Zika virus‚ microcephaly and macular atrophy Zika virus and

Transcription

issn 0004-2749
versão impressa
Arquivos brasileiros
publicação oficial do conselho brasileiro de oftalmologia
Janeiro/feVereiro 2016
d e
79 01
Zika virus‚ microcephaly and
macular atrophy
Zika virus and bilateral acute
hypertensive uveitis
Thermography and lacrimal system
obstruction
Intrastromal corneal ring delays
corneal grafting
Cryopreserved human corneal
endothelial cells
indexada nas bases de dados
MEDLINE | EMBASE | ISI | SciELO
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Arq Bras Oftalmol. São Paulo, v. 79, issue 1, pages 1-68, Jan/Feb. 2016
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CONSELHO BRASILEIRO
DE OFTALMOLOGIA
ISSN 0004-2749
(Printed version)
ISSN 1678-2925
Frequency of publication: Bimonthly
Arq Bras Oftalmol. São Paulo, v. 79, issue 1, pages 1-68, Jan/Feb. 2016
Contents
Editorial
V
Oliver Sacks and his legacy to vision science and ophthalmology
Oliver Sacks e o seu legado para a ciência da visão e a oftalmologia
Eduardo Melani Rocha, Luiza Aikawa da Silveira Rocha, Galton Carvalho Vasconcelos, Monica Alves
Original Articles
1
0QIUIBMNPMPHJDBMöOEJOHTJOJOGBOUTXJUINJDSPDFQIBMZBOEQSFTVNBCMFJOUSBVUFSVT;JLBWJSVTJOGFDUJPO
Achados oftalmológicos em lactentes com microcefalia e infecção presumida pelo vírus Zika
Camila V. Ventura, Mauricio Maia, Bruna V. Ventura, Vanessa Van Der Linden, Eveline B. Araújo, Regina C. Ramos, Maria Angela W. Rocha, Maria Durce C. G. Carvalho,
Rubens Belfort Jr., Liana O. Ventura
4
A study of the vitreoretinal interface in patients with age-related macular degeneration
Estudo da interface vitreorretiniana em pacientes com degeneração macular relacionada à idade
Maíra de França Martins, Edio Volpatto, Paula Emery, Pedro Duraes Serracarbassa
9
Serous retinal detachment in patients with macular edema secondary to branch retinal vein occlusion
Descolamento seroso de retina em pacientes com edema macular secundário à oclusão de ramo da veia retiniana
Erkan Celık, Emine Doğan, Elif Betul Turkoglu, Burçin Çakır, Gursoy Alagoz
12
Mean platelet volume in patients with retinal artery occlusion
Volume médio de plaquetas em pacientes com oclusão da artéria da retina
Muhammed Şahin, Alparslan Şahin, Harun Yüksel, Fatih Mehmet Türkcü, Adnan Yıldırım
15
Comparison of pain scores between patients undergoing panretinal photocoagulation using navigated or pattern scan
laser systems
Comparação de graduação de dor entre os pacientes submetidos à panfotocoagulação usando sistemas de laser navegado ou de padrão de varredura
Umit Ubeyt Inan, Onur Polat, Sibel Inan, Safiye Yigit, Zeki Baysal
19
Congenital and developmental cataract: axial length and keratometry study in Brazilian children
Catarata congênita e do desenvolvimento: estudo do comprimento axial e da ceratometria em crianças brasileiras
Rodrigo Bueno do Prado, Virgílio Figueiredo Silva, Silvana Artioli Schellini, Antonio Carlos Lottelli Rodrigues
24
Sociodemographic status of severely disabled and visually impaired elderly people in Turkey
Estado sociodemográfico de pacientes idosos com incapacidades graves e deficiência visual na Turquia
Sertaç Argun Kıvanç, Berna Akova-Budak, Osman Okan Olcaysü, Sadık Görkem Çevik
30
Intrastromal corneal ring segments delay corneal grafting in patients with keratoconus
Segmentos de anéis intracorneanos protelam o transplante de córnea em pacientes com ceratocone
Luiz Arthur F. Beniz, Gustavo H. Queiroz, Carlos F. Queiroz, Wanessa L. Lopes, Leiser F. Moraes, José Beniz
33
Effects of prostaglandin analogs on blood flow velocity and resistance in the ophthalmic artery of rabbits
Efeitos dos análogos da prostaglandina na velocidade do fluxo sanguíneo e resistência na artéria oftálmica de coelhos
Amália Turner Giannico, Leandro Lima, Gillian C. Shaw, Heloisa H. A. Russ, Tilde Rodrigues Froes, Fabiano Montiani-Ferreira
37
Characterization of cryopreserved primary human corneal endothelial cells cultured in human serum-supplemented media
Caracterização de células endoteliais corneanas humanas primárias criopreservadas cultivadas em meio suplementado com soro humano
Lucas Monferrari Monteiro Vianna, Hao-Dong Li, Jeffrey D. Holiman, Christopher Stoeger, Rubens Belfort Jr., Albert S. Jun
Case Reports
42
Contact lens fitting in a patient with Alport syndrome and posterior polymorphous corneal dystrophy: a case report
Adaptação de lentes de contato em paciente com síndrome de Alport e distrofia polimorfa posterior: relato de caso
Juliana Maria da Silva Rosa, Marcelo Vicente de Andrade Sobrinho, César Lipener
44
Aniridia after blunt trauma and presumed wound dehiscence in a pseudophakic eye
Aniridia após trauma contuso e deiscência presumida da incisão em um olho pseudofácico
Kyeong Hwan Kim, Wan Soo Kim
46
Using thermography for an obstruction of the lower lacrimal system
Utilização da termografia de uma obstrução da via lacrimal baixa
Marco Antonio de Campos Machado, João Amaro Ferrari Silva, Marcos Leal Brioschi, Norma Allemann
48
Choroidal melanoma recurrence after episcleral brachytherapy and transpupillary thermotherapy
Recorrência melanoma de coroide após a braquiterapia episcleral e termoterapia transpupilar
Yrbani Lantigua-Dorville, Maria Antonia Saornil, Ciro García-Alvarez, Elena García-Lagarto
50
&BSMZQPTU-"4*,øBQBNQVUBUJPOJOUIFUSFBUNFOUPGBHHSFTTJWFCSBODIJOHLFSBUJUJTBDBTFSFQPSU
Amputação precoce de pedículo de LASIK para o tratamento de ceratite ramificada agressiva: relato de caso
John Au, Thomas Plesec, Karolinne Rocha, William Dupps Jr., Ronald Krueger
53
Combined transscleral fixation of an artificial iris prosthesis with an intraocular lens
Combinação de fixação transescleral de prótese de íris artificial com lente intraocular
Uzeyır Gunenc, Taylan Ozturk, Gul Arikan, Mahmut Kaya
Review Articles
56
Vitamin A and the eye: an old tale for modern times
A vitamina A e o olho: uma velha história em tempos modernos
Jacqueline Ferreira Faustino, Alfredo Ribeiro-Silva, Rodrigo Faeda Dalto, Marcelo Martins de Souza, João Marcello Fortes Furtado, Gutemberg de Melo Rocha,
Monica Alves, Eduardo Melani Rocha
Letters to the Editor
62
Preoperative usage of ultrasound biomicroscopy in pediatric cataract
Uso pré-operatório de biomicroscopia ultrassônica em catarata pediátrica
Abdullah Kaya
63
;JLBWJSVTSFMBUFEIZQFSUFOTJWFJSJEPDZDMJUJT
Iridociclite hipertensiva associada à infecção por Zika vírus
Bruno M. Fontes
65
Instructions to Authors
Editorial
Oliver Sacks e o seu legado para a ciência da visão e a oftalmologia
Eduardo MElani rocha1, luiza aikawa da SilvEira rocha1, Galton carvalho vaSconcEloS2, Monica alvES3
A little boy enchanted by chemistry and the periodic table elements, a motorcycle young man who crossed a
continental country in so many directions, scuba diver and olympic weightlifter, an obsessive researcher and a
dedicated physician. These are some facets of a brilliant human being. Oliver Wolf Sacks was born in London in
July 9, 1933, graduated in Medicine at Oxford University, England, specialized in Neurology in California, USA, and
worked most of his life in New York City, USA(1). The reason to bring him to an editorial in ABO (Arquivos Brasileiros
de Oftalmologia), a journal dedicated to vision and ophthalmology, is because early in his professional career
he became a writer, describing neurological patients, with particular and talented reports on ocular conditions,
visual symptoms and neuro-ophthalmologic correlations in his writings.
Talented clinicians are becoming rare, talented clinicians with writing talent are even more so. Dr. Oliver Sacks
must be known by the present and future generations of physicians as a writer that wrote in a way that allowed
the reader to know about the disease, but, more importantly, to know how the patient felt and dealt with his
condition, through poetic lines of his numerous books and articles
He became a bestselling and awarded author all over the world, with writings that gave voice, face and action
to patients with chronic, sometimes uncommon, and severe diseases. He published 14 books and authored or
co-authored 58 papers. So far, 14 of his writings became documentaries and three of his tales, including the
famous “Awakenings” inspired films(2).
Overall, he taught the physicians to consider the patient’s perspective in the first place. In his recent published autobiography “On the Move: a life”, he revealed that his style was inspired by medical writers of the XIX
century(3). This influence was clear in references used in his books, in particular in “An Anthropologist on Mars”,
where in seven dramatic stories, he revealed his deep sensitivity to the vision complaints of his patients. The first
case described the suffering of a painter who became color blind after a car accident. The fourth case described
a middle age individual who experienced to see again after decades of blindness. In the fifth and sixth cases
he described patients with different conditions that had in common an intense visual memory and capacity to
draw these views. All of those reports were fulfilled with beautiful wording and illustrations, as well as detailed
local descriptions and medical references, dating back to the beginning of the XVIII century(4).
Among the visual symptoms addressed in his papers were visual hallucinations, metamorphosis and visual
agnosia(5-7). These papers are strongly recommended reading, not just because of the clear and thoughtful
presentation, but also because these subjects are challenging and usually neglected during medical training.
For those who read the “The Island of Colorblind” it will be always engraved on our minds the intriguing
condition of a society where total congenital colorblindness is the norm, and how adaptation may occur(8). These
reflections may teach how to cope with patient fragilities face to a condition that leads to visual deficiency and
how adaptation and acceptance may improve their lives.
Other books, including “Migraine”, his first one, addressed the visual symptoms of this condition with a rich
description and interpretation of the mechanisms, but even for those not related to the eye care, it is certainly
worthwhile reading (Table 1). As he wrote in his autobiography “It seems to me that I discover my thoughts
through the act of writing, in the act of writing”(3).
To understand his patients conditions profoundly he used to search their symptoms and diseases pathways.
This was beautifully reflected in the many partnership he had along his career, such as Crick, Hubel, Wiesel and
Edelman; Nobel laureates who were also important contributors in his works, as many other that influenced
him such as Thom Gun, Luria and Auden. He showed a wonderful way to go further and a great example to be
followed by researchers and clinicians.
His last book was originated by articles published in the New York Times, describing his joy with the life
experience apart from his own drama fighting against an ocular melanoma, first diagnosed in 2006, which
revealed metastases on January 2015(9). It was called “Gratitude” and was a posthumous publication. Sadly, Dr.
Oliver Sacks died on August 30 of 2015. Based on the last words of his autobiography, it is clear that his literature
legacy is not yet finished(3).
Sumitted for publitcation: November 13, 2015
Accepted for publitcation: November 17, 2015
1
2
3
Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de
Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.
Departamento de Oftalmologia e Otorrinolaringologia, Faculdade de Medicina da Universidade
Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
Departamento de Oftalmologia e Otorrinolaringologia, Faculdade de Ciências Médicas, Universidade
Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
http://dx.doi.org/10.5935/0004-2749.20160001
Funding: Financial Support: CNPq, NAP-FTO USP.
Disclosure of potential conflict of interest: None of the authors have any potential conflict of
interest to disclose.
Corresponding author: Eduardo Melani Rocha. Departamento de Oftalmologia, Otorrinolaringologia
e Cirurgia Cabeça e Pescoço. Faculdade de Medicina de Ribeirão Preto - USP. Av. Bandeirantes,
3.900 - Ribeirão Preto, SP - 14049-900 - Brazil - E-mail: [email protected]
V
Table 1. Oliver Sacks books related to visual symptoms and ocular diseases
Title
Year published
Migraine
1970
The man who mistook his wife for a hat
1985
Seeing voices
1989
An anthropologist on Mars
1995
The island of the colorblind
1997
The mind’s eye
2010
Hallucinations
2012
On the move: a life
2015
REFERENCES
1. Wikipedia: the free encyclopedia [Internet]. St. Petersburg (FL): Wikimedia Foundation; 2001. Oliver Sacks.[cited 2015 Nov 17]. Available from: https://en.wikipedia.org/
wiki/Oliver_Sacks
2. Oliver Sacks, M.D [Homepage]. [Cited 2015 Nov 15]. Available from: http://www.
oliversacks.com/inspired-by-sacks/
3. Sacks OW. On the move: a life. Canada: Alfred Knopf; 2015.
4. Sacks OW. An Anthropologist on mars. New York: Alfred Knopf; 1995.
5. Sacks O. Regaining binocular stereoscopic vision in adulthood. A case report. A neurologist’s notebook. Stereo Sue. Why two eyes are better than one. (Reprinted with
VI
6.
7.
8.
9.
permission from The New Yorker, June 19, 2006). Binocul Vis Strabismus Q. 2006;21(3):
160-9. Comment in: Binocul Vis Strabismus Q. 2006;21(3):170.
Herrmann C Jr, Aguilar MJ, Sacks OW. Hereditary photomyoclonus associated with diabetes mellitus, deafness, nephropathy, and cerebral dysfunction. Neurology. 1964; 14:212-21.
Blom JD, Sommer IE, Koops S, Sacks OW. Prosopometamorphopsia and facial hallucinations. Lancet. 2014;384(9958):1998.
Sacks, O. The Island of the colorblind. New York: Alfred Knopf; 1997.
Sacks O. My own life: Oliver Sacks on learning he has terminal cancer. New York Times
[Internet]. 2015 Feb 19. [Cited 2015 Nov 15]. Barczyk H. The opinion pages. Available
from: http://www.nytimes.com/2015/02/19/opinion/oliver-sacks-on-learning-he-hasterminal-cancer.html?_r=1
Original Article
Ophthalmological findings in infants with microcephaly and presumable intra-uterus
Zika virus infection
Achados oftalmológicos em lactentes com microcefalia e infecção presumida pelo vírus Zika
caMila v. vEntura1-3, Mauricio Maia3, Bruna v. vEntura1-3, vanESSa van dEr lindEn4, EvElinE B. araújo1,2, rEGina c. raMoS5, Maria anGEla w. rocha5,
Maria durcE c. G. carvalho5, ruBEnS BElfort jr.3, liana o. vEntura1,2
ABSTRACT
RESUMO
Purpose: In 2015, a twenty-fold increase in the prevalence of microcephaly in
Brazil was reported, and the Ministry of Health associated this abnormal prevalence
with the maternal-fetal Zika virus (ZIKV) transmission.
Methods: We assessed the ophthalmological findings of ten mothers and their
infants that had been clinically diagnosed with ZIKV-related microcephaly and
presented ocular abnormalities, born from May to December 2015.
Results: Seven mothers (70.0%) referred symptoms during pregnancy (malaise,
rash and arthralgia), of which six (85.7%) were in the first trimester. At the time
of exam, no ophthalmological abnormalities were identified in the mothers and
they did not report ocular symptoms during pregnancy. Serology was negative
in all infants for Toxoplasmosis, Rubella, Cytomegalovirus, Syphilis and Human
Immunodeficiency Viruses. Ocular findings included macular alterations (gross
pigment mottling and/or chorioretinal atrophy) in fifteen eyes (75.0%), and optic
nerve abnormalities (hypoplasia with double-ring sign, pallor, and/or increased
cup-to-disk ratio) in nine eyes (45.0%).
Conclusions: Patients presented normal anterior segment and important macular
and optic nerve abnormalities. Further studies will assess the visual significance
of these alterations.
Introdução: No ano de 2015, foi identificado no Brasil um aumento da prevalência
de microcefalia em vinte vezes. Esta malformação foi associada pelo Ministério da
Saúde à transmissão vertical do Zika vírus (ZIKV).
Método: Investigamos dez lactentes com diagnóstico clínico presumido de microcefalia relacionada à ZIKV, que apresentavam anormalidades oculares, nascidos entre
maio e dezembro de 2015.
Resultados: Sete mães (70,0%) relataram sintomas (mal-estar, rash e artralgia)
durante a gestação, sendo seis (85,7%) no primeiro trimestre. No dia da avaliação
nenhuma alteração ocular foi identificada nas mães e elas não relataram sintomas
oculares durante a gestação. Sorologia foi negativa para toxoplasmose, rubéola,
citomegalovírus, sífilis e vírus da imunodeficiência adquirida (HIV) em todos os
lactentes. Os achados oculares incluíram alterações maculares (depósito pigmentar
grosseiro e/ou atrofia coriorretiniana) em 15 olhos (75,0%) e alterações do nervo óptico
(hipoplasia do disco com sinal do duplo anel, palidez e/ou aumento da escavação
papilar) em nove olhos (45,0%).
