitreous body is liquid.

Posterior vitreous cortex adheres to the inner

retinal surface in the normal human eye, most

prominently at the vitreous base, the optic disc, a-

long the major retinal vessels, and in a fascial man-

ner to the entire posterior pole. Spontaneous po-

sterior vitreous detachment (PVD) and vitreous li-

quefaction can develop, usually because of age-re-

lated changes in the human eye. Separation of the

vitreous from the fovea can alleviate macular tra-

ction and, thus, may greatly reduce the risk for ma-

cular hole formation. Complete PVD may also

prevent retinal neovascularization in eyes with dia-

betic retinopathy and retinal vein occlusion. Vi-

Ophthalmologia, 22, 1 : 22 - 27, 2010

Chemical vitrectomy: a threat for vitreoretinal surgeonsor a useful tool?

E. Papavasileiou1,2, G. Morphis1, D. Dereklis2, I. Vasiliadis2

1 Vitreoretinal Derartment, St Pauls’ Eye Unit, Liverpool, UK2 A′ University Ophthalmological Clinic of AXEPA Hospital, Thessaloniki

treous surgical procedures have been performed to

relieve vitreoretinal tractions or adhesions to facili-

tate reattachment of a detached retina and to redu-

ce retinal edema. The level of difficulty of vitreous

surgery depends on the presence or absence of

PVD and the degree of adhesion between the vi-

treous body and the retina. In particular, diseases

such as proliferative diabetic retinopathy, macular

hole, and proliferative vitreoretinopathy are associa-

ted with pathologic changes at the vitreoretinal in-

terface induced by anomalous PVD.

Incomplete vitreoretinal separation, a clinical

entity called vitreoschisis, which has been described

particularly in diabetic eyes, has been proposed as

a major cause of disease progression and treatment

failure. Moreover, there is experimental evidence

from adult primates that mechanical separation of

the hyaloid from the retina is not only insufficient

to provide complete vitreoretinal separation but

frequently causes damage to the macula and the

optic disc, including breaks and separation of the

ILM from the retina and avulsion of nerve fibers

and ganglion cells.

Posterior vitreous detachment

Posterior vitreous detachment (PVD) results

from weakening of the adhesion between the po-

sterior vitreous cortex and the ILL, in conjunction

with liquefaction within the vitreous body. Wea-

kening of the posterior vitreous cortex/ILL adhe-

sion at the posterior pole allows liquid vitreous to

Ophthalmologia, 22, 1 (2010) 23

Fig. 1. Right eye OCT: Stage II macular hole. (diameter < 400 Ìm). Focal vitreomacular adhesion surrounded by elevationof the posterior vitreous cortex.

Fig. 2. Closure of the macular hole. No vitreomacular traction.

enter the retrocortical space via the prepapillary

hole and perhaps the premacular vitreous cortex as

well. Volume displacement from the central vitre-

ous to the preretinal space causes the observed col-

lapse of the vitreous body.

For PVD to occur without complications, two

different processes must occur concurrently and to

a similar extent: weakening of vitreoretinal adhesion

and vitreous liquefaction.

Anamalous PVD

Anomalous PVD results when the extent of vi-

treous liquefaction exceeds the degree of vitreore-

tinal interface weakening, resulting in traction e-

xerted at the vitreoretinal interface. There can be

various untoward effects of anomalous PVD. Ef-

fects upon the retina include hemorrhage, retinal

tears and detachment, vitreomacular traction syn-

dromes, and some cases of diffuse diabetic macular

edema. Proliferative diabetic retinopathy can be

greatly aggravated by anomalous PVD. Effects u-

pon vitreous involve posterior vitreoschisis, where

splitting of the posterior vitreous cortex and for-

ward displacement of the vitreous body leave the

outer layer of the split posterior vitreous cortex still

attached to the retina. This can result in macular

pucker, contribute to macular holes, or complicate

proliferative diabetic retinopathy.

The techniques and instruments for vitreous

surgery have greatly improved in recent years. Ho-

wever, the surgical removal of the vitreous cortex is

still difficult in some patients and carries the risk

for complications such as retinal breaks, retinal de-

tachment, and retinal nerve fiber damage, especially

in younger patients.

Currently, removal of the ILM is considered

the most efficient technique to eliminate vitreo-

macular traction. Peeling of the ILM, however, in-

volves direct intervention on the macula by mecha-

nical means, and although ILM peeling (without

the use of indocyanine green) is generally regarded

as a safe and feasible surgical maneuver, it remains

challenging for the surgeon, and potentially can re-

sult in macular damage. Therefore, the desire for

complete vitreoretinal separation and the potential

risk of aggressive ILM peeling suggests the need

for pharmacologic vitreous separation to minimize

mechanical trauma to the retina.

The limits of conventional vitreoretinal surgery

include: 1. Incomplete vitreous cortex removal. 2.

Surgery of advanced stages of the disease. 3. The lack

of neuroprotection and antiproliferative agents. 4.

Ill-defined cleavage planes when removing tissue

from the retina. Pharmacology-assisted vitrectomy

helps to overcome the limits of conventional vitreore-

tinal surgery by addressing: 1. Pharmacological vi-

treolysis. 2. Earlier, less traumatic intervention. 3.

Neuroprotection and antiproliferative agents. 4. Se-

lective staining of distinct structures of the vitre-

oretinal interface, such as cortical vitreous, cellular

proliferation, and internal limiting membrane.12

Pharmacologic vitreolysis – experimental enzymes

Therefore, it would be helpful to have a bio-

chemical agent that could cleave the vitreoretinal

interface selectively without damaging the retina. If

the vitreous gel can be liquefied or if enzymes, ei-

ther alone or in combination with vitrectomy, can

weaken adhesion of the vitreous to the retina, these

changes would decrease the risk for surgical com-

plications.

Several enzymes have been explored for this

purpose. Plasmin, one of these enzymes, is a non-

specific protease that can be isolated from the pa-

tient’s own serum. The efficacy of plasmin in indu-

cing PVD has been demonstrated in several stu-

dies. In clinical studies, autologous plasmin has

been used, but a considerable amount of time is re-

quired to isolate plasmin from patient plasma.

Plasmin, however, has as yet not been availa-

ble or approved for intravitreal application in hu-

mans.17

Microplasmin, a recombinant protein, is a

truncated form of the human plasmin with retained

protease activity. Microplasmin is in phase 2 de-

velopment as the first neuroprotective agent with

thrombolytic potential for the treatment of ische-

mic stroke.18

Recombinant microplasmin (ThromboGenics

Ltd., Dublin, Ireland) is currently under clinical

development for systemic administration in pati-

ents with thromboembolic disease. Microplasmin

consists of the catalytic domain of plasmin and sha-

res the same catalytic properties as human plasmin.

The molecular mass of microplasmin (28 kDa) is

lower than the molecular mass of human plasmin

(88 kDa), thus, in theory, enabling the molecule to

24 Ophthalmologia, 22, 1 (2010)

penetrate epiretinal tissue more effectively than

plasmin obtained from pooled plasma or autolo-

gous plasmin.

Hyaluronidase

Hyaluronidase is a naturally occurring enzyme

that digests proteoglycans, primarily hyaluronan.

Purified ovine hyaluronidase (provided by Dr

Hampar Karageozian, ISTA Pharmaceuticals, Ir-

vine, California) was diluted with phosphate-buf-

fered saline (PBS) and added to the model vitreous

solutions of hyaluronan (0.1 mg/mL) at concentra-

tions of 100 IU/mL (n = 5) and 1,000 IU/mL (n =

5). This was the same drug as that used in the re-

cent FDA clinical trials in the United States. It was

hoped that studying the molecular biology of

hyaluronidase action in these experiments could

shed some light on the negative results obtained in

the recent Phase III FDA clinical trial.

Collagenase

Collagenases comprise a group of enzymes

that degrade collagen. Just as there are as many as

18 different types of collagen, there are many sub-

types of collagenase. 15

Microplasmin is effective in inducing PVD

and appears to be safe for the ocular ultrastructure.

The major advantage of microplasmin compared

with mechanical ILM peeling for complete vitreo-

retinal separation lies in the unchanged reactivity

of retinal glial cells and neurons. Compared with

autologous plasmin, microplasmin ensures the ap-

plication of a pure substance at a defined dose. 17

Possible complications of enzymaticmanipulation of the vitreous

Pharmacologic manipulation of the vitreoreti-

nal interface presents the inherent risk of causing a

retinal tear or detachment. Although no reports to

date have specifically addressed this concern, a re-

tinal tear is an intrinsic risk during PVD creation,

especially in patients with abnormal vitreoretinal

adhesions, such as lattice degeneration. In addi-

tion, increasing the vitreous cavity oxygen in adults

can lead to advancing nuclear sclerotic cataract

and perhaps late glaucoma.

In their study of microplasmin, Gandorfer et

al.13 did not report any adverse effects. In our stu-

dy, a transient decrease in a- and b-wave amplitu-

des was seen in eyes that received high doses of mi-

croplasmin. In addition, animals injected with the

highest dose of 250 Ìg showed ERG changes even

90 days after injection. Verstraeten et al.17 repor-

ted that an intravitreous injection of plasmin cau-

sed a transient decrease in ERG b-wave amplitude

with excellent recovery. Their histologic observa-

tions showed that the retina was not damaged, and

they suggested that the decrease in the ERG re-

sulted from the high osmolarity of the plasmin so-

lution. In our animals receiving 125 Ìg or less mi-

croplasmin, there was a gradual recovery of the

ERG amplitudes over several days; at 14 days after

injection, a-wave and b-wave amplitudes were com-

parable to those of the control eyes injected with

BSS. We believe that 125 Ìg is the safe dosage to

inject into the vitreous of rabbits, and our results

showed that with this dose of microplasmin, PVD

developed within 60 minutes. In terms of enzymat-

ic action, 125 Ìg microplasmin is equivalent to 2 U

plasmin (Sigma-Aldrich, Poole, United Kingdom),

which causes complete vitreous separation in

porcine eyes and in human donor eyes.15,16

Results of clinical trials with microplasmin

The European MIVI 2T was a phase 2, rando-

mized, double-masked clinical trial of micropla-

smin intravitreal injection for nonsurgical treat-

ment of VMT. Inclusion criteria was evidence of

VMT by ultrasound and optical coherence tomo-

graphy with the presence of macular thickening

>250 Ìm. Common conditions included VMT, ma-

cular holes, or tractional DME. Visual acuity (VA)

had to be 20/40 or worse in the study eye and 20/

400 or better in the fellow eye. Two cohorts of 15

patients received 75 Ìg or 125 Ìg of microplasmin

or sham with a 4:1 randomization of microplasmin

vs sham. Follow-up data were collected for 6

months. Of the 30 patients enrolled, 16 (53%) had

VMT, 6 (20%) had macular holes, and 8 (27%)

had tractional DME. Intravitreal injection of mi-

croplasmin was well tolerated with no adverse

events including retinal tears, retinal detachments,

or endophthalmitis reported.

Results showed complete VMT resolution in 9

Ophthalmologia, 22, 1 (2010) 25

26 Ophthalmologia, 22, 1 (2010)

eyes (40%) with the best results (50% resolution)

seen with the higher dose of microplasmin (125 Ìg).

Closure of macular holes without vitrectomy occur-

red in 50% of eyes. A >3-line improvement of VA

occurred in 4 patients (17%). Interestingly, micro-

plasmin has been reported to create a PVD with

100% effectiveness in patients with an apparently

normal vitreoretinal interface. From the MIVI 2T

trial we know that microplasmin relieves VMT in

40% of patients with an abnormal vitreoretinal in-

terface. Certainly a phase 3 clinical trial examining

the nonsurgical treatment of macular holes and

VMT is warranted. Currently, the phase 2b MIVI

III trial is enrolling patients to determine the use of

microplasmin as a surgical adjunct in vitrectomy sur-

gery and early results appear encouraging. We are

awaiting the final results of this trial.

Future directions

ThromboGenics previously announced plans

to proceed into Phase III clinical development of

microplasmin based on the encouraging results.

The two pivotal trials in the current Phase III pro-

gram (MIVI-TRUST, Microplasmin IntraVitreous

Injection – Traction Release without Surgical Tre-

atment) are multi-centre, randomized, placebo

controlled, double-masked trials which will evalua-

te 125Ìg of microplasmin versus placebo in the in-

travitreal treatment of patients with focal vitreo-

macular adhesion. The trials will enroll approxima-

tely 320 patients each across approximately 40 cen-

tres in the United States (TG-MV-006) and 40 cen-

tres in Europe and North America (TG-MV-007).

The primary endpoint of both trials is the non-

surgical resolution of focal vitreomacular adhesion

after one month. Additional measures of efficacy

and safety will also be assessed at various intervals

over six months in both studies.

Diabetic retinopathy

ThromboGenics has also started a MIVI-II

(DME) Phase IIa trial in Europe to evaluate mi-

croplasmin injection for the non-surgical treatment

of Diabetic Macular Edema, a form of Diabetic Re-

tinopathy. MIVI-II (DME) is a sham injection con-

trolled, dose ascending (25, 75, 125 Ìg) trial evalua-

ting the safety and efficacy of microplasmin in 60

patients across eight sites in Europe. Completion

of enrolment in MIVI-II is expected at end 2008.20

Previous reports have shown that O2 levels in

the vitreous cavity increase following pars plana

vitrectomy. In addition, stabilization of PDR and

DME often occurs following vitrectomy, possibly

due to increased oxygenation and removal of the

vitreous scaffold. It is not known whether “chemi-

cal vitrectomy” has the same effect, but prelimina-

ry data are promising.19

In addition, enzymatic creation of a PVD to

increase the rate of O(2) exchange within the vi-

treal space may have potential application for

treatment of retinal ischemic disease.8

Conclusion

Invisible by design vitreous was long unseen as

important in ocular physiology and as a cause of

retinal pathology. In recent years the importance

of vitreous in the pathogenesis of various reti-

nopathies has been increasingly appreciated, and

vitreous is being treated with ever-evolving the-

rapeutic modalities, for the most part surgical. The

future, however, will see an increase in the use of

pharmacologic agents for therapy and prevention.

In the future, vitreous surgery will be enhanced

by pharmacologic adjuncts to facilitate vitreoretinal

separation and vitreous removal. Eventually, these

vitreolytic agents will obviate the need for such

surgery by reducing the role of vitreous in retinopa-

thy and thereby prevent disease. Pharmacologic vit-

reolysis is an emerging form of drug therapy that is

based upon recent advances in our understanding

of vitreous biochemistry and the role of anomalous

PVD in the pathophysiology of vitreoretinopathies.

Bibliography

1. Benz MS, Packo KH, Gonzalez V, Pakola S, Bezner D,Haller JA, Schwartz SD. A Placebo-Controlled Trial of

Microplasmin Intravitreous Injection to Facilitate Po-

sterior Vitreous Detachment before Vitrectomy.

Ophthalmology 2010.

