of Ocular Surface Squamous Neoplasia Herpes simples Ceratite pelo vírus

Volumen IV
No.2
Junio 2005
Interferon Alfa 2b in the Medical Management
of Ocular Surface Squamous Neoplasia
Aaleya F. Koreishi, MD and Carol L. Karp, MD
Ceratite pelo vírus
Herpes simples
Denise de Freitas, MD
Aspectos Genéticos y Oftalmológicos
del
Síndrome de Axenfeld Rieger
Rodolfo A. Pérez Grossmann, MD
Junio 2005
MENSAJE DEL PRESIDENTE
A todos los miembros de la Asociación Panamericana de Oftalmología:
sumir la presidencia de la Asociación Panamericana de Oftalmología es probablemente el mayor honor al que pueda aspirar un
oftalmólogo Latinoamericano. La APAO es una organización supranacional que incluye, sin excepción, a todos los países de este continente
con tres lenguas oficiales y más de 15,000 miembros en ella. Es también,
sin duda, de las organizaciones supranacionales existentes en el mundo
la más activa e intensa. De hecho, en su género, es un modelo y aspiración de las otras entidades supranacionales que se integran dentro del
Concilio Internacional de Oftalmología.
Nuestra asociación se reúne en forma bianual y sin interrupciones desde
hace más de 50 años. Acaba de concluir el XXV Congreso Panamericano
celebrado en la Ciudad de Santiago, Chile. Más de 2,500 oftalmólogos
estuvieron presentes. La organización fue perfecta gracias al esfuerzo
que efectuó el Comité Organizador que
encabezó brillantemente el Dr.Juan
Verdaguer. Los trabajos del Congreso
se desarrollaron en un ambiente académico, de interés y cordialidad. El
Congreso de Santiago fue un placer
para todos aquellos que tuvimos la
oportunidad de asistir.
Los Congresos Panamericanos son el
Enrique Graue
momento cúspide de nuestra AsociaPresidente de la Asociación Panamericana
de Oftalmología.
ción, en su organización empeñamos
muchos esfuerzos y atención pues
reflejan fielmente el estado de la Oftalmología de este continente y son
la oportunidad que tenemos de presentarnos, aquilatarnos, conocernos
y estrechar amistades.
La actividad académica que en ellos se despliega es de tal intensidad
que en Santiago estuvieron presentes más de 1200 oftalmólogos que
activamente presentaron sus experiencias y compartieron conocimientos. Por ello, el próximo año en febrero del 2006, en Sao Paulo, en
conjunción con el Congreso Mundial de Oftalmología, la APAO se reunirá a esta organización como parte integral del Congreso y tendremos
en él, la oportunidad de exponer nuestra oftalmología ante el resto del
mundo en un ambiente único, precarnaval, en la hermosa ciudad de
Sao Paulo. Ese será el XXVI Congreso de nuestra asociación.
Para el año 2007, en el mes de mayo, en Cancun, México, nos volveremos
a reunir. Para el efecto ya se encuentra trabajando activamente el comité
Organizador de lo que será el XXVII Congreso Panamericano.
Para el año 2009 ya se han propuesto dos ciudades de nuestro continente;
Cartagena en Colombia y Punta del Este en Uruguay. En ambos casos los
comités nacionales se han comenzado a integrar y a elaborar sus propuestas para que en la asamblea de Directores en Chicago, en este año, se
vote y defina la sede del XXVIII Congreso Panamericano de Oftalmología.
Si bien los congresos son un componente muy importante de cualquier
agrupación médica, en la APAO no lo son todo. Nuestra agrupación tiene
una intensa actividad que abarca otras muchas ramas. Anualmente se
organizan cursos regionales en donde se revisan con finalidades educativas temas de actualidad. Para el efecto este año nos reuniremos en
Tucumán Argentina y en Chihuahua, México. Un Comité específico de
nuestra asociación se encarga de estos cursos de corta duración.
La Asociación esta también activa en las políticas regionales de
prevención de ceguera; de promoción de bancos de ojos; en este boletín;
en la comunicación electrónica en la página web; en la educación médica
de nuestros residentes; en la organización de cursos básicos en oftalmología; en la génesis de políticas regionales de relaciones profesionales y
A
en la formación de jóvenes oftalmólogos que serán los líderes de nuestra
profesión en el futuro; en el otorgamiento de becas para la superación
académica y de investigación; en la Academia Americana de Oftalmología
con cursos Preacademia y de resumen de lo mejor que se presenta en
ella; en la formación de personal paramédico y en todas aquellas actividades que puedan ayudar a superar la oftalmología intercontinental o que
puedan afectar su desarrollo. En todo ello esta presente la Asociación
Panamericana de Oftalmología.
Al asumir la Presidencia de la misma, asumo con ello el compromiso de
continuar haciendo todo lo anterior, que es mucho y bueno.
Empezaremos por poner un especial énfasis en la educación y
estándares de las residencias en Latinoamérica, Para el efecto, este año,
iniciaremos con un curso en combinación con Internacional Council of
Ophthalmology y la Asociación de Profesores Universitarios de Oftalmología ( AUPO) de los Estados Unidos de Norteamérica encaminado a
" Enseñar a enseñar " a aquellos encargados de las residencias de oftalmología de nuestro continente.
Como siempre, nada de lo que se quiera hacer será posible sin la
participación de todos nosotros, de ustedes como miembros titulares de
nuestra asociación, de las mesas directivas de cada una de las sociedades nacionales, de sus representantes delegados a la Asamblea del
Board of Directors y del propio Comité Ejecutivo la Asociación.
Con la participación de todos conseguiremos una mejor Asociación
Panamericana de Oftalmología.
To all the members of the Pan-American Association of Ophthalmology:
o assume the presidency of the Pan-American Association of
Ophthalmology is probably the greatest honor to which a Latin
American ophthalmologist can aspire. The PAAO is a supranational organization that includes, without exception, all the countries of this continent
with three official languages and more than 1500 members. Moreover, it
is without a doubt, the most active and intensive of all the supranational
organizations in the world. As a result, it is a model for other supranational
entities that belong to the International Council of Ophthalmology.
Our association has met every two years without interruption for more
than 50 years. At the recent 25th Pan-American Congress in Santiago,
Chile, more than 2500 ophthalmologists were present. The organization
was perfect as designed by the organizing committee led brilliantly by Dr.
Juan Verdaguer. The activities of the Congress took place in an academic
atmosphere one of interest and cordiality. The Congress in Santiago was
a pleasure for all those who had the opportunity to participate.
The Pan-American congresses are the apex of our association, in whose
organization we invest great effort and attention, reflecting accurately the
state of ophthalmology on this continent and gives the opportunity to
present and test ideas, to make acquaintances and to extend friendships.
The academic activity developed with such intensity that in Santiago there
were more than 1200 ophthalmologists who presented their experiences
and imparted their knowledge. Next year in February 2006, in Sao Paulo,
in conjunction with the World Congress of Ophthalmology, PAAO will join
as an integral part of that congress, and we will have the opportunity to
export our ophthalmology to the entire world in an atmosphere of unity,
just before carnival in the lovely city of Sao Paulo. This will be the 26th
congress of our association.
In May 2007 in Cancun, Mexico, we will meet once again. The organizing
committee of the 27th Pan-American Congress is already at work.
For 2009, two sites have been proposed: Cartagena in Colombia and
Punta del Este in Uruguay. In both cases, the national committees have
T
VISIONPAN-AMERICA : 1 :
Junio 2005
PRESIDENT’S MESSAGE UMA MENSAGEM DO PRESIDENTE
begun to develop their proposals for the Executive Committee in Chicago
this year, who will vote on the site of the 28th Pan-American Congress of
Ophthalmology.
Even though congresses are a very important component of any medical
association, in the PAAO, they do not represent all that we have to offer.
Our association is intensely active in a variety of areas. Annually, the PAAO
organizes regional courses where the educational goals are practical
themes. With this intent, we will meet this year in Tucuman, Argentina and
in Chihuahua, Mexico. A special committee of our association designs
these short courses.