Conclusões: Os pacientes apresentaram segmento anterior normal e importantes e
anormalidades maculares e do nervo óptico. Estudos futuros vão avaliar a importância
destas alterações visuais.
Keywords: Microcephaly; Zika virus; Ocular findings; Vertical transmission; Retina
Descritores: Microcefalia; Zika vírus; Achados oculares; Transmissão vertical, Retina
INTRODUCTION
Zika virus (ZIKV) is a neurotropic flavivirus related to the Dengue,
Yellow Fever and West Nile viruses(1). Even though it was first identified in the world in 1947(1), the first autochthone transmission in Brazil
was confirmed only in April 2015(2). Since then, it is estimated that
more than one million Brazilians had ZIKV infection, reflecting the
virus’ capacity to cause large-scale outbreaks where the biological
vector Aedes aegypti is endemic(2,3).
Six months following the beginning of the ZIKV outbreak, there
was an unusual increase in newborns with microcephaly in Brazil.
In 2015, 1,248 new suspect cases were registered, representing a
twenty-fold increase when compared to recent years(3).
Maternal-fetal transmission of ZIKV has been previously demonstrated(4). In Brazil, ZIKV has been detected in the amniotic fluid of two
pregnant women of babies with microcephaly and in the tissue of a
newborn with microcephaly that died after birth(3). Thus, the Brazilian Ministry of Health has associated this malformation with ZIKV
intra-uterus infection(3).
Our group recently published the first report on retinal findings
of three infants with microcephaly and presumed ZIKV vertical infec-
Submitted for publication: January 15, 2016
Accepted for publication: January 17, 2016
1
2
3
4
5
Fundação Altino Ventura (FAV), Recife, PE, Brazil.
Hospital de Olhos de Pernambuco (HOPE), Recife, PE, Brazil.
Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina (EPM), Universidade
Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Hospital Barão de Lucena, Recife, PE, Brazil.
Hospital Universitário Oswaldo Cruz (HUOC), Recife, PE, Brazil.
http://dx.doi.org/10.5935/0004-2749.20160002
Funding: No specific financial support was available for this study.
Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of
Corresponding author: Rubens Belfort Jr. Departamento de Oftalmologia. Escola Paulista de Medicina. Rua Botucatú, 831 - São Paulo, SP - 04023-062 - Brazil - E-mail: [email protected]
Approved by the following research ethics committee: Altino Ventura Foundation (protocol
#1.361.143) and was conducted at the Altino Ventura Foundation.
Arq Bras Oftalmol. 2016;79(1):1-3
1
Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection
tion.(5) Here we assessed more patients through a complete ophthalmological exam and report our findings.
METHODS
We report the findings of 10 infants with microcephaly, as defined
by an occipitofrontal circumference more than two standard deviations below the mean for age and sex(3), with clinical diagnosis of ZIKV
vertical infection, and previously diagnosed with ophthalmological
abnormalities referred to the Altino Ventura Foundation, in Recife,
Brazil, for ophthalmologic examination on December 14, 2015.
RESULTS
Six (60.0%) were female. Their mean age at the day of the exam
was 1.9 ± 0.9 months (range: 0.7 to 2.9 months). Computerized tomography scans evidenced cerebral calcifications in all patients. They
were born during the ZIKV infection outbreak, and seven (70.0%) of
the mothers had dengue-like symptoms (malaise, rash and arthralgia)
during pregnancy, of which six (85.7%) were in the first trimester. The
mean age of mothers’ at labor was 29.1 ± 7.3 years (range: 19 to 42
years). Since the infants had negative serology for Toxoplasmosis,
Rubella, Cytomegalovirus and Human Immunodeficiency Virus (HIV),
they were clinically diagnosed with presumable intra-uterus ZIKV in-
fection. At birth, their mean gestational age was 38.3 ± 0.5 weeks (range: 37.6 to 39 weeks), their mean cephalic perimeter was 28.8 ± 1.5 cm
(range: 26 to 31.5 cm), and their mean weight was 2,901 ± 461.6 g
(range: 2,105 to 3,800 g).
The mothers’ ocular examinations were normal. The infants had
normal anterior segment structures; a mean axial length measured
with immersion ultrasound of 18.4 ± 0.6 mm (range: 17.6 to 19.3 mm)
in the right eye (OD) and 18.3 ± 0.4 mm (range: 17.6 to 19.1 mm) in
the left eye (OS).
Horizontal nystagmus was observed in one infant (10.0%). Pupils
were normally reactive, with no afferent pupillary defect, and Hirschberg
testing revealed exophoria in four patients (40.0%) and esophoria in
two (20.0%). Cycloplegic refraction showed a mean spherical equivalent of -0.40 ± 2.40 diopters (D) (range: -3.50 to +2.00) in OD and
0 ± 2.50 D (range: -3.00 to 3.50 D) in OS. The preferential looking
behavior of all infants was present.
Retinal evaluation revealed, optic nerve and macular alterations
were 17 eyes (85%) (Table 1). Optic nerve findings consisted of hypoplasia with the double-ring sign, pallor, and increased cup-to-disk
ratio. The macular abnormalities were foveal reflex loss, mild to gross
pigment mottling and sharply demarcated circular areas of chorioretinal atrophy (Figure 1-3). In all eyes, the retina and choroid were attached, and the retinal vessels had normal distribution and appearance.
Table 1. Funduscopic findings in ten infants with microcephaly and presumable intra-uterus Zika virus infection
Infant
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
10
Eye
D
S
D
S
D
S
D
S
D
S
D
S
D
S
D
S
D
S
D
S
Optic nerve head hypoplasia
X
X
X
X
X
X
X
Optic nerve double-ring sign
Optic nerve head pallor
Cup-to-disk ratio >0.5
X
X
X
X
X
Cup-to-disk ratio >0.7
Foveal reflex loss
X
X
X
X
X
X
Mild macular pigment mottling
Gross macular pigment mottling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
*= sharply demarcated circular area of chorioretinal atrophy on the macula.
Figure 1. Wide-angle fundus image (Retcam®) of the right eye of infant number
8 showing an optic disc hypoplasia with double-ring sign associated with one
sharply demarcated chorioretinal atrophy on the macula.
2
X
X
Chorioretinal macular atrophy*
No ophthalmic abnormalities
X
Figure 2. Wide-angle fundus image (Retcam®) of the right eye of infant number
10 with microcephaly showing an optic disc hypoplasia associated with gross
macular pigment mottling.
X
Ventura CV, et al.
Figure 3. Wide-angle fundus image (Retcam®) of the left eye of infant number
10 with microcephaly showing an optic disc hypoplasia associated with gross
macular pigment mottling and two juxtafoveal chorioretinal atrophic lesions.
DISCUSSION
The 2015 Brazilian ZIKV infection outbreak was the first to have
an association between this virus and the severe complication of
newborns with microcephaly(2,3). In January 2016, we published the first
report of funduscopic lesions related to this condition(5). In the present
paper, we report the ophthalmologic assessment of 10 infants with
abnormal ophthalmic exam, born with ZIKV-related microcephaly.
Seven mothers had dengue-like symptoms in the first or second
trimester of pregnancy, and Toxoplasmosis, Rubella, Cytomegalovirus
and HIV were ruled out by serology. Since approximately 80% of patients with ZIKV infection are asymptomatic, the lack of symptoms
does not rule out the infection(3). Additionally, the only available
method to diagnose ZIKV infection is real time polymerase chain
reaction (PCR), which is useful to detect the virus in the acute phase of illness (first 5 days of acute infection). Since the dengue-like
symptoms were present months before labor, this test is not helpful
in confirming the infection in our infants(3). Thus, the diagnosis of
Zika-related microcephaly was considered when the clinical criteria
of the Brazilian Ministry of Health was fulfilled(3).
All patients had normal anterior segment structures and axial
length(6). Four patients (40.0%) presented myopia, differently than the
hyperopia usually seen in infants(6).
The West Nile Virus, another flavivirus, can cause chorioretinal scars
and granularity when maternal-fetal transmission occurs(7). In our
previous report of three cases of intra-uterus ZIKV infection, gross
macular pigment mottling and macular chorioretinal atrophy were
detected(5). Similarly, in the present report, fifteen eyes (75.0%) had
these macular abnormalities, which had not been reported in other
ZIKV outbreaks worldwide(5). In addition, optic nerve alterations were
observed for the first time. Nine eyes (45.0%) had optic nerve hypoplasia, pallor and increased cup-to-disk ratio. Optic nerve hypoplasia
has been previously associated with cytomegalovirus intra-uterus
infection(8). However, in the present series, these other causes of the
chorioretinal and optic nerve abnormalities were ruled out(9).
The physiopathology of the lesions presented by these infants
may be related to the virus or toxin leading to an inflammatory
reaction. This could result in severe cerebral findings (abnormal
development and cerebral calcification), as well as ocular lesions. We
hypothesize that ZIKV may cause more severe ocular abnormalities
when the infection occurs in the first or second trimester of pregnancy, following the reasoning of other vertical infections, such as
Toxoplasmosis, Rubella and Cytomegalovirus(9). Furthermore, other
unknown factors such as the amount of viral circulation and the
immunologic response of mother and fetus, may play an important
role on the abnormalities observed in the newborns.
In conclusion, we reported the ophthalmologic findings of 10
infants with ZIKV-related microcephaly born during the ZIKV infection
outbreak in Brazil with abnormal ocular exams. The patients had normal anterior segment structures, and important macular and optic
nerve abnormalities. Further studies will assess the visual significance
of these alterations, which will be important to understand the natural
history of this new and devastating manifestation of the ZIKV disease.
REFERENCES
1. Balm MN, Lee CK, Lee HK, Chiu L, Koay ES, Tang JW. A diagnostic polymerase chain
reaction assay for Zika virus. Journal of medical virology 2012;84:1501-5.
2. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de
Vigilância das Doenças Transmissíveis. Protocolo de vigilância e resposta à ocorrência
de microcefalia relacionada à infecção pelo vírus Zika / Ministério da Saúde, Secretaria
de Vigilância em Saúde, Departamento de Vigilância das Doenças Transmissíveis. –
Brasília: Ministério da Saúde; 2015:1-55. Available at: http://portalsaude.saude.gov.br/
images/pdf/2015/dezembro/09/Microcefalia---Protocolo-de-vigil--ncia-e-resposta--vers--o-1----09dez2015-8h.pdf [Accessed: January 15, 2015].
3. Centro de Operações de Emergências em Saúde Pública sobre Microcefalias (COES).
Monitoramento dos casos de microcefalia no Brasil até a Semana Epidemiológica
47. Informe Epidemiológico - Semana Epidemiológica 47. 2015. Available at: http://
portalsaude.saude.gov.br/images/pdf/2015/novembro/30/coes-microcefalias--informe-epidemiol--gico---se-47.pdf. [Accessed: December 17, 2015].
4. Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal
transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro
Surveill. 2014;19(13):pii=20751. Available at: http://www.eurosurveillance.org/
ViewArticle.aspx?ArticleId=20751
5. Ventura CV, Maia M, Bravo-Filho V, Gois AL, Belfort Jr R. Zika virus in Brazil and macular
atrophy in a child with microcephaly. Lancet. 2015. Published Online: 07 January
2016. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736
(16)00006-4/abstract
6. Gordon RA, Donzis PB. Refractive development of the human eye. Archives of ophthalmology 1985;103:785-9.
7. Alpert SG, Fergerson J, Noel LP. Intrauterine West Nile virus: ocular and systemic findings. American journal of ophthalmology 2003;136:733-5.
8. Kaur S, Jain S, Sodhi HB, Rastogi A, Hamlesh. Optic nerve hypoplasia. Oman J Ophthalmol. 2013 May; 6(2)77-82.
9. Mets MB, Chhabra MS. Eye manifestations of intrauterine infections and their impact
on childhood blindness. Survey of ophthalmology 2008;53:95-111.
3
Original Article
Estudo da interface vitreorretiniana em pacientes com degeneração macular relacionada à idade
Maíra dE frança MartinS1, Edio volpatto2, paula EMEry3, pEdro duraES SErracarBaSSa3
ABSTRACT
Purpose: To assess whether hyaloid adhesion is more prevalent in patients with
age-related macular degeneration (AMD) than in control patients and to evaluate whether it is more prevalent in exudative AMD than in non-exudative AMD.
Methods: This was a cross-sectional, controlled analytical study. Patients from
the Ophthalmology Department of the Public Service Hospital of the State of
São Paulo were included if they were diagnosed with AMD that was confirmed
by fundus biomicroscopy and fluorescein angiography. Patients were divided
into three groups: patients without a vitreoretinal disease (controls), patients with
exudative AMD, and patients with non-exudative AMD. For the optimal study of
the vitreoretinal interface, all patients were subjected to spectral-domain optical
coherence tomography (SD-OCT; Cirrus HD-OCT, version 4000; Carl Zeiss Meditec)
and ultrasonography (UltraScan®, Alcon). Results with p values of ≤0.05 were considered statistically significant.
Results: We assessed 75 eyes of 23 patients with AMD (14 women and nine men)
and 15 the control patients (11 women and four men). In total, 33 eyes had AMD
that was consistent with the inclusion criteria, of which 11 had the non-exudative
form (non-atrophic) and 22 had the exudative form (11 active and 11 disciform
scars). Adherence was observed in eight eyes in the control group (26.67%), in
seven eyes with exudative AMD (31.82%), and in five eyes with non-exudative
AMD (45.45%).
Conclusion: Patients with exudative and non-exudative forms of AMD did not
present with higher vitreoretinal adhesion than control patients as assessed by
SD-OCT and ultrasound. Moreover, patients with exudative AMD (neovascular
membrane and disciform scar) did not reveal a higher adherence than those with
non-exudative AMD when evaluated by the same methods.
RESUMO
Objetivo: Avaliar se a adesão hialoidea é mais prevalente em pacientes com degeneração macular relacionada a idade (DMRI) (exsudativa e não exsudativa) comparado
ao grupo controle e avaliar se a prevalência é maior na forma exsudativa comparada
a forma não exsudativa.
Métodos: Trata-se de um estudo transversal, analítico, de grupo controle, com os pacientes atendidos no Departamento de Retina do Serviço de Oftalmologia do Hospital
do Servidor Público Estadual de São Paulo (HSPE), que tiveram o diagnóstico de DMRI
confirmado após a biomicroscopia de fundo e angiofluoresceinografia. Os pacientes
foram divididos em três grupos, um composto por pacientes sem doenças vitreorretinianas (30 olhos), outro pacientes com DMRI exsudativa (22 olhos) e o terceiro grupo
por pacientes com DMRI não exsudativa (11 olhos). Para melhor estudo da interface
vitreorretiniana, todos os pacientes foram submetidos aos exames de SD-TCO (Cirrus
HD-TCO, versão 4000; Carl Zeeis Meditec) e ultrassonografia (UltraScan®, Alcon).
Foram considerados significativos os resultados com valor de p≤0,05.
Resultados: Foram avaliados 75 olhos de 23 pacientes com DMRI e 15 no grupo controle, sendo que apenas 33 olhos que apresentavam DMRI obedeciam aos critérios de
inclusão, sendo 11 pertencentes à forma seca (nenhuma forma atrófica) e 22 à forma
exsudativa (11 de forma ativa e 11 disciforme). A adesão foi encontrada em oito olhos
no grupo controle (26,67%), em sete olhos com DMRI exsudativa (31,82%) e em cinco
olhos no grupo DMRI não exsudativa (45,45%).
Conclusão: Neste estudo, pacientes com DMRI (formas exsudativa e não exsudativa)
não apresentaram maior adesão vitreorretiniana quando comparados ao grupo
controle, ao serem avaliados através SD-TCO (Cirrus HD-TCO, versão 4000; Carl Zeeis
Meditec) e ultrassonografia (UltraScan®, Alcon). Neste estudo, pacientes com DMRI
exsudativa (ativa e disciforme) não apresentaram maior adesão quando comparados
à forma seca, ao serem avaliados pelos mesmos métodos.
Keywords: Macular degeneration/ultrasonography; Macula lutea; Tomography
optical coherence/methods; Tissue adhesion
Descritores: Degeneração macular/ultrassonografia; Macula lútea; Tomografia de
coerência óptica/métodos; Aderências teciduais
INTRODUCTION
Age-related macular degeneration (AMD) is a disease initially characterized by the presence of drusen and abnormal pigmentation of
the retinal pigment epithelium (RPE) and later by geographic atrophy,
choroidal neovascularization, RPE detachment, and fibrosis. Of the
four leading causes of blindness, AMD is the only one for which prophylaxis and treatment remains unclear. This is mainly because of a
lack of knowledge with regard to its etiology and pathophysiological
mechanisms involved in the different stages of the disease(1). Currently,
there are several treatments; however, none of these appear to be
sufficiently effective. Therefore, a more extensive study of AMD pathophysiology is necessary to optimize treatment(2-9).