2. Chen W, Mo W, Sun K, Huang X, Zhang YL, Song HY. Mi-

croplasmin degrades fibronectin and laminin at vi-

treoretinal interface and outer retina during enzyma-

tic vitrectomy. Curr Eye Res 34(12): 1057-64, 2009.

3. Goldenberg DT, Trese MT. Pharmacologic vitreodynamics

and molecular flux. Dev Ophthalmol 44: 31-6, 2009.

4. Gandorfer A. Microplasmin-assisted vitrectomy. Dev

Ophthalmol 44: 26-30, 2009.

Ophthalmologia, 22, 1 (2010) 27

5. Gandorfer A. Objective of pharmacologic vitreolysis. Dev

Ophthalmol 44: 1-6, 2009.

6. de Smet MD, Gandorfer A, Stalmans P, Veckeneer M, Fe-ron E, Pakola S, Kampik A. Microplasmin intravitreal

administration in patients with vitreomacular traction

scheduled for vitrectomy: the MIVI I trial. Ophthal-

mology 116(7): 1349-55, 2009.

7. Lopez-Lopez F, Rodriguez-Blanco M, Gómez-Ulla F, Mar-ticorena J. Enzymatic vitreolysis. Curr Diabetes Rev

5(1): 57-62, 2009.

8. Giblin FJ, Quiram PA, Leverenz VR, Baker RM, Dang L,Trese MT. Enzyme-induced posterior vitreous detach-

ment in the rat produces increased lens nuclear pO2

levels. Exp Eye Res 88(2): 286-92, 2009.

9. de Smet MD, Valmaggia C, Zarranz-Ventura J, Wille-

kens B. Microplasmin: ex vivo characterization of its

activity in porcine vitreous. Invest Ophthalmol Vis Sci

50(2):814-9, 2008.

10. Gandorfer A. Experimental evaluation of microplasmin

– an alternative to vital dyes. Dev Ophthalmol 42: 153-

9, 2008.

11. Gandorfer A. Enzymatic vitreous disruption. Eye (Lond)

22(10): 1273-7, 2008.

12. Gandorfer A. The need for pharmacology in vitreoreti-

nal surgery SOE Lecture 2007 Klin Monbl Augen-

heilkd 224(12): 900-4, 2007.

13. Quiram PA, Leverenz VR, Baker RM, Dang L, Giblin FJ,Trese MT. Microplasmin-induced posterior vitreous

detachment affects vitreous oxygen levels. Retina

27(8): 1090-6, 2007.

14. Chen W, Huang X, Ma XW, Mo W, Wang WJ, Song HY.

Enzymatic vitreolysis with recombinant microplas-

minogen and tissue plasminogen activator. Eye

(Lond) 22(2): 300-7, 2008.

15. Sebag J. Molecular biology of pharmacologic vitreolysis.

Trans Am Ophthalmol Soc 103: 473-94, 2005.

16. Sebag J, Ansari RR, Suh KI. Pharmacologic vitreolysis

with microplasmin increases vitreous diffusion coeffi-

cients. Graefes Arch Clin Exp Ophthalmol 245(4):

576-80, 2007.

17. Gandorfer A, Rohleder M, Sethi C, Eckle D, Welge-Lüs-sen U, Kampik A, Luthert Ph, Charteris D. Posterior

Vitreous Detachment Induced by Microplasmin In-

vestigative Ophthalmology and Visual Science 45:

641-7, 2004.

18. Sakuma T, Tanaka M, Mizota A, Inoue J, Pakola S. Safe-

ty of In Vivo Pharmacologic Vitreolysis with Recom-

binant Microplasmin in Rabbit Eyes Investigative

Ophthalmology and Visual Science 46: 3295-9, 2005.

19. Quiram PA, Goldenberg D. Macular Surgery and Enzy-

matic Manipulation of the Vitreous Cavity: An Introdu-

ction to Chemical Vitrectomy Retinal Physician 2008.

Refractive surgery became a popular treat-

ment of myopia, hyperopia, and astigmatism in

adults. Frequently, ophthalmologists are being

asked whether refractive surgery is appropriate for

children with refractive errors. Also, in many cases

the refractive surgery could be a good alternative,

especially in difficult paediatric cases where the

traditional treatments had failed.

Although several reviews of paediatric re-

fractive surgery have already been published1-3 the

purpose of this review is to summarize the publi-

shed data and to present the available literature to

address the controversial issues.

There are no prospective randomized clinical

trials to prove the safety and efficacy of refractive

surgery in children. However, some doctors treat

some cases, when the traditional treatments have

failed4. The refractive surgery in children has been

used either to treat asymmetric or unilateral high

myopia, hypermetropia, bilateral hypermetropia,

myopia, with amblyopia, not responding to tradi-

tional treatment (spectacles, contact lenses, pena-

lization therapy)5–11, to treat accommodative eso-

tropia, or in younger children with amblyopia with

bad compliance to amblyopia traditional the-

rapy.12-21

Myopia

According to the literature, photorefractive

keratectomy (PRK), LASIK and phakic intraocu-

lar lenses (IOLs) have been used to treat children

with myopia, with spherical equivalents from -0.75

D to -25.0 D, although the targeted correction was

sometimes less than the total amount, for various

reasons.11,12,22 The range of myopic correction

which was attempted by PRK was -0.75 D to -17.7

D, and by LASIK was -2.5 D to -23.0 D. Phakic

IOLs used to treat myopia ranging between -8.0 D

and -18.0 D10,23.

Ophthalmologia, 22, 1 : 28 - 31, 2010

Pediatric refractive surgery

N. Kozeis, N. Papadopoulou, S. Tyradelis, P. Tahiaos

Paediatric Eye department Eye department Hippokrateion Hospital of Thessaloniki

Refractive surgery in children is debatable. The primaryindications are anisometropic amblyopia and bilateralhigh myopia. The major concerns are the changing of re-fraction due to growth of the eye and the long-term impli-cations. The most popular procedures are photorefractivekeratectomy and laser subepithelial keratomileusis fol-lowed by laser in situ keratomileusis. The preliminary da-ta showed that refractive surgery can be successfully per-formed in children and that the short term complicationrate seems to be similar to that in adults.

∏ ÂÊ·ÚÌÔÁ‹ Ù˘ ‰È·ıÏ·ÛÙÈ΋˜ ¯ÂÈÚÔ˘ÚÁÈ΋˜ ÛÙ· ·È‰È¿Â›Ó·È ˘fi Û˘˙‹ÙËÛË. OÈ Î‡ÚȘ ÂӉ›ÍÂȘ ÛÙȘ Ôԛ˜ÚÔÙ›ÓÂÙ·È Ë ÂÊ·ÚÌÔÁ‹ Ù˘, Â›Ó·È Ë ·ÓÈÛÔÌÂÙÚˆ›· Ô˘ÌÔÚ› Ó· Ô‰ËÁ‹ÛÂÈ Û ·Ì‚Ï˘ˆ›·, ηıÒ˜ Î·È Ë ˘„ËÏ‹·ÌÊÔÙÂÚfiÏ¢ÚË Ì˘ˆ›·. ™ÎÂÙÈÎÈÛÌfi˜ ·ÊÔÚ¿ ÛÙËÓÌÂÙ·‚·ÏÏfiÌÂÓË ‰È¿ıÏ·ÛË Ô˘ ·ÎÔÏÔ˘ı› ÙËÓ ·Ó¿Ù˘ÍËÙÔ˘ Ì·ÙÈÔ‡, ηıÒ˜ Î·È ÔÈ Èı·Ó¤˜ ÌÂÏÏÔÓÙÈΤ˜ ÂÍÂÏ›ÍÂȘ.OÈ Ù¯ÓÈΤ˜ Ô˘ Û˘ÓÈÛÙÒÓÙ·È Â›Ó·È Ë ÊˆÙԉȷıÏ·ÛÙÈ΋ÎÂÚ·ÙÂÎÙÔÌ‹ Î·È Ë laser ˘ÔÂÈıËÏȷ΋ ÎÂÚ·ÙƠ̂ϢÛË,·ÎÔÏÔ˘ıÔ‡ÌÂÓË ·fi in situ ÎÂÚ·ÙƠ̂ϢÛË. Δ· ÚÒÙ·ÛÙÔȯ›· Â›Ó·È ÂÓı·ÚÚ˘ÓÙÈο, ˆÛÙfiÛÔ, ÌÂÁ·Ï‡ÙÂÚ˜ ÌÂ-ϤÙ˜ ··ÈÙÔ‡ÓÙ·È ÁÈ· ·ÛʷϤÛÙÂÚ· Û˘ÌÂÚ¿ÛÌ·Ù·.

¢È·ıÏ·ÛÙÈ΋ ¯ÂÈÚÔ˘ÚÁÈ΋ ÛÙ· ·È‰È¿¡. ∫Ô˙¤Ë˜, ¡. ¶··‰fiÔ˘ÏÔ˜, ™. Δ˘Ú·‰¤Ï˘, ¶. Δ·¯È¿Ô˜

Hyperopia

A few cases of hyperopia have been reported.

PRK was used to treat anisometropic hyperopia

with spherical equivalents ranging from +2.7 D to

+8.5 D.5,17,18 Others reported high hyperopia

treatment with LASIK4 PRK and LASIK have also

been used to treat hyperopia with accommodative

esotropia in older children and adults. PRK has

been successfully performed on infants as young as

1 or 2 year of age and LASIK has been performed

on children as young as 5 years of age, with the a-

dult equipment12-14,18. Laser subepithelial kerato-

mileusis (LASEK) and phakic IOLs have also been

used in young children, from 3 to 16 years12,24. Ma-

ny of these young children were reported to have

coexisting cerebral palsy, autism and other de-

velopmental delays, being intolerant of glasses and

contact lenses.

In general, children older than 7 or 8 years of

age seem to tolerate the procedure well under to-

pical anesthesia, most of the times with preme-

dication6,9,11,14,18,22,25,26. Very young children requ-

ire general anesthesia, either using a trans-portable

laser (wheeled), or the anesthesia equipment is

transported into a non-hospital-based laser facility.

Various agents have been used as nitrous oxide se-

voflurane, halothane, intravenous propofol, and in-

travenous ketamine.5,8,12,13,15,16

In cases of general anaesthesia, where fixation

by the patient can not be achieved, the ablation has

been centered over the pupil, and a fixation ring is

generally used to achieve the desired position of the

eye8,24. However this is not the an ideal technique.

An eye tracking device was used in several series.

Since the pediatric eye responds differently to

surgery than the adult eye27,28, one could expect in-

creased incidence of corneal complications. Howe-

ver, this is not reported.

Photorefractive keratectomy

Some studies reported corneal haze after

PRK, with an incidence of 4% of these eyes to have

line loss of BCVA. At the final follow-up of 108

eyes treated with PRK or LASEK for myopia, no

haze or trace haze was reported in 73% of eyes,

mild haze in 17%, and moderate haze in 10%, and

no eyes had severe haze. In PRK for hyperopia,

75% had no or trace haze and 25% had mild haze

at the final follow-up examination. No eyes had

moderate or severe haze after undergoing PRK for

hyperopia.5,9,12,13,16-18

Transient, moderate to severe haze has been

reported in children after PRK associated with

treatment of high amounts of myopia and failure to

comply with steroid regimens postoperatively5,13,

16,22. The risk of loss of BCVA secondary to corneal

haze after PRK to treat high amounts of myopia in

children seems to be similar to that observed in a-

dults, however, transient severe haze may exacer-

bate amblyopia in children.13,29-31

LASIK

In children underwent LASIK, epithelial in-

growth, Bowman wrinkles, mild diffuse lamellar

keratitis, and herpes simplex keratitis were each re-

ported in 0.9% of eyes, and persistent haze and in-

traoperative free flaps were each reported in 1.9%

of eyes.8,11,15,26 A loss of any line of BCVA was re-

ported in 7.5% of these patients. Endothelial cell

loss is similar to the rate of adults.32-35

Today no ideal refractive surgery for a child ex-

ists. LASIK has the advantage of faster visual reha-

bilitation, ability to correct larger refractive errors,

and potential to undergo enhancements, but it has

the distinct disadvantage of flap vulnerability in the

active child. PRK offers resiliency to childhood

trauma but is more likely to have prolonged visual

recovery and may provide less refractive correction.

Newer techniques, as LASEK and PRK with mito-

mycin C are being investigated for children13.

However, the refractive outcomes in children

have been less predictable and less is known about

postoperative stability.

In most series, the 65-75% of the treated for

myopia eyes with PRK and LASEK were within 1.0

to 1.5 D less of the attempted correction, posto-

peratively.12,13,18,36,37

Myopic regression after PRK in children oc-

curs, but longer follow-up is needed to determine

whether it differs from the regression in adults.

Myopic regression has also been noted after LA-

SIK in children.26

Visual Outcomes

In some patients visual acuities could not be

obtained because of their very young age or deve-

Ophthalmologia, 22, 1 (2010) 29

lopmental delays. Only a few patients were repor-

ted with lost BCVA after refractive surgery, mainly

due to corneal haze.8,11,13, 22

PRK & LASIK for accommodative esotropia

There is an increasing interest in refractive

surgery in treating accommodative esotropia with

LASIK and PRK in older children and young ad-

ults.19,20,21,38-41 Mainly in patients with refractive

accommodative esotropia, well controlled with

spectacles or contact lenses. Postoperatively, all

patients were orthophoric without correction. We-

re also reported cases of partial and nonaccommo-

dative esotropia. What was not expected was that

postoperative alignment could not be predicted by

preoperative accommodative status. In fact, pati-

ents who were classified preoperatively as “nonac-

commodative” demonstrated a reduction in mani-

fest esotropia, while some who classified as “fully

accommodative” preoperatively showed no redu-

ction in esodeviation after LASIK. This unex-

pected finding could not be completely attributed

to residual hyperopia. In addition, complications

were much more common in these cases, with 25%

of patients developing visually significant flap stri-

ae, 8% experiencing decentration, and 4% having

diffuse lamellar keratitis. Furthermore, BCVA de-

creased by 1 or 2 lines in 23% of patients. Refrac-

tive surgery is promising for the correction of re-

fractive accommodative esotropia associated with

low to moderate amounts of hyperopia in young

adults. However, it may be less predictable in pa-

tients with higher amounts of hyperopia.

References

1. Primack JD, Azar NF, Azar DT. Pediatric refractive

surgery. Int Ophthalmol Clin 41: 19-34, 2001.

2. Drack AV, Nucci P. Refractive surgery in children.

Ophthalmol Clin North Am 14: 457-466, 2001.

3. Haw WW, Alcorn DM, Manche EE. Excimer laser refra-

ctive surgery in the pediatric population. J Pediatr

Ophthalmol Strabismus 36:173-177, 1999.

4. Davidorf JM. Pediatric refractive surgery. J Cataract Re-

fract Surg 26: 1567-1568, 2000.

5. Singh D. Photorefractive keratectomy in pediatric pa-

tients. J Cataract Refract Surg 21: 630-632, 1995.

6. Nano Jr, HD Muzzin S, Irigaray F. Excimer laser photo-

refractive keratectomy in pediatric patients. J Cata-

ract Refract Surg 23: 736-739, 1997.