The Association is also active in regional politics for the prevention of
blindness; in the promotion of eye banking; in this publication; in communication via our web page; in the medical education of our residents; in
organizing basic courses in ophthalmology; in regional politics, professional relations, and in the development of young ophthalmologists who
will be the leaders of our profession in the future; in supporting academic
scholarships and research; in the American Academy of Ophthalmology
with pre-Academy courses and the "Best of the AAO"; in the promotion of
paramedical personnel in all the activities that can assist and help develop
intercontinental ophthalmology. And in all these areas, the Pan-American
Association of Ophthalmology is a presence.
In assuming the presidency of the PAAO, I take on the responsibility to
continue all that I have described. We are beginning to place emphasis on
the education of residency directors in Latin America. To this end, this year
in conjunction with the International Council of Ophthalmology (ICO) and
the Association of University Professors of Ophthalmology (AUPO) from
the United States, we will initiate a course called "Educating the Educator" for
those responsible for ophthalmology residency programs on our continent.
As always, nothing that we would like to do would be possible with the
participation of all of us, including you, the membership of the association,
the directorship of each of the national societies, your representatives on
the Board of Directors, and the Executive Committee of the association.
With everyone's participation, we will contribute to an even better PanAmerica Association of Ophthalmology.
A todos os membros da Associação Pan-Americana de Oftalmologia:
ssumir a presidência da Associação Pan-Americana de Oftalmologia
é provavelmente a maior honra a que pode aspirar um oftalmologista
latino-americano. A APAO é uma organização supranacional que inclui,
sem exceção, todos os países deste continente com três línguas oficiais e
possui mais de 15.000 membros. É também, sem dúvida, dentre todas as
organizações supranacionais existentes no mundo, a mais ativa e intensa.
Como resultado, em seu gênero, é um modelo e aspiração das outras
entidades supranacionais que se integram dentro do Concílio Internacional de Oftalmologia.
Nossa associação se reúne de forma bienal e sem interrupções há
mais de 50 anos. Acaba de concluir o XXV Congresso Pan-Americano
realizado na cidade de Santiago, Chile. Mais de 2.500 oftalmologistas
estiveram presentes. A organização foi perfeita graças ao esforço
realizado pelo comitê organizador liderado brilhantemente pelo Dr
Juan Verdaguer. As atividades do congresso se desenvolveram em
um ambiente acadêmico, de interesse e cordialidade. O congresso em
Santiago foi um prazer para todos aqueles que tiveram a oportunidade
de participar.
Os congressos pan-americanos são o ápice de nossa organização, na
organização destes empreendemos muitos esforços e atenção, pois eles
refletem fielmente o estado da Oftalmologia deste continente e são a
A
: 2 : VISIONPAN-AMERICA
oportunidade que temos de nos apresentarmos, nos conhecermos e
estreitarmos as amizades.
A atividade acadêmica desenvolvida e de tal intensidade que em Santiago
estiveram presentes mais de 1.200 oftalmologistas que ativamente apresentaram suas experiências e compartilharam conhecimentos. No
próximo ano, em Fevereiro de 2006, em São Paulo, em conjunção com o
Congresso Mundial de Oftalmologia, a APAO se juntará a esta
organização, como parte integral do congresso e teremos a oportunidade
de expor nossa Oftalmologia frente a todo o mundo em um ambiente
único, pré-carnaval, na bonita cidade de São Paulo. Este será o XXVI
Congresso de nossa associação.
Par o ano de 2007, no mês de Maio em Cancun, México, voltaremos a nos
reunir. Para isto o comitê organizador do XXVII Congresso Pan-Americano já se encontra trabalhando. Para o ano de 2009 foram propostas
duas cidades de nosso continente; Cartagena na Colômbia e Punta Del
Este no Uruguai. Em ambos os casos os comitês nacionais já começaram
a integrar e a elaborar as suas propostas para que na assembléia dos
diretores em Chicago, neste ano, se vote e se defina a sede do XXVIII
Congresso Pan-Americano de Oftalmologia.
Apesar dos congressos serem um componente muito importante de
qualquer associação médica, na APAO eles não representam tudo.
Nossa associação tem uma intensa atividade que engloba vários outros
ramos. Anualmente se organizam cursos regionais, onde se revisam,
com finalidades educativas, temas da atualidade. Com este intuito, nos
reuniremos este ano em Tucumán, Argentina e em Chihuahua, México.
Um comitê específico de nossa associação se encarrega destes cursos
de curta duração.
A associação está também ativa nas políticas regionais de prevenção da
cegueira; na promoção de banco de olhos; nesta revista; na
comunicação através da página eletrônica; na educação médica de
nossos residentes; na organização de cursos básicos em oftalmologia;
na gênese de políticas regionais, de relações profissionais e na formação de jovens oftalmologistas que serão os líderes de nossa
profissão no futuro; no fornecimento de bolsas acadêmicas e de
pesquisa; na Academia Americana de oftalmologia com cursos préacademia e de resumo do melhor apresentado nesta; na formação de
paramédicos e em todas as atividades que podem ajudar a oftalmologia
intercontinental a superar e desenvolverse. Em tudo isso, a Associação
Pan-Americana de Oftalmologia está presente.
Ao assumir a presidência da mesma, assumo também o compromisso de
continuara fazendo tudo já descrito, que é muito bom. Começaremos por
dar ênfase na educação e padrões das residências na América Latina.
Para isto, neste ano, iniciaremos com um curso conjunto com o
Internacional Council of Ophthalmology e a Associação de Professores
Universitários de Oftalmologia (AUPO), dos estados Unidos, destinado a
"Ensinar a ensinar" os responsáveis pelas residências em Oftalmologia
do nosso continente.
Como sempre, nada do que se quer fazer será possível sem a
participação de todos nós, de vocês como membros titulares de nossa
associação, das mesas diretivas de cada uma das sociedades nacionais, de seus representantes na assembléia do Board of Directors e do
próprio comitê executivo da própria associação.
Com a participação de todos conseguiremos uma melhor Associação
Pan-Americana de Oftalmologia.
Enrique Graue
Presidente de la Asociación Panamericana de Oftalmología.
President Pan-American Association of Ophthalmology.
Presidente Associação Pan-Americana de Oftalmologia.
Junio 2005
Leadership Development
EDITORIAL
by
Zélia M Corrêa
and Michael Brennan
Leadership
Development
s we move into 2005, it is time to acknowledge the
achievements and failures of 2004 in order to set the objectives
for the future.
We, from the PAAO's "Curso de Liderazgo" Committee and the
recently created Leadership Committee, have a lot to be proud of at
this time. The PAAO's "Curso de Liderazgo" that started as only a
promise to develop future leaders is quickly becoming a reality,
thanks to the hard work and support from the organizers, staff and
PAAO Executive Committee. The first leadership class just
graduated during the American Academy of Ophthalmology's
Annual Meeting in New Orleans and the second class began their
activities at the same time. The seeds planted by the "Curso" seem
to be of good quality and fertile, since many graduates and current
students are actively participating in their national societies,
subspecialty societies and other professional related activities and
community service. In addition, the results of the projects developed
by the first class have already come to fruition in some Latin
American and European countries such as Costa Rica, Puerto Rico,
El Salvador, Venezuela, Dominican Republic, Chile, Brazil, Mexico,
Portugal and Spain. These motivated colleagues have demonstrated the strength and energy of the future generation of leaders for
Latin-American Ophthalmology. In light of this, there is nothing more
appropriate than acknowledging those who are willing to prepare for
the job:
A
2003-2004 Class
2004-2005 Class
José Manuel Benítez, MD, PhD
Madrid, Spain
Emilio A. Arce, MD
San Juan, Puerto Rico
Fernando L. Colombo, MD
Caracas, Venezuela
Fernando Barria, MD
Concepcion, Chile
José J. Flores-Rivera, MD
Santa Tecla, El Salvador
Javier Córdoba, MD
San José, Costa Rica
Natalio J. Izquierdo, MD
San Juan, Puerto Rico
Sergio Byron Deutschmann, MD
Guatemala City, Guatemala
Luis Izquierdo, Jr., MD
Lima, Peru
Marco A. De La Fuente, MD
Mexico City, Mexico
Miguel Angel López Pimentel, MD
Sto Domingo, Dominican Republic
H. Fernando Gómez, MD
Bogotá, Colombia
Paulo Henrique Morales, MD
São Paulo, Brazil
Lelia Marroquín, MD
Lima, Peru
Eduardo Silva, MD PhD
Figueira da Foz, Portugal
Francisco José Muñoz, MD
Madrid, Spain
José Luis Tovilla-Canales, MD
Mexico City, Mexico
Paola Pacheco, MD
Montevideo, Uruguay
Gonzalo Vargas, MD
Santiago, Chile
Karen Salcedo, MD
Caracas, Venezuela
Lihteh Wu, MD
San José, Costa Rica
Leon O Vaughan, MD
Kingston, Jamaica
As we set our plans for the future, it is important to invite every
member of the PAAO to get involved. Find out what you can do for
our profession and your community. But most of all encourage the
young ophthalmologists of your country to join this program and
become more active in your national society and the PAAO. Our past
and current "Curso" participants are the best resource and
information for their country's National Society. Remember that
finding the right people for future "Curso de Liderazgo" classes is a
challenge, However it is essential to keep this program successful
and perpetuate the concept of speaking with ONE VOICE. Only then
the echo of our ideas will be heard in every country of Latin America.