AMD appears to be a multifactorial disease. Genetics is likely to play a
key role in its occurrence; furthermore, oxidative stress, ischemia, aging
of RPE, and inflammation were other possible etiological factors(10,11).
A tyrosine-histidine change at the 402th amino acid position in the
Submitted for publication: May 27, 2015
Accepted for publication: November 6, 2015
1
2
3
Curitiba, Paraná, PR, Brazil.
Campo Grande, Mato Grosso do Sul, MS, Brazil.
Department of Ophthalmology, Retina section, Hospital do Servidor Público do Estado de São
Paulo, HSPE, São Paulo, SP, Brazil.
4
Corresponding author: Maíra de França Martins. Rua Capitão Souza Franco, 95 - Curitiba, PR
80730-420 - Brazil - E-mail: [email protected]
Approved by the following research ethics committee: Hospital do Servidor Público do Estado de
São Paulo. CEEA: 17729713.0.0000.5463.
http://dx.doi.org/10.5935/0004-2749.20160003
Martins MF, et al.
complement factor H on the chromosome 1 is strongly associated
with AMD(12-14), along with factors such as race, age, and smoking. An
inflammatory cycle is also believed to be involved (including immune
complex formation, complement activation, extracellular matrix proteolysis, and choroidal T cell and other cell activations), which damages
RPE with concomitant degeneration of photoreceptor cells that can
extend into more internally located retinal layers.
Although AMD primarily comprises the external layers of the
retina, the vitreous may play a role in its etiopathogenesis and/or progression and that inflammation most likely begins in RPE and may
even reach the vitreoretinal interface(15). Moreover, some reports have
demonstrated a higher rate of vitreoretinal adhesion in AMD(16-22),
perhaps contributing to the unfavorable evolution in some cases and/or
an insignificant response to intravitreal anti-vascular endothelial growth
factor (anti-VEGF).
This study aimed to assess whether hyaloid adhesion is more prevalent in patients with AMD than in control patients and to evaluate
whether the prevalence is higher in exudative or non-exudative AMD.
METHODS
This is a cross-sectional analytical study with a control group.
Patients were recruited from the Ophthalmology Department of the
Public Service Hospital of the State of São Paulo. Patients who received a diagnosis of AMD that was confirmed by fundus biomicroscopy
and fluorescein angiography from May 2010 to November 2014 were
included. Eyes in all stages of non-exudative (drusen, pigment alterations, and atrophy) and exudative AMD (active or disciform scar) were
included. The study was approved by the Ethics Committee of Hospital do Servidor Público do Estado de São Paulo and all patients read
and then signed a consent form prior to the initiation of the study.
We excluded all patients presenting with other vitreoretinal afflictions concomitant with AMD and/or previous eye surgery and/or any
previous intraocular treatment, such as laser or intravitreal injection
and/or previous history of ocular trauma or myopia equal or higher
than two diopters.
For optimal study of the vitreoretinal interface, all patients underwent ultrasonography (USG; UltraScan®, Alcon) and spectral-domain
optical coherence tomography (SD-OCT) imaging (Cirrus HD-OCT,
version 4000; Carl Zeiss Meditec). All USG examinations were performed by the same examiner using the transpalpebral contact
technique with a 10-MHz probe and 75-dB gain in modes A and B.
SD-OCT was performed by a different examiner following drug-induced mydriasis (10% phenylephrine, 3 drops); however, with respect to
the USG examinations, all procedures were performed by the same
examiner. We used the 5-line raster scan mode (4,096 A-scans on
each of the five lines) and Macular Cube 512 × 128. Only the macular
area was evaluated.
Adherence was considered when an average reflectivity line was
observed to be partially adherent to the nerve fiber layer. Adhesion
was excluded when this line was observed above the nerve fiber
layer. When the line was not observed, USG was evaluated to determine whether the hyaloid was anterior or not detached. We considered
adherence to be present when the hyaloid was visually adherent to
the retinal surface of the macular area in SD-OCT, when it was visually
adherent to the macula in USG and SD-OCT, and when the hyaloid
was not visible by either method. Non-adherence was considered
when the hyaloid was visually non-adherent to the retinal surface in
the macular area in the SD-OCT, when it was visually non-adherent
to the macula in USG and SD-OCT, whether by total or partial hyaloid
detachment (adherent to the optic nerve).
For comparative analysis, we selected patients without vitreoretinal alterations, with similar average ages, and who did not meet the
exclusion criteria.
To investigate the relationship between vitreoretinal adhesion
and AMD, we performed a non-parametric Fisher’s exact test consi-
dering two forms of the disease: exudative (active membrane or disciform scar) and non-exudative AMD (drusen or geographic atrophy),
with a third group serving as the control. Age uniformity was verified
by analysis of variance (F=1.959, p=0.131). Results with p values of
≤0.05 were considered statistically significant.
RESULTS
We assessed 75 eyes of 23 patients with AMD (14 women and
nine men) and 15 in control group (11 women and four men). In total,
33 eyes had AMD that was consistent with the inclusion criteria; of
which 11 had the non-exudative form (non-atrophic) and 22 had the
exudative form (11 active and 11 disciform scars).
In the AMD group, we observed two patients with the non-exudative form in one eye each and the disciform scar in the contralateral
eye, one patient with disciform scars in both eyes, three patients with
the non-exudative form in one eye each and a choroidal neovascular
membrane (CNVM) in the other eye, five patients with disciform scars
in one eye each and CNVM in the other eye, one patient with the nonexudative form in both eyes, and one patient with CNVM in both eyes.
Twelve eyes were excluded from the study for the following reasons: Ten were pseudophakic (three disciform, one atrophic, and six
active CNVM) and two had already received an anti-VEGF injection.
One was excluded for having received intravitreal injections (active
form) and another for undergoing laser treatment (disciform scar).
The average age of the patients was similar across the groups
(Table 1).
All eyes were assessed by SD-OCT and USG in a complementary
manner, and adhesion was found in 7/22 (31.82%) eyes with exudative AMD, in 5/11 (45.45%) eyes with non-exudative AMD, and in 8/30
(26.67%) eyes in the control group. Non-adhesion was diagnosed in
15/22 (68.18%) eyes with exudative AMD, in 6/11 (54.55%) eyes with
non-exudative AMD, and in 22/30 (73.33%) eyes within the control
group (Table 2). While separately evaluating cases of exudative AMD,
we found adhesion in 6/22 (27.27%) eyes with active neovascular
membranes and in 1/22 (4.54%) eyes with disciform scars. Adhesion
was absent in 5/22 (22.72%) eyes with active neovascular membranes
and in 10/22 (45.45%) eyes with disciform scars.
Table 1. Average age, standard deviation, and 95% confidence intervals for patients in each study group. Analysis of variance (F=1.959,
p=0.131) was used for verification, and no difference in age was observed the three groups
Group
Average ± standard deviation
95% confidence interval
Control
69.64 ± 06.19
67.24-72.04
Dry AMD1
77.18 ± 09.61
70.72-83.64
Exudative AMD
72.45 ± 11.64
67.01-77.90
AMD= age-related macular degeneration.
1
Table 2. Comparison1 of vitreoretinal adhesion rates between age-related macular degeneration (AMD) and control groups
Vitreoretinal adhesion
Group
Adhesion
No adhesion
Total
Control
8 (26.67%)
22 (73.33%)
30
Exudative AMD (p=0.762)
7 (31.82%)
15 (68.18%)
22
Dry AMD (p=0.280)
5 (45.45%)
06 (54.55%)
11
20
43
63
Total
Absolute frequency and percentage within each group [control, non-exudative agerelated (dry) macular degeneration and exudative age-related macular degeneration]
related to vitreoretinal adhesion, evaluated by spectral domain optical coherence tomography and ultrasonography.
1
5
In six patients with AMD, SD-OCT revealed vitreoretinal adhesion
(Figure 1), whereas USG detected two cases of partial posterior vitreous detachment (PVD), with both being adherent to the macula,
as shown in figure 2 (in four cases, there was no PVD). In the 25 cases
of AMD in which the hyaloid was not visible by SD-OCT (Figure 3),
USG detected total PVD in five eyes, mobile vitreous membranes in
six eyes, and partial PVD in 14 eyes (adherent to the optic nerve). In
one of the two cases in which SD-OCT revealed total detachment of
the hyaloid in the macular area, while USG revealed no detachment.
USG detected mobile vitreous membranes in all nine cases in the
control group that had hyaloid adhesion in the macula on SD-OCT
examination. In 19 cases in which the hyaloid was not visualized in
SD-OCT, USG detected eight cases of partial PVD (adherent to the
optic nerve), eight cases of total PVD, and three cases with mobile
vitreous membranes. In the two cases in which the hyaloid was
non-adherent, USG revealed partial PVD in one case (adherent to the
optical nerve) and total PVD in the other case.
Moreover, vitreoretinal adhesion was not associated with AMD
presence. The proportion of patients with and without adhesion
who were evaluated by SD-OCT and USG did not differ between the
AMD (non-exudative and exudative) and control groups (X2=0.682;
p=0.432). Thus, given the study conditions, vitreoretinal adhesion was
neither higher nor lower in patients with AMD than in control patients.
The proportion of patients with and without adhesion who were
evaluated by SD-OCT and USG did not differ between the non-exudative and exudative AMD groups (X2=0.589; p=0.471). Thus, given
the study conditions, vitreoretinal adhesion was neither higher nor
lower in patients with the exudative form than in those with the
non-exudative form.
The proportion of patients with and without adhesion who were
evaluated by OCT and US did not differ between the non-exudative
AMD and control groups (X2=1.312, p=0.280) or between the exudative AMD and control groups (X2=0.164, p=0.762).
Figure 1. Image obtained with spectral domain optical coherence tomography
(Cirrus HD-OCT), showing the hyaloid adhering to the macular area (arrows).
DISCUSSION
There is still much speculation regarding the role of hyaloid in
AMD. The vitreous is an important component in the pathophysiology of several retinal diseases, and hyaloid adhesion is a poor prognostic factor in some. Consequently, questions have been raised
regarding the supposed role of hyaloid adhesion in AMD, with several
theories being postulated. On the one hand, hyaloid adhesion has
been only considered as a risk factor of AMD progression, whereas
on the other hand, it has been only considered to be part of its pathophysiology. In other studies, it has been considered as a poor
prognostic factor, predisposing either to the development of the
exudative form or to a worse response to treatment.
Some studies suggest that hyaloid adhesion may induce a mild
chronic retinal inflammation(18,19). This is then posited to hinder oxygen penetration and to cause chronic ischemia or VEGF retention in
the macular area. Furthermore, hyaloid traction may lead to RPE disruption, which is known to induce the appearance of the neovascular
membrane. Embryological, molecular, and structural similarities have
been demonstrated between Bruch’s membrane and the internal
limiting membrane, thus supporting the theory that hyaloid may play
a role in AMD(23).
We assessed the presence of vitreoretinal adhesion in patients
with AMD to test its prevalence against that of a control group. When
the hyaloid detachment develops close to the retina, the presence of
vitreoretinal adhesion or traction can be difficult to diagnose using
USG; therefore, we used SD-OCT for optimal assessment. However,
SD-OCT images in cases with either total hyaloid adhesion in the macular area or total detachment with hyaloid anteriorization are similar
(the hyaloid is invisible); thus, the use of USG becomes indispensable.
Figure 2. Image obtained by ultrasonography using a 10-MHz transducer. The
hyaloid adhering to the neovascular membrane is visible.
Figure 3. Image obtained by spectral domain optical coherence tomography (Cirrus
HD-OCT). The hyaloid is not evident.
6
Martins MF, et al.
Furthermore, we chose not to distinguish between adhesion and
traction because it has already been performed in some studies. Therefore, the objective was limited to assessing whether the prevalence
of adherent hyaloid was higher in patients with AMD than in patients
of the same age without AMD because it is known that the incidence
of PVD increases with age.
In this analysis, we did not observe a higher vitreoretinal adhesion
in patients with AMD than in the control patients, and we did not
determine higher adhesion rates in patients with the exudative form
than in those with the non-exudative form.
However, the evidence for a higher prevalence of vitreous adhesion in AMD remains conflicting. Some studies demonstrated higher
hyaloid adhesion at all stages of AMD(17,19,20), whereas others demonstrated higher adhesion rates in the initial phases only(18).
Vitreomacular adhesion was assessed in patients with AMD(17) by
dividing patients into exudative AMD, non-exudative AMD, and control groups. The presence of hyaloid adhesion in the macular area was
analyzed by OCT/confocal scanning laser ophthalmoscopy, whereas
the presence of total PVD was evaluated by fundus biomicroscopy.
Adhesion in patients with AMD was higher than in control patients;
however, there was no difference between patients with exudative
AMD and those with non-exudative AMD.
In another study(20), patients were divided in the same manner;
however, only the presence of total PVD was assessed with USG. This
approach also led to identifying a higher percentage of total PVD in
the control group; however, no difference was observed when nonexudative and exudative AMD were compared.
In another analysis(24), when adhesion was assessed by SD-OCT
(Spectralis OCTTM; Heidelberg Engineering, Heidelberg, Germany) and
fundus biomicroscopy in patients with active exudative AMD only,
the result was different because of the higher rate of non-adhesion
within the study group.
Another study(25) evaluated cases of non-exudative AMD that
were classified as high risk (i.e., category IV according to the Age-Related Disease Study) using patients with a CNVM in one eye and nonexudative high-risk AMD in the contralateral eye. Hyaloid adhesion
was assessed by the time-domain OCT (OCT3, Carl Zeiss, Meditech,
Dublin, CA), SD-OCT (Cirrus Version, Carl Zeiss) and the presence of
the Weiss ring on biomicroscopy examination, thus concluding that
there was no significant influence of vitreomacular adhesion on the
development of the exudative form.
Furthermore, another study with a similar design(22) assessed hyaloid adhesion by SD-OCT (Stratus OCT3, Zeiss Humphrey, San Leandro,
CA) in patients with CNVM in one eye and no signs of CNVM or drusen
in the contralateral eye. The authors concluded that vitreoretinal
adhesion might be a risk factor for exudative AMD because most eyes
with adhesion exhibited active exudative AMD.
In another study(19), patients were divided in a similar manner
as in previous studies(17,20) but with the control group comprising
contralateral eyes, as detailed elsewhere (22,25). Using USG and SD-OCT
(Stratus III, Carl Zeiss, San Leandro, California, USA) to verify the status of the hyaloid, the authors discovered higher adhesion rates
in patients with exudative AMD than in controls and patients with
non-exudative AMD.
In an alternative assessment of hyaloid adhesion in AMD(18), two
groups were formed; one with druse in one eye and CNVM in the contralateral eye and another with atrophy in one eye and disciform disease
in the contralateral eye. The presence of vitreomacular adhesion was
evaluated by SD-OCT (OCT-SLO, OCT1000, and Stratus III OCT), and
the presence of PVD was evaluated by USG. Similar to a previous
study(22), it was concluded that total PVD might be protective against
CNVM, whereas adhesion may be a risk factor for CNVM.
Further, in an evaluation of cases of CNVM using SD-OCT (OCT3,
Carl Zeiss)(21), it was reported that most cases presented with abnormalities in the vitreoretinal interface.
When analyzing the existing studies, one will notice contradictory and inconclusive results, with many different methodologies, apparatuses, and groups being analyzed.
Given the results of this study, we believe that the hyaloid does
not have a significant role in AMD pathophysiology. However, in cases
of adhesion and CNVM, we observed that the hyaloid was always
adherent in the membrane area, suggesting that a relationship could
indeed exist between CNVM and hyaloid adhesion, as demonstrated
in other studies(15,18,19,21,22).
A possible explanation is that a more intense retinal inflammation
could be present in some cases of exudative AMD.
Nevertheless, questions remain as to whether such an inflammation would be a cause or consequence. Similarities in molecular
composition and structural organization of the vitreoretinal interface
and between the retina and RPE suggest that both interfaces may be
subject to the same aging processes and that abnormalities of the
first may alter or amplify the degenerative processes of the latter and
vice-versa(23).
In this study, AMD stages (CNVM vs. disciform) were not separately evaluated; however, the percentage of adhesion in eyes with
CNVM (27.7%) was higher than in eyes with disciform disease (4.54%).
We failed to determine higher adhesion rates in the exudative group
because of perhaps the high incidence of non-adhesion in the disciform group (10/22).
Moreover, it is possible that hyaloid detachment is a natural process in AMD evolution, such as atrophy and disciform scar formation,
which develops once the appearance of Muller cells would affect
the integrity of the internal limiting membrane, thereby promoting
hyaloid detachment. This hypothesis is consistent with previous observations(18) and with our finding that adhesion occurred in 27.7%
of the eyes with CNVM and in only 4.54% of those with disciform disease. However, further discussion is beyond the scope of this paper.