7. Rashad KM. Laser in situ keratomileusis for myopic ani-

sometropia in children. J Refract Surg 15: 429-435,

1999.

8. Agarwal A, Agarwal T, Siraj AA, et al. Results of pediatric

laser in situ keratomileusis. J Cataract Refract Surg

26: 684-689, 2000.

9. Nucci P, Drack AV. Refractive surgery for unilateral high

myopia in children. J AAPOS 5: 348-351, 2001.

10. Chipont EM, Garcia-Hermosa P, Alio JL. Reversal of

myopic anisometropic amblyopia with phakic intrao-

cular lens implantation. J Refract Surg 17: 460-462,

2001.

11. Rybintseva LV, Sheludchenko VM. Effectiveness of laser

in situ keratomileusis with the Nidek EC-5000 exci-

mer laser for pediatric correction of spherical aniso-

metropia. J Refract Surg 17: S224-S228, 2001.

12. Leibole MA, Berdy GJ, Packwood E, et al. Laser refra-

ctive (LASEK and PRK) surgical correction of high

anisometropic myopia in amblyopic children. Annual

Meeting of ARVO, Fort Lauderdale, Florida, 2002.

13. Astle WF, Huang PT, Ells AL, et al. Photorefractive kera-

tectomy in children. J Cataract Refract Surg 28: 932-

941, 2002.

14. Paysse EA, Hamill MB, Koch DD, et al. Epithelial he-

aling and ocular discomfort after photorefractive ke-

ratectomy in children. J Cataract Refract Surg 29:

478-481, 2003.

15. Davis JS, Dhaliwal DK, Kira DT, et al. Treatment of pe-

diatric anisometropic myopia with laser in situ kerato-

mileusis (LASIK): a pilot study. Annual Meeting of

AAPOS, Orlando, Florida, 2001.

16. Alio JL, Artola A, Claramonte P, et al. Photorefractive

keratectomy for pediatric myopic anisometropia. J

Cataract Refract Surg 24: 327-330, 1998.

17. Guthrie ME, Salvador G, Wright KW. Pediatric PRK for

hyperopic anisometropic amblyopia. Annual meeting

of ARVO, Fort Lauderdale, Florida, 2001.

18. Paysse EA, Coats DK, Hamill MB, et al. Photorefractive

keratectomy for anisometropia in children with am-

blyopia refractory to conventional treatment. Presen-

ted at the 28th Annual Meeting of AAPOS, Seattle,

Washington, 2002.

19. Moldanado-Bas A, Hoyos J. Strabismus: accommodative

component treated by LASIK. Rev Bras Oftalmol 57:

757-760, 1998.

20. Stidham DB, Borissova O, Borissov V, et al. Effect of hy-

peropic laser in situ keratomileusis on ocular align-

ment and stereopsis in patients with accommodative

esotropia. Ophthalmology 109: 1148-1153, 2002.

21. Nucci P, Serafino M, Hutchinson AK Photorefractive ke-

ratectomy for the treatment of purely refractive ac-

commodative esotropia. J Cataract Refract Surg 29:

889-894, 2003.

22. Bluestein EC, Hutchinson AK, Saunders RA, et al. Pedia-

30 Ophthalmologia, 22, 1 (2010)

Ophthalmologia, 22, 1 (2010) 31

tric photorefractive keratectomy for the treatment of

myopic anisometropic amblyopia. Annual Meeting of

the American Academy of Ophthalmology, New Or-

leans, Louisiana, 2001.

23. Lesueur L, Arne JL. Phakic posterior chamber lens im-

plantation in children with high myopia. J Cataract

Refract Surg 25: 1571-1575, 1999.

24. Astle WF, Huang PT. Refractive surgery in children.

ASCRS Annual Symposium, Philadelphia, Pennsyl-

vania, 2002.

25. Terrell J, Bechara SJ, Nesburn N, et al. The effect of globe

fixation on ablation zone centration in photorefractive

keratectomy. Am J Ophthalmol 119: 612-619, 1995.

26. Nassaralla BR, Nassaralla JJ. Laser in situ keratomi-

leusis in children 8 to 15 years old. J Refract Surg

2001, 17: 519-524, 2001.

27. Hosal BM, Biglan AW. Risk factors for secondary mem-

brane formation after removal of pediatric cataract. J

Cataract Refract Surg 28: 302-309, 2002.

28. Aasuri MK, Garg P, Gokhle N, et al. Penetrating kerato-

plasty in children. Cornea 19: 140-144, 2000.

29. Williams DK. Multizone photorefractive keratectomy

for high and very high myopia: long-term results. J Ca-

taract Refract Surg 23: 1034-1041, 1997.

30. Kremer I, Kaplan A, Novikov I, et al. Patterns of late cor-

neal scarring after photorefractive keratectomy in

high and severe myopia. Ophthalmology 106: 467-

473, 1999.

31. Kesinbora H. Long-term results of multizone photore-

fractive keratectomy for myopia of -6.0 to -10.0 dio-

pters. J Cataract Refract Surg 26: 1484-1491, 2000.

32. Perez-Santonja JJ, Sakla HF, Alio JL. Evaluation of en-

dothelial cell changes one year after excimer laser in

situ keratomileusis. Arch Ophthalmol 115: 841-846,

1997.

33. Stulting RD, Thompson KP, Waring 3rd, GO et al. The ef-

fect of photorefractive keratectomy on the corneal en-

dothelium. Ophthalmology 103: 1357-1365, 1996.

34. Hersh PS, Stulting RD, Steinert RF, et al. Results of phase

III eximer laser photorefractive keratectomy for my-

opia. Ophthalmology 104: 1535-1553, 1997.

35. Hersh PS, Brint SF, Maloney RK, et al. Photorefractive

keratectomy versus laser in situ keratomileusis for

moderate to high myopia: a randomized prospective

study. Ophthalmology 105: 1512-1523, 1998.

36. Autrata R, Rehurek J, Holousova M. Photorefractive ker-

atectomy in high myopic anisometropia in children.

Cesk Slov Oftalmol 55: 216-221, 1999.

37. Loewenstein A, Lipshitz I, Levanon D, et al. Influence of

patient age on photorefractive keratectomy for myo-

pia. J Refract Surg 13: 23-26, 1997.

38. Mulvihill A, MacCann A, Flitcroft I, et al. Outcome in re-

fractive accommodative esotropia. Br J Ophthalmol

84: 746-749, 2000.

39. Swan KC. Accommodative esotropia: long range follow-

up. Ophthalmology 90: 1141-1145, 1983.

40. Hoyos-Chacon JE, Cigles M, Pradas J, et al. Hyperopic

LASIK in refractive accommodative esotropia. Invest

Ophthalmol Vis Sci 41: S692, 2000.

41. Nemet P, Levinger S, Nemet A. Refractive surgery for re-

fractive errors which cause strabismus. Binocul Vis

Strabismus Q 17: 187-190, 2003.

Introduction

The visual evoked potentials method aims at

the occipital activation with the use of intermittent

visual stimuli of the retina (flash).1-3 The responses

are recorded and their mean value is extracted in a

waveform, in order to eliminate the noise factor.4

The currently used variation, which is technically

superior, was introduced in 1969 by Regan and

Heron and is based on the rapid changes in a chec-

kered picture observed by the patient (pattern shift

visual evoked responses-PSVER).1,2 The reference

electrode (Fz) is placed in the frontal area whilst

the recording one (Qz) is 5cm above the external

occipital protuberance.3

Review

The recorded waveform consists of three

peaks, but the value of clinical interest refers to

the highest one (P100).3 When the above method is

applied individually to each eye it can reveal a de-

lay in the nerve thrust conduction through the o-

ptical fibers, even when other techniques fail (o-

ptical fields, optic disk examination, pupil reflex-

es, MRI).1,2,5 Especially when the stimulus is ap-

plied in one half of the optic field it is possible to

detect a unilateral, functional lesion beyond chi-

asm.1,3

It is well known that a probable myelin lesion

delays the nerve conductivity, whereas the axonal

deficits reduce the potential range.3 Therefore, the

clinician mostly evaluates the latent time of P100.

The range and morphology of the potential are of

less diagnostic significance since they are difficult

to quantitate.1,3,6 Considering the above facts, it is

understandable how valuable PSVERs are in the

substantiation of the active or residual optic neu-

ritis.1,2,7 While during its acute phase there is usu-

ally no recording, as the neuritis progresses to hea-

ling there appears a P100 delay. It is worth mentio-

Ophthalmologia, 22, 1 : 32 - 34, 2010

Visual evoked potentials: contemporarydiagnostic applications

ª. Parava1, E. Kanonidou2, A. Praidou2, P. Beredimas1

1 Department of Neurology, Psychiatric Hospital Petras Olympou, Katerini, Greece.2 Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

Visual evoked potentials constitute an established me-thod of monitoring the function integrity of the optic path-way. The sensitivity and non-invasiveness of the actualtechnique render its contribution in the everyday patientapproach invaluable. The following review aims at high-lighting the importance of visual evoked potentials in thediagnosis and follow-up of various clinical cases.

Δ· ÔÙÈο ÚÔÎÏËÙ¿ ‰˘Ó·ÌÈο Û˘ÓÈÛÙÔ‡Ó Ì›· ηıÈÂڈ̤-ÓË Ï¤ÔÓ Ì¤ıÔ‰Ô ·Ó›¯Ó¢Û˘ ‚Ï·‚ÒÓ Ù˘ ÔÙÈ΋˜ Ô‰Ô‡.∏ ¢·ÈÛıËÛ›· Î·È Ë ÌË ÂÂÌ‚·ÙÈÎfiÙËÙ¿ ÙÔ˘˜ ˆ˜ Ù¯ÓÈ΋˜Î·ıÈÛÙ¿ ÙË ¯Ú‹ÛË ÙÔ˘˜ ·Ó·fiÛ·ÛÙÔ ÎÔÌÌ¿ÙÈ Ù˘ ηıË-ÌÂÚÈÓ‹˜ ÎÏÈÓÈ΋˜ Ú¿Í˘. ™ÎÔfi˜ Ù˘ ·ÚÔ‡Û·˜ ·Ó·-ÛÎfiËÛ˘ Â›Ó·È Ë Î·Ù¿‰ÂÈÍË Ù˘ ¯ÚËÛÈÌfiÙËÙ·˜ ÙˆÓ ÔÙÈ-ÎÒÓ ÚÔÎÏËÙÒÓ ‰˘Ó·ÌÈÎÒÓ ÛÙË ‰È¿ÁÓˆÛË Î·È ÎÏÈÓÈ΋ ·-Ú·ÎÔÏÔ‡ıËÛË ÂÙÂÚfiÎÏËÙˆÓ ÎÏÈÓÈÎÒÓ ÔÓÙÔًوÓ.

OÙÈο ÚÔÎÏËÙ¿ ‰˘Ó·ÌÈο: ™‡Á¯ÚÔÓ˜ ‰È·ÁÓˆÛÙÈΤ˜ ÂÊ·ÚÌÔÁ¤˜ª. ¶·Ú¿‚·, ∂. ∫·ÓÔÓ›‰Ô˘, ∞. ¶Ú·˝‰Ô˘, ¶. ªÂÚ‰‹Ì·˜

ning that although the neuritis is clinically restored

the P100 delay is permanent (90-95%).2 Similar

findings are observed in compressive and traumat-

ic lesions of the optic nerve, in ischemic optic

neuropathy and hereditary Leber neuropathy.1,2,7,8

P100 delay can also be recorded in patients with

glaucoma and diabetes mellitus and rarely in the

presence of toxical and nutritional amblyopias.1,9

On the contrary, the awaited changes in latent time

values in patients with decreased visual acuity

(<4/10) are minor and are highly related with a sig-

nificant PSVERs potential decrease.1 Thus, it is al-

ways recommended that the patient wears his/her

glasses during the examination.3

Visual evoked potentials are also commonly

used in the examination of subclinical multiple

sclerosis types as well as in the evaluation of the di-

sease’s progress and in the therapeutic effect of the

chosen medication in diagnosed patients.2,10,11 In

these cases, pathological findings vary from 50-

90%3 in different studies and in 1/3 of the suspici-

ous for demyelinating disease cases reveal a second

lesion along the optic nerve. 1

Recent literature on the subject suggests that

the above method is used as screening test in neu-

rofibromatosis.12 Other authors consider its use in

Whiplash injury evaluation.13 Contemporary stu-

dies examine the use of visual evoked potentials to

determine possible endocranial lesions in patients

with periorbital hemangiomas and even to prog-

nose occipital typhlosis due to basilar artery ob-

struction.15

Discussion

Visual evoked potentials can detect functional

lesions in the visual pathway beyond cheasm with

more sensitivity compared to clinical examination

and MRI. Still, they lack in specifity since the con-

ductivity delay is a very common finding in a hete-

rogeneous group of pathological conditions. Under

specific terms, though, they clarify the optic nerves’

function in patients with subjective complaints o-

therwise hard to clarify. In every case, normal vi-

sual evoked potentials values exclude a serious i-

schemic, neoplasmatic and demyelinating lesion of

the optic nerve.

Conclusion

The visual evoked potentials technique con-

stitutes a valuable part of the neurophysiological

examination in a wide range of neurological con-

ditions with eye involvement. Its low cost, the re-

petitiveness and its non-intrusive character esta-

blish it as an excellent diagnostic tool in every day

clinical practice.

References

1. Victor M., Ropper A. H. ¡Â˘ÚÔÏÔÁ›·. π·ÙÚÈΤ˜ ÂΉfiÛÂȘ

¶. Ã. ¶·Û¯·Ï›‰Ë˜, 2Ë ¤Î‰ÔÛË, ∞ı‹Ó·, 2003.

Ophthalmologia, 22, 1 (2010) 33

10µV

0

-10

0 100 200 300 ms

P100

N75

N135

Fig. 2. Normal waveform of pattern shift visual evoked re-sponses-PSVER.Odom J. V., Bach M., Barber C.et al.: Visual evokedpotentials standard (2004). Documenta Ophthalmo-logica 2004; 108: 115–123.

Fpz

Nasion

Oz

Inion

E1

Fig. 1. Visual evoked potentials technique base on rapidpattern shift.Sivakumar R.M.E., Ravindran G.M.E.: Identificationof Intermediate Latencies in Transient Visual EvokedPotentials. Academic Open Internet Journal 2006; 17.

34 Ophthalmologia, 22, 1 (2010)

2. Chiappa K. H. Evoked Potentials in Clinical Medicine.

Raven Press, 2nd ed, New York, 1990.

3. §ÔÁÔı¤Ù˘ π., ª˘ÏˆÓ¿˜ π. ¡Â˘ÚÔÏÔÁ›·. University Studio

Press, 3Ë ¤Î‰ÔÛË, £ÂÛÛ·ÏÔÓ›ÎË, 1996.

4. Aminoff MJ, Greenberg DA, Simon RP. Clinical Neuro-

logy. The McGraw-Hill Companies, Inc., 6th edition,

USA, 2005.