On behalf of the Organizing Committee of the PAAO's Curso de
Liderazgo, I would like to congratulate the first and second "Curso
de Liderazgo" classes and all of those who participated, supported
and/or contributed to this challenging project! Thank you for
believing we can create a better professional environment in which
we all care for our patients..
Rita A. Yee, MD
Panama City, Panama
VISIONPAN-AMERICA : 3 :
Junio 2005
Interferon Alfa 2b in the Medical Management
of Ocular Surface Squamous Neoplasia
Aaleya F. Koreishi, MD and Carol L. Karp, MD
Miami, Florida, U.S.A.
Correspondence and Reprint Requests to: Carol L. Karp, MD, Bascom Palmer Eye Institute,
University of Miami School of Medicine, 900 NW 17th Street, Miami, FL 33136
Neither of the authors has proprietary or financial interest in any product mentioned.
ABSTRACT
Interferons are glycoproteins that bind to cell-surface receptors and
lead to anti-viral, anti-proliferative, and anti-angiogenic properties.
Interferons have been used successfully in many different diseases
throughout medicine, and recently success has been demonstrated
for the treatment of ocular surface neoplasias. Traditional treatment
for corneal and conjunctival intraepithelial neoplasia and squamous
cell carcinoma includes surgical excision and adjunctive cryotherapy.
The use of chemotherapeutic agents, including interferon alfa 2b
(IFN a2b), mitomycin C (MMC) and 5-fluorouracil (5-FU), has limited
the need for extensive surgical manipulation of the ocular surface
and potentially decreases recurrence rates. This article will focus on
the use of IFN in the treatment of corneal and conjunctival intraepithelial neoplasia and squamous cell carcinoma.
INTERFERONS
The Interferons (alpha, beta, and gamma) are a group of
glycoproteins, produced naturally as part of an immunologic response, that bind to cell-surface receptors, and trigger an intracellular
cascade resulting in antiproliferative, antiviral, immunomodulating
and antiangiogenic properties1. The exact mechanism of action has
not yet been elucidated2. Interferon Alfa 2b (IFN a2b) is a
recombinant form of naturally occurring interferon-a. The United
States Food and Drug Administration has approved IFN a2b for the
treatment of chronic hepatitis B and C, AIDS-related Kaposi's
sarcoma, malignant melanoma, hairy cell leukemia, chronic myelogenous leukemia, follicular lymphoma and condyloma accuminata. It
has been used successfully in the treatment of squamous cell
carcinoma and basal cell carcinoma of the skin3, as well as in cervical
intraepithelial neoplasia. IFN a2b has been reported in the literature
to be an effective treatment for ocular lesions including Herpes
simplex keratitis4, Kaposi's sarcoma of the conjunctiva5, conjunctival
MALT6, and Behcet's disease7.
The anti-viral properties of IFN are evident by the successful use
of IFN a2b in the treatment of herpes simplex keratitis (HSV),
condyloma acuminate (HPV), and Kaposi's sarcoma (human herpes
virus 8). Human papilloma virus (HPV) can infect cutaneous and
mucosal epithelium and result in squamous cell tumors of the skin
and intraepithelial neoplasia of the cervix8. HPV infection has also
been demonstrated in association with conjunctival and corneal
intraepithelial neoplasia (CIN) and squamous cell carcinoma
(SCCA)9, 10, 11. The anti-viral properties of IFN a2b may play an
important role in the response of HPV-associated CIN to this
treatment.
Although IFN therapy has shown promising results in the diseases
discussed above, systemic use leads to many side-effects such as
flu-like symptoms, hypotension, tachycardia, somnolence and
anorexia.1 Local (subcutaneous or subconjunctival) injections may
be associated with flu-like symptoms which can be controlled with
acetaminophen12. Retinal cotton wool spots and vasculopathy was
reported in one patient undergoing high-dose subcutaneous IFN a2b
treatment for renal cell carcinoma13. Ocular topical drops are well
tolerated, with only mild follicular conjunctivitis reported14.
Corneal and Conjunctival Intraepithelial Neoplasia
CIN is a pre-cancerous lesion on a continuum with SCCA. These
tumors most commonly occur in older patients and tend to affect
men more often than woman. Salient risk factors include ultraviolet
light exposure15, 16 human papillomavirus infection (HPV),9,10,11
immunosuppression (HIV/AIDS)17, smoking, petroleum product
exposure18, and genetic predisposition in conditions such as
xeroderma pigmentosa19.
Clinically, CIN presents as a gelatinous, papillomatous and/or
Figure 1A
Figure 1B
leukoplakic growth on the ocular surface most commonly at the
Figure 1:
limbus in the interpalpebral zone (Figure 1) Corneal involvement
1A. Typical appearance of papillary, gelatinous CIN in the interpalpebral
presents as a frosted-glass appearance with fimbriated edges
zone. 1B. Leukoplakic CIN at the limbus.
(Figure 2). SCCA tends to present as a larger, more elevated lesion
with fixation to underlying sclera. Although some authors feel that the diagnosis of CIN/SCCA can be made reliably by clinical examination
alone, pathologic confirmation is warranted, as other lesions may be confused with CIN/SCCA. The differential diagnosis includes pannus,
pingueculae, nodular conjunctivitis/episcleritis, keratoacanthoma, and non-pigmented conjunctival nevi/melanoma.
: 4 : VISIONPAN-AMERICA
Junio 2005
phototherapeutic
keratectomy34, and IFN
a2b35, 36, 37, 38, 39, 40, 41, 42.
The use of IFN a2b is
appealing because it
has fewer observed
side-effects than other
Figure 2A
Figure 2B
chemotherapeutic
Figure 2:
agents12, 43, IFN a2b
2A. Corneal involvement of CIN demonstrating fimbriated edges. 2B.
used as a subconjuncLimbal CIN with both conjunctival and corneal components. The
extent of corneal involvement can be appreciated with Rose Bengal
tival injection and/or
staining to delineate the fimbriated edges.
as a topical drop
has successfully treaTraditional treatment of CIN includes
ted cases of primary and recurrent
surgical excision with tumor-free margins.
CIN/SCCA. It has also been used in
Most surgeons now advocate the use of
conjunction with other treatment modalities
adjunctive cryotherapy to the limbus and
or after treatment failure. The standard
conjunctival margins in a double- or tripleformulations of topical drops (1 million
freeze-slow-thaw technique20, 21. Erie et al22
units/ml) and subconjunctival injection (3
studied the recurrence of surgically treated
million units/ml) are listed in Table 1.
CIN in 98 patients. Eighty-two patients underwent surgical excision alone, 9 had
Review of the literature
adjunctive radiation, 6 had adjunctive thioTable 2 summarizes the available literature
tepa, and one had an enucleation. The
on the treatment of CIN/SCCA with IFN a2b.
recurrence rate was 53% if surgical margins
The first reported case in the English
were positive and only 5% if the surgical
literature35 demonstrated successful treatmargins were tumor-free. Similarly, Tabin et
ment of a recurrent, pathologically-proven,
al23 found that the main prognostic factor in
epithelial dysplastic lesion of the conjunctiva
determining recurrence is involvement of
and cornea using only topical IFN a2b twice
surgical margins. The rate of recurrence
a day. The lesion regressed visibly after one
was 39% overall, but 56% of incompletely
week of treatment and the IFN a2b was
excised lesions recurred, versus 33% of
tapered over 2 months. No recurrence was
completely excised lesions. In their study
seen for 9 months.
group, most patients underwent surgical
The majority of initial reports described
excision alone, four patients had radiation
the
use of subconjunctival/perilesional inadjunctively, and five patients underwent
jection
of IFN a2b with supplemental topical
adjunctive cryotherapy to the limbus. A
drops.