As demonstrated by a few studies, the hyaloid may only act as a
poor prognostic factor for improving visual acuity following treatment,
particularly when there is a traction in the macular area(24,26-28). In those
cases, there is a disruption of the retinal layers that was caused not only
by CNVM but also by hyaloid traction, thus leading to a worse visual
prognosis. Alternatively, if the hypothesis of inflammation equally
developing in the vitreoretinal interface and between the retina and
RPE is confirmed, it would be conceivable that more severe degrees
of inflammation result in both CNVM and in adhesion/traction/epiretinal membranes, as observed in a study(21). To improve visual prognosis
of those cases, removal of the hyaloid may be justifiable.
We believe that despite the limited sample size of this study, the
role of the hyaloid remains questionable. Further research must continue with greater degrees of standardization in the groups evaluated
and in the methods used.
It is important to pay special attention to the study of the hyaloid
in cases with high-risk non-exudative AMD, as performed by a previous
study(25), particularly before recommending vitrectomy as a preventive measure against CNVM or macular atrophy(29).
Thus, it must be evaluated whether performing vitrectomy would
adequately treat AMD. Finally, it is necessary to clarify whether removing the vitreous would reduce the incidence of AMD or just that of
CNVM or if it would affect visual prognosis.
CONCLUSION
In this study, when assessed by SD-OCT and USG, patients with exudative and non-exudative forms of AMD did not present with higher
vitreoretinal adhesion than control patients without AMD. Moreover,
exudative AMD (CNVM and disciform) was not associated with higher
levels of adhesion when compared with non-exudative AMD.
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Original Article
Serous retinal detachment in patients with macular edema secondary to
branch retinal vein occlusion
Descolamento seroso de retina em pacientes com edema macular secundário à oclusão de ramo
da veia retiniana
Erkan cElik1, EminE Doğan1, Elif BEtul turkoGlu1, Burçin çakir1, GurSoy alaGoz1
ABSTRACT
RESUMO
Purpose: The aim of the present study was to evaluate visual acuity (VA) and central
macular thickness (CMT) to assess the influence of serous retinal detachment (SRD)
in eyes with macular edema (ME) secondary to branch retinal vein occlusion (BRVO).
Methods: Sixty-one eyes with BRVO from 61 patients with ME were analyzed
and divided into two groups according to the spectral domain optical coherence
tomography (OCT) findings of SRD and cystoid macular edema (CME). All patients
underwent complete ophthalmic examinations and OCT measurements (Cirrus,
Carl Zeiss Meditec Inc, Dublin, CA). Patients with marked retinal hemorrhage,
diabetic retinopathy, previous laser photocoagulation, and/or intravitreal injection
were excluded.
Results: The mean age of included patients (37 males, 24 females) was 65.4 ±
11.4 (53-77) years. There were 21 patients with SRD and 40 patients with CME.
All of the 21 patients with SRD had CME. VA was significantly worse in the SRD
group compared with the CME (non-SRD) group (0.82 ± 0.34 logMAR vs 0.64 ±
0.38 logMAR; P=0.005). Conversely, CMT was significantly greater in the SRD group
than in the CME group (465 ± 115 µ vs 387 ± 85 µ; P=0.00004).
Conclusion: SRD may be associated with decreased VA. The prognosis of patients
with BRVO and SRD requires further investigation.
Objetivo: O objetivo deste estudo foi investigar a acuidade visual (VA) e espessura
macular central (CMT) para avaliar a influência do descolamento seroso da retina
(SRD) em olhos com edema macular (ME) secundário a oclusão de ramo da veia da
retina (BRVO).
Método: Sessenta e um olhos de 61 pacientes com oclusão de ramo da veia da retina
e edema macular foram analisados e divididos em dois grupos, de acordo com os
achados na a tomografia de coerência óptica por domínio espectral (OCT), de edema
macular cistóide (CME) e descolamento seroso da retina. Todos os pacientes foram
submetidos a exame oftalmológico completo e exame de tomografia de coerência
óptica (Cirrus, Carl Zeiss Meditec Inc, Dublin, CA). Os pacientes com hemorragia acentuada da retina, retinopatia diabética, fotocoagulação a laser e/ou injeção intravítrea
prévia foram excluídos.
Resultados: A idade média dos pacientes (37 homens, 24 mulheres) foi de 65,4 ± 11,4
(53-77) anos. Havia 21 pacientes com SRD e 40 pacientes com edema macular cistóide.
Todos os 21 pacientes com SRD também apresentaram edema macular cistóide. VA
foi significativamente pior no grupo SRD do que no grupo edema macular cistóide
(non-SRD) (0,82 ± 0,34 vs 0,64 ± 0,38 logMAR, p=0,005). Por outro lado, a espessura
macular central foi significativamente maior no grupo descolamento seroso da retina
do que no grupo edema macular cistóide (465 ± 115 μ vs 387 ± 85 μ, p=0,00004).
Conclusão: Observou-se que o descolamento seroso da retina em si pode estar relacionado à diminuição de acuidade visual. Os prognósticos dos pacientes com
oclusão de ramo da veia da retina e descolamento seroso da retina precisam ser
adequadamente investigados.
Keywords: Macular edema/etiology; Retinal detachment; Retinal vein occlusion/
complications; Optical coherence tomography; Visual acuity
Descritores: Edema macular/etiologia; Descolamento retiniano; Oclusão da veia
retiniana/complicações; Tomografia de coerência óptica; Acuidade visual
INTRODUCTION
Branch retinal vein occlusion (BRVO) is the second most common
retinal vascular disorder after diabetic retinopathy(1,2). The typical
presentation of BRVO is painless visual loss with flame-shaped retinal hemorrhages, cotton wool spots, and venous dilatation largely
localized to the area drained by the occluded branch retinal vein(3).
In BRVO, increased intravascular pressure causes dysfunction of the
endothelial blood-retinal barrier, resulting in increased vascular
permeability, eventually leading to cystoid macular edema (CME).
Increased interstitial oncotic pressure can also interrupt capillary perfusion and lead to ischemia(4,5).
Macular edema is the most frequent cause of visual loss in patients with BRVO. Optical coherence tomography (OCT) studies have
demonstrated that macular edema secondary to BRVO is frequently
associated with CME, serous retinal detachment (SRD), and inner retinal thickening. SRD has been reported in 15%-80% of patients with
BRVO(6-8). Although the mechanism underlying SRD has yet be fully
elucidated, extensive leakage of fluid from capillaries in the ischemic
retina affected by BRVO may lead to accumulation in the subretinal
space and thus cause serous detachment(9). Recently, studies have
demonstrated that SRD and the loss of the photoreceptor layer leads
to damage to the retinal pigment epithelium and neurosensory retina, contributing to the poor visual prognosis of BRVO(10-12).
In the present study, we aimed to assess the effect of SRD on both
visual acuity (VA) and central macular thickness (CMT) in patients
with BRVO and macular edema.
Submitted for publication: April 14, 2015
Accepted for publication: October 20, 2015
1
Sakarya University Medical Education and Research Hospital, Sakarya, Turkey.
Disclosure of potential conflicts of interest: None of the authors have any potential conflict of
Corresponding author: Elif Betul Turkoglu. Akdeniz University Medical Education and Research
Hospital. Antalya, 07100 - Turkey - E-mail: [email protected]
http://dx.doi.org/10.5935/0004-2749.20160004
9
Serous retinal detachment in patients with macular edema secondary to branch retinal vein occlusion
METHODS
We retrospectively reviewed the medical records of 61 eyes of 61
patients with macular edema secondary to BRVO, previously examined at the Department of Ophthalmology, Sakarya University Medical Education and Research Hospital, from February 2010 to January
2014. The present study was approved by the Institutional Review
Board and adhered to the tenets of the Declaration of Helsinki.
Each patient had unilateral BRVO. All patients had CME and/or
SRD (≥300 µ on OCT). Patients were divided into two groups according to the spectral domain OCT findings of SRD and CME: patients
with CME (Group 1) and patients with SRD (Group 2). All eyes in the
SRD group had CME. CME was defined as hypo-reflective intraretinal
cavities on OCT. On the other hand, SRD was defined as the presence
of a non-reflective cavity with minimal shadowing of the underlying
tissues due to subretinal fluid accumulation leading to the detachment of the neurosensory retina. The exclusion criteria included prior
ocular surgery, diabetic retinopathy, previous laser photocoagulation
and/or intravitreal injection, history of ocular inflammation, and marked
retinal hemorrhage, including macular bleeding involving the subfoveal or intrafoveal spaces.
At initial examination, patients underwent complete ophthalmologic examinations, including VA, slit-lamp biomicroscopy, funduscopy, fundus color photography, fluorescein angiography, and
spectral-domain OCT (Cirrus, Carl Zeiss Meditec Inc, Dublin, CA) analysis to measure the CMT and evaluate the presence or absence of
CME/SRD. OCT images were obtained from each eye following pupil
dilation by the same operator using the Macular Cube 512*128 scan
Table 1. Clinical features of the CME and SRD groups
Findings
CME (N: 40)
SRD (N: 21)
P value
Age (years)
65.2 ± 6.3
65.8 ± 5.6
0.611
16/24
8/13
0.887
04.4 ± 1.9
04.2 ± 2.2
0.684
28
15
0.885
Gender (female/male)
Duration of BRVO (months)
Hypertension
BRVO= branch retinal vein occlusion; CME= cystoid macular edema; SRD= serous retinal
detachment.
protocols. Scans with a signal strength of ≥7 were used for analysis.
Retinal thickness was defined as the distance between the inner retinal surface of the neurosensory retina and the retinal pigment epithelium. Best-corrected VA was measured using a Snellen Chart and
then converted into a logarithm of the minimum angle of resolution
(logMAR) for statistical comparison.
Statistical analysis was performed with Python version 2.7.6 and
scipy library version 0.13.3. The results are presented as the mean ±
standard deviation. Welch’s test was used to compare normally distributed unpaired continuous variables between groups. Two-tailed
P-values of less than 0.05 were considered statistically significant.
RESULTS
The characteristics of the CME and SRD groups are summarized
in table 1. Of the 61 patients with BRVO, 40 were assigned to the CME
group and 21 to the SRD group. All 21 patients in the SRD group had
both SRD and CME.
No differences in mean age, female/male ratio, duration of BRVO,
and prevalence of hypertension were observed between the CME
and SRD groups (P=0.611, P=0.887, P=0.684, and P=0.885, respectively; Table 1).
VA was significantly worse in the SRD group compared with the
CME (non-SRD) group (0.82 ± 0.34 logMAR vs 0.64 ± 0.38 logMAR,
P=0.005). Conversely, CMT was significantly greater in the SRD group
than in the CME group (465 ± 115 µ vs 387 ± 85 µ, P=0.00004; Figure 1).
DISCUSSION
This retrospective study evaluated the relationship between the
presence of SRD and VA and CMT in BRVO patients with macular
edema. Although SRD is a common feature on OCT images, there is a
lack of data regarding the influence of SRD on VA, CMT, and response
to therapies in BRVO patients. In the present study, 21 of 61 eyes
(34%) with macular edema secondary to BRVO demonstrated retinal
swelling with SRD. Additionally, all SRD patients also had CME. Eyes
with SRD had greater foveal thickness with CME. We also observed
significantly lower mean VA (logMAR) in the SRD group compared to
the CME group, corroborating previous reports(10-13).
Macular edema is the leading cause of visual impairment in BRVO
and may be accompanied by various morphological changes. The
application of OCT imaging has provided qualitative analysis of the
VA= visual acuity; CMT= central macular thickness, SRD= serous retinal detachment; CME= cystoid macular edema.
Figure 1. VA and CMT in the SRD and CME (non-SRD) groups. VA was significantly worse in the SRD group compared with the CME (non-SRD) group.
CMT was significantly greater in the SRD group than in the CME group.
10
Celık E, et al.
different retinal layers(14). The morphological diversity of the retinal
changes associated with macular edema include sponge-like retinal
swelling, cystic changes, and SRD(15). Retinal swelling and CME are
typically caused by leakage from retinal vessels observed as retinal
thickening and oval hyporeflective areas with intraretinal cystoid
spaces on OCT. In SRD, fluid accumulates between the neurosensory
retina and the RPE, seen as hyporeflective spaces on OCT(14,15).
A variety of mechanisms have posited to underlie the pathogenesis of SRD. It was previously thought that SRD was associated with
hemodynamic overload and disrupted function of the retinal pigment epithelium due to retinal ischemia(16). Marmor and Murakami
speculated that vitreal hyperosmolarity may be a possible mechanism underlying the development SRD by allowing the flow of fluid
from the vitreous to the choroid(17,18). Ota suggested that small breaks
on the external surface of the neurosensory retina, which connects
the swollen outer retina, may also be responsible for SRD(7). In the
present study, we performed a detailed analysis of the macula and
inner/outer segment of photoreceptors by OCT and found no defects
on the external surface of the retina above the site of SRD in any of
the evaluated eyes.
The inner half of the fovea includes an inverted cone-shaped
zone of Müller cells (the Müller cell cone), the apex of which is located
at the external limiting membrane (ELM) of the fovea centralis. The
cytoplasm of cells in the Müller cell cone extends obliquely outward
and forms the internal limiting membrane at the clivus of the foveal
depression(19,20). In eyes with BRVO, leakage from the affected retinal
capillaries accumulates around the fovea and causes retinal thickening,
which may cause the internal limiting membrane at the clivus of the
fovea to protrude, leading to the development of CME(15). In this case,
the cytoplasm of the Müller cell cone extends perpendicularly in the
walls of the foveal cystoid spaces. When leakage increases, further
traction on the Müller cell cone leads to traction on the inner and outer
segments of the foveal photoreceptors resulting in a small area of
retinal detachment at the fovea. Subsequently, SRD occurs when the
ELM barrier breaks down at the fovea(15). Loss of the ELM barrier often
results in damage to foveal photoreceptors in the outer segment and
VA impairment(10). Thus, the mean VA of the SRD group may have been
significantly worse as a result of damage to foveal photoreceptor cells
due to foveal detachment. In addition, all SRD patients in the present
study also had CME. Therefore, we believe SRD itself may decrease VA.
In the present study, we observed greater CMT in the SRD group
compared to the CME group, corroborating previous reports. In BRVO
patients, SRD occurs as a result of transudation of extracellular fluid
into the subretinal space with the site of detachment being determined by foveal architecture, particularly the presence of the Müller
cell cone(21,22). Furthermore, when the barrier function of the ELM
breaks down due to traction on the Müller cell cone, intraretinal fluid
moves into the subretinal space resulting in an increase of SRD and
alleviation of retinal edema(12,15). This process may have contributed
to the greater CMT in the SRD group compared to the CME group.
Inflammatory factors may be strongly associated with the occurrence of SRD in BRVO patients. Noma et al.(23) reported that vitreous
fluid levels of VEGF and sICAM-1, potent vasopermeability factors,
were higher in BRVO patients with SRD compared to those with CME.
They also reported significantly worse VA in the SRD group compared
with the CME group and significantly greater CMT in the SRD group.
They proposed that worse VA in the SRD group may be related to
photoreceptor cell damage caused by macular detachment and/or
functional impairment secondary to ischemia with high vitreous fluid
levels of VEGF and ICAM-1(23). In another study evaluating the efficacy
of intravitreal triamcinolone acetonide for CME with SRD in BRVO,
triamcinolone acetonide was thought to reduce CMT by decreasing
retinal capillary permeability via an effect on tight junctions and/or
inhibition of signaling cascades involving VEGF and the VEGF receptor(13). Moreover, decreased retinal capillary permeability may
relieve traction on the Muller cell cone resulting in decreased SRD.
Corticosteroids may also prevent the production of various inflammatory molecules that promote leukocyte adhesion and breakdown of
the blood-retinal barrier(13).
The limitations of the present study were its retrospective nature,
small sample size, lack of functional mapping by microperimetry (macular sensitivity), and lack of BRVO patients with SRD only.
In conclusion, the mean VA was significantly worse in the SRD
group compared with the CME group, and eyes with SRD had greater
CMT. We observed that SRD itself may be related to decreased VA.
Further detailed studies with a larger number of patients are required
to confirm the role of SRD as a predictive factor of VA and prognosis.
REFERENCES
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2. Hayreh SS. Retinal vein occlusion. Indian J Ophthalmol. 1994;42(3):109-32.
3. Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J
Thromb Haemost. 2010;8(9):1886-94.
4. Rehak J, Rehak M. Branch retinal vein occlusion: pathogenesis, visual prognosis, and
treatment modalities. Curr Eye Res. 2008;33(2):111-31.
5. Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol. 2010;30(4):809-16.
6. Keane PA, Sadda SR. Predicting visual outcomes for macular disease using optical
coherence tomography. Saudi J Ophthalmol. 2011;25(2):145-58.
7. Ota T, Tsujikawa A, Murakami T, Ogino K, Muraoka Y, Kumagai K, et al. Subfoveal serous
retinal detachment associated with extramacular branch retinal vein occlusion. Clin
Ophthalmol. 2013;7:237-41.