5. Osborn A.G. Diagnositic Neuroradiology. St. Louis, Mo-

sby/Year Book, 1994.

6. Aminoff M.J. Evoked potential studies in neurological di-

agnosis and management. Ann Neurol 28: 706–710,

1990.

7. Balcer LJ. Optic Neuritis. N Engl J Med 354: 1273, 2006.

8. Mahapatra A.K. Visual evoked potentials in optic nerve

injury. Does it merit a mention? Acta Neurochirur-

gica 112: 47-49, 1991.

9. Morio G, Mariani E, et al. Visual Evoked Potential in

NIDDM. A longitudinal study. Diabetologia 38: 573-

6, 1995.

10. Gronseth GS, Ashman EJ. Practice parameter: the use-

fulness of evoked potentials in identifying clinically

silent lesions in patients with suspected multiple scle-

rosis (an evidence-based review): report of the Quali-

ty Standards Subcommittee of the American Aca-

demy of Neurology. Neurology 55: 7-15, 2000.

11. Noseworthy JH, Lucchinetti C, Rodriguez M, WeinshenkerBG. Multiple Sclerosis. N Engl J Med 343: 938, 2000.

12. Jabbari B, Maitland CG, Morris LM, et al. The Value of

Visual Evoked Potential as a Screening Test in Neu-

rofibromatosis. Arch Neurol 42(11): 1072-1074, 1985.

13. Mikula I, Mi¡kov S, Negovetiç R, Demarin V. Visual Evo-

ked Potentials (VEP) In Whiplash Injuries. Acta clin

Croat 2000; 39(1)

14. Ioannidis AS, Liasis A, Syed S, Harper J, Nischal KK. The

value of visual evoked potentials in the evaluation of

periorbital hemangiomas. Am J Ophthalmol 140(2):

314-6, 2005.

15. Abraham FA, Melamed E, Lavy S. Prognostic Value of

Visual Evoked Potentials in Occipital Blindness follo-

wing Basilar Artery Occlusion. Appl Neurophysiol 38:

126-135, 1975.

Introduction

Argon-Laser photocoagulation is a significant

method for the management of retinal tears and

the prevention of retinal detachment. Our purpose

was to assess the management of patients with reti-

nal tears that were treated with argon-Laser pho-

tocoagulation by residents in Ophthalmology in

the setting of AHEPA University Hospital.

Materials and Methods

12 patients with a mean age of 65 years old were in-

cluded in the study. 7 patients (60%) had undergone

cataract surgery in the past (pseudophakic). All the pa-

tients complained of flashes (photopsia) as the primary

symptom. Following the slit lamp examination, a retinal

tear was detected in the superior temporal quadrant in 8

patients (70%), in the superior nasal quadrant in 3 pa-

tients (25%) and in another location in 1 patient (5%).

Results

The detected retinal tears were treated with

Argon-Laser photocoagulation and the patients

were all re-examined between 2 and 7 weeks after

treatment. After 1 year period, the following com-

plications were detected: intravitreous hemorrha-

ge in 1 patient (Fig. 1), which was absorbed in a pe-

Ophthalmologia, 22, 1 : 35 - 37, 2010

Management of patients with retinal tears treatedwith Argon-Laser photocoaculation

in a Greek referral center

E. Kanonidou, A. Praidou, V. Konidaris, P. Zotta, A-K. D. Alexandridis

1st Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

Argon-Laser photocoagulation is a significant method forthe management of retinal tears and the prevention ofretinal detachment. Our purpose was to assess the ma-nagement of patients with retinal tears that were treatedwith argon-Laser photoagulation by residents in Ophthal-mology in the setting of AHEPA University Hospital.

∏ Laser ʈÙÔËÍ›· ·ÔÙÂÏ› ÌÈ· ηٷÍȈ̤ÓË ÂÂÌ-‚·ÙÈ΋ ̤ıÔ‰Ô Ô˘ Ú·ÁÌ·ÙÔÔÈÂ›Ù·È Ì ÛÙfi¯Ô ÙËÓ Â-Úȯ·Ú¿ÎˆÛË ·ÌÊÈ‚ÏËÛÙÚÔÂȉÈÎÒÓ ÚˆÁÌÒÓ Î·È ÙËÓ ·Ô-ÙÚÔ‹ ·ÔÎfiÏÏËÛ˘ ·ÌÊÈ‚ÏËÛÙÚÔÂȉԇ˜. ™ÎÔfi˜ Ù˘ÌÂϤÙ˘ Â›Ó·È Ó· ·ÍÈÔÏÔÁËı› Ë ÔÚ›· ·ÛıÂÓÒÓ ÛÙÔ˘˜ÔÔ›Ô˘˜ ‰È·ÁÓÒÛÙËΠڈÁÌ‹ ·ÌÊÈ‚ÏËÛÙÚÔÂȉԇ˜ ÛÙÔÈ·ÙÚÂ›Ô ÂÊËÌÂÚ›·˜ ÙÔ˘ ÓÔÛÔÎÔÌ›Ԣ Ì·˜ Î·È ·ÓÙÈÌÂÙˆ-›ÛÙËΠ̠Argon-Laser ʈÙÔËÍ›·.

¶·Ú·ÎÔÏÔ‡ıËÛË ÔÚ›·˜ ·ÛıÂÓÒÓ Ì ·ÌÊÈ‚ÏËÛÙÚÔÂȉÈ΋ ÚˆÁÌ‹ Ô˘ ·ÓÙÈÌÂÙˆ›ÛÙËηÓÌ Argon-Laser ʈÙÔËÍ›· ÛÙÔ È·ÙÚÂ›Ô ÂÊËÌÂÚ›·˜

Ù˘ OÊı·ÏÌÔÏÔÁÈ΋˜ KÏÈÓÈ΋˜ ÙÔ˘ ¡ÔÛÔÎÔÌ›Ԣ Ì·˜∂. ∫·ÓÔÓ›‰Ô˘, ∞. ¶Ú·˝‰Ô˘, μ. ∫ÔÓȉ¿Ú˘, ¶. ∑ÒÙÙ·, ∞-∫. ¢. ∞ÏÂÍ·Ó‰Ú›‰Ë˜

Clinical and laboratory studiesEditor: N. Georgiadis

e-mail: gnick@med.auth.gr

riod of time less than a month and macular pucker

in another one (Fig, 2, 3)

Conclusions

The results of the management of retinal tears

treated with argon-Laser photocoagulation by

young ophthalmologists at the Outpatients Oph-

thalmology Department of our hospital during the

period of the follow up are considered satisfactory.

Discussion

Retinal tears appear as discontinuities in the

retinal surface resulting from dynamic vitreoretinal

traction. They may develop at sites with strong vi-

treoretinal adhesions, especially the vitreous base.

They may also be associated with underlying weak-

ness in the peripheral retina, referred as predispo-

sing degeneration, such as lattice degeneration. As

the vitreous attachments around the margins of the

lattice degeneration are strong, the tractions deve-

loped during posterior vitreous detachment may

lead to a retinal tear.

The most common pathogenetic mechanism

of retinal tears is related with the posterior retinal

detachment procedure. Some eyes with liquefacti-

on of the vitreous gel develop a hole in the poste-

rior hyaloid membrane, through which fluid from

the centre of the vitreous cavity passes into the

newly formed retrohyaloid space and leads to a de-

tachment of the sensory retina from the pigment

epithelium. The symptoms related with retinal te-

ars are photopsia and floaters due to the dynamic

vitreoretinal traction.

The vast majority of retinal tears are found in

patients with no predisposing conditions. However,

it has been postulated that a number of systemic

conditions such as Marfan syndrome, Ehlers-Dan-

los syndrome and homocystinuria as well as a num-

ber of ocular conditions such as Wagner’s heredi-

tary vitreoretinal degenerations, Stickler syndro-

me and the liquefaction and posterior detachment

of the vitreous gel may lead to the development of

retinal tears1.

Argon-Laser was invented in 1964 and was pri-

marily used in chorioretinal photocoagulation in la-

te 1960’s. It was firstly applied in human retina from

L’Esperance in 19682. It is widely used for the mana-

gement of choroidal neovascularisation associated

with age related macular degeneration, ocular hi-

stoplasmosis and idiopathic neovascularisation. The

main aim of its application is to diminish the visual

loss danger3. It is also applied in patients with diabe-

36 Ophthalmologia, 22, 1 (2010)

Fig. 1. Intravitreous hemorrhage in a patient with retinaltear treated with Argon-Laser photocoagulation.

Fig. 2. Macular pucker developed in a patient with retinaltear treated with Argon-Laser photocoagulation (fun-dus image).

Fig. 3. Macular pucker developed in a patient with retinaltear treated with Argon-Laser photocoagulation (opti-cal coherence tomography image).

Ophthalmologia, 22, 1 (2010) 37

tic retinopathy in pan-retinal photocoagulation.

Full thickness defects in the sensory retina such

as retinal holes or tears consist a predisposing con-

dition for retinal detachment. In elderly patients or

in patients suffering from myopia or pheudophacic

patients, retinal detachment is effectively treated

with argon laser, in the absence of significant proli-

ferative vitreoretinopathy or opacities of the media.

Argon green (wave length 514,5 nm) and argon

blue-green (wave length 488,0 nm) laser are mainly

used for the management of retinal tears in every-

day clinical practice. It has been found that the ma-

nagement of retinal tears with argon-laser photoco-

agulation prevents the development of the retinal

detachment in 90% of the cases6,7.

References

1. Greven CM. Retinal breaks. In: Yanoff M, Duker JS

(Ed): Ophthalmology, 2nd ed., pp: 978-980, Mosby, St

Louis, 2004.

2. L’Esperance FA Jr. An ophthalmic argon laser photoco-

agulation system: design, construction and laboratory

investigations. Trans Am Ophthalmol Soc 66: 827-

904, 1968.

3. Macular Photocoagulation Study Group: Argon laser pho-

tocoagulation for neovascular maculopathy. Three-

year results from randomized clinical trials. Arch

Ophthalmol 104: 694-701, 1986.

4. The Diabetic Retinopathy Study Research Group: Photo-

coagulation treatment of proliferative diabetic retino-

pathy. Clinical application of Diabetic Retinopathy

Study (DRS) findings (report no. 8). Ophthalmology

88: 583-600, 1981.

5. Little HR. Treatment of proliferative diabetic retinopa-

thy. Long-term results of argon laser photocoagu-

lation. Ophthalmology 92: 279-283, 1985.

6. Newell FW. Retinal detachment. In: Newell FW (Ed):

Ophthalmology: Principles and Concepts, 6th ed, pp:

338-341, Mosby, St Louis, 1986.

7. L’Esperance FA. Peripheral retinal structural abnorma-

lities. In: L’Esperance (Ed): Ophthalmic Lasers, 3rd

ed., pp: 291-297, 302-308, Mosby, St Louis, 1989.

Ophthalmologia, 22, 1 : 38 - 42, 2010

Bilateral papilledema in Chiari I malformation

∞. Praidou1, ∂. Kanonidou1, V. Konidaris1, S. Maloutas1,D. Paraskevopoulos2, I. Magras1,2, K. Boboridis1

1 1st Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece 2 Neurosurgical Department, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece

Purpose: To present a case of Chiari I malformation andbilateral papilledema, that was resolved after neurosur-gical decompression. Materials and Methods: A femalepatient aged 16 years old complained about headachessince 8 months, progressively worsening in duration andmagnitude, accompanied by ear noises. The initial visualacuity was 9-10/10 unaided bilateral, the visual fields exa-mination was performed and bilateral papilledema wasdetected at fundus examination. Cranial magnetic re-sonance imaging (MRI) was performed and herniation ofthe cerebellar tonsils below the foramen magnum wasfound. Results: The patient underwent suboccipital de-compression surgery. Resolution of signs and symptomsof increased intracranial pressure was followed and im-provement of bilateral papilledema was detected. Con-clusions: Chiari I malformation is a congenital malforma-tion of the hindbrain manifesting as herniation of the cere-bellar tonsils below the foramen magnum. Patients maybenefit from suboccipital decompression because of re-solution of signs and symptoms of increased intracranialpressure and bilateral papilledema following the surgicalintervation.