Hu
et al36 reported one case treated
trend toward longer time to recurrence was
with this combination. Impression cytology
observed when adjunctive treatment was
confirmed clinical suspicion, diagnosing
rendered at the time of surgical excision.
severe squamous dysplasia/CIN. As the
24
Peksayar et al reported low rates of recupatient refused surgical intervention, the
rrence, in only 2 of 22 eyes (9%), when
lesion was treated with 2 subconjunctival
using adjunctive cryotherapy to the surgical
injections, 1 week apart, and topical drops
margins, limbus and episclera. One recufour times a day. Early regression was norrence was noted in the primary tumor
ted at 3 weeks and the lesion resolved by 2
group and one out of 3 previously treated
months. The drops were continued for 2 weeks.
lesions recurred. They followed patients for
No recurrence was noted for 10 months.
5 to 12 years, but both recurrences occuVann and Karp12 reported the largest series
rred within 2 years.
(6 eyes) of histologically proven CIN treated
In eyes with recurrent disease, or
with injection of IFN a2b followed by topical
extensive tumor involvement, the surgical
IFN a2b four times a day. The patients were
approach may lead to significant ocular
seen at 1 week, and if the lesion did not
surface morbidity in terms of limbal stemdemonstrate regression, re-injection 3 times
cell deficiency and scarring. Other treatper week was instituted. Overall, patients
ment strategies have been tested in an
required one to 11 injections, resolving
attempt to limit surgical manipulation of the
25,
26
27
between 3 and 6 weeks. All patients
, vitamin A ,
ocular surface: radiation
28,
29,
30,
31
32,
33
remained tumor-free for a follow up of 2-11
Mitomycin C
, 5-fluorouracil
,
months. There appeared to be a dosedependent response, larger lesions requiring more injections.
Kobayashi et al40 report a case of
recurrent (after cryotherapy), histologically
proven CIN treated with 2 subconjunctival
injections, 1 week apart, and topical drops 4
times a day for 12 weeks. The lesion
disappeared clinically by 2 weeks. Side
effects included superficial punctuate
keratopathy, which resolved after stopping
the drops, and fever after the first injection,
which was treated with Diclofenac.
Subconjunctival IFN a2b injections may
be used as a post-operative adjunct to subtotal excision of CIN in order to limit
potential stem cell compromise and resulting ocular surface disease. Chen at al42
partially excised a large limbal lesion,
involving 9 clock hours of limbus, positive
for both HPV-16 and 18, and treated it with
two injections 2 and 3 weeks postoperatively. The lesion regressed completely after 7 weeks. No evidence of recurrence was noted for 32 months. Interestingly, the patient's other eye also had a
smaller CIN lesion which was totally
excised initially, had no adjunctive IFN
treatment, and recurred after 10 months.
In order to minimize the side-effects from
subconjunctival injections, several authors
have reported the successful use of topical
IFN a2b to treat CIN. Schechter37 described
one case of extensive, recurrent CIN
treated with topical IFN a2b for a total of 5
months, 4 times a day for 2 months followed
by two times a day for three months. No
recurrence occurred for the 19 month
follow-up period.
Karp et al38 reviewed their experience
with topical IFN treatment of 5 eyes with
histologically proven CIN. Duration of
treatment ranged from 4 to 22 weeks
(average, 12 weeks). One eye experienced
a recurrence after 1 year and was retreated
successfully over 6 weeks, with no recurrence for 8 months. After clinical improvement was noted, the drops were tapered in
3 patients, and discontinued without a taper
in 2 patients. The follow up after treatment
was between 7 and 28 months.
The use of topical IFN a2b as the only
therapy for presumed primary CIN was
studied by Schechter et al39 in seven
patients. The diagnosis was made clinically,
as none of the patients underwent pathologic diagnosis. One patient was asked to
increase the frequency to six times a day,
VISIONPAN-AMERICA : 5 :
Junio 2005
Table 1: Formulation of IFN a2b for Ophthalmic Use
Interferon a2b
1 million units/ml
From Bascom Palmer Pharmacy,
Miami, FL.
1. Draw 0.83 ml from vial of INTRON A solution (18 million units/3ml)
and Q.S. to 5 ml with Bacteriostatic Water for Injection, USP.
2. Transfer solution to 15 ml amber dropper bottle
3. Label, refrigerate, 30-day expiration date
Interferon a2b
3 million units/ml
From Bascom Palmer Pharmacy,
Miami, FL.
1. Draw up 2.5 ml from vial of INTON A solution (18 million units/3ml)
and Q.S. to 5 ml with Bacteriostatic Water for Injection, USP
2. Transfer solution to 15 ml amber dropper bottle.
3. Label, refrigerate, 30-day expiration date.
Table 2: Summary of Literature Review on IFN a2b for CIN/SCCA
Author
Number of
cases
Tumor
Description
IFN a2b
Treatment
Time to
Resolution
Treatment
Duration
Tumor Free
Follow-up
Hu et al, 1998
1
Impression
Cytology-severe
dysplasia
Injection x 2
and topical QID
2 months
2.5 months
10 months
Early regression noted at 3
weeks.
Vann and Karp,
1989
6
Histologyprimary CIN or
recurrence of
histologically
proven CIN
Injection (range, 3-6 weeks
1-11; average, (average, 4.5)
5) and topical
QID
2-11 months
(average, 7.2)
Injection at start, then 3
X/week if no response at 1
week follow-up. Dosedependent response noted
(larger lesions need more).
Kobayashi et al,
2002
1
Histology-CIN,
s/p cryo x 2
with recurrence
Injection x 2
and topical QID
1 year
Superficial punctuate
keratopathy, resolved after
stop drops, fever after
injection, resolve with
Diclofenac.
Histologybilateral CIN,
HPV 16, 18
Injection x 2
and
Chen et al,
2004
1
(bilateral
involvem
ent)
2 weeks
(clinical
resolution)
12 weeks
7 weeks
32 months
Comments
Partial surgical excision, large
lesion. IFN injections post-op.
Other eye had complete
excision without IFN
treatment (recurred after 10
months).
Maskin, 1994
1
Pathologyepithelial
dysplasia
Topical BID
2 months
9 months
Schechter,
1999
1
Extensive
recurrent CIN
Topical QID 2
months, BID 3
months
5 months
19 months
Karp et al,
2001
5
Histology-CIN
Topical QID
(tapered in 3pt,
stopped in 2pts)
4-22 weeks
(average
11.6)
7-28
months
(average
17.6)
1 eye recurred after 1 year,
re-treated 6 weeks, no
recurrence 8 months.
Schechter et al,
2002
7
Clinical CIN
Topical QID (1
18-188 days
pt increased to (average, 77)
6x a day after 8
wks, 1 pt started
on 6 x a day)
57-188
days
(average,
106)
9-18
months
(average,
14)
4/7 patients with follicular
conjunctivitis.
Boehm and
Huang, 2004
7
Clinical
Topical QID
diagnosis of
recurrent CIN (#
of recurrences:
1, 2, 2, 3, 6)
6-24 weeks
(average,
14.1)
8-17
months
(average,
11.7)
Initial treatment was surgical
excision, cryotherapy,
radiation and/or topical MMC.
Regression noted at 2
weeks.First case reported.
Junio 2005
as no regression was noted after 8 weeks. Another patient was
started at 6 times per day. Similar to Karp, resolution occurred after
an average of 77 days and total treatment averaged 106 days. Four
out of the seven patients experienced follicular conjunctivitis, which
generally lead to earlier discontinuation of the drops. No clinical
recurrences were noted over an average of 14 months.