8. Sekiryu T, Iida T, Sakai E, Maruko I, Ojima A, Sugano Y. Fundus autofluorescence and
optical coherence tomography findings in branch retinal vein occlusion. J Ophthalmol.
2012;2012:638064.
9. Otani T, Yamaguchi Y, Kishi S. Movement of intraretinal fluid from distant branch
retinal vein occlusion to the submacular space. Clin Ophthalmol. 2013;7:81-6.
10. Noma H, Funatsu H, Mimura T, Shimada K. Visual function and serous retinal detachment
in patients with branch retinal vein occlusion and macular edema: acase series. BMC
Ophthalmol. 2011;11:29.
11. Karacorlu M, Ozdemir H, Karacorlu SA. Resolution of serous macular detachment after
intravitreal triamcinolone acetonide treatment of patients with branch retinal vein
occlusion. Retina. 2005;25(7):856-60.
12. Tsujikawa A, Sakamoto A, Ota M, Kotera Y, Oh H, Miyamoto K, et al. Serous retinal detachment associated with retinal vein occlusion. Am J Ophthalmol. 2010;149(2):291-301.
13. Noma H, Funatsu H, Mimura T, Shimada K. Comparison of the efficacy of intravitreal
triamcinolone acetonide for cystoid macular edema with versus without serous retinal detachment in branch retinal vein occlusion: influence on macular sensitivity
and morphology. BMC Ophthalmol. 2012;12(39):1-10.
14. Otani T, Kishi S. Correlation between optical coherence tomography and fluorescein
angiography findings in diabetic macular edema. Ophthalmology. 2007;114(1):104-7.
15. Spaide RF, Lee JK, Klancnik JK Jr, Gross NE. Optical coherence tomography of branch
retinal vein occlusion. Retina. 2003;23(3):343-7.
16. Battaglia Parodi M, Isola V. Branch retinal vein occlusion and exudative retinal detachment: pathogenetical aspects. Ophthalmologica. 1994;208(1):29-31.
17. Marmor MF. Control of subretinal fluid: experimental and clinical studies. Eye (Lond).
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18. Murakami T, Tsujikawa A, Miyamoto K, Sakamoto A, Ota M, Ogino K, et al. Relationship
between perifoveal capillaries and pathomorphology in macular oedema associated
with branch retinal vein occlusion. Eye (Lond). 2012;26(6):771-80.
19. Yamada E. Some structural features of the fovea centralis in the human retina. Arch
Ophthalmol. 1969;82(2):151-9.
20. Gass JD. Muller cell cone, an overlooked part of the anatomy of the fovea centralis:
hypotheses concerning its role in the pathogenesis of macular hole and foveomacular retinoschisis. Arch Ophthalmol. 1999;117(6):821-3.
21. Yamaguchi Y, Otani T, Kishi S. Serous macular detachment in branch retinal vein occlusion.
Retina. 2006;26(9):1029-33.
22. Shroff D, Mehta DK, Arora R, Narula R, Chauhan D. Natural history of macular status in
recent-onset branch retinal vein occlusion: an optical coherence tomography study.
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factors and serous macular detachment in branch retinal vein occlusion. Retina. 2012;
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11
Original Article
Volume médio de plaquetas em pacientes com oclusão da artéria da retina
muhammED Şahin1, alparslan Şahin1, harun yükSEl1, fatih MEhMEt türkcü1, adnan yildiriM1
ABSTRACT
RESUMO
Purpose: The aim of this study was to investigate the mean platelet volume (MPV)
of patients with retinal artery occlusion (RAO).
Methods: Thirty-seven patients diagnosed with RAO and 32 control subjects were
included in this retrospective study. Retinal artery occlusion was diagnosed on the
basis of clinical examination and fundus fluorescein angiography. All participants
underwent complete ocular examination, and MPV, hematocrit, hemoglobin, and
platelet counts were recorded. RAO patient data were compared with those of
the control subjects.
Results: Patients with RAO had significantly higher MPV values (7.96 ± 1.2 fL)
compared with control subjects (7.33 ± 0.7 fL, p<0.001). No significant difference
was found with regard to platelet count between the RAO group and the control
group (262 ± 70.1 × 109/L and 251 ± 56.6 × 109/L, respectively, p=0.50). MPV was
an independent predictor of RAO [odds ratio (OR)=0.50; 95% confidence interval
(CI)=0.28-0.89; p=0.019).
Conclusions: Our results demonstrated that MPV values were significantly higher
in patients with RAO, suggesting that larger platelets may contribute to the pathogenesis of the RAOs.
Objetivo: O objetivo deste estudo foi investigar o volume plaquetário médio (MPV)
de pacientes com oclusão da artéria da retina (RAO).
Métodos: Trinta e sete pacientes com diagnóstico de RAO e 32 indivíduos do grupo
controle foram incluídos neste estudo retrospectivo. A oclusão da artéria da retina foi
diagnosticada com base em exame clínico e angiofluoresceinografia. Todos os participantes foram submetidos ao exame ocular completo. MPV, hematócrito, hemoglobina
e contagem de plaquetas dos participantes foram registrados. Os dados dos pacientes
com RAO foi comparado com os de sujeitos do grupo controle.
Resultados: Pacientes com RAO apresentaram valores significativamente mais elevados MPV (7,96 ± 1,2 fL) em comparação aos indivíduos do grupo controle (7,33 ± 0,7 fL)
(p<0,001). Nenhuma diferença significativa foi encontrada no número de plaquetas
entre os grupos RAO e controle (262 ± 70,1 109/L and 251 ± 56,6 109/L, respectivamente,
p=0,50). MPV foi um preditor independente de RAO (odds ratio (OR)=0,50; intervalo de
confiança de 95% (IC)=0,28-0,89; p=0,019).
Conclusões: Os resultados demonstraram que os valores de MPV foram significativamente maiores nos pacientes com RAO, sugerindo que plaquetas maiores podem
contribuir na patogênese da RAO.
Keywords: Mean platelet volume; Blood platelets; Retinal artery occlusion; Retinal
diseases; Retinal vessels
Descritores: Volume plaquetário médio; Plaquetas; Oclusão da artéria retiniana; Doenças retinianas; Vasos retinianos
INTRODUCTION
Retinal arterial occlusion (RAO) is a rare cause of irreversible and
profound vision loss, particularly in patients over the age of 60 years
of age, despite the existence of various treatment modalities(1,2). RAOs
are classified according to the anatomic region of the occlusion as
central retinal artery occlusion (CRAO), branch retinal artery occlusion
(BRAO), and cilioretinal artery occlusion (CLRAO)(3).
CRAO was first described by von Graefes in 1859(4). Patients with
CRAO present with sudden, painless, severe visual loss. BRAO causes
sudden segmental visual loss associated with visual field damage(5).
The incidence of CRAO has been estimated to be approximately 0.85
in 100,000 per year(6). CRAO constitutes 57% of acute RAOs, whereas
BRAO and CLRAO constitute 38% and 5% of acute RAOs, respectively(7).
CRAO by virtue of its pathogenesis shares important risk factors with
other vascular diseases such as ischemic heart disease and cerebrovascular disease(8). The majority of RAOs are either thrombotic or
embolic in nature(6). Arterial occlusions in the eye are almost always
due to micro-embolism and the major source of micro-emboli is
plaque(s), which may be present with or without significant stenosis
of the carotid artery. Therefore, absence of significant stenosis of the
carotid artery does not necessarily rule out the carotid artery as the
source of micro-embolism(9). The most frequent retinal emboli are
represented by cholesterol emboli (74.0%), platelet fibrin emboli
(15.5%), and calcific emboli (10.5%)(10).
Platelets have an important role in the pathogenesis of thrombo-occlusive disease. Mean platelet volume (MPV) is an indicator of
platelet size and has been known to be a marker of platelet activity.
Large platelets are more reactive than small platelets and produce
more thromboxane A2, express more glycoprotein Ib and glycoprotein
IIb/IIIa receptors, and aggregate more easily(11,12).
In the present study, we aimed to investigate the platelet activity
in the development of RAO through MPV. To the best of our knowledge,
we are the first to report MPV in patients with RAO.
1
Departments of Ophthalmology, School of Medicine, Dicle University, Diyarbakir, Turkey.
METHODS
The study protocol was approved by the local ethic committee,
and the study was performed in accordance with the Declaration
of Helsinki. The patients who were diagnosed with RAO (i.e., CRAO,
BRAO, or CLRAO) between January 2011 and December 2014 were
reviewed retrospectively. All subjects underwent a full ocular examination, including measurement of visual acuity and intraocular pressure (IOP), slit lamp biomicroscopic anterior segment, and fundus
examination. We also performed fundus fluorescein angiography
(FFA) and optic coherence tomography in all patients.
Corresponding author: Muhammed Şahin. Department of Ophthalmology, School of Medicine,
Dicle University - Diyarbakir - Turkey - E-mail: [email protected]
12
http://dx.doi.org/10.5935/0004-2749.20160005
Şahin M, et al.
Age, gender, ocular pathology, systemic disease, and complete
blood count (CBC) parameters [i.e., MPV, hemoglobin (hb), hematocrit
(htc), and platelet count] were recorded. The diagnosis was based on
the sudden visual loss accompanied by one or more of the following
signs as observed by slit-lamp biomicroscopy with a 90-diopter lens:
(1) reduced and thinned retinal artery flow; (2) fragmentation of the
blood column in retinal arterioles; (3) retinal opacification combined
with absent or poor residual retinal blood flow; and (4) the presence
of a cherry-red spot (for CRAO). FFA revealed diminished blood flow
in the retinal arteries. These findings were compared with the fellow
unaffected eye. Patients with any systemic disease other than hypertension (HT) and diabetes mellitus (DM) were excluded from the
study. Patients with anemia (htc <38.0%), any cardiovascular disease,
such as heart valve disease treated with anticoagulant, congestive
heart failure, chronic renal failure, stroke, history of smoking, and
history of alcohol consumption were excluded; patients with glaucoma and with a history of any ocular surgery or trauma, and giant
cell arteritis were also excluded. Age- and gender-matched subjects
in the control group were recruited from an outpatient clinic of the
same ophthalmology department.
Blood samples were taken at the time of RAO diagnosis. CBC
samples drawn into vacutainer tubes containing 0.04 mL of 7.5%
K3 salt of EDTA were analyzed within an hour after sampling with a
commercially available analyzer (CELL-DYN 3700, Abbott Diagnostics,
Abbott Park, IL, USA). MPV, platelet count, hb, and htc were recorded.
Normal MPV values ranged between 7.0 and 10.4 fL.
STATISTICAL ANALYSIS
All values are given as means ± SD. For statistical analysis, the
SPSS statistical software package version 18.0 for Windows (SPSS,
Chicago, IL) was used. The Kolmogorov-Smirnov test was applied to
test the distribution pattern of each data. Student’s t-test was used
for normally distributed data in the group comparisons. P value <0.05
was considered statistically significant. Univariate logistic regression
analysis was used to assess associations among MPV, htc and hb
levels, HT, DM, age, and gender with RAO.
RESULTS
Of the 45 patients with RAO that were consecutively examined,
37 patients were eligible for the study. The control group consisted
of 32 subjects, and the mean age of the RAO group and the control
group was 55.4 ± 18.9 and 57.7 ± 13.1 years, respectively. The male-tofemale ratio was 17:20 in the RAO group and 18:14 in the control
group. There were no statistical difference in age and sex between
the groups (p=0.41 and p=0.22, respectively) (Table 1). There was no
Table 1. Demographic and clinical features of RAO patients and control
individuals
RAO
Control
P value
55.4 ± 18.9
57.7 ± 13.1
0.410
Gender (M/F)
17/20
18/14
0.220
HT
6/37
4/32
Age
HT and DM
2/37
2/32
13.7 ± 1.7
14.2 ± 1.2
0.180
41.2 ± 4
41.9 ± 3.8
0.470
262.2 ± 70.1
251.7 ± 56.6
0.500
MPV (fL)
7.96 ± 1.2
7.33 ± 0.7
<0.001
IOP (mmHg)
14.6 ± 2.9
13.9 ± 2
0.100
VA (Snellen)
0.18 ± 0.3
0.75 ± 0.3
<0.001
Hb (g/dL)
Hct (%)
Plt (103/µL)
RAO= retinal artery occlusion; HT= hypertension; DM= diabetes mellitus; Hb= hemoglobin; Hct= hematocrit; Plt= platelet count; MPV= mean platelet volume; VA= visual acuity;
IOP= intraocular pressure.
difference between the control and the RAO groups with respect to
the presence of HT and DM.
Mean platelet volume was significantly higher in patients with
RAO than in the control group (7.96 ± 1.2 fL vs. 7.33 ± 0.7 fL, p<0.001).
In contrast, the mean platelet count was higher in the control group
compared with the RAO group, although not statistically significant
(p=0.50). Logistic regression analysis showed that MPV was an independent predictor of RAO [odds ratio (OR)=0.50; 95% confidence
interval (CI)=0.28-0.89; p=0.019].
DISCUSSION
The present study showed increased levels of MPV in patients with
RAO. To the best of our knowledge, this is the first study that shows
the relationship between high MPV values and RAO.
Several mechanisms such as thrombosis, embolization, vasculitis,
and vasospasm are attributed to RAO(13). Thrombosis resulting from
atherosclerotic plaques is the major cause of CRAO(14). Rupture of an
atherosclerotic plaque triggers platelet aggregation and consequently thrombus formation. It is likely that most CRAOs are due to a thrombosis at the level of the lamina cribrosa(15). Emboli may be seen in up
to 20% of patients with CRAO and up to 68% of those with BRAO(16).
These emboli are believed to typically arise from ulcerated atherosclerotic plaques or thrombi within internal or carotid arteries, or from
cardiac valves.
The platelets have a key role in the pathogenesis of thrombo-embolic disorders. Since larger platelets store and release larger amounts
of serotonin, β-thromboglobulin, and thromboxane A2, they are more
reactive and prone to aggregation(12,17). MPV is an indicator of the size
and activity of platelets. Increased values of MPV have been shown
to be a risk factor for deep venous thrombosis, acute myocardial infarction, stroke, and acute ischemic cerebrovascular events(18-21). Bath
and Butterworth reported that platelet hyperactivity results in an
increase in MPV(22). In our study, the MPV values were significantly
higher compared with the control group, suggesting that large platelets may contribute to the pathogenesis of RAO. Logistic regression
analysis revealed that MPV is an independent predictor of RAO. The
presence of high MPV in these patients may have increased their risk
of developing RAO.
Platelets have an important role in the initiation of atherosclerotic
lesions and subsequent complications(23). Their role in carotid atherosclerosis has been demonstrated in previous studies. P-selectin stored in the secretory granules of the platelets is crucial for the growth
and maturation of atherosclerosis plaques, including the presence of
smooth muscle cells and calcification(24). Burger and Wagner suggested that platelets and their P-selectin also actively promote advanced
development of atherosclerotic lesions.
Heidrich et al. reported that platelet aggregation test (PAT III)
values were elevated in all patients with acute RAO(25). Therefore, high
platelet aggregation can be one cause of long-term retinal capillary
occlusion in patients with RAOs. Paterson et al. studied the role of
platelets in retinal circulation and suggested that platelet aggregates
cause vessel occlusion either by embolization or by localized thrombosis of the arterial or venous branch of retinal vessels(25,26). Moreover,
BRAO has been observed following platelet transfusion in humans(27).
Finally, in an experimental study, RAO was developed by infusing
aggregated platelets(28). These studies suggest a role for platelets in
the development of retinal artery occlusions.
Serotonin, a vasoconstrictor amine, is released by platelet aggregation on atherosclerotic plaques in the carotid artery. It was demonstrated in an experimental model that serotonin can cause transient or
complete occlusion or impaired blood flow in the central retinal artery
by producing a transient spasm in atherosclerotic monkeys; this may
contribute to the development of RAO(29).
MPV has been studied in a few ocular vascular disorders. Our team
reported an increase in MPV in patients with retinal vein occlusion
(RVO) and ocular Behçet’s disease(30,31). Ateş et al. found a significant
13
increase in MPV in patients with diabetic retinopathy(32). In addition,
the role of platelets in RVO was also studied by Leoncini et al.(33), who
reported an increased platelet response to thrombin in patients with
RVO. Moreover, they suggested that platelet hyperaggregability inducing thrombus formation is an important factor in the onset and/or
development of RVO.
Our study has some limitations: it was a retrospective analysis
with a relatively small number of patients, which is inherent to investigations of rare diseases. With the lack of data on body mass index
and lipid profiles, thrombin time, prothrombin time, and INR and no
carotid artery Doppler ultrasound performed on patients, the results
merely demonstrate the hematologic status at the acute stage of
RAO within 48 hours. Thus, these results may not reflect the status of
the patients over longer periods.
In conclusion, the present study demonstrated that MPV values
were significantly higher in patients with RAO than in controls. Despite the retrospective design of our study, we suggest that MPV may
be used as a predictive tool for identifying the risk of developing RAO.