™ÎÔfi˜: ∏ ·ÚÔ˘Û›·ÛË ÂÚÈÛÙ·ÙÈÎÔ‡ Ì ۇӉÚÔÌÔChiari Ù‡Ô˘ I Î·È ·ÌÊÔÙÂÚfiÏ¢ÚÔ Ô›‰ËÌ· ÔÙÈÎÒÓ Ó‡-ÚˆÓ, Ô˘ ˘Ô¯ÒÚËÛ ÌÂÙ¿ ·fi ÙËÓ ·ÔÛ˘ÌÈÂÛÙÈ΋ Ó¢-ÚÔ¯ÂÈÚÔ˘ÚÁÈ΋ ¤̂·ÛË. ÀÏÈÎfi Î·È ª¤ıÔ‰Ô˜: ∞ÛıÂ-Ó‹˜ ËÏÈΛ·˜ 16 ÂÙÒÓ ·ÈÙÈ¿Ù·È ·fi 8 Ì‹ÓÔ˘ ÂÂÈÛfi‰È· ÎÂ-Ê·Ï·ÏÁ›·˜ ÌÂوȷ›· Î·È ÈÓÈÔ·˘¯ÂÓÈο, ÚÔԉ¢ÙÈο ÂÈ-‰ÂÈÓÔ‡ÌÂÓ· Û ¤ÓÙ·ÛË Î·È ‰È¿ÚÎÂÈ·, ÌÂ Û˘ÓÔ‰¤˜ ÂÌ‚Ô¤˜ˆÙÒÓ. ∏ ·Ú¯È΋ ÔÙÈ΋ Ô͇ÙËÙ· ‹Ù·Ó 9-10/10 ¯ˆÚ›˜ ‰ÈfiÚ-ıˆÛË ·ÌÊÔÙÂÚfiÏ¢ڷ, ¤ÁÈÓ·Ó ÔÙÈο ‰›· Î·È ‚˘ıÔ-ÛÎÔÈο ·Ó¢ڤıËΠ·ÌÊÔÙÂÚfiÏ¢ÚÔ Ô›‰ËÌ· ÔÙÈÎÒÓÓ‡ڈÓ. ∞fi ÙË Ì·ÁÓËÙÈ΋ ÙÔÌÔÁÚ·Ê›· ÂÁÎÂÊ¿ÏÔ˘ (MRI)‚Ú¤ıËΠ¯·ÌËÏ‹ ı¤ÛË ÙˆÓ ·Ì˘Á‰·ÏÒÓ Ù˘ ·ÚÂÁÎÂÊ·-Ï›‰·˜, Ô˘ ÚÔ‚¿ÏÏÔ˘Ó ÛÙÔ ‡„Ô˜ ÙÔ˘ Ô‰fiÓÙÔ˜, ‰È·Ì¤-ÛÔ˘ ÙÔ˘ ÈÓÈ·ÎÔ‡ ÙÚ‹Ì·ÙÔ˜ Î·È ÌÈÎÚfi˜ Ô›ÛıÈÔ˜ ÎÚ·ÓÈ·Îfi˜‚fiıÚÔ˜. ∞ÔÙÂϤÛÌ·Ù·: ∏ ·ÛıÂÓ‹˜ ˘Ô‚Ï‹ıËΠ۠¯ÂÈ-ÚÔ˘ÚÁÈ΋ ¤̂·ÛË ˘ÈÓȷ΋˜ ÎÚ·ÓÈÂÎÙÔÌ›·˜, ·ÔÛ˘-Ì›ÂÛ˘ ÈÓÈ·ÎÔ‡ ÙÚ‹Ì·ÙÔ˜ Î·È ÂÍ·›ÚÂÛË ÙÔ˘ ÔÈÛı›Ô˘ Ùfi-ÍÔ˘ ÙÔ˘ ∞1 ÛÔÓ‰‡ÏÔ˘ Î·È ËÏÂÎÙÚÔη˘ÙËÚÈ·ÛÌfi ÙˆÓ Â-Ù¿ÏˆÓ Ù˘ ·ÚÂÁÎÂÊ·Ï›‰·˜. ∞ÎÔÏÔ‡ıËÛ ˘Ô¯ÒÚËÛËÙˆÓ Û˘ÌÙˆÌ¿ÙˆÓ Î·È Â˘ÚËÌ¿ÙˆÓ ·˘ÍË̤Ó˘ ÂÓ‰ÔÎÚ¿ÓÈ-·˜ ›ÂÛ˘ Î·È ‚˘ıÔÛÎÔÈο ‚ÂÏÙ›ˆÛË ÙÔ˘ Ôȉ‹Ì·ÙÔ˜ ÙˆÓÔÙÈÎÒÓ Ó‡ڈÓ. ™˘ÌÂÚ¿ÛÌ·Ù·: ΔÔ Û‡Ó‰ÚÔÌÔ ChiariÙ‡Ô˘ I Â›Ó·È Û˘ÁÁÂÓ‹˜ ·ÓˆÌ·Ï›· ÙÔ˘ ÔÈÛı›Ô˘ ÂÁÎÂÊ¿-ÏÔ˘, Ô˘ ÂΉËÏÒÓÂÙ·È Ì ÚÔ‚ÔÏ‹ ÙˆÓ ·Ì˘Á‰·ÏÒÓ Ù˘·ÚÂÁÎÂÊ·Ï›‰·˜ οو ·fi ÙÔ ÈÓÈ·Îfi ÙÚ‹Ì·. OÈ ·ÛıÂÓ›˜˘Ô‚¿ÏÏÔÓÙ·È Û ˘ÈÓȷ΋ ·ÔÛ˘ÌÈÂÛÙÈ΋ ¤̂·ÛË Ì·ÔÙ¤ÏÂÛÌ· ÙËÓ ˘Ô¯ÒÚËÛË ÙÔ˘ Ôȉ‹Ì·ÙÔ˜ ÙˆÓ ÔÙÈÎÒÓÓ‡ڈÓ, fiˆ˜ ›Û˘ Î·È ÙˆÓ ˘ÔÏÔ›ˆÓ ¢ÚËÌ¿ÙˆÓ Î·ÈÛ˘ÌÙˆÌ¿ÙˆÓ ·˘ÍË̤Ó˘ ÂÓ‰ÔÎÚ¿ÓÈ·˜ ›ÂÛ˘.

AÌÊÔÙÂÚfiÏ¢ÚÔ Ô›‰ËÌ· ÔÙÈÎÒÓ ÓÂ‡ÚˆÓ Û ۇӉÚÔÌÔ Chiari Ù‡Ô˘ π∞. ¶Ú·˝‰Ô˘, ∂. ∫·ÓÔÓ›‰Ô˘, μ. ∫ÔÓȉ¿Ú˘, ™. ª·ÏÔ‡Ù·˜,

¢. ¶·Ú·Û΢fiÔ˘ÏÔ˜, π. ª¿ÁÚ·˜, ∫. ªÔÌÔÚ›‰Ë˜

Cases reportsEditor: ¡. Papadopoulos

e-mail: papado@med.auth.gr

Introduction

Chiari’ syndrome, type I, is a congenital mal-

formation of the hindbrain manifested with he-

rniation of the cerebellar tonsils below the foramen

magnum1,2. The frequency of the syndrome rea-

ches 1-2 in 1000 births. The first detailed descri-

ption was made in Prague in 1891 and 1896 by Chi-

ari, while at the same time in 1894, in Heidelberg,

Arnold described the herniation of the medulla ob-

longata through the foramen magnum. The her-

niation of the cerebellar tonsils is considered pa-

thological when there is a displacement exceeding

5 mm below the foramen magnum2. Very often

other abnormalities of the adjacent bone and neu-

ral structures and also syringomyelia2 are observed.

Symptoms may appear in childhood, early a-

dulthood and later on, with an increasing frequency

in third and fourth decade1-4. The most common

symptoms of Chiari I malformation are headache

and pain, weakness and paresthesias of the extre-

mities. Often, the only symptom is irritability while

in many cases the herniation of the cerebellar tonsils

is asymptomatic. Clinical findings of the syndrome

include numbness, muscular weakness, spasticity,

gait abnormalities, gallbladder and bowel dysfun-

ction. Neuroophthalmologic indications associated

with Chiari I malformation consist of ocular motili-

ty disorders that include downbeat nystagmus, pare-

sis of cranial nerve VI, convergence or divergence

palsy and esotropia9, symptoms that are reduced

importantly after the decompressive surgery. Pa-

tients with Chiari I malformation, if left untreated,

may develop hydrocephalus. Papilledema has been

associated with Chiari I malformation, without how-

ever establishing its causal pathogenesis11. In those

patients papilledema can mimic the clinical picture

of pseudotumor cerebri (PTC) 2,12.

Chiari I malformation can be treated surgical-

ly and particularly with suboccipital decompression

which opens the outlet of the fourth ventricle, nor-

malizing the craniospinal pressure and the cere-

brospinal fluid flow on either side of foramen mag-

num; this results to the remission of the papillede-

ma and the other symptoms of elevated intracra-

nial pressure2,13.

Because of the problems regarding Chiari I

malformation pathogenesis, the thorough study of

each case is interesting, since it is possible to con-

tribute to the diagnosis of the causal pathogenesis,

the clinical course and the early complications of

the syndrome to the functionality of the central

nerve system and the patient’s viability. The pur-

pose of the present study is the presentation of a

case of Chiari I malformation and bilateral papil-

ledema that showed remission after the decom-

pressive neurosurgery.

Case report

A 16-year-olds patient was referred for ophthalmo-

logic examination in the university ophthalmologic clin-

ic of AHEPA Hospital, while she was inpatient in the

neurosurgery department of the same hospital. The pa-

tient was complaining for headaches in the frontal and

occipitocervical area, which worsened in magnitude and

duration with accompanying tinnitus. The patient re-

ported also weakness and numbness in the upper ex-

tremities, gait instability and balance disorder. The pa-

tient’s past medical history was normal.

The clinical examination showed: height 1.75 m,

weight 80 kgr and blood pressure (BP) 140/80 mmHg.

The ophthalmologic examination revealed that the ini-

tial unaided visual acuity was 9-10/10 in both eyes and

color vision using the Ishihara pseudoisochromatic color

plates was normal. The examination of the visual fields

showed inferior arcuate scotoma bilaterally. The pupil-

lary reflexes, the ocular motility and the slit-lamp exami-

nation were normal. Fundoscopy showed bilateral pa-

pilledema (Fig. 1,2). The neurological examination sho-

wed neck pain while bending and reported inability to

raise the head occasionally (head drop attacks), while

Lhermitte’s sign was negative. Furthermore the patient

had full-range motility of the upper and lower extre-

mities.

The patient was referred for complete laboratory

tests that included: full blood count, biochemical and

hormonological test. Imaging tests included: cranial CT

and MRI, spinal column MRI and thorax X-ray. The

cranial MRI revealed the low position of the cerebellar

tonsils projecting in the level of the toothed vertebra,

through the foramen magnum and small posterior cra-

nial fossa (Fig. 3,4); findings indicating Chiari I malfor-

mation. Accompanying MRI findings were: small-sized

fourth ventricle, stenosis of Sylvius aqueduct, hydroce-

phalus above the aqueduct and dilation of the third ven-

tricle.

The patient underwent suboccipital craniectomy,

decompression of the foramen magnum and exclusion of

the posterior arch of the first cervical vertebra (C1) and

electrocauterization of the cerebellar lamina. Postope-

ratively a comparative imaging examination was perfor-

med (Fig. 5-8). The remission of the symptoms of high

intracranial pressure followed, along with the gradual

improvement of the headaches and the balance disor-

Ophthalmologia, 22, 1 (2010) 39

40 Ophthalmologia, 22, 1 (2010)

Fig. 1, 2. Bilateral papilledema in patient with Chiari I malformation.

Fig. 3, 4. Pre-operative cranial MRI, sagitall (left) and coronal (right) view, with herniation of the cerebellar tonsils on theforamen magnum.

Fig. 5, 6. Post-operative cranial CT-scans, transversal view, where the exclusion of the posterior arch of first cervicalvertebra (C1) and part of the suboccipital craniectomy are shown.

Ophthalmologia, 22, 1 (2010) 41

ders. Furthermore, the fundoscopy showed improve--

ment of the papilledema (Fig. 9,10), and gradual im-

provement was noticed in the visual fields test while the

visual acuity and color vision were normal.

Discussion

Milhorat and associates reported the clinical

findings in 364 patients with Chiari I malformation

symptoms. Among these patients, nine (2%) had

papilledema. Seven of the nine patients had nor-

mal-sized ventricles without indications of hydro-

cephalus in the cranial MRI11.

The mechanism for the increase of the intra-

cranial pressure in patients with Chiari I malfor-

mation is not completely understood. Heiss and as-

sociates reported that the restoration of the intra-

cranial pressure normal value is due to the reha-

bilitation of the anatomic obstacles in the foramen

magnum that occlude partially the subarachnoid

area in the foramen magnum functioning in that

way as an embolus for the partially obctructed su-

barachnoid space of the spinal cord. As it has been

reported in other studies, the intracranial pressure

returns to normal values after the suboccipital de-

compressive surgery 14.

In conlusion, the papilledema is a rare mani-

festation of Chiari I malformation and may mimic

pseudotumor cerebri (idiopathic intracranial hy-

pertension)2. The patients with symptompatology

similar to the malformation are recommended to

undergo a cranial MRI to reach a diagnosis. The

suboccipital decompressive surgery can consist a

selection treatment and prevent the appearance of

complications (hydrocephalus,etc.) in patients with

elevated intracranial pressure and papilledema in

the frame of Chiari I malformation2.

Fig. 9, 10. Post-operative improvement of papilledema.

Fig. 7. Post-operative cranial CT-scan, transversal view, ina parenchyma window CT.

Fig. 8. Post-operative cranial MRI (sagittal view) that showsthe foramen magnum decompressed and free of signs.

42 Ophthalmologia, 22, 1 (2010)

References

1. Barkovich AJ, Wippold FJ, Sherman JL, Citrin CM. Signi-

ficance of cerebellar tonsillar position on MR. AJNR

Am J Neuroradiol. 7: 795-799, 1986.

2. Vaphiades MS, Eggenberger ER, Miller NR, Frohman L,Krisht A. Resolution of papilledema after neurosurgi-

cal decompression for primary Chiari I malformation.

Am J Ophthalmol 133: 673-678, 2002.

3. Cai C, Oakes WJ. Hindbrain herniation syndromes: the

Chiari malformations (I and II). Semin Pediatr Neu-

rol 4: 179-191, 1997.

4. Meadows J, Kraut M, Guarnieri M, Haroun RI, Carson BS.Asymptomatic Chiari I malformations identified on

magnetic resonance imaging. J Neurosurg. 92: 920-

926, 2000.

5. Paul KS, Lye RH, Strang FA, Dutton J. Arnold–Chiari

malformation. Review of 71 cases. J Neurosurg. 58:

183-187, 1983.

6. Elster AD, Chen MYM. Chiari I malformations: Clinical

and radiologic reappraisal. Radiology 183: 347–353,

1992.

7. Pedersen RA, Troost BT, Abel LA, Zorub D. Intermittent

downbeat nystagmus and oscillopsia reversed by su-

boccipital craniectomy. Neurology 30: 1239-1242,

1980.

8. Lewis AR, Kline LB, Sharpe JA. Acquired esotropia due

to Arnold–Chiari I malformation. J Neuro-ophthal-

mol 16: 49-54, 1996.

9. Weeks CL, Hamed LM. Treatment of acute comitant es-

otropia in Chiari I malformation. Ophthalmology 106:

2368-2371, 1999.

10. Welch K, Shillito J, Strand R, Fischer EG, Winston KR.Chiari I “malformations”—an acquired disorder? J

Neurosurg 55: 604-609, 1981.

11. Milhorat TH, Chou MW, Trinidad EM, et al. Chiari I

malformation redefined: clinical and radiographic fin-

dings for 364 symptomatic patients. Neurosurgery 44:

1005-1017, 1999.

12. Smith JL. Whence pseudotumor cerebri? J Clin Neuro-

ophthalmol 5: 55-56, 1985.

13. Sakamoto H, Nishikawa M, Hakuba A, Yasui T, KitanoS, Nakanishi N, Inoue Y. Expansive suboccipital cra-

nioplasty for the treatment of syringomyelia associa-

ted with Chiari malformation. Acta Neurochir. 141:

949-961, 1999.

14. Heiss JD, Patronas N, DeVroom HL, et al. Elucidating

the pathophysiology of syringomyelia. J Neurosurg.

91: 553-562, 1999.

Introduction

The Vogt-Koyanagi-Harada (VKH) syndro-

me is an idiopathic, multisystem (affecting the u-

vea, skin, ears, meninges) systematic autoimmune

condition against melanocyte-containing tissues. It

is actually considered to be an autoimmune disease

to melanin having MHC class II (CD4 Th cells)

and HLA DR4 locus which contains 19 alleles lo-

cated in DRB1 site to be associated with the con-

ditionl2.

The VHK syndrome characteristics include

granulomatous uveitis, as well as attendant neuro-

logical and auditory clinical signs. The first descri-

ption of poliosis (bleaching) of eyelashes and eye-

brows in combination with ocular inflammation is

dated from the 10th century in the Persia. First, Ba-

bel in 1932 observed that certain unpublished de-

scriptions by Vogt (1906), Harada (1926) and Koy-

anagi (1929) are actually constituting varieties of

the same nosologic entity, that was named by him

as Vogt – Koyanagi – Harada disease1. The VKH

disease offends mainly black a-vised races as

Asians, American and native Indians and it is not

common in Caucasians.