Recently, recurrent CIN lesions and their response to topical IFN
a2b were reported by Boehm and Huang.41 All patients had
undergone surgery, cryotherapy, radiation and/or topical MMC
treatment, and pathologic diagnosis of their primary lesion. Three
patients had 1 recurrence, 2 patients had 2 recurrences, one patient
had 3 recurrences, and one patient had 6 recurrences. Of the seven
patients studied, 6 had a clinical resolution in an average of 14.5
weeks. The treatment was continued for 14.1 weeks. Although one
patient developed a recurrent lesion at a different site and was
restarted on treatment, the tumor-free follow-up period for the others
averaged 11.7 months.
Summary/
Clinical significance
Indications of use
The gold standard includes surgical excision and adjuvant
cryotherapy as the primary treatment option. The role of adjuvant
chemotherapy or chemotherapy as a primary treatment is especially
helpful for lesions demonstrating recurrence, large, annular limbal
lesions which might lead to limbal stem cell def, non-resectable
lesions, and, and lesions in patients who are not surgical candidates
(although confirmatory pathologic diagnosis is still recommended).
IFN a2b is one of the available choices for adjuvant treatment.
Treatment protocol
Use of subconjunctival IFN a2b (3 million U/ml, 0.5cc, Scherring
Plough, NJ) with topical drops (1 million units/ml): Large lesions,
multiple recurrences after extensive ocular surface surgery, and
patients who want a potentially quicker recovery may be treated with
subconjunctival injections. The injections can be given 1 week apart
and up to 3 times per week. The patient is monito-red for response.
Once the tumor has resolved, the injections are stopped and topical
Figure 3A
Figure 3B
Figure 3:
3A. CIN before treatment. 3B. Resolution of CIN after
treatment with IFNa2b injections and topical drops.
Figure 5A
Figure 5B
Figure 5:
5A. Corneal CIN pre-treatment. (Pending permission from
Ophthalmology). 5B. Resolution after 7 weeks of topical IFN
a2b treatment. (Pending permission from Ophthalmology)
drops are continued for one month. Figures 3 and 4 demonstrate
clinical appearance of CIN lesions treated with this protocol.
Use of topical IFN a2b (1 million units/ml): Smaller lesions may be
treated with topical drops alone. The usual frequency is four times a
day, although clinicians have increased to 6 times a day dosing if
sufficient regression is not noted, or if the lesion is very large. The
drops are usually continued through complete tumor resolution and
may be tapered afterwards. Discontinuation after a set period of time
(1 month) after tumor resolution has also been successful. This
decision may be made depending on the initial size of the lesion,
time to response, and side effects. Figure 5 shows the clinical
resolution of corneal CIN after topical IFN a2b treatment.
Side-effects
Although side-effects have been reported, IFN a2b has a milder
side-effect profile than the other chemotherapeutic options inclu-ding
MMC and 5-FU. The only systemic side-effect reported during ocular
use of subcon-junctival injections is fever and chills, which is
transient and treated with acetaminophen. Topical IFN a2b may elicit
a follicular con-junctivitis, or superficial punctuate keratitis. Both of
these side-effects resolve after cessation of the medication.
CONCLUSION
IFN a2b provides a valuable tool against ocular surface neoplasia,
specifically CIN/SCCA. Although surgical excision with adjunctive
cryotherapy continues to be the gold standard for most CIN/SCCA,
indi-vidual patient circumstances may warrant a less invasive
approach. Topical treatment with IFN a2b is ideal for patients who
have a compromised ocular surface, who are not good surgical
candidates or who do not want invasive procedures, if the lesion size
is relatively small or mostly corneal. As topical treatment seems to
take longer to reach tumor resolution, subconjunctival injections may
be more effective for larger lesions. The use of IFN a2b in ophthalmology is only just becoming apparent and future investigation will
best determine the ideal dosing regiment. Further long term studies
are needed to better assess recurrence rates and other adverse
effects, and to prospectively compare results to surgical excision.
Figure 4A
Figure 4B
Figure 4:
4A. Leukoplakic CIN before treatment. 4B. Appearance after
4 injections of IFN a2b with concomitant topical drops.
Junio 2005
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Junio 2005
Ceratite pelo vírus
Herpes simples
Denise de Freitas, MD
UNIFESP/EPM
Rua Botucatu, 822 CEP 04023-062 São Paulo, SP, Brasil
[email protected]
A autora não tem interesse financeiro no assunto.
INTRODUÇÃO
O vírus herpes simples (HSV) causa uma infecção primária que é, na grande maioria das vezes, assintomática e auto-limitada. O HSV é um
importante agente etiológico das ceratites, podendo se manifestar na forma infecciosa e imunológica, as quais requerem tratamentos
específicos e diferentes entre si. O pronto reconhecimento e tratamento de cada manifestação diminuem a morbidade da doença.
Manifestações clínicas e tratamento das diferentes formas de ceratite herpética
As manifestações clínicas da doença herpética ocular no segmento anterior do olho podem ser didaticamente divididas em:
1. Doença ocular primária:
manifesta-se mais freqüentemente como vesícu-las ao redor do olho (Figura 1), com ou sem concomitante envolvimento da conjuntiva e da córnea. Estas vesículas ulceram e evoluem para crostas em
um prazo médio de 7 dias.
O tratamento da infecção primária é controverso por tratar-se de uma infecção auto-limitada
e benigna na grande maioria dos casos. Nos recomendamos que o tratamento das lesões de pele
próximas ao olho, principalmente aquelas com acometimento das pálpebras (blefarite), seja feito
com antiviral tópico local na pele e no olho, com dosagem terapêutica. Na tabela 1 podemos obFigura 1:
servar os antivirais de uso tópico utilizados no tratamento da infecção ocular pelo herpes simples e
respectivas posologias terapêuticas e profiláticas.Lesões extensas de pele ou múltiplos focos de acometimento podem ser tratados com
antiviral sistêmico (Tabela 2). Orientamos, também, a limpeza das lesões de pele com sabonete neutro.
Tabela 1. Antivirais de uso tópico utilizados no
tratamento da infecção ocular pelo herpes simples.
CONCENTRAÇÃO,
APRESENTAÇÃO
DOSAGEM
TERAPÊUTICA*
DOSAGEM
PROFILÁTICA
Trifluoridina
1,0%, gotas
9x/dia
4-5x/dia
Trifluoridina
1,0%, pomada
5x/dia
2-3x/dia
Aciclovir
3,0%, pomada
5x/dia
2-3x/dia
Idoxuridina
0,1%, gotas
9x/dia
4-5x/dia
Idoxuridina
0,5%, pomada
5x/dia
2-3x/dia
Vidarabina
3,0%, pomada
5x/dia
2-3x/dia
DROGA
* período de tratamento de 7 a 14 dias,
conforme a necessidade, podendose diminuir
a freqüência caso seja observado sinal de
toxicidade
Tabela 2. Antivirais de uso sistêmico para o tratamento
da infecção pelo herpes simples
DROGA
APRESENTAÇÃO
(COMPRIMIDOS)
DOSAGEM
TERAPÊUTICA*
DOSAGEM
(ADULTO)
Aciclovir
1,0%, gotas
9x/dia
4-5x/dia
Valaciclovir
1,0%, pomada
5x/dia
2-3x/dia
Fanciclovir
3,0%, pomada
5x/dia
2-3x/dia
*posologia extrapolada do tratamento do herpes genital.
VISIONPAN-AMERICA : 9 :
Junio 2005
2. Doença ocular recorrente:
Podem manifestar-se nas formas de
blefarite, conjuntivite, ceratite e uveíte.
O acometimento corneano pode ser
classificado em:
2.1. Ceratite Epitelial:
Causada pela ação direta do vírus vivo
replicando no epitélio da córnea. Pode
iniciar-se com uma ceratite ponteada que
evolui par a formação de linhas e figuras
clássicas de dendritos (Figura 2) e úlceras
em formato de mapas geográficos (Figura 3).
Estas lesões são melhor observadas com
o uso de rosa bengala. O dendrito da
infecção pelo herpes simples é geralmente
central, único (mas podendo ser múltiplo),
apresenta ramificações com, classicamente,
bulbo terminal. A lesão epitelial geográfica é
o dendrito que perdeu seu padrão linear
estendendo-se na forma de úlcera. Tem as
bordas geralmente edemaciadas e que
coram com rosa bengala.