Further studies are needed to confirm the predictive value of MPV in
RAO risk assessment.
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8. Schmidt DP, Schulte-Mönting J, Schumacher M. Prognosis of central retinal artery
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Original Article
Comparison of pain scores between patients undergoing panretinal
photocoagulation using navigated or pattern scan laser systems
Comparação de graduação de dor entre os pacientes submetidos à panfotocoagulação
usando sistemas de laser navegado ou de padrão de varredura
uMit uBEyt inan1, onur polat2, SiBEl inan1, SafiyE yiGit1, zEki BaySal1
ABSTRACT
RESUMO
Purpose: To compare the pain responses of patients with proliferative diabetic
retinopathy (PDR) undergoing panretinal photocoagulation (PRP) using either
pattern scan laser (PASCAL) or navigated laser photocoagulation (NAVILAS).
Methods: Patients diagnosed with PDR were randomly assigned to undergo either
PASCAL or NAVILAS photocoagulation treatment. PRP was performed using the
multi-shot mode with a spot size of 200-400 µm and a pulse duration of 30 ms to
obtain a white-grayish spot on the retina. Parameters were identical in both procedures. After 30 min of PRP application, patients were asked to verbally describe
their pain perception as either “none,” “mild,” “moderate,” “severe,” or “very severe”
using a verbal rating scale (VRS) and visual analog scale (VAS) by indicating a score
from “0” to “10,” representing the severity of pain from “no pain” to “severe pain.”
Results: A total of 60 eyes of 60 patients (20 females and 40 males) diagnosed
with PDR were treated. The mean age of patients was 62.22 ± 9.19 years, and
the mean diabetes duration was 195.47 ± 94.54 months. The mean number of
laser spots delivered during PRP was 389.47 ± 71.52 in the NAVILAS group and
392.70 ± 54.33 in the PASCAL group (p=0.57). The difference in pain responses
between patients in the NAVILAS and PASCAL groups was significant with regard
to the mean VRS (1.10 ± 0.67 and 1.47 ± 0.69, respectively; p=0.042) and mean VAS
(2.13 ± 1.17 and 2.97 ± 1.35, respectively; p=0.034) scores.
Conclusions: Pain responses in patients undergoing PRP with a 30-ms pulse duration were significantly milder in the NAVILAS group than in the PASCAL group.
Objetivo: Comparar as respostas de dor de pacientes com retinopatia diabética proliferativa (PDR) submetidos à panfotocoagulação retiniana (PRP) usando laser de
padrão de varredura (PASCAL) ou fotocoagulação navegada a laser (NAVILAS).
Métodos: Pacientes com diagnóstico de PDR foram aleatoriamente designados para
submeter-se ao tratamento de fotocoagulação com PASCAL ou NAVILAS. A PRP foi
realizada no modo “multi-shot” com diâmetro do laser de 200-400 µm e duração do
pulso de 30 ms, utilizados para se obter uma mancha branca-acinzentada na retina.
Os parâmetros foram idênticos em ambos os procedimentos. Após 30 minutos da PRP,
os pacientes foram solicitados a descrever verbalmente a sua percepção da dor como
quer “nenhuma,” “leve,” “moderada,” “intensa” ou “dor muito intensa” por meio de uma
escala de avaliação verbal (VRS) e também por meio de uma escala visual analógica
(VAS), indicando uma pontuação de “0” a “10” representando a intensidade da dor de
“nenhuma dor” a “dor intensa.”
Resultados: Um total de 60 olhos de 60 pacientes (20 mulheres e 40 homens) com
diagnóstico de PDR foram tratados. A média de idade dos pacientes foi de 62,22 ± 9,19
anos e a média de duração da diabete foi 195.47 ± 94,54 meses. O número médio de
pulsos de laser emitidos durante a PRP foi 389,47 ± 71,52 no grupo NAVILAS e 392,70
± 54,33 no grupo PASCAL (p=0,57). A diferença nas respostas de dor entre os
pacientes nos grupos NAVILAS e PASCAL foi significativa em relação às médias de VRS
(1,10 ± 0,67 e 1,47 ± 0,69; p=0,042) e VAS (2,13 ± 1,17 e 2,97 ± 1,35; p=0,034).
Conclusões: As respostas de dor em pacientes submetidos à PRP com pulsos de 30 ms
de duração foram significativamente menores nos pacientes do grupo NAVILAS em
relação ao grupo PASCAL.
Descritores: Retinopatia diabética; Desenho de equipamento; Fotocoagulação a laser;
Medição da dor
Keywords: Diabetic retinopathy; Equipment design; Laser coagulation; Pain measurement
INTRODUCTION
Diabetic retinopathy is the leading cause of vision loss in the elderly(1). Almost 95% of diabetes-related visual impairment, however, is
preventable by early diagnosis and photocoagulation therapy(2). A
number of multi-center trials have consistently demonstrated the
benefits of photocoagulation in high-risk patients with proliferative
diabetic retinopathy (PDR)(3,4).
Panretinal photocoagulation (PRP) is painful, and a substantial number of patients are therefore undertreated and at an increased risk of
developing blindness(5). Compared with the widely used conventional
Submitted for publication: October 9, 2015
1
2
Department of Ophthalmology, Faculty of Medicine, Afyon Kocatepe University, Afyonkarahisar,
Turkey.
Ophthalmology Clinic, Afyonkarahisar State Hospital, Afyonkarahisar, Turkey.
http://dx.doi.org/10.5935/0004-2749.20160006
laser, new technologies provide more comfortable, less harmful and
time-saving treatments because of sub-threshold and multi-shot laser
photo coagulators(6,7).
The pattern scan laser (PASCAL; Opti-Medica Corp., Santa Clara,
California, USA) is a new generation semi-automatic and multi-shot
photocoagulator, which uses either a single or predetermined pattern
array with pulse durations as short as 10-30 ms(8,9). Navigated laser
photocoagulation (NAVILAS; OD-OS GmbH, Teltow, Germany) is another novel computer-based double-frequency ND:YAG laser photocoagulation system (532 nm), which, apart from offering retina navigation, has similar technical specifications as PASCAL (single or prede-
Corresponding author: Onur Polat. Ophthalmology Clinic. Afyonkarahisar State Hospital, Afyonkarahisar - 03200 - Turkey - E-mail: [email protected]
15
Comparison of pain scores between patients undergoing panretinal photocoagulation using navigated or pattern scan laser systems
termined pattern array, 10-30-ms pulse duration)(10,11). Compared with
conventional lasers, both modalities use shorter laser pulses, cause relatively less thermal damage to adjacent retinal tissues and are therefore
possible to produce relatively less painful photocoagulation. Whether
one of these new laser platforms produce less pain than the other
during the panretinal photocoagulation is not extensively investigated.
In this study, we sought to compare pain responses in patients
undergoing PRP with either PASCAL or NAVILAS for PDR.
METHODS
PATIENTS
Among patients presenting with visual complaints between June
and September 2014, those diagnosed with PDR were enrolled in the
study. Patients were randomly assigned to receive either NAVILAS
or PASCAL photocoagulation therapy. Ethical committee approval
and informed consent from patients were obtained, and the study
adhered to the tenets of the Helsinki Declaration.
The inclusion criteria were as follows: being older than 18-years,
having a diagnosis of diabetes mellitus type 1 or 2, and presenting
with a high risk of PDR. A high risk of PDR was defined as neovascularization of the optic disc, neovascularization associated with vitreous
or preretinal hemorrhages (NVEs), or neovascularization greater than
one-half of the disk area in size accompanying vitreous or preretinal
hemorrhage regardless of NVE location.
Patients with a low risk of PDR, those with poor compliance, and
pregnant women were excluded. Additionally, patients with a history
of focal/grid photocoagulation or PRP, orbital trauma or surgery; those
presenting with inflammatory signs; those with significantly increased corneal or lens thickness; and those with vitreous hemorrhage
were also excluded.
All patients were subject to the following assessments: slit-lamp
biomicroscopy, intraocular pressure measurement with Goldmann
applanation tonometry, fundus fluorescein angiography, and ophthalmologic examination including fundus assessment.
months. Patient demographics are presented in table 1. There were
no significantly differences between the groups in terms of mean
age, gender, and mean diabetes duration.
The mean number of laser spots delivered during PRP was 389.47 ±
71.52 in the NAVILAS group and 392.70 ± 54.33 in the PASCAL group.
The difference was not significant (p=0.57).
The difference in pain response between patients in the NAVILAS
and PASCAL groups was significant with regard to both mean VRS
(1.10 ± 0.67 vs. 1.47 ± 0.69, respectively; p=0.042) and mean VAS
(2.13 ± 1.17 vs. 2.97 ± 1.35, respectively; p=0.034) scores (Table 2).
While no patients in the PASCAL group reported “no pain” in the
VRS assessment, four (13.3%) in the NAVILAS group reported “no pain”
associated with PRP application. A total of 11 of 30 patients reported
experiencing moderate or severe pain during PASCAL laser treatment
compared with 6 of 30 treated with the NAVILAS laser. None of the
patients in either groups reported “very severe pain.” Patient distribution according to VRS is presented in figure 1.
DISCUSSION
The advent of photocoagulation in 1967 was a critical step in the
treatment of diabetic retinopathy and maculopathy(12). PRP treatment
may cause considerable pain and discomfort in some patients and
Table 1. Demographic characteristics of study individuals
NAVILAS
Gender (F/M)
PASCAL
P
8/22
12/18
0.270**
Age (mean ± SD)
063.3 ± 009.4
061.1 ± 9.1
0.351**
Duration of diabetic disease
(mean ± SD)
206.8 ± 101.1
184.1 ± 87.8
0.480**
*= chi-square test; **= independent t-test.
LASER APPLICATION
Patients were randomly assigned to either the PASCAL (30 patients) or NAVILAS (30 patients) groups. All patients were treated by
the same surgeon and underwent a single PRP session. Treatments
were performed under topical anesthesia.
The spot size (200-400 µm) and pulse duration (30 ms) used to
obtain a white-grayish spot on the retina were identical in both procedures. To objectively compare pain responses, PRP was used in the
multi-shot mode and was applied within similar retinal areas, and the
total number of spots delivered was equivalent.
Table 2. Pain scores associated with NAVILAS laser and PASCAL laser
treatments
NAVILAS
PASCAL
P
Verbal score
1.10 ± 0.67
1.47 ± 0.69
0.042
VAS
2.13 ± 1.17
2.97 ± 1.35
0.034
VAS= visual analog scale; p= Mann-Whitney U test.
PAIN PERCEPTION
After 30 min of PRP application, patients were asked to verbally
describe their pain perception as either “none,” “mild”, “moderate”,
“severe”, or “very severe” through a verbal rating scale (VRS). Additionally, they were asked to specify the severity of pain through a visual
analog scale (VAS) by indicating a score from “0” to “10,” representing
the severity of pain from “no pain” to “severe pain.”
Statistical analyses were performed using the SPSS (Statistical Package for Social Sciences Inc., Chicago, IL, ABD) version 17.0 software. Data
distribution was assessed by the Kolmogorov-Smirnov test. Comparisons were performed using the Mann-Whitney U test and t-test for
independent samples.
RESULTS
A total of 60 eyes of 60 patients (20 females and 40 males) diagnosed with PDR were treated. The mean age of patients was 62.22
± 9.19 years, and the mean duration of diabetes was 195.47 ± 94.54
16
Figure 1. Number of patients subject to photocoagulation treatment by the two laser
systems (PASCAL or NAVILAS) according to expressed verbal score.
Inan UU, et al.
may consequently yield reluctance to continuing treatment sessions,
thus leading to visual deterioration. By changing laser parameters,
however, it may be possible to improve comfort and reduce pain(13). In
the current study, we found that patients undergoing PRP treatment
with the NAVILAS system experienced significantly less pain than
those treated with the PASCAL system with a pulse duration of 30 ms.
The Diabetic Retinopathy and Early Treatment Diabetic Retinopathy studies, using a single-shot conventional laser device, established
the minimum laser power levels in PRP treatment with a spot size
of 200-500 mm and a pulse duration of 100-200 ms(14,15). Novel laser
treatment systems, however, use the multi-shot mode with short
pulse duration, thereby providing shorter, less demanding, and less
painful treatment sessions(16). Furthermore, studies have shown that
a short pulse duration does not negatively influence PRP treatment
efficacy(16-18).
Targeting the retinal pigment epithelium while preserving
adjacent photoreceptors through micro-air bubble formation formed
around melanosomes is a novel target therapy modality of laser
photocoagulation. The critical threshold between thermal and mechanical damage is 50 ms(19-21). Owing to the use of shorter pulses,
novel laser therapy techniques cause only mechanical but not thermal damage, limiting the damage to the retinal pigment epithelium
and preserving the inner retinal layers and sensory-rich chorioretinal
tissues(17). Consequently, patients usually report less pain, most probably because retinal sensitivity is better preserved as compared with
pain in conservative approaches(9,17). Recent studies have consistently
shown that patients treated with either the PASCAL or NAVILAS laser
system modalities experienced less pain as compared with those
treated with conventional laser treatment modalities(9,10,17,22).
The reason why patients treated with the NAVILAS system experience less pain than those treated with the PASCAL system may in part
be attributed to the fact that the former uses infrared light instead of
the bright slit-lamp light used in the latter. Infrared light is known to
cause less photostimulation(16).
Additionally, both conventional and PASCAL treatment systems
require the tilting and moving of a contact lens for treating the peripheral retina, which may cause discomfort(23). The NAVILAS system,
on the contrary, uses a specifically designed contact lens and does
not require tilting of the lens for the examination and treatment of
the retinal periphery(24). The tilting of the lens is also related to laser
focusing, significantly influencing spot size and energy density at
the level of the retina(23). Focusing is performed by moving the slit
lamp closer or further away from the eye in the PASCAL laser system,
where laser and image foci may not be identical. On the other hand,
the NAVILAS laser system enables the documentation of focus settings
adjusted prior to treatment to achieve a clear focused retinal image
and focused laser beam(25). As a recent study revealed, laser spots delivered during NAVILAS photocoagulation are more accurate than those
delivered using the PASCAL system. Thus, inadvertent laser application
is minimized, collateral damage within the retina is decreased, and
the preservation of retinal sensitivity is improved, eventually resulting
in more comfort and less pain(24).
Response to pain among individuals may vary depending on factors
such as culture, gender, threshold of pain, degree of fundus pigmentation, and history of previous laser treatment(17,26). None of the patients
included in this study had a previous history of laser treatment. Additionally, randomization provided a more objective assessment of pain.
Nevertheless, these factors may still, in part, account for the difference
observed in the perception of pain.
Our review of literature identified two additional trials, both conducted by Chablani et al.(16,24), comparing differences in the perception
of pain between patients with PDR undergoing NAVILAS or PASCAL
photocoagulation. In both studies, a pulse duration of 100 ms was
used, and it was found that treatment-related pain was significantly
milder following NAVILAS than following PASCAL photocoagulation(24).
In the current study, however, we found that treatment with a pulse
duration of 30 ms also resulted in milder pain in patients treated with
NAVILAS compared with those treated with PASCAL. This issue has
rarely been investigated and merits further consideration with long-term
follow-up studies on larger groups.
While the relatively small number of spots delivered may appear
to be a limitation, the main purpose of the study was to compare pain
responses and not treatment efficacy. In the Diabetic Retinopathy Clinical Research Network (DRCR.net) clinical trial, no clinical difference
was found when comparing PRP in one session versus that in four
sessions in terms of pain perception(27). One limitation was the small
sample size. Additionally, we followed all patients and performed the
second and third treatment sessions after one week at the latest and
eventually completed PRP treatments within one month at the latest.
To conclude, the new, navigated laser approach provided by the
NAVILAS system enables the delivery of multiple laser spots in a relatively shorter time with improved accuracy and efficacy, significantly
reducing pain and improving patient compliance.
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Original Article
Congenital and developmental cataract: axial length and keratometry study in
Brazilian children
Catarata congênita e do desenvolvimento: estudo do comprimento axial e da ceratometria em
crianças brasileiras
rodriGo BuEno do prado1, virGílio fiGuEirEdo Silva1, Silvana artioli SchEllini1, antonio carloS lottElli rodriGuES1
ABSTRACT
RESUMO
Purpose: To evaluate the ocular axial length (AL) and keratometry (K) in Brazilian
children with congenital/developmental cataract, assess the differences and
evolution of AL and K according to age, and establish functional models of AL
and K as function of age.
Methods: Children with congenital/developmental cataract aged 1.5 months old
to 8 years old and no other ocular diseases were included. All eyes with unilateral
cataract, the left eyes from children with bilateral cataracts, and healthy eyes
from children with unilateral cataract were analyzed. After the administration of
anesthesia, K was measured with a portable automatic keratometer, and AL was
measured with a contact biometer. Cataract surgery was performed immediately
after the measurements were taken. The data were statistically analyzed, and
a linear regression with an age logarithm was used to model the relationship.