The prevalence of the VKH syndrome varies

worldwide, however, the majority of studies show

us that is responsible for the 8% of all uveitis2,4. It

Ophthalmologia, 22, 1 : 43 - 46, 2010

Diagnostic dilemmas in Vogt Koyanagi Harada Syndrome

N. Papadopoulos, T. Empeslidis, D. Papadopoulou, G. Magioris, S. Androudi

1st Department of Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece

Purpose: To present rare case of typical Vogt-Koyanagi-Harada disease (VKH) and we explore the various dia-gnostic dilemmas. Methods: A 39 years old woman ofLatin-American origin (Saint Dominikos) presented her-self at the emergencies department of the A′ UniversityOphthalmology Clinic of A.H.E.P.A Hospital complaing ofbilateral sadden visual loss. Slit lamp examination disclo-sed bilateral severe iridocyclitis and bilateral multifocalserous detachments of the retina. There were concommi-tant characteristic coetaneous skin blisters with white ha-los in the upper limbs. Results: The results of the inve-stigation were consistent of the uveal-meningitic syndro-me, Vogt-Koyanaki-Harada. Conclusion: The pathoge-nesis of VKH is thought to be related to an aberrant T cell-mediated immune response directed against self-an-ti-gens found on melanocytes. VKH has been linked to hu-man leukocyte antigen DR4 (HLA-DR4) and HLA-Dw53,with strongest associated risk for HLA-DRB1*0405 hap-lotype.

™ÎÔfi˜. ¶·ÚÔ˘Û›·ÛË ÂӉȷʤÚÔÓÙÔ˜ ÂÚÈÛÙ·ÙÈÎÔ‡·ÛıÂÓÔ‡˜ Ô˘ ¿Û¯ÂÈ ·fi Vogt-Koyanagi-Harada Î·È·Ó¿Ï˘ÛË Ù˘ ‰È·ÊÔÚÈ΋˜ ‰È¿ÁÓˆÛ˘. ª¤ıÔ‰Ô˜. °˘Ó·›Î·39 ÂÙÒÓ ·fi ÙÔÓ ÕÁÈÔ ¢ÔÌ›ÓÈÎÔ ÚÔÛ‹Ïı ÛÙ· ›ÁÔÓÙ·Ù˘ ∞′ ¶·ÓÂÈÛÙËÌȷ΋˜ ÎÏÈÓÈ΋˜ ÙÔ˘ ÓÔÛÔÎÔÌ›Ԣ ∞Ã∂¶∞Ì ·ÌÊÔÙÂÚfiÏ¢ÚË ·ÒÏÂÈ· fiÚ·Û˘. ∫·Ù¿ ÙËÓ ÎÏÈÓÈ΋ÂͤٷÛË ‰È·ÈÛÙÒıËΠÈÚȉÔ΢ÎÏ›Ùȉ·, ·ÓÙ›‰Ú·ÛË ÚÔÛı›-Ô˘ ı·Ï¿ÌÔ˘ Î·È ÔÚÒ‰ÂȘ ·ÔÎÔÏÏ‹ÛÂȘ ·ÌÊÈ‚ÏËÛÙÚÔÂÈ-‰Ô‡˜. ∂Í·Óı‹Ì·Ù· ̠Ϣ΋ ¿Ïˆ ·Ú·ÙËÚ‹ıËÎ·Ó ÛÙÔ‰¤ÚÌ· ÛÙ· ¿ÎÚ·. ∞ÔÙÂϤÛÌ·Ù·. ∏ ·ÛıÂÓ‹˜ ˘Â‚Ï‹ıËÛ ϋÚË ÂÚÁ·ÛÙËÚÈ·Îfi, ‚ÈÔ¯ËÌÈÎfi, ·ÓÔÛÔÏÔÁÈÎfi ¤ÏÂÁ¯ÔÔ˘ ‹Ù·Ó ·ÚÓËÙÈÎfi˜, Ì ‚¿ÛË ÙÔ ÈÛÙÔÚÈÎfi Î·È ÙÔÓ ÎÏÈÓÈÎfi¤ÏÂÁ¯Ô Ë ‰È¿ÁÓˆÛË Â›Ó·È Û‡Ó‰ÚÔÌÔ Vogt-Koyanaki-Harada. ™˘˙‹ÙËÛË. ∏ ·ıÔÁ¤ÓÂÈ· ÙÔ˘ Û˘Ó‰ÚfiÌÔ˘ Vogt-Koyanaki-Harada Û¯ÂÙ›˙ÂÙ·È Ì ÙËÓt T ÏÂÌÊÔ΢ÙÙ¿ÚˆÓ·ÓÔÛÔÔÈËÙÈ΋ ·ÓÙ›‰Ú·ÛË Î·Ù¿ ÈÛÙÒÓ Ô˘ ÂÚȤ¯Ô˘Ó ÌÂ-Ï·Ó›ÓË.(ÌÂÏ·ÓÔ·ÙÙ·Ú·). ΔÔ VKH Û‡Ó‰ÚÔÌÔ ¤¯ÂÈ Ï¢ÎÔ-·ÙÙ·Ú· ηٿ ·ÓÙÈÁfiÓÔ˘ DR4 (HLA-DR4) Î·È HLA-Dw53,Î·È ÛÙÂÓ‹ Û¯¤ÛË Ì ÙÔ ·ÏfiÙ˘Ô HLA-DRB1*0405.

¢È·ÊÔÚÈ΋ ‰È¿ÁÓˆÛË ÛÙÔ Vogt-Koyanagi-Harada Û‡Ó‰ÚÔÌÔN. ¶··‰fiÔ˘ÏÔ˜, £. ∂ÌÂÛÏ›‰Ë˜, ¢. ¶··‰ÔÔ‡ÏÔ˘, °. ª·ÁÎÈÒÚ˘, ™. ∞Ó‰ÚÔ‡‰Ë

is reported, also, that in Brazil it appears to be the

main cause of autoimmune non-inflammatory u-

veitis4,6. However, in the United States of America

the percentage varies between 1% and 4% of the

reported uveitis7. The disease usually affects pati-

ents of the age group between 20 and 50 years old.

There have been several cases reported in child-

ren8. The majority of studies reports a higher inci-

dence of the syndrome among the women rather

than men9,10, but in Japanese studies that has not

been confirmed11,12.

Methods

A 39 year old female patient presented herself at

the emergency ophthalmology department of our clinic

suffering from bilateral visual reduction. On slit lamp

examination it was found an intense anterior chamber

reaction (++++). Her best corrected visual acuity was

R. E. 3/10 (+ 4sph) and on her left eye was (L.E.) 4/10

(+4sph). Bilateral iridocyclitis and serous retinal de-

tachments were documented during her admission to

our ward. The patient was having coetaneous exan-

themas (see pic. 1) in her legs and hands as well. From

the history it was elicited vision disturbance a month pri-

or coming to us, and hearing difficulties at around the

same time.

One day following her admission her bilateral vi-

sion was reduced to finger counting. The patient un-

derwent the following investigations:

Full blood count, liver function tests, Na, K, serum

tests of blood and CFS analysis (IgG, IgA, IgM, C3,C4),

CRP, ANA, ANCA, Anti-DNA, ENA, HLA identifi-

cation, biopsy of the skin, OCT of the eye and FFA (flu-

orescein angiography), Brain and adnexa CT scan.

There were no abnormalities detected.

Results

The differential diagnoses of the patient’s con-

dition included:

Sarcoidosis, CRS (central serous retinopathy),

metastatic carcinoma of the choroids, uveal effu-

sion syndrome, posterior scleritis, eclampsia.

There were no investigation results linking the

above mentioned diseases and therefore the dia-

gnosis had to be on the basis of the clinical findings

taking into consideration the patient’s medical his-

tory and place of origin.

The patient’s reported history of hearing dif-

44 Ophthalmologia, 22, 1 (2010)

Fig. 1. a) The characteristic exanthema in VKH with thesurrounding halo b) Multiple follicles with halos. Figure 2

ficulties, the skin rashes and the eye findings in-

cluding the anterior and posterior segment of the

eye involment concluded that the diagnosis of

VKH disease as a rare case in our region has a sub-

stantial ground.

The patient was treated with oral steroids with

doses initially high 1mg/kg and azathioprine was

added few days following her admission 2 tablets of

50mg per day. The patient was regularly assessed at

our clinic and her visual acuity improved to 5-6/10

in the right eye and 5/10 in the left. Currently the

patient is on 8 mg maintenance dose of steroids

and azathioprine 50 mg. Any complications of the

syndrome can be treated accordingly.

Discussion

The VKH is a granulomatous condition affe-

cting other parts of the body as well as the eyes. As

clinicians based at a very busy university hospital

we have to be alerted on patients presenting with

bilateral visual loss, and a detailed family and medi-

cal history is of paramount importance. The pati-

ent’s place of origin can give us some diagnosis di-

rection as well.

Furthermore the presence of signs and sym-

ptoms from other organs of the patient’s body play

a significant role in the final diagnosis of the condi-

tion. In our case the hearing disturbance in accor-

dance with the skin findings gave us a strong dia-

gnostic profile of a disease affecting the melanin in

the melanocytes and subsequently helped the most

in the diagnosis. Our investigation should focus on

the diseases that is likely the patient can suffer and

avoid unnecessary ones. In cases where we don’t ha-

ve retinal serous detachments the differential dia-

gnosis from sarcoidosis can be difficult. The Chest

X-ray and the AME in blood is very helpful. Ultra-

sound and the loud symptoms of pain can help us

in the differential diagnosis from posterior scleritis.

As in all the autoimmune conditions our treat-

ment options are rather limited. In our case the pa-

tient responded well on steroids

References

1. Pattison EM. Uveomeningoencephalitic syndrome (Vogt-

Koyanagi-Harada). Arch Neurol 12: 197-205, 1965.

2. Sugiura S. Vogt-Koyanagi-Harada disease. Jpn J Oph-

thalmol 22: 9-35, 1978.

3. Kotake S, Furudate N, Sasamoto Y, Yoshikawa K, Goda C,Matsuda H. Characteristics of endogenous uveitis in

Hokkaido, Japan. GraefesArch Clin Exp Ophthalmol

235: 5-9, 1997.

4. Read RW. Vogt-Koyanagi-Harada disease. Ophthalmol

Clin NorthAm 15: 333-41, 2002.

5. Gomi CF, Makdissi FF, Yamamoto JH, Olivalves E. [An

epidemiologic study on uveitis.] Rev Med (Sas o

Paulo) 76 101-8, 1997.

6. Fernandes LC, Orewfice F. [Clinical and epidemiological

aspects of uveitis in reference services from Belo Ho-

rizonte, from 1970 to 1993.] Part II. Rev Bras Oftal 55:

19-32, 1996.

7. Snyder DA, Tessler HH. Vogt-Koyanagi-Harada syndro-

me. AmJ Ophthalmol 90: 69-75, 1980.

8. Cunningham ET Jr, Demetrius R, Frieden IJ, Emery HM,Irvine AR, Good WV. Vogt-Koyanagi-Harada syndro-

me in a 4-year old child. Am J Ophthalmol 120: 675-

7, 1995.

9. Nussenblatt RB. Clinical studies of Vogt-Koyanagi-Hara-

da’s disease at the National Eye Institute, NIH, USA.

Jpn J Ophthalmol 32: 330-3, 1988.

10. Rubsamen PE, Gass JD. Vogt-Koyanagi-Harada syndro-

me. Clinical course, therapy, and long-term visual out-

come. Arch Ophthalmol 109: 682-7, 1991.

11. Ohno S, Minakawa R, Matsuda H. Clinical studies of

Vogt-Koyanagi-Harada’s disease. Jpn J Ophthalmol

32: 334-43, 1988.

12. Sasamoto Y, Ohno S, Matsuda H. Studies on corticoste-

roid therapy in Vogt-Koyanagi-Harada disease. Oph-

thalmologica 201: 162-7, 1990.

13. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,Arellanes-Garcia L, Pivetti-Pezzi P, Tessler HH, Usui M.

Revised diagnostic criteria for Vogt-Koyanagi-Hara-

da disease: report of an international committee on

nomenclature. Am J Ophthalmol 131:647-52, 2001.

14. Kamondi A, Szegedi A, Papp A, Seres A, Szirmai I. Vogt-

Ophthalmologia, 22, 1 (2010) 45

Fig. 3. Color picture of the right posterior pole.

46 Ophthalmologia, 22, 1 (2010)

Koyanagi-Harada disease presenting initially as ase-

ptic meningoencephalitis. Eur J Neurol 7: 719-22,

2000.

15. Kawano Y, Tawara A, Nishioka Y, Suyama Y, SakamotoH, Inomata H. Ultrasound biomicroscopic analysis of

transient shallow anterior chamber in Vogt-Koyanagi-

Harada syndrome. Am J Ophthalmol 121: 720-3,

1996.

16. Nakamura H, Tsukamoto H, Shibahara R, Nagai M, Mi-shima HK. Ultrasound biomicroscopy in the manage-

ment of Vogt-Koyanagi-Harada disease. Acta Oph-

thalmol Scand 78: 718-9, 2000.

17. Kishi A, Nao-I N, Sawada A. Ultrasound biomicroscop-

ic findings of acute angle-closure glaucoma in Vogt-

Koyanagi-Harada syndrome. Am J Ophthalmol 122:

735-7, 1996.

18. Friedman AH, Deutsch-Sokol RH. Sugiura’s sign. Peri-

limbal vitiligo in the Vogt-Koyanagi-Harada syndro-

me. Ophthalmology 88: 1159-65, 1981.

19. Goto H, Rao NA. Sympathetic ophthalmia and Vogt-

Koyanagi-Harada syndrome. Int Ophthalmol Clin 30:

279-85, 1990.

20. Lubin JR, Ni C, Albert DM. Clinicopathological study of

the Vogt-Koyanagi-Harada syndrome. Int Oph-

thalmol Clin 22: 141-56, 1982.

21. Hayasaka Y, Hayasaka S. Almost simultaneous onset of

Vogt-Koyanagi-Harada syndrome in co-workers, fri-

ends, and neighbors. Graefes Arch Clin Exp Oph-

thalmol 242: 611-3, 2004.

22. Bassili SS, Peyman GA, Gebhardt BM, Daun M, GanibanGJ, Rifai A. Detection of Epstein-Barr virus DNA by

polymerase chain reaction in the vitreous from a pa-

tient with Vogt-Koyanagi-Harada syndrome. Retina

16: 160-1, 1996.

23. Schlaegel TF Jr, Morris WR. Viruslike inclusion bodies in

subretinal fluid in uveo-encephalitis. Am J Ophthal-

mol 58: 940-5, 1964.

24. Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1

typing of Vogt-Koyanagi-Harada’s disease by PCR-

RFLP and the strong association with DRB1*0405

and DRB1*0410. Br J Ophthalmol 78: 223-6, 1994.

25. Goldberg AC, Yamamoto JH, Chiarella JM, Marin ML,Sibinelli M, Neufeld R, Hirata CE, Olivalves E, Kalil J.HLA-DRB1*0405 is the predominant allele in Brazi-

lian patients with Vogt-Koyanagi-Harada disease.

Hum Immunol 59: 183-8, 1998.