O tratamento da ceratite epitelial inclui o
debridamento (com um cotonete seco
retiram-se todas as células que coram com
a rosa bengala) e a introdução do antiviral
tópico (Tabela 1).
2.2. Ceratopatia Neurotrófica:
São ulcerações do epitélio corneano, de
fundo transparente, de formato ovóide ou
arredondado, localizadas geralmente no
centro da córnea e que apresentam as
bordas elevadas devido ao empilhamento do
epitélio (Figura 3) que fica impossibilitado de
se deslizar para promover a cicatrização da
úlcera. Quando crônicas, podem apresentar
um estroma mais opaco, de coloração
acizentada, assim como neovascularização
superficial em formato de coroa ao redor da
úlcera ("pannus" que tenta cicatrizar a lesão).
Nestas úlceras mais crônicas é importante
afastar a suspeita de infecção secundária
através da pesquisa laboratorial.
A ceratopatia neurotrófica herpética é
secundária a má inervação corneana entre
outros fatores como comprometimento do
filme lacrimal, toxicidade medicamentosa,
alteração e inflamação da membrana
basal etc.
A escolha do tratamento mais apropriado
vai depender do tamanho, gravidade,
tempo de aparecimento da ulceração e das
outras tentativas de tratamento já efetuadas.
Pode variar desde tratamentos clínicos não
intervencionistas como lubrificação intensa,
curativo oclusivo e lente de contato
: 10 : VISIONPAN-AMERICA
terapêutica, até procedimentos cirúrgicos
como tarsorrafia (ou provocação de ptose
pela aplicação de toxina botulínica),
obstrução de pontos lacrimais e recobrimento
conjuntival. O uso de membrana amniótica
como tecido para recobrimento tem sido
avaliado em nosso Serviço em caracter
experimental.
2.3. Ceratite Estromal:
São controversas em relação à fisiopatologia
(manifestação de cunho imunológico e ou
inflamatório não específico e ou infeccioso
viral ativo). As ceratites estromais são
classificadas em:
2.3.1. ceratite estromal necrosante:
Provável invasão do estroma por infecção
viral ativa com desencadeamento de
inflamação. Clinicamente apresenta-se com
ulceração, necrose do tecido corneano e
densa infiltração estromal (Figura 4). Estes
casos tendem a evoluir com afinamento,
formação de descemetocele e perfuração.
2.3.2. ceratite estromal imune:
Provavelmente um processo imunológico
primário. Clinicamente o estroma pode
apresentar-se com inflamação, de leve a
severa, na forma de infiltração focal,
multifocal ou difusa (Figura 5). O epitélio é
geralmente íntegro com exceção nos casos
de associação de ceratite epitelial (infecção
viral ativa) ou ceratopatia neurotrófica.
Uma outra manifestação da ceratite
estromal imune é o anel imunológico que
pode apresentar-se na forma de anel único
ou múltiplo, completo ou incompleto, de
infiltrado e edema de intensidade
variável. Outro achado freqüente desta
ceratite é a neovascularização que pode
ocorrer em qualquer nível da córnea e
nos casos de infiltração severa
desenvolve-se com maior rapidez. A
neovascularização também pode se
desenvolver as custas de inflamação
crônica de baixa intensidade.
As ceratites estromais herpéticas são
tratadas dependendo da severidade e
localização da inflamação na córnea e da
perda de tecido. Se a ceratite não envolve
o eixo visual, não há neovascularização
cor-neana e o olho encontra-se calmo
opta-se pela observação prescrevendo-se
lubrificantes e ou cicloplégicos para
promover um melhor conforto para o
paciente. Se a reação inflamatória é severa,
localizada próxima ou no ao eixo visual e a
Figura 2
Figura 3
Figura 4
Figura 5
Junio 2005
neovascularização é presente ou mostra
sinais de desenvolvimento, opta-se pelo uso
de corticóide. O tipo e freqüência do
corticóide vão depender da severidade da
inflamação. Deve-se fazer a profilaxia
antiviral quando se usa corticóide no
tratamento da ceratite herpética para evitar
a recorrência da infecção epitelial viral ativa.
Esta profilaxia fica na dependência do tipo e
freqüência do corticóide utilizado. A
redução do corticóide deve ser feita
lentamente e na dependência da resposta
clínica, recorrência da inflamação, tolerância
e efeitos colaterais em relação ao colírio.
Não se deve diminuir em mais do que 50%
a freqüência de uso do corticosteróide
tópico para evitar-se o efeito rebote da
inflamação (termo em inglês conhecido
como "flare dose").
É importante lembrar que os corticosteróides são totalmente contra-indicados na
vigência de infecção epitelial herpética
ativa. Eles não aumentam a incidência de
recorrência da ceratite epitelial viral mas, se
esta ocorrer, será agravada pelo seu uso
uma vez que os corticosteróide promovem
a replicação viral.
Existem autores que preferem iniciar o
tratamento da ceratite estromal herpética
com uma dosagem baixa de corticosteróide
tópico que é aumentada conforme a
necessidade. Outros preferem iniciar com
uma dosagem mais alta reduzindo-a
conforme a melhora clínica. A Tabela 3
exemplifica o nosso sistema de uso do
corticosteróide tópico, que deve ser feito
sempre com profilaxia antiviral, quer seja
tópica ou sistêmica, no tratamento das
ceratites estromais herpéticas.
2.4. Endotelite:
Reação inflamatória primária no endotélio
corneano, sendo que um componente
infeccioso de replicação viral ativa pode
estar implicado na fisiopatogenia da inflamação. Pode apresentar-se na forma
difusa, linear ou de disco (Figura 6), com
precipitados ceráticos atrás da lesão ou em
forma de linha, com edema estromal e
algumas vezes epitelial e, em algumas
casos, irite. Estes olhos são geralmente
calmos, sem qualquer sinal inflamatório
(hiperemia, lacrimejamento etc) e a córnea
freqüentemente não desenvolve neovascularização. O tratamento, como na ceratite
estromal, inclui o uso de corticóide
(Tabela3) e antiviral sistêmico (Tabela 2).
Em especial, casos onde há infecção epitelial
Tabela 3. Uso do corticóide tópico
no tratamento das ceratites
estromais herpéticas.
Semana
Dexametasona 0,1%
ou Prednisona 1,0%
1
8x/dia
2
6x/dia
3
4x/dia
4
5
2x/dia
1x/dia
Semana
Dexametasona 0,005%
ou Prednisona 0,1%
6
7
4x/dia
3x/dia
8
2x/dia
9
1x/dia
10
3x/semana
viral e inflamação estromal associadas, devese tratar primeiro a infecção epitelial e
somente após o controle iniciar o uso do
corticosteróide tópico. Quando há a
associação de ceratopatia neurotrófica e
inflamação estromal, deve-se primeiro
fechar o defeito epitelial e depois desinflamar o estroma com o uso cauteloso do
corticosteróide.
A indicação do uso de antiviral oral ainda
é controversa em algumas manifestações
da doença ocular herpética. Existe uma
tendência de concordância em se prescrever o antiviral oral nos casos de [1]
infecção primária extensa e severa, [2] em
casos selecionados de ceratouveíte,
endotelite, iridociclite e trabeculite, [3]
pacientes imunocomprometidos, nas profilaxias [4] de pacientes com doença ocular
herpética com alta freqüência de recorrência
e [6] nos pacientes submetidos a transplante
de córnea.
Figura 6
REFERENCES
1. Dawson, C., et al., Design and organization of the herpetic eye
disease study (HEDS). Curr Eye Res, 1991. 10(105): p. 10.
2. Dawson, C., et al., Herpetic Eye Disease Study.You can help. Arch
Ophthalmol, 1996. 114(1): p. 89-90.
3. Wilhelmus, K., et al., Herpetic Eye Disease Study. A controlled
trial of topical corticosteroids for herpes simplex stromal keratitis.
Ophthalmology, 1994. 101(12): p. 1883-95.
4. Barron, B., et al., Herpetic Eye Disease Study. A controlled trial
of oral acyclovir for herpes simplex stromal keratitis.
Ophthalmology, 1994. 101(12): p. 1871-82.