Results: Forty-four eyes with cataract were included in this analysis, comprising
15 eyes with unilateral cataract and 29 left eyes from children with bilateral cataracts.
The mean age was 27.3 months with a mean AL of 20.63 ± 2.11 mm and a mean
K of 44.94 ± 2.44 D. The K value was significantly steeper and the AL value was
significantly shorter in younger children (P<0.001). No significant differences were
found neither between eyes with unilateral and bilateral cataracts nor between
eyes with unilateral cataract and their corresponding healthy eyes (P>0.05).
Conclusion: The values of K and AL significantly change with age, especially during
the first 6 months of life. A linear functional relationship between K and AL with
the logarithm of age and between K and AL was established.
Objetivo: Avaliar o comprimento axial (AL) e a ceratometria (K) de olhos de crianças
brasileiras com catarata congênita/desenvolvimento, analisar diferenças e evoluções
de acordo com a idade e estabelecer modelos funcionais de comprimento axial e
ceratometria em função da idade e entre eles.
Métodos: Crianças com catarata congênita/desenvolvimento com idade de 1,5 meses
a 8 anos de idade e sem outras doenças oculares foram incluídas. Todos os olhos
com catarata unilateral, o olho esquerdo de crianças com catarata bilateral e o olho
sadio de crianças com catarata unilateral foram analisados. Após a administração
de anestesia, a ceratometria foi obtida com um ceratômetro automático portátil e o
comprimento axial medido com um biômetro de contato. Em seguida, a cirurgia de
catarata foi realizada. Os dados foram analisados estatisticamente, a regressão linear
com o logaritmo da idade foi utilizado para modelar os relacionamentos.
Resultados: Todos os olhos com catarata unilateral (n=15) e um olho selecionados
aleatoriamente a partir dos casos bilaterais (n=29) foram incluídos na análise (total=
44 olhos). A idade média foi de 27,3 meses, as médias do comprimento axial e da
ceratometria foram respectivamente 20,63 ± 2,11 mm e 44,94 ± 2,44 dioptrias. A ceratometria foi significativamente mais curvo e comprimento axial significantemente
mais curto em crianças mais jovens (P<0,001). Não foram encontradas diferenças
significativas na comparação entre os olhos com cataratas unilaterais e bilaterais e comparando os olhos com catarata unilateral a correspondentes olhos saudáveis (P>0,05).
Conclusão: Os valores de ceratometria e comprimento axial mudam significativamente
com a idade, principalmente nos primeiros seis meses de vida. Foi estabelecida uma
relação funcional linear entre comprimento axial e ceratometria com o logaritmo da
idade e entre ceratometria e comprimento axial.
Keywords: Cataract/congenital; Cornea/pathology; Axial length, eye; Lenses, intraocular; Corneal topography/methods
Descritores: Catarata/congênito; Córnea/patologia; Comprimento axial do olho;
Lentes intraoculares; Topografia da córnea/métodos
INTRODUCTION
Congenital cataracts are the major cause of preventable and/or
treatable childhood blindness(1,2), accounting for 8%-39% of cases
of childhood blindness(3). The worldwide prevalence of congenital
cataracts has been estimated to be between 1 and 15 per 10,000
children(1).
Surgical treatment for congenital cataract has developed over
the last few decades, allowing cataract removal in children younger
than 1 year. Congenital cataract deprives the retina of light during
periods of greater neural plasticity, and surgery is the primary treat-
ment to prevent amblyopia; however, it only partially solves the
problem because the aphakic eye has a refractive error that must
be corrected(4,5).
Biometric calculation of a growing eye is challenging, and intraocular lenses (IOLs) implanted for emmetropia will produce a myopic
shift with axial growth(6). Portable devices for biometric calculation
may not be available for some of congenital/developmental cataract surgeons. Therefore, the selection of the IOL power at the time
of implantation is based on tables of biometric measurements by
age in normal eyes, which have biometric characteristics that may
Submitted for publication: 17 November, 2014
1
Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Botucatu Medical
School, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil.
Funding: This study was supported by Research program for the Brazilian National Health System
(PPSUS-SP), National Council for Scientic and Technological Development- Brazil (CNPq), and
São Paulo Research Foundation-Brazil (FAPESP).
Corresponding author: Antonio Carlos Lottelli Rodrigues. Faculdade de Medicina de Botucatu UNESP. Depto. OFT/ORL/CCP. Rubião Júnior, s/n, Botucatu, SP - 18618-970 - Brazil
E-mail: [email protected]
Approved by the following research ethics committee: Botucatu Medical School Ethics Committee
under number 3358.
http://dx.doi.org/10.5935/0004-2749.20160007
19
differ from the characteristics of eyes with cataracts, or on tables of
biometric data in cataract eyes collected from populations in specific
ethnicity (5,7).
The objective of this study was to evaluate the ocular axial length
(AL) and keratometry (K) in Brazilian children with congenital/developmental cataract to assess the differences and evolution according
to age as well as to establish functional models of AL and K in function
of age and between K and AL.
METHODS
This retrospective observational study was approved by the
Botucatu Medical School Ethics Committee; we analyzed the medical records of patients undergoing cataract surgery for congenital/
developmental cataract at the Clinical Hospital of Botucatu Medical
School, São Paulo, Brazil.
Prematurely born children as well as those with glaucoma, retinal
disease, microphthalmia, traumatic cataract, pathological myopia, lens
subluxation, or other ocular diseases were not included.
Ocular biometric data were obtained under general anesthesia
by an experienced ophthalmologist, and cataract surgery was performed immediately after these measurements were made. The
keratometric measurements were obtained using a regularly calibrated handheld autorefract keratometer (Retinomax K-Plus 2; Righton,
Tokyo, Japan). AL measurement was performed with a contact
ultrasonic biometer (model 1000A; Sonomed, New York, NY, USA).
The ultrasound velocity used was 1532 m/s for the anterior chamber,
1641 m/s for the lens, and 1532 m/s for the vitreous.
All eyes with unilateral cataract and the left eyes in children with
bilateral cataracts were selected and included in the analysis. In children with unilateral cataract, the affected eyes were compared with
the healthy eye. The biometric data were transferred to Microsoft
Excel 2007 (Redmond, WA, USA). The statistical analyses for the paired
samples were performed using Student’s t-test.
The assessment of the relationship between the child’s age in
months and the ocular biometric measurements was calculated
with Pearson’s correlations. The linear regression analysis using the
logarithm of a patient’s age as an independent variable was adjusted
to obtain the estimates of the mean ocular parameters (K and AL). We
considered P values <0.05 as statistically significant.
RESULTS
A total of 44 children were included in the study, and 28 (63%)
were male. The median and mean age at the time of cataract surgery were 12.5 months and 27.3 months, respectively (range: 1.5-92
months). Twenty-nine children (66%) had bilateral cataracts, and 15
children (34%) had a unilateral cataract.
The eyes with unilateral cataract were not significantly different
in terms of the mean AL and K with the left eyes in the bilateral cases
(P>0.05) (Table 1).
The 44 analyzed eyes had a mean AL of 20.63 mm (range 17.27 mm24.96 mm) and a mean K of 44.94 D (range 40.00 D-53.00 D). The
calculations of the mean, standard deviation, confidence interval,
median, and variable range for AL and K according to the age groups
are shown in table 2. The mean of AL increased with age, whereas the
mean of K decreased. These relationships were statistically significant
(P<0.001). If the AL observations were divided into those from children under and over 12 months old, the relative variability expressed
by the coefficient of variation showed homogeneity of the response
between the two age groups.
The linear regression analyses performed using the natural
logarithm (ln) of the patient’s age (in months) as an independent
variable are shown below by the following equations: AL=16.66 +
(1.476 × ln age); R2=0.74, P<0.001 and K=46.97 + (-0.752 × ln age);
R2=0.14, P<0.001.
A graphical representation of AL and K according to the patients’
age and the fitted curves derived from the model above are shown
in figures 1 and 2. AL and K change markedly with an increase in age.
Table 2. Mean, standard deviation, confidence interval, median, and
range of the axial length (AL) and keratometry (K) values according to
the age group of 44 eyes with unilateral cataract and one randomly
chosen eye from the bilateral cataract cases
Age groups
(months)
n
Mean ± SD
95% CI
Median
Range
AL (mm)
0-5
09
18.45 ± 0.77
17.95-18.95
18.43
17.27-19.83
6-17
15
19.34 ± 0.90
18.89-19.79
19.64
17.85-21.22
18-59
11
22.19 ± 0.92
21.62-22.76
21.93
20.80-23.36
60-96
09
22.07 ± 1.53
22.08-23.06
22.74
20.82-24.96
Total
44
20.63 ± 2.11
20.01-21.25
19.97
17.27-24.96
K (D)
0-5
09
46.86 ± 3.30
44.71-49.01
46.00
43.00-53.00
6-17
15
44.83 ± 1.86
43.89-45.77
45.00
41.75-49.00
18-59
11
44.18 ± 1.40
43.28-45.08
44.25
41.75-46.25
60-96
09
44.16 ± 2.60
42.47-45.85
44.50
40.00-49.00
Total
44
44.94 ± 2.44
44.22-45.66
44.75
40.00-53.00
AL= axial length; K= keratometry; D= diopter; SD= standard deviation; CI= confidence
interval; Student’s t-test.
Table 1. Axial length (AL) and mean keratometry (K) values according
to the laterality of the cataracts
Groups
n
Unilateral
15
Bilateral
P value
29
Mean ± SD
Age (months)
AL (mm)
K (D)
27.7 ± 27.1
20.6 ± 2.0
44.8 ± 2.7
Median
18
20.8
44.5
Range
2-75
17.9-24.7
41.7-53.0
Mean ± SD
27.1 ± 27.7
20.6 ± 2.2
45.0 ± 2.4
Median
10
19.9
45.0
Range
1-92
17.3-25.0
40.0-51.0
0.960
0.990
0.629
AL= axial length; K= keratometry; D= diopter; SD= standard deviation; Student’s t-test.
20
AL=16.66 + (1.476 × ln age); R2=0.74; P<0.001.
Figure 1. Distribution of axial length (AL) values of 44 eyes of children with unilateral
cataracts and randomly selected eyes in the bilateral cases.
Prado RB, et al.
The highest rates of ocular axial growth and corneal flattening are
observed in the first 6 months of life.
The dispersion values of AL according to K and the inverse relationship between them are shown in figure 3. The equation provided
for the graph is K=52.91 -0.385 × AL (mm), with R2=0.11 (P<0.05).
Table 3 shows a comparison of the biometric measurements
between eyes with a unilateral cataract and the corresponding
healthy eye, with no significant differences found in the AL and K
values (P>0.05).
Tests of the two regressions for the AL and K logarithm models
showed that there were no statistically significant differences between eyes with cataract from different genders, eyes with unilateral
cataract and the ones with bilateral cataracts, and normal eyes and
eyes with cataract in children with unilateral cataract (P>0.05).
Table 4 estimates AL and K according to age (in months) based on
the following equations: AL=16.66 + (1.476 × ln age) and K=46.97 +
(-0.752 × ln age), from figures 1 and 2 and the IOL for emmetropia and
for minimizing myopic shift in adulthood, using suggestions from
some authors(8), according to age, based on the estimated values of
AL and K.
DISCUSSION
The development of cataract surgery in children has created the
need to study the biometric and refractive changes that occur with
ocular growth(9,10). In the first months of extra-uterine life, the human
eye experiences axial growth accompanied by flattening of the
corneal curvature(11,12). When this process occurs uneventfully, the
decrease of the refractive power of the lens focuses the image on
the retina because of the increased AL. During this rapid biometric
change, emmetropia is maintained(13).
Eyes presenting cataract have different biometric measurements
from normal eyes, and various factors, such as the child’s age at
surgery, aphakia, pseudophakia, cataract laterality, and visual deprivation have been reported to influence axial growth(12).
Table 3. Comparison of the mean, median, and standard deviation of
axial length (AL) and the mean keratometry (K) values of both eyes of
15 children with unilateral cataract
n
Cataract eye
Healthy eye
15
15
AL (mm)
K (D)
Mean ± SD
20.6 ± 2.0
44.8 ± 2.7
Median
20.8
44.5
Range
17.9-24.7
41.7-53.0
Mean ± SD
21.3 ± 1.7
44.4 ± 1.5
Median
20.9
44.5
Range
18.8-24.8
42.0-48.5
0.061
0.649
P value
AL= axial length; K= keratometry; mm= millimeter; D= diopter; SD= standard deviation.
Student’s t-test.
K=46.97 + (-0.752 × ln age); R2=0.14; P<0.001.
Figure 2. Distribution of the mean keratometry (K) values of 44 eyes of children with
unilateral cataracts and randomly selected eyes in the bilateral cases.
K=52.91-0.385 × AL; R2=0.11; P<0.05.
Figure 3. Distribution of the mean keratometry (K) values for axial length (AL) values.
Table 4. Axial length (AL) and keratometry (K) values estimated by
age according to the linear regression analysis performed using the
natural logarithm (ln) of the patient’s age as an independent variable:
AL=16.66 + (1.476 × ln age) and K=46.97 + (-0.752 × ln age), as well
as the intraocular lens (IOL) power calculated for emmetropia based
on the values of K and AL using the Hoffer Q formula with pACD=5.26
(A-constant=118.5). The indicated desired refraction to minimize late
myopia shift8 and the ideal IOL power to obtain the desired refraction
are also demonstrated
IOL to
emmetropia
(D)
Desired
refraction
(D)
Ideal IOL power
for desired
refraction (D)
Age
(months)
AL
(mm)
K (D)
3
18.28
46.14
+41.36
+9.00
+26.90
6
19.30
45.62
+35.73
+8.00
+23.11
9
19.90
45.32
+32.95
+7.00
+22.06
12
20.33
45.10
+31.14
+6.00
+21.93
18
20.93
44.80
+28.81
+6.00
+19.53
24
21.35
44.58
+27.31
+5.00
+19.67
30
21.68
44.41
+26.18
+5.00
+18.51
36
21.95
44.28
+25.29
+5.00
+17.58
42
22.18
44.16
+24.56
+5.00
+16.82
48
22.37
44.06
+23.97
+4.00
+17.87
54
22.55
43.97
+23.42
+4.00
+17.30
60
22.70
43.89
+22.97
+3.00
+18.45
66
22.84
43.82
+22.56
+3.00
+18.03
72
22.97
43.75
+22.19
+2.00
+19.21
AL= axial length; K= keratometry; mm= millimeter; D= diopter; IOL= intraocular lens.
21
Researchers have reported the existence of a passive ocularstretching component that is genetically determined and an active
component that is observed when the image is not formed on the
retina(13). Supporting this hypothesis, several studies have observed
increased AL in eyes with visual deprivation(14). This increase occurs in
human eyes as well as in the eyes of primates and other animals(6,13).
Several studies have demonstrated flattening of the K values in older children(11,15). A previous study reported mean K values of 47.50 D
in newborns and 43.69 D in children aged 2-4 years and concluded
that K values reach adulthood values at the age of approximately 3
years (16). In the present study, the eyes with congenital and developmental cataract showed K values that were significantly more curved
in children younger than 6 months old. Although it presented a poor
correlation (R2=0.14), the value of K was inversely related to the ages
of the children up to 18 months. After this age, corneal flattening
tends to stabilize.
It has been demonstrated that normal eyes have a smaller
myopic shift in comparison to aphakic eyes(11). The reason for this
difference is that phakic eyes exhibit a decline in the refractive power
of the crystalline lens from +34.4 D to +18.8 D with growth, which
does not occur with an implanted IOL(11). Therefore, children with
pseudophakia might present a large myopic change in adulthood
if the implanted IOL aims for emmetropia at the time of surgery(6).
Two papers have described K and AL measurements in North
American children with congenital cataract(5,17). Further, a study in
Italy showed the AL and K values of a Caucasian pediatric population
with congenital/developmental cataract(7). Databanks containing
biometric information from eyes with pediatric cataract allow estimation of the ocular values of AL and K based on age. These data
facilitate the selection of IOL power in children with cataract when it
is not possible to measure AL and K.
In accordance with the results from another study(18), Brazilian
children showed corneal flattening and increased AL with age. In
the study by Ingaki(18), there was no significant difference between
K and AL in a comparison of eyes with unilateral and bilateral cataracts. The same results were obtained from comparing healthy eyes
and affected eyes in children with unilateral cataract. Additionally, in
studies of AL and K in North American children, lower AL and greater
K were found in eyes with unilateral cataract compared with the AL
and K values in healthy eyes, although the difference in the K value
was not statistically significant(5,17). As visually impaired eyes tend to
have greater axial growth(12), the absence of differences between the
AL value of healthy eyes and that of eyes in children with unilateral
cataract might have resulted from later diagnosis and treatment in
our sample, which could have resulted in worsened visual prognosis
for these eyes(19).
Regarding gender, previous studies have reported steeper corneas
and shorter AL in girls than in boys; however, these results were not
observed in our sample(5,17).