26. Damico FM, Cunha-Neto E, Goldberg AC, Iwai LK, Ma-rin ML, Hammer J, Kalil J, Yamamoto JH. T cell recog-

nition and cytokine profile induced by melanocyte e-

pitopes in HLA-DRB1*0405-positive and -negative

Vogt-Koyanagi-Harada uveitis patients. Invest Oph-

thalmolVis Sci 46: 2465-71, 2005.

27. Gocho K, Kondo I, Yamaki K. Identification of autorea-

ctive T cells in Vogt-Koyanagi-Harada disease. Invest

Ophthalmol Vis Sci 42: 2004-9, 2001.

28. Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S.

Tyrosinase family proteins are antigens specific to

Vogt-Koyanagi-Harada disease. J Immunol 165: 7323-

9, 2000.

29. Yamaki K, Kondo I, Nakamura H, Miyano M, Konno S,Sakuragi S. Ocular and extraocular inflammation in-

duced by immunization of tyrosinase related protein 1

and 2 in Lewis rats. Exp Eye Res 71: 361-9, 2000.

30. Yamada K, Senju S, Nakatsura T, Murata Y, Ishihara M,Nakamura S, Ohno S, Negi A, Nishimura Y. Identifica-

tion of a novel autoantigen UACA in patients with

panuveitis. Biochem Biophys Res Commun 280: 1169-

76, 2001.

31. Chan CC, Palestine AG, Nussenblatt RB, Roberge FG,Benezra D. Anti-retinal auto-antibodies in Vogt-Koya-

nagi-Harada syndrome, Behcet’s disease, and sympa-

thetic ophthalmia. Ophthalmology 92: 1025-8, 1985.

32. Rutzen AR, Ortega-Larrocea G, Schwab IR, Rao NA. Si-

multaneous onset of Vogt-Koyanagi-Harada syndro-

me in monozygotic twins. Am J Ophthalmol 119(2):

239-40, 1995.

33. Gass JD. Acute posterior multifocal placoid pigment e-

pitheliopathy. Arch Ophthalmol 80(2): 177-85, 1968.

34. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Hara-

da syndrome. Surv Ophthalmol 39: 265-92, 1995.

35. Oshima Y, Harino S, Hara Y, Tano Y. Indocyanine green

angiographic findings in Vogt-Koyanagi-Harada di-

sease. Am J Ophthalmol 122: 58-66, 1996.

The diagnosis of chorioretinal diseases largely

depends on their clinical presentation rather than

etiologic or systemic investigations. We report on a

patient whose examination revealed a peculiar fun-

dus pattern, almost completely different from di-

sorders such as multifocal choroiditis, presumed o-

cular histoplasmosis, myopic degeneration, acute

multifocal placoid pigment epitheliopathy, vitiligi-

nous chorioretinitis, and punctate outer retinal to-

xoplasmosis. It resembled punctate inner choroi-

dopathy, described by Watzke in 1984.38

Case report

A 56 year old white myopic female patient was

referred to our macular clinic with rapidly deteriorating

vision in her right eye. She had a history of poor vision

in the right eye for years and a two month history of

blurred vision, central photopsia, light flashes, and para-

central scotomas in the right eye . She was in good he-

alth, she had had no recent systemic illness and her o-

cular history was significant only for moderate myopia.

Her medical history was unremarkable.

Fundus examination revealed multiple yellowish

subretinal lesions at the level of the inner choroid and

retinal pigment epithelium throughout the posterior

pole (Fig. 1). Results of examination of the left fundus

were normal. Best corrected vision was 1/60 in the right

eye and 6/6 in the left eye. The anterior segments and

intraocular pressures were normal. The right fundus

showed characteristic multiple pigmented atrophic scars

in the posterior pole and mid-periphery in the absence of

vitreous cells. There was a macular scar in the right eye.

In the left eye she had myopic fundus, but the macula

area looked normal. OCT (Fig. 2) confirmed a partial

thichness macular hole in the right eye with epiretinal

membrane formation in the posterior pole and high

reflectivity under the areas of choroiretinal atrophy.

Early hypofluorescence with some mild staining of

the lesions in late frames was seen on fluorescein an-

giography (Fig. 7,8). ICG demonstrated some unusual

changes (Fig. 5,6). In the right eye several areas of ob-

vious hypofluorescence, which corresponded with the

site of the visible subretinal lesions were observed, whe-

reas larger choriodal vessels were noted to cross these

areas. No such changes were observed in the left eye.

She was given the diagnosis of punctate inner cho-

roidopathy and no treatment was recommended.

Comment

Punctate inner choroidopathy (PIC) is an idi-

opathic ocular inflammatory disease first descri-

bed by Watzke and associates in 1984.1 It usually

affects young, myopic women. Small yellow-white

lesions at the level of the retinal pigment epithe-

lium (RPE) choroid are seen in the posterior pole

and midperipheral retina, often bilaterally. Once

inactive, these lesions leave variably pigmented

punched out scars. The anterior segment and vitre-

ous are typically quiet.21

The white dot syndromes are inflammatory

diseases of unknown etiology which share several

clinical features. The presence or absence of visual

field defects, abnormal electroretinograms, lesions

on indocyanine green angiography, and specific

antiretinal antibodies may give us clues to their pa-

thogenesis.29

Punctate inner choroidopathy is an idiopathic

inflammatory ocular disorder characteristically seen

in young myopic women. Visual prognosis is gene-

rally good but sight threatening choroidal neovascu-

larisation may develop in up to 40% patients.23

Ophthalmologia, 22, 1 : 47 - 54, 2010

Punctate inner choroidopathy—a case reportand literature review

E. Papavasileiou1,2, G. Morphis1, L. Razis2, A. Gratsonidis2

1 Vitreoretinal Unit, St Paul’s Eye Unit, Liverpool, UK2 Laser & Ophthalmos Eye Centre

It is supposed that myopia, young age and fe-

male sex are general high-risk factors for the de-

velopment of focal choroidopathy. Women have a

significantly higher risk of developing bacteremia

before the age of 50 years than do men. The atte-

nuated choroidal vessels in myopia might elevate

the risk for infectious thrombosis in the chorio-

capillary layer. When combined, these risk factors

could significantly lower the infectious threshold,

leading to infections outside areas endemic for

48 Ophthalmologia, 22, 1 (2010)

Fig. 1. Multiple, round, yellow spots in the posterior poleof the right eye.

Fig. 2. OCT OD: Partial thichness macular hole, epire-ti-nal membrane formation. High reflectivity under the a-reas of choroiretinal atrophy.

Fig. 4. Red free picture OD: Multiple white areas at the po-sterior pole.

Fig. 3. Autofluorescence picture OD: Multiple black areasat the posterior pole.

Fig. 5. ICG, 0.30’ OD: Several areas of obvious hypoflu-orescence, which corresponded with the site of the visi-ble subretinal lesions were observed, whereas largerchoriodal vessels were noted to cross these areas.

Ophthalmologia, 22, 1 (2010) 49

Fig. 8. FA 4.35’ Mild staining of the lesions in late frames was seen on fluorescein angiography.

Fig. 6. ICG 3.36’ Late frames.

Fig. 7. FA 0,31′ ∂arly hypofluorescence was seen on fluo-rescein angiography.

particularly virulent agents. The more general term

multifocal inner choroiditis, proposed by Krill in

1968, should be maintained to emphasise the mul-

tifactorial genesis of this disease. Patients go to an

ophthalmologist when secondary complications

such as subretinal neovascular membranes have

developed; this makes the search for causes of the

primary infection difficult, if not impossible. 37

In MPC cases showing clinical inflammatory

findings, infiltration of B lymphocytes was also ob-

served histopathologically, suggesting that the pre-

sence of inflammatory cells in the anterior cham-

ber or vitreous body clinically is an indicator of

active inflammatory CNV. However,in a study it is

clarified that MCP eyes without intraocular inflam-

mation and PIC eyes are not different in histopa-

thological findings.2

The etiology of punctate inner choroidopathy

(PIC) and acute zonal occult outer retinopathy (A-

ZOOR) are currently unknown, although both di-

seases are hypothesized to be part of the spectrum

of a single disorder.10 In a article it is hypothesized

that PIC and AZOOR may have some common

etiologic or pathogenic background.19

PIC and MFCPU (Multifocal choroiditis with

panuveitis) appear to have different clinical chara-

cteristics at presentation. Patients with PIC had a

higher frequency of CNV (choroidal neovasculari-

zation) at presentation but lower frequencies of

structural complications from intraocular inflam-

mation and a lower frequency of visual impairment

at presentation.8

Multifocal choroiditis and punctate inner cho-

roidopathy cause scattered acute chorioretinal le-

sions in the fundus. Secondary choroidal neova-

scularization and, more rarely, diffuse subretinal fi-

brosis without obvious neovascularization are as-

sociated with both syndromes and cause severe vis-

ual loss. Both disorders are of unknown etiology

and have many similarities. 27

The different types of white spots occurring in

the fundus are analysed. A. Acute white spots, va-

nishing later on. 1. Multiple Evanescent White Dot

Syndrome. 2. Cat scratch disease. 3. AIDS micro-

angiopathy. 4. Cotton-wool spots. 5. Acute vitelli-

form maculopathy. B. Acute white spots with coale-

scence and diffuse scarring. 1. Acute posterior mul-

tifocal placoid pigment epitheliopathy. 2. Serpi-

ginous choroïditis (geographic choroïditis). 3. Her-

pes retinitis. C. Acute white spots becoming white

scars with variable pigmentation. 1. Multifocal cho-

roiditis—classical form. 1a. Punctate inner choroi-

dopathy. 1b. Diffuse subretinal fibrosis. 2. Toxopla-

smic retinochoroiditis. 3. Tuberculous chorioreti-

nitis. 4. Syphilitic chorioretinitis. 5. Lyme disease.

6. Sarcoidosis. 7. Sympathetic ophthalmia. 8. Vogt-

Koyanagi-Harada disease. 9. Bacterial retinocho-

roiditis. 10. Fungal retinochoroiditis—Can-dida.

11. Pneumocystis carinii choroiditis. D. Late white

spots with or without initial white-orange spots. Bir-

dshot chorioretinitis.26

Diagnostic tests:

In both PIC and POHS, CNV is the major

sight threatening complication.

Patients with subfoveal CNV have the most

guarded prognosis. In many of these latter cases the

visual acuity decreases to levels of 20/200 or worse,

even with treatment.21

Idiopathic CNV can be an early manifestation

of inflammatory chorioretinal diseases, including

MEWDS, MFC, and PIC.4

Management of PIC-related CNVM creates

diagnostic and therapeutic challenges. The pro-

blem is exacerbated as the pathology is often se-

quentially bilateral and sight threatening. Owing to

the rarity of such cases, there is a paucity of eviden-

ce on which to base the treatment strategies. A hi-

story of pregnancy should always be elicited before

investigation with FFA, and women warned of the

potential for disease exacerbation with limited the-

rapeutic options during pregnancy. Spontaneous

resolution of CNVM is common in PIC, and

should be borne in mind while treating pregnant

women. Peri/intraocular steroid injection repre-

sents a reasonable option for sight-threatening

CNVM in the better-seeing eye.6

Choroidal neovascularisation if smaller than

100 Ìm in diameter may resolve spontaneously.

However, subfoveal choroidal neovascularisation

occurs in 40% of the patients.

Diagnostic tests:

The fluorescein and indocyanine green angio-

graphic findings indicate that punctate inner cho-

roidopathy affects the choriocapillaris as well as

the retinal pigment epithelium and photorece-

ptors. However, it is still not known whether the

primary pathology is in the retinal pigment epithe-

lium, the photoreceptors or the choriocapillaris.28

Therapy options:

The white dot syndromes are a heterogeneous

group of rare inflammatory disorders affecting the

retina, the retinal pigment epithelium, and the cho-

50 Ophthalmologia, 22, 1 (2010)

Ophthalmologia, 22, 1 (2010) 51

roid. Not all of these diseases actually cause white

dots, but they all have unique lesions in the fundus.

White dots are seen in acute posterior multifocal

placoid pigment epitheliopathy, serpiginous choroi-

ditis, birdshot chorioretinopathy, multifocal cho-

roiditis with panuveitis, diffuse subretinal fibrosis

syndrome, punctate inner choroidopathy, multiple

evanescent white dot syndrome, and diffuse unila-

teral subacute neuroretinitis. Some of these condi-

tions share an association with systemic infectious

diseases. In addition, treatment of these diseases is

similar. Some can be treated with immunosuppres-

sive therapy. Other treatment options include laser

photocoagulation, topical or systemic steroid therapy,

photodynamic therapy, and, most recently, anti-va-

scular endothelial growth factor agents and subma-

cular surgery. The new development in treatment

may alter the visual prognosis of the patients,

leading to a better outcome in visual acuity.9

A few studies have reported on the outcome

of patients with PIC and subfoveal CNV managed

with the above treatments. Thus, Flaxel and col-

leagues6 presented a series of 10 eyes (eight pa-

tients) treated with high dose oral steroids. In eight

eyes improvement or stabilisation of vision occur-

red, although in two of these VA was 6/60 or less.

Olsen and associates28 performed submacular sur-

gery in five patients (six eyes), four of whom re-

ceived systemic or periocular steroids concomitan-

tly. Visual improvement was observed in all cases,

with postoperative visual acuities ranging from

20/20 to 20/200. Recurrences were common. Bro-

wn and colleagues3 reported on three patients trea-

ted with subfoveal surgery; two of them had been

treated previously with systemic steroids. In all

patients final VA was 20/50 or better, but no infor-

mation regarding follow up and recurrence of

CNV was given.

Several studies have reported on the outcome

of patients with subfoveal CNV secondary to

POHS. In a small (n=25) pilot randomised con-

trolled trial no statistically significant difference in

visual outcome was found between eyes treated

with argon laser photocoagulation and untreated

eyes. At one year follow up the VA of patients in

both groups had dropped from an average of

20/125 to 20/200. Argon laser photocoagulation is

contraindicated for subfoveal lesions.

Martidis and colleagues retrospectively revie-

wed a series of 18 patients treated with either oral

prednisolone or sub-Tenons triamcinolone. Seven

patients in the prednisolone group and five in the

triamcinolone group showed improvement or sta-

bilisation in vision. Thirteen patients (72%) ho-

wever, had a final VA of 20/100 or less despite tre-

atment. Thomas et al presented the clinical out-

come of 67 consecutive patients treated with sub-

macular surgery. Twenty six eyes (39%) had re-

ceived previous laser treatment. VA improved in

34% and stabilised in 49% after a mean follow up

of 10.5 months. In 24 patients (36%) VA was

≤20/200. CNV recurred in 37% of cases. The Sub-

macular Surgery Trial is currently underway to cla-

rify the role of this form of therapy in the ma-

nagement of subfoveal CNV in patients with PIC.

Previous case studies have reported good re-

sults in some patients with intensive high dose im-

munosuppression. However, not all patients re-

spond well to this form of therapy. Furthermore, in

some instances, even when an initial good response

is observed following this treatment, recurrence of

the CNV and visual loss can occur when the immu-

nosuppression therapy is reduced.