5. Anonymous, A controlled trial of oral acyclovir for iridocyclitis
caused by herpes simplex virus. The Herpetic Eye Disease Study
Group. Arch Ophthalmol, 1996. 114(9): p. 1065-72.
6. Wilhelmus, K., et al., Risk factors for herpes simplex virus
epithelial keratitis recurring during treatment of stromal keratitis
or iridocyclitis. Herpetic Eye Disease Study Group. Br J
Ophthalmol, 1996. 80(11): p. 969-72.
7. Anonymous, A controlled trial of oral acyclovir for the prevention
of stromal keratitis or iritis in patients with herpes simplex virus
epithelial keratitis. The Epithelial Keratitis Trial. The Herpetic Eye
Disease Study Group. Arch Ophthalmol, 1997. 115(9): p. 1196.
8. Anonymous, Acyclovir for the prevetion of recurrent herpes
simplex virus eye disease. Herpetic Eye Disease Study Group. N
Engl J Med, 1998. 339(5): p. 300-6.
9. Moyes, A., Antiviral therapy after penetrating keratoplasty for
herpes simplex keratitis. Arch Ophthalmol, 1994. 112: p. 601-607.
10. Beyer, C., et al., Oral acyclovir reduces the incidence of recurrent
herpes simplex keratitis in rabbits after penetrating keratoplasty.
Arch Ophthalmol, 1989. 107(8): p. 1200-5.
11. Foster, C. and N. Barney, Systemic acyclovir and penetrating
keratoplasty for herpes simplex keratitis. Doc Ophthalmol, 1992.
80(4): p. 363-9.
12. vanRooij, J., et al., A retrospective study on the effectiveness of
oral acyclovir to prevent herpes simplex recurrence in corneal
grafts. Eur J Ophthalmol, 1995. 5(4): p. 214-8.
13. Kaufman, HE., Varnell, ED., Thompson, HW. Trifluridine,
cidofovir, and penciclovir in the treatment of experimental herpetic
keratitis. Arch Ophthalmol, 1998. 116:6 p. 777-80.
VISIONPAN-AMERICA : 11 :
Junio 2005
Aspectos Genéticos y Oftalmológicos
del
Síndrome de Axenfeld Rieger
Rodolfo A. Pérez Grossmann, MD
Instituto de Glaucoma y Catarata
Lima-Perú
E
n 1920 Axenfeld describió por primera vez un paciente con una línea blanca en la parte posterior de la cornea periférica
que lo denomino embriotoxon posterior de la córnea (1). En 1935 Rieger reportó casos con alteraciones similares pero
asociado a alteraciones del iris como corectopia, atrofia de iris con formación de agujeros; definiéndolo como disgenesias
mesodermales de la cornea y del iris (2).
Tradicionalmente se han designado tres condiciones:
- Anomalía de Axenfeld, limitada a alteraciones periféricas del segmento anterior.
- Anomalía de Rieger, con alteraciones periféricas del segmento anterior y alteraciones del iris.
- Síndrome de Rieger, con alteraciones oculares y extraoculares.
El Síndrome de Axenfeld Rieger representa un amplio espectro de alteraciones del desarrollo del segmento anterior del
ojo y también alteraciones extraoculares, debido a la alteración en la formación de estructuras originadas en las células
de la cresta neural.
El compromiso ocular es bilateral y la alteración es asimétrica, quiere decir que puede existir compromiso en diferente grado en
el mismo paciente y frecuentemente esta asociado a glaucoma. Los defectos extraoculares más comúnmente comprometen los
dientes y los huesos faciales.
GENÉTICA
Esta alteración ocurre en aproximadamente 1 de cada
10,000 niños nacidos vivos (3). Es un defecto autosómico
dominante con un espectro amplio de fenotipos que depende
del grado de expresión de uno o más genes relacionados con
la formación del segmento anterior. En algunos casos asociados a malformaciones sistémicas, particularmente a nivel
de los dientes y huesos de la cara.
Se han descrito tres locus y dos genes asociados a este
síndrome:
El primer gen ha sido descrito en el año 1997, el PITX 2 en
el cromosoma 4q25 responsable del síndrome de Rieger
tipo 1; posteriormente fue descrito el segundo locus para el
síndrome de Rieger (RIEG2) en el cromosoma 13q14
mediante análisis de ligación genética y finalmente en el año
1998 el gen FOXC1 o FKHL7 fue implicado en un forma
dominante de glaucoma congénito que revelo posteriormente
ser responsable del síndrome de Axenfeld Rieger estando
ubicado en el cromosoma 6p25.
Asimismo en América Latina se ha descrito una mayor
ligación genética al gen PITX 2 en la población brasilera (4).
Mutaciones en estos genes pueden causar una variedad de
fenotipos que comparten cuadros característicos con el
síndrome de Axenfeld-Rieger; como son: la anomalía de
Axenfeld, anomalía de Rieger, Síndrome de Rieger, anomalía
: 12 : VISIONPAN-AMERICA
o síndrome de iridodisgenesia, hipoplasia de iris y el
glaucoma familiar por iridodisplasia (5). Asimismo las mutaciones PITX2 se asocian a una alta incidencia de glaucoma
(6), que podría estar producido por mutaciones puntuales o
microdelecciones del gen PITX2, para lo cual el PCR cuantitativo seria de mucha ayuda en estos pacientes para su
detección(7).Todos comparten una sobre posición genotípica y
fenotípica (8), con un 50% de riesgo de desarrollar glaucoma.
Genes relacionados al síndrome de Rieger:
El PITX2 ó RIEG I en el cromosoma 4p25
El FKHL7 o FOXC1 en el cromosoma 6p25
ALTERACIONES OCULARES
Las estructuras mas comúnmente comprometidas son:
La córnea periférica, el seno camerular y el iris.
CORNEA
En la córnea periférica se observa una línea de Schwalbe
prominente y desplazada anteriormente. A la biomicroscopía
se observa como un anillo de color blanquecino en la parte
posterior de la cornea periférica, cerca al limbo. En algunos
casos se limita solo a la región temporal y en otros se puede
observar en los 360 grados de la cornea periférica (fotos 1 y 2).
Junio 2005
En algunos casos puede existir esta línea de Schwalbe
prominente, como un defecto aislado referido solo como
embrio-toxon posterior (9), el cual se puede observar en
alrededor de el 8 al 15% de la población general.
Usualmente la córnea es de apariencia normal,
pudiendo estar ocasionalmente asociado a megalocórnea, a microcórnea (10) o a opacidades de la córnea
central.
El endotelio corneal es normal a la microscopía
especular, pudiendo estar alterada en su forma y
tamaño en los glaucomas de larga data o con cirugía
previa (11).
Impreso por Printer Colombiana S.A.
SENO CAMERULAR
En la gonioscopía se observa típicamente una prominencia
de la línea de Schwalbe cuya extensión y desplazamiento anterior es variable, en algunos casos se nota
como suspendida de la córnea (12) (Foto 2).
Prolongaciones el iris periférico a la línea de Schwalbe
prominente que forman una especie de puentes y en
algunas áreas con inserción en la malla trabecular. En
algunos pacientes se observa una o dos prolongaciones
del iris, mientras que en otras llega a tapizar casi por
completo la malla trabecular con la presencia de algunas
áreas libres. Debajo de estas pro-longaciones anómalas
del iris se encuentra un ángulo abierto con una malla
trabecular que se aprecia en algunas áreas libres. El
espolón escleral esta oculto por el iris periférico el cual se
inserta en la porción posterior de la malla trabecular (13).
Foto 1: Se observa el embriotoxon posterior
(Flecha negra), como una línea blanquecina en la
cornea periférica en los 360 grados. Obsérvese
también la pupila ubicada excéntricamente.
Foto 2: Vista del embriotoxon
posterior o prominencia de la línea
de Schwalbe al corte de la lámpara
de hendidura (Flecha blanca).
Foto 3 y 4: Se observa la línea de Schwalbe prominente, con prolongaciones del iris periférico a
la línea de Schwalbe o embriotoxon posterior (Flecha); detrás del cual se observa la malla
trabecular.