Prospective randomised controlled clinical tri-

als have demonstrated the value of photodynamic

therapy (PDT) in the treatment of subfoveal CNV

secondary to age related macular degeneration and

degenerative myopia. The role of PDT in the ma-

nagement of other causes of subfoveal neovascu-

larisation remains to be elucidated.

To date, it is unclear which is the best way of

treating patients with inflammatory CNVs. It is

possible, however, that PDT may be most effective

in achieving closure of already formed blood

vessels, whereas immunosuppressive therapies may

be most efficient during the early stages of en-

dothelial cell migration and proliferation. There-

fore, the selection of one or other treatment would

be dependant on the stage of development of the

CNV, which will vary greatly from patient to pa-

tient. In principle, early lesions should respond

well to immunosuppression, while formed CNV

will require PDT. It would be also expected that

most cases should do well with a combination of

both forms of therapy.

vPDT is a beneficial resource in stabilizing and

also improving VA in PIC patients affected with

subfoveal and juxtafoveal CNV, although one third

of the patients retain poor visual acuity.13

In a report, visual and angiographic outcomes

of a consecutive series of patients with inflamma-

tory subfoveal and juxtafoveal CNV secondary to

52 Ophthalmologia, 22, 1 (2010)

POHS and PIC unresponsive to systemic immuno-

suppression that were treated with PDT were pre-

sented. All patients experienced an improvement

in vision after this form of therapy, associated with

a decreased activity in the CNV.21

The vaso-occlusive effect of PDT combined

with the vasostatic and anti-inflammatory effect of

systemic oral prednisolone appears to be a safe and

effective option in the primary treatment of

subfoveal CNV in patients with PIC.1

PDT for subfoveal CNV may stabilise, but ra-

rely improves, visual acuity in eyes with choroidal

neovascularisation secondary to inflammatory cho-

rioretinal disease.16

A nearly two-year follow-up study suggests

that PDT could be helpful for patients with sub-

foveal classic CNV related to PIC or POHS-like.17

Although spontaneous resolution of the le-

sions can occur without any treatment, oral stero-

ids in PIC may help achieve improved vision more

rapidly.18

The role of PDT in the management of in-

flammatory CNV is, to date, unclear.

With one exception, the size of the CNV in the

patients included in this series was relatively small.

This may have affected favourably the outcome

achieved following PDT.

Although the results of this study should be

treated cautiously because of its retrospective na-

ture, the lack of a control group, and the small

number of patients treated, PDT appears to be a

useful option in the management of patients with

inflammatory CNVs unresponsive to immunosup-

pressive therapies.21

PDT is a safe and effective treatment option for

CNV secondary to inflammatory conditions. The

results are better than for CNV secondary to AMD.

For juxtafoveal CNV, the results are similar to those

of subfoveal CNV with no additional safety

concerns. Based on this observation, we consider

PDT as treatment of choice for subfoveal CNV se-

condary to inflammatory chorioretinal diseases and

for selected cases with juxtafoveal CNV.22

Retreatment was indicated if there was any

fluorescein leakage from the choroidal neovascu-

larisation. Retreatment was deferred if the visual

acuity remained stable or improved and the lesion

fulfilled all the following criteria: (1) minimal or no

subretinal fluid on biomicroscopic examination;

(2) flat scar-like appearance; (3) minimal fluore-

scein leakage without progression beyond the bo-

undaries of the previous treatment or involvement

of the fovea.

PDT appears to be a useful option in the ma-

nagement of patients with inflammatory CNVs un-

responsive to immunosuppressive therapies.21

Combined PDT with IVTA seems to be a pro-

mising treatment strategy in the treatment of idio-

pathic CNV and CNV secondary to PIC as it resul-

ted in fewer treatment sessions and superior visual

improvement. Further study to assess its long-term

safety and efficacy as the first line treatment is

warranted.7

Intravitreal bevacizumab injections resulted in

visual and anatomic improvements in eyes with i-

diopathic CNV and CNV attributable to CSC or

PIC. Further studies are warranted to assess the

long-term safety and the regimen for optimal ef-

ficacy of intravitreal bevacizumab.11

It has been reported that interferon B-1A leeds

to resolution of activity (choroiditis and choroidal

neovascularization) of chronic recurrent punctate

inner choroidopathy.15

In a study it has been reported the feasibility

and safety profile of 2-mg and 6-mg fluocinolone a-

cetonide implants after long-term follow-up in eyes

with choroidal neovascularization (CNV).

Long-term follow-up demonstrates a signifi-

cant complication rate with the sustained release of

high-dose intraocular corticosteroids. The compli-

cations are treatable, and eyes can retain good vi-

sion. This therapeutic approach warrants further

study to identify if lower doses of corticosteroids

may reduce the complication rate yet still be effe-

ctive in treating ocular disease.20

In a study it has been proposed to use systemic

oral prednisolone at an initial dose of 1 mg/kg (60-

80 mg for 3-5 days and the dose will subsequently

tapered.30

Subfoveal choroidal neovascularization in

punctate inner choroidopathy may be managed

with submacular surgery. Recurrences are common

and may result in substantial loss of vision. Choroi-

dal neovascular membranes with an accompanying

fibrotic reaction are responsible for the stellate or

dumbbell-shaped areas of subretinal fibrosis. No

beneficial effect was demonstrated using cortico-

steroid treatment of the choroidal neovasculariza-

tion.31

Prognosis:

Most patients with PIC retained visual acuity

of 20/40 or better. In nearly one third of patients

with PIC, CNV developed. Severe visual loss in

these diseases was usually due to subfoveal CNV.

Patients with DSF syndrome (diffuse subretinal fi-

brosis syndrome) had a poor prognosis due to fi-

brosis and atrophy involving the macula.33

Punctate inner choroidopathy recurrences are

common. However secondary neovascular mem-

branes are described, in general the visual outcome

is good.36

μÈ‚ÏÈÔÁÚ·Ê›·

1. ∑iaja K, Kubicka-Trzaska A, Karska-Basta I, Romanow-ska-Dixon B. Punctate inner choroidopathy - a case re-

port and literature review. Klin Oczna 111(4-6): 142-

144, 2009.

2. Shimada H, Yuzawa M, Hirose T, Nakashizuka H, HattoriT, Kazato Y. Pathological findings of multifocal cho-

roiditis with panuveitis and punctate inner choroido-

pathy. Jpn J Ophthalmol 52(4): 282-288, 2008.

3. Rosen E, Rubowitz A, Ferencz JR. Exposure to verteporfin

and bevacizumab therapy for choroidal neovascula-

rization secondary to punctate inner choroidopathy

during pregnancy. Eye (Lond.) 23(6): 1479, 2009.

4. Machida S, Fujiwara T, Murai K, Kubo M, Kurosaka D. I-

diopathic choroidal neovascularization as an early

manifestation of inflammatory chorioretinal diseases.

Retina 28(5): 703-710, 2008.

5. Vossmerbaeumer U, Spandau YH, V Baltz S, Wickenhaeu-ser A, Jonas JB. Intraviteal bevacizumab for choroidal

neovascularisation secondary to punctate inner cho-

roidopathy. Clin Experiment Ophthalmol 36(3): 292-

4, 2008.

6. Sim DA, Sheth HG, Kaines A, Tufail A. Punctate inner

choroidopoathy-associated choroidal neovascular

membranes during pregnancy. Eye (Lond.) 22(5):

725-725, 2008.

7. Chan WM, Lai TY, Lau TT, Lee VY, Liu DT, Lam DS.Combined photodynamic therapy and intravitreal

triamcinolone for choroidal neovascularization

secondary to punctate inner chroroidopathy or of i-

diopathic origin: one-year results of a prospective se-

ries. Retina 28(1): 71-80, 2008.

8. Kedhar SR, Thorne JE, Wittenberg S, Dunn JP, Jabs DA.Multifocal choroiditis with panuveitis and punctate in-

ner choroidopathy: comparison of clinical characteri-

stics at presentation. Retina 27(9): 1174-1179, 2007.

9. Matsumoto Y, Haen SP, Spaide RF. The white dot syndro-

mes. Compr Ophthalmol Update. 8(4): 179-200, 2007.

10. Saito A, Saito W, Furudate N, Ohno S. Indocyanine gre-

en angiography in a case of punctate inner choroido-

pathy associated with acute zonal occult outer retino-

pathy. Jpn J Ophthalmol 51(4): 295-300, 2007.

11. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal beva-

cizumab (avastin) for choroidal neovascularization se-

condary to central serous chorioretinopathy, secon-

dary to punctate inner choroidopathy, or of idiopathic

origin. Am J Ophthalmol 143(6): 977-983, 2007.

12. Gerstenblith AT, Thorne JE, Sobrin L, Do DV, Shah SM,Foster CS, Jabs DA, Nguyen QD. Punctate inner cho-

roidopathy: a survey analysis of 77 persons. Ophthal-

mology 114(6): 1201-1204, 2007.

13. Coco RM, de Souza CF, Sanabria MR. Photodynamic

therapy for subfoveal and juxtafoveal choroidal neo-

vascularization associated with punctate inner choroi-

dopathy. Ocul Immunol Inflamm, 15(1): 27-9, 2007.

14. Fong KC, Thomas D, Amin K, Inzerillo D, Horgan SE.Photodynamic therapy combined with systemic corti-

costeroids for choroidal neovascularisation secondary

to punctate inner choroidopathy. Eye (Lond.) 22(4):

528-533, 2008.

15. Cirono AC, Mathura JR, Jampol LM. Resolution of

activity (choroiditis and choroidal neovascularization)

of chronic recurrent punctate inner choroidopathy

after treatment with interferon B-1A. Retina 26(9):

1091-1092, 2006.

16. Lim JI, Flaxel CJ, LaBree L. Photodynamic therapy for

choroidal neovascularisation secondary to inflamma-

tory chorioretinal disease. An Acad Med Singapore

35(3): 198-202, 2006.

17. Postelmans L, Pasteels B, Coquelet P, Caspers L, Veroug-straete C, Leys A, Wirix M, Mauget-Faysse M, Quanran-ta M, Snyers B, Smets E. Photodynamic therapy foor

subfoveal classic choroidal neovascularization related

to punctate inner choroidopathy (PIC) or presumed

ocular histoplasmosis-like syndrome (POHS-like).

Ocul Immunol Inflamm 23(5): 361-366, 2005.

18. Levy J, Shneck M, Klemperer I, Lifshitz T. Punctate inner

choroidopathy: resolution after oral steroid treatment

and review of the literature. Can J Ophthalmol 40(5):

605-608, 2005.

19. Taira K, Nakazawa M, Takano Y, Ota T. Acute zonal

occult outer retinopathy in t he fellow eye 5 years after

presentation of punctate inner choroidopathy. Grae-

fes Arch Clin Exp Ophthalmol 244(7): 880-882, 2006.

20. Holekamp NM, Thomas MA, Pearson A. The safety

profile of long-term, high-dose intraocular

corticosteroid delivery. Am J Ophthalmol 139(3): 421-

428, 2005.

21. Leslie T, Lois N, Christopoulou D, Olson JA, Forrester JV.Photodynamic therapy for inflammatory choroidal ne-

ovascularisation unresponsive to immunosuppression.

Br J Ophthalmol 89(2): 147-150, 2005.

22. Wachtlin J, Heimann H, Behme T, Foerster MH. Long-

term results after photodynamic therapy with verte-

porfin for choroidal neovascularizations secondary to

inflammatory chorioretinal diseases. Graefes Arch

Clin Exp Ophthalmol 241(11): 899-906, 2003.

23. Chatterjee S, Gibson JM. Photodynamic therapy: a treat-

ment option in choroidal neovascularisation seconda-

ry to punctate inner choroidopathy. Br J Ophthalmol

Ophthalmologia, 22, 1 (2010) 53

54 Ophthalmologia, 22, 1 (2010)

87(7): 925-927, 2003.

24. Pérez Olivœn S, Torrfin C, Marcuello B, Ferrer E, Ruiz O,Honrubia F. A case of punctate inner choroidopathy:

differential diagnosis. Arch Soc Esp Ofthalmol 77(11):

631-634, 2002.

25. Brueggeman RM, Noffke AS, Jampol LM. Resolution of

punctate inner choroidopathy lesions with oral pred-

nisone therapy. Arch Ophthalmol 120(7): 2002.

26. Verougstraete C. White spots syndromes. Bull Soc Belge

Ophthalmol 279: 67-78, 2001.

27. De Meyer V, Lafaut BA, Van de Sompel W, De Laey JJ.Multifocal choroiditis with panuveitis and punctate in-

ner choroidopathy: a mini review. Bull Soc Belge

Ophthalmol 273: 115-124, 1999.

28. Akman A, Kadayifcilar S, Aydin P. Indocyanine green

angiographic findings in a case of punctate inner cho-

roidopathy. Eur J Ophthalmol 8(3): 191-194, 1998.

29. Brown J, Folk JC. Current controversies in the white dot

syndromes. Multifocal choroiditis, punctate inner

choroidopathy, and the diffuse subretinal fibrosis syn-

drome. Ocul Immunol Inflamm 6(2): 125-127, 1998.

30. Flaxel CJ, Owens SL, Mulholland B, Schwartz SD, GregorZJ. The use of corticosteroids for choroidal neovascu-

larisation in young patients. Eye (Lond) 12: 266-272,

1998.

31. Olsen TW, Capone A, Sternberg P, Grossniklaus HE,Martin DF, Aaberg TM. Subfoveal choroidal neovascu-

larization in punctate inner choroidopathy. Surgical

management and pathologic findings. Ophthalmology

103(12): 2061-2069, 1996.

32. Ip M, Gorin MB. Recurrence of a choroidal neovascular

membrane in a patient with punctate inner choroido-

pathy treatment with daily doses of thalidomide. Am J

Ophthalmol 122(4): 594-595, 1996.

33. Brown J, Folk JC, Reddy CV, Kimura AE. Visual progno-

sis of multifocal choroiditis, punctate inner coroido-

pathy and the diffuse subretinal fibrosis syndrome.

Ophthalmology 103(7): 1100-1105, 1996.

34. Reddy CV, Brown J, Folk JC, Kimura AE, Gupta S, Wal-ker J. Enlarged blind spots in chorioretinal inflamma-

tory disorders. Ophthalmology 103(4): 606-617, 1996.

35. Adelberg DA, Del Priore LV, Kaplan HJ. Surgery for

subfoveal membranes in myopia, angioid streaks, and

other disorders. Retina 15(3): 198-205, 1995.

36. Hoerauf H, Laqua H. Punctate inner choroidopathy Klin

Monbl Augenheilkd 204(6): 535-537, 1994.

37. Scheider A. Multifocal inner choroiditis. Ger J Oph-

thalmol 2(1): 1-9, 1993.

38. Ildem B, Sener C. Punctate inner choroidopathy and its

differential diagnosis. Ann Ophthalmol 23(4): 153-

155, 1991.

39. Watzke RC, Packer AJ, Folk JC, Benson WE, Burgess D,Ober RR. Punctate inner choroidopathy. Am J Oph-

thalmol 98(5): 572-584, 1984.