VISIONPAN-AMERICA : 13 :
Preserva la visión alcanzando las menores
presiones-objetivo en más pacientes
Investigadores de diversos estudios, (AGIS, Shirakashi, Shields)
han comprobado que alcanzar y mantener la PIO entre 14 y 15 mmHg
reduce la progresión de pérdida del campo visual1,2,3.
Lumigan® alcanza la PIO-objetivo de 14/15 mmHg en un mayor número
de pacientes:
®
vs. timolol 4
®
vs.
dorzolamida/
timolol 5
®
vs. latanoprost 6
Porcentaje de Pacientes que
alcanzaron la PIO-Objetivo ≤14
21%
9%
17%
2%
19%
9%
Porcentaje de Pacientes que
alcanzaron la PIO-Objetivo ≤15
31%
16%
24%
9%
29%
14%
Lumigan ® (bimatoprost) Forma farmacéutica y pr
esentación.
Composición. Cada ml contiene: 0,3 mg de bimatoprost. Vehículo: cloreto de sódio, fosfato de sódio
presentación.
esentación.Frascos cuenta-gotas conteniendo 5 ml de solución oftalmológica estéril de bimatoprost a 0,03%. USO ADULTO.Composición.
hepta-hidratado, ácido cítrico mono-hidratado, ácido clorídrico y/o hidróxido de sódio, cloruro de benzalconio y agua purificada qsp. Indicaciones. LUMIGAN® (bimatoprost) es indicado para la reducción de la presión intra-ocular elevada en pacientes con glaucona o hipertensión
ecauciones y Adver
tencias. Advertencias. Fueron relatados aumento gradual del crescimiento
Contraindicaciones. LUMIGAN® (bimatoprost) está contraindicado en pacientes con hipersensibilidad al bimatoprost o cualquier otro componente de la fórmula del producto. Pr
Precauciones
Advertencias.
ocular.Contraindicaciones.
de las pestañas en el largo y espesura, y oscurecimiento de las pestañas (en 22% de los pacientes después 3 meses, y 36% después 6 meses de tratamiento), y, oscurecimiento de los párpados (en 1 a <3% de los pacientes después 3 meses y 3 a 10% de los pacientes después
6 meses de tratamiento). También fue relatado oscurecimiento del íris en 0,2% de los pacientes tratados durante 3 meses y en 1,1% de los pacientes tratados durante 6 meses. Algunas de esas alteraciones pueden ser permanentes. Pacientes que deben recibir el tratamiento
ecauciones LUMIGAN® (bimatoprost) no fue estudiado en pacientes con insuficiencia renal o hepática y por lo tanto debe ser utilizado con cautela en tales pacientes.Las lentes de contacto deben
de apenas uno de los ojos, deben ser informados a respecto de esas reacciones. Pr
Precauciones
ser retiradas antes de la instilación de LUMIGAN® (bimatoprost) y pueden ser recolocadas 15 minutos después. Los pacientes deben ser advertidos de que el producto contiene cloruro de benzalconio, que es absorvido por las lentes hidrofílicas.Si más que un medicamento
de uso tópico ocular estuviera siendo utilizado, se debe respetar un intervalo de por lo menos 5 minutos entre las aplicaciones.No está previsto que LUMIGAN® (bimatoprost) presente influencia sobre la capacidad del paciente conducir vehículos u operar máquinas, sin embargo,
así como para cualquier colírio, puede ocurrir visión borrosa transitoria después de la instilación; en estos casos el paciente debe aguardar que la visión se normalice antes de conducir u operar máquinas. Interacciones medicamentosas.
medicamentosas.Considerando que las concentraciones
circulantes sistemicas de bimatoprost son extremadamente bajas después múltiplas instilaciones oculares (menos de 0,2 ng/ml), y, que hay varias vías encimáticas envueltas en la biotransformación de bimatoprost, no son previstas interacciones medicamentosas en humanos.
eacciones adversas. LUMIGAN® (bimatoprost) es bien tolerado, pudiendo causar eventos adversos oculares leves a moderados y no graves.Eventos adversos ocurriendo en 10-40% de los pacientes que recibieron doses únicas diarias, durante
No son conocidas incompatibilidades. RReacciones
3 meses, en orden decreciente de incidencia fueron: hiperenia conjuntival, crecimento de las pestañas y prurito ocular.Eventos adversos ocurriendo en aproximadamente 3 a < 10% de los pacientes, en orden decreciente de incidencia, incluyeron: sequedad ocular, ardor ocular,
sensación de cuerpo estraño en el ojo, dolor ocular y distúrbios de la visión.Eventos adversos ocurriendo en 1 a <3% de los pacientes fueron: cefalea, eritema de los párpados, pigmentación de la piel periocular, irritación ocular, secreción ocular, astenopia, conjuntivitis alérgica,
lagrimeo, y fotofobia.En menos de 1% de los pacientes fueron relatadas: inflamación intra-ocular, mencionada como iritis y pigmentación del íris, ceratitis puntiforme superficial, alteración de las pruebas de función hepática e infecciones (principalmente resfriados e infecciones
de las vías respiratorias).Con tratamientos de 6 meses de duración fueron observados, además de los eventos adversos relatados más arriba, en aproximadamente 1 a <3% de los pacientes, edema conjuntival, blefaritis y astenia. En tratamientos de asociación con betabloqueador,
durante 6 meses, además de los eventos de más arriba, fueron observados en aproximadamente 1 a <3% de los pacientes, erosión de la córnea, y empeoramiento de la acuidad visual. En menos de 1% de los pacientes, blefarospasmo, depresión, retracción de los párpados,
Posología y Administración.
hemorragia retiniana y vértigo.La frecuencia y gravedad de los eventos adversos fueron relacionados a la dosis, y, en general, ocurrieron cuando la dosis recomendada no fue seguida.Posología
Administración.Aplicar una gota en el ojo afectado, una vez al día, a la noche.
La dosis no debe exceder a una dosis única diaria, pues fue demostrado que la administración más frecuente puede disminuir el efecto hipotensor sobre la hipertensión ocular.LUMIGAN® (bimatoprost) puede ser administrado concomitantemente con otros productos oftálmicos
tópicos para reducir la hipertensión intra-ocular, respetándose el intervalo de por lo menos 5 minutos entre la administración de los medicamentos. VENTA BAJO PRESCRIPCIÓN MÉDICA.“ESTE PRODUCTO ES UM MEDICAMENTO NUEVO AUNQUE LAS INVESTIGACIONES HAYAN
INDICADO EFICACIA Y SEGURIDAD, CUANDO CORRECTAMENTE INDICADO, PUEDEN SURGIR REACCIONES ADVERSAS NO PREVISTAS, AÚN NO DESCRIPTAS O CONOCIDAS, EN CASO DE SOSPECHA DE REACCIÓN ADVERSA, EL MÉDICO RESPONSABLE DEBE SER NOTIFICADO.
1. The AGIS Investigators: The Advanced Glaucoma Intervetion Study - The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. Am. J. Ophthalmol, 130 (4): 429-40, 2000. 2. Shirakashi, M. et al: Intraocular Pressure-Dependent Progression of Visual
Field Loss in Advanced Primary Open-Angle Glaucoma: A 15-Year Follow-Up. Ophthalmologica, 207: 1-5, 1993. 3. Mao, LK; Stewart, WC; Shields, MB: Correlation Between Intraocular Pressure Control and Progressive Glaucomatous Damage in Primary Open-Angle Glaucoma. Am.
J. Ophthalmol, 111: 51-55, 1991. 4. Higginbotham, EJ et al. One-Year Comparison of Bimatoprost with Timolol in Patients with Glaucoma or Ocular Hypertension. Presented at American Academy Ophthalmology, Nov 11-14, 2001. 5. Gandolfi, S et al. Three-Month Comparison of Bimatoprost
and Latanoprost in Patients with Glaucoma and Ocular Hypertension. Adv. Ther, 18 (3): 110-121, 2001. 6. Coleman, AL et al: A 3-Month Comparison of Bimatoprost with Timolol/Dorzolamide in Patients with Glaucoma or Ocular Hypertension. Presented at American Acedemy of
Ophthalmol, New Orleans, La, 2001.
Mejor comodidad posológica:
1 vez al día.
No requiere refrigeración.
Presentación conteniendo 3 ml.