To avoid the development of high myopia with axial growth,
some authors recommend that after the calculation of the IOL for
emmetropia, 20% of the IOL power should be subtracted in young
children (<8 months of age), and 10% should be subtracted in children aged between 2 and 3 years(16). Others propose tables with
residual hyperopia from +12.00 to +0.50 based on the age of the children, from 3 months to 14 years(8). After the surgical treatment, optical
correction or contact lenses are prescribed for residual hyperopia,
which decreases with age. Table 4 shows suggestions, based on our
data, for IOL implantation according to age for emmetropia and for
minimizing late myopia using the suggestions from some authors(8)
when AL and K cannot be measured.
When K measurement is not possible because of the unavailability of manual keratometers, refractive powers of 28, 27, 26, 24, and
22 of the implanted IOL are suggested for ALs of 17, 18, 19, 20, and
21 mm, respectively(20). We suggest that when only AL can be measured, the K value should be calculated using the equation: K=52.910.385 × AL (mm) (Figure 3) or based on age.
22
The selection of the power of the IOL for implantation in a growing eye represents a major challenge. The use of a published table
alone to decide IOL power is not recommended. The tables are only
intended as a starting point toward appropriate IOL power selection,
which is a multifactorial decision customized for each child based
on many variables, particularly age, laterality, amblyopia status, likely
compliance with glasses, and a family history of myopia(8).
The main limitation of this study is the K values. The measurements were performed with a manual keratometer which, although
reproducible in awake patients, may not be as reliable in our sample
where most of the measurements were performed on patients under
anesthesia without fixation. These conditions probably influenced
these values and their relationships with age and AL, generating a
poor correlation (R2=0.11). These findings have already been described by other authors, who also found weaker relationships between
K and age, with R2 varying from 0.31(17) to 0.20(7), as well as between
K and AL (R2=0.32)(17), despite the larger sample sizes. Due to the
difficulty of obtaining these values, the measurement method used
in the present study still seems to be the best manner to obtain K
values; however, a device that allows more accurate measurements
may establish prediction models with more precise estimates of K in
relation to age and AL.
CONCLUSION
The values of K and AL change significantly with age, especially
in the first 6 months of life. A linear functional relationship between
K and AL with the logarithm of age and between K and AL was
established for this Brazilian pediatric sample with congenital/developmental cataract.
ACKNOWLEDGMENT
Research program for the Brazilian National Health System (PPSUSSP), National Council for Scientific and Technological DevelopmentBrazil (CNPq), and São Paulo Research Foundation-Brazil (FAPESP).
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4. Wright KW. Visual development, amblyopia, and sensory adaptations. In: Wright KW,
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Wilson ME, Saunders RA, Trivedi RH, editors. Pediatric Ophthalmology: Current Thought
and A Practical guide. Heidelberg, Germany: Springer; 2009. p. 311-24.
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(Lond). 1999;13(Pt 1):83-92.
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Prado RB, et al.
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15. Asbell PA, Chiang B, Somers ME, Morgan KS. Keratometry in children. CLAO J.
1990;16(2):99-102.
16. Ehlers N, Sorensen T, Bramsen T, Poulsen EH. Central corneal thickness in newborns
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Arch Ophthalmol. 1986;104(7):1026-7.
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23
Original Article
Sociodemographic status of severely disabled and visually impaired
elderly people in Turkey
Estado sociodemográfico de pacientes idosos com incapacidades graves e deficiência visual na Turquia
SErtaç arGun kivanç1,2, BErna akova-Budak2, oSMan okan olcaySü1, Sadik GörkEM çEvik3
ABSTRACT
RESUMO
Purpose: To identify the prevalence of ophthalmologic diseases in elderly patients
who had been classified as severely disabled and to identify the ophthalmologic
conditions leading to visual impairment and blindness.
Methods: The medical records of 2806 patients who had applied to the Health
Board of the Erzurum Region Training and Research Hospital between January 2011
and December 2012 were reviewed. One hundred ninety-nine patients aged >64
years who were classified as severely disabled with disability rates of over 50%,
and who were unable to care for themselves or to move and/or communicate
without help were included in the study.
Results: The most frequently seen disabilities were neurological (47.2%) and those
resulting from eye diseases (17.1%). The most common ophthalmologic diseases
were cataract, glaucoma, and age-related macular degeneration. The mean
right and left eye visual acuities were 1.17 ± 1.10 logMAR and 1.13 ± 1.0 logMAR,
respectively. Of the 60 patients with ophthalmologic diseases or conditions, 33
were blind (visual acuity worse than 20/400) and 10 were visually impaired (visual
acuity worse than 20/70 but better than 20/400). Cataracts were the main cause
of blindness. The mean age of the patients who were still being followed up at
the time of application to the disability board was significantly lower than that of
the others (p=0.015). Seventy-nine percent of the blind patients were from rural
areas, and 88% of these had no regular follow-up. Among the blind and visually
impaired, significantly more patients from urban areas had social security insurance
(SSI) than those from rural areas (p=0.043). Nearly 64% of the blind patients were
women. The follow-up rate was significantly lower in women (p=0.025). According
to multinomial logistic regression analysis, the visually impaired and blind patients
were more likely to have lower follow-up rates than the other types of severely
disabled patients (OR: 0.231, 95% Cl: 0.077-0.688, p=0.009).
Conclusions: Blindness gives rise to severe disability, and the most common ophthalmologic diseases that cause severe disabilities in elderly patients are cataract,
glaucoma, and age-related macular degeneration. Sociodemographic factors that
may affect the accessibility of visually impaired and blind people to health services
include their place of residence and gender.
Objetivo: Identificar a prevalência de doenças oftalmológicas em pacientes idosos
que tinham sido considerados como incapacitados graves, e para identificar as condições oftalmológicas que levam à deficiência visual e cegueira.
Métodos: Prontuários de 2806 pacientes que tinham solicitado ao conselho de
saúde do hospital de treinamento e pesquisa da região de Erzurum entre janeiro de
2011 e dezembro de 2012, foram revistos. Cento e noventa e nove idosos com mais
de 64 anos, que foram considerados como incapacitados graves nos quais as taxas
de incapacidade são mais de 50% e não são capazes de cuidado próprio e não são
capazes de mover-se e/ou comunicar-se sem ajuda, foram incluídos no estudo.
Resultados: As deficiências mais frequentemente observados são neurológicas (47,2%) e
doenças oculares (17,1%). As doenças oftalmológicas mais frequentemente observadas
foram catarata, glaucoma e degeneração macular relacionada à idade. Média de
acuidade visual em olho direito e esquerdo foram 1,17 ± 1,10 e 1,13 ± 1,0 logMAR,
respectivamente. Dos 60 pacientes, 33 apresentaram cegueira (acuidade visual
pior que 20/400), 10 tinham deficiência visual (acuidade visual pior do que 20/70,
melhor do que 20/400). A catarata foi a principal causa de cegueira. A idade média
dos pacientes com acompanhamento no momento da solicitação ao conselho foi
significativamente menor do que os demais (p=0,015). Setenta e nove por cento dos
pacientes cegos eram da área rural e 88% deles não tinham acompanhamento regular.
Entre cegos e deficientes visuais, a taxa de posse do seguro de segurança social (SSI)
foi significativamente maior em pacientes de área urbana (p=0,043). Quase 64% dos
pacientes cegos eram mulheres. A taxa de acompanhamento foi significativamente
menor nas mulheres (p=0,025). De acordo com a análise de regressão logística multinominal, os pacientes com deficiência e cegos visuais eram mais propensos a ter
menor taxa de acompanhamento do que os outros pacientes com deficiência grave
(OR: 0,231, 95% Cl: 0,077-0,688, e p=0,009).
Conclusões: A cegueira gera incapacitação grave. As doenças oftalmológicas mais
frequentemente observadas que causam deficiência grave em pacientes idosos são a
catarata, glaucoma e degeneração macular relacionada à idade. O local de residência
e o gênero são fatores sociodemográficos que podem ter impacto sobre o acesso à
saúde de pessoas com deficiência visual e cegos.
Keywords: Blindness; Cataract; Disabled people; Aging
Descritores: Cegueira; Catarata; Pessoas com deficiência; Envelhecimento
INTRODUCTION
The mean expected lifespan for humans rose from the 40s at the
beginning of the 20th century to the 80s at the beginning of the 21st
century(1). Populations are increasingly aging worldwide, and the
high rates of development of chronic health conditions over the
aging process increase the rates of morbidity and mortality and are
associated with disability(2-3). The Global Burden of Disease estimated
that 190 million individuals had a severe disability in 2010, including
conditions such as quadriplegia, severe depression, and blindness(4).
Blindness has socioeconomic consequences in all societies, with the
costs of lost productivity, rehabilitation, and education of the blind
constituting a significant economic burden for individuals, their families, and societies(5). Visually impaired and blind elderly people usually
face restrictions in their ability to participate in various activities. Decreased participation and activity loss are associated with increased
risk of functional and cognitive decline; in addition, these patients are
at risk of social isolation and may suffer from loneliness(6-10). Worldwide,
161-258 million individuals are estimated to be visually impaired, and
1
2
3
Department of Ophthalmology, Erzurum Region Training and Research Hospital, Erzurum, Turkey.
Department of Ophthalmology, School of Medicine, Uludag University, Bursa, Turkey.
Department of Ophthalmology, Şevket Yılmaz Training and Research Hospital, Bursa, Turkey.
24
Corresponding author: Sertaç Argun Kıvanç. Department of Ophthalmology, School of Medicine,
Uludag University - Gorukle, Bursa - Turkey - E-mail:[email protected]
http://dx.doi.org/10.5935/0004-2749.20160008
Kıvanç SA, et al.
in 33-39 million of this population, vision is reduced to the level of
blindness(11-13). In Turkey, according to the Turkish Statistical Institute,
85.7% of the disabled do not work, with half of these not able to work
due to severe disability. Further, 37.2% of these individuals do not
work due to ocular disability. According to the 2011 data from the
Social Security Institution of the Republic of Turkey, approximately
$2.9 billion was allocated for disabled people, with $2 billion (71.5%)
spent on the severely disabled and their relatives. Ophthalmologic
disability accounted for 8.4% of the total disabilities(14,15). Therefore,
blindness and visual impairment are amongst the most important
public health problems. An international, comprehensive classification system has been developed by the World Health Organization
(WHO) to define health and health-related conditions, as well as the
functionality and limits of humans, in standard language and settings.
This system, called the International Classification of Functioning,
Disability, and Health, has been used as a classification system in
studies of disabled individuals. In Turkey, a disability rate determined
by a regional health board, including physicians specialized in related diseases, is taken into account. In addition to the international
standards, these measures are used along with the Balthazar formula
when assessing the total disability level of an individual(16). In order to
receive disability and nursing care benefits, the disability level of the
individual must be at least 50% for them to be evaluated as “severely
disabled” by the board. In this study, we aimed to identify the rate
of ophthalmologic diseases in patients who had been evaluated as
being severely disabled and to identify the specific ophthalmologic
conditions leading to visual impairment and blindness among subjects aged 65 years or older.
able to care for themselves (feeding, dressing, bathing, etc.) and are
not able to move and/or communicate without help.
HEALTH INSURANCE STATUS
The patients were divided into two groups in terms of health insurance status. The first group had social security insurance (SSI) and
was defined as those who had a job or whose close relatives had a
job with a fixed amount of tax from their salaries allocated to the
Social Security Insurance. Patients in this group can apply to a tertiary
medical center or hospital without official referral. The second group
did not have social security insurance (No-SSI), had a low income, and
many of them did not have a job. They lack social security insurance,
so the government provides them with health insurance. However,
according to the health regulations, if they want access to a tertiary
medical center or hospital, they need to be referred officially by a local
physician. Otherwise, they would need to pay all health expenses
themselves without the support of insurance from the government.
PATIENT GROUPS
The patients were divided into two groups according to the number of physician visits per year. The first group included the patients
who visited their physicians at least once a year. The second group
included patients who only visited the hospital when applying to
the disability board. The patients were also grouped according to
whether their place of residence was in a rural or urban area.
ASSESSMENT OF VISUAL IMPAIRMENT AND BLINDNESS
Vision was defined and classified according to the WHO recommendations. Visual impairment was defined as a visual acuity of
worse than 20/70 but equal to or better than 20/400, or a corresponding visual field loss of less than 20°, in the better eye with the best
possible correction. Blindness was defined as a visual acuity of worse
than 20/400, or a corresponding visual field loss to less than 10°, in
the better eye with the presenting distance visual acuity.
METHODS
PATIENT SELECTION
The medical chart records of patients who had applied to the
Health Board of the Erzurum Region Training and Research Hospital between January 2011 and December 2012 were reviewed. One
hundred ninety-nine patients aged over 64 years who were assessed
as being “severely disabled” out of 2806 patients(17) were included in
the study and were retrospectively analyzed following approval of the
Ethics Board of the Erzurum Region Training and Research Hospital. The
present study complied with the tenets of the Declaration of Helsinki.
The health insurance status, number of visits, time spent under the
supervision of a physician, patient’s place of residence (urban/rural),
age, gender, whole body functional disability rate, medical branch of
disability, ophthalmologic functional disability rate, vision, and anterior/posterior segment examination were recorded.
We analyzed the data using the SPSS 17 (SPSS, Inc., Chicago, IL, USA)
program. For quantitative data, we used t-tests to compare groups
with normally distributed parameters.
Pearson’s chi-square test was performed to compare qualitative
data. The statistical significance was set at p<0.01 and p<0.05.
RESULTS
A total of 199 severely disabled patients who were over 64 years
old were included in the present study, with 125 women (62.8%)
and 74 men (37.2%). In terms of insurance, 89 were in the No-SSI
group, and 110 were in the SSI group. Fifty-six individuals applied to
the disability board from urban areas, and 143 patients applied from
rural areas. The mean age was 79.29 ± 6.92 years (range: 65-97 years).
The mean TBDR was 88.75 ± 7.96 (range: 60-100). All the patients had
the mean major disability rate (MDR) (Table 1). The most common
disabilities according to the medical specialty are shown in table 2.
Neurological diseases were the most common, with 94 patients (47.2%),
DISABILITY RATE
The total body disability rate (TBDR) and severity of disability were
determined by a health board in a tertiary center. The disability rate
is determined by the board, which includes physicians specializing in
internal medicine, ophthalmology, ear nose throat, general surgery
or orthopedics, neurology, and psychiatry, in addition to the international standards; these measures are used along with the Balthazar formula when identifying the TBDR of an individual(17). “Severely disabled”
is defined as individuals with a disability rate over 50% who are not
Table 1. Demographics of severely disabled patients
N
%
Age (years)
TBDR
Mean ± SD
Mean ± SD
Place of residence
Urban
Rural
Social security status
SSI
No-SSI
Regular follow-up
Yes
No
Gender
Male
074
037.2
79.3 ± 7.0
89.6 ± 7.0
19
055
037
37
22
052
Female
125
062.8
79.3 ± 6.9
88.3 ± 8.5
37
088
073
52
29
096
199
100.0
79.3 ± 6.9
88.8 ± 8.0
56
143
110
89
51
Total
P value
0.552
0.249
148
0.308
TBDR= total body disability rate; N= number; SD= standard deviation; SSI= social security insurance; No-SSI= no social security insurance.
25
Among the 199 severely disabled patients, we compared the characteristics of the 60 patients with visual impairment or blindness
with the other severely disabled patients by univariate analysis. There
was a significant difference in terms of the follow-up status (Table 7). To
assess the associations of the place of residence, SSI status, follow-up
status, and gender with visual condition, we performed a multinomial
logistic regression analysis. The visually impaired and blind patients
were more likely to have a lower follow-up rate than the other severely
disabled patients (OR: 0.231, 95% Cl: 0.077-0.688, p=0.009).
followed by eye diseases, with 34 patients (17.1%). The most common
ophthalmologic diseases were cataract, glaucoma, and age-related
macular degeneration (AMD). Table 3 shows the ocular diseases,
causes of blindness, and visual impairment, as well as their rates for
each eye. The mean right and left eye visual acuities were 1.17 ± 1.10
logMAR and 1.13 ± 1.0 logMAR, respectively. Of the 60 patients with
ophthalmologic diseases or conditions, 33 were blind and 10 had
visual impairment. In total, 90 eyes suffered from blindness (63 eyes)
and visual impairment (27 eyes). Cataract was the main cause for
blindness, followed by glaucoma. However, seven eyes had neovascular glaucoma, and the cause of neovascularization was unclear
from the medical charts.
Cataract was the most common cause for visual impairment. No
significant differences were noted in the age, TBDR, ophthalmologic
disability rate, visual acuity of the right eye, and visual acuity of the left
eye between the sexes. Further, there were no significant differences
in TBDR, ophthalmologic disability rate, and the visual acuities of the
right and left eyes between the patients who were being followed
up at the time of application to the disability board and the ones
who were not. Further, the mean age of the patients who were being
followed up at the time of application to the disability board was
significantly lower than that of the patients who were not being
followed up at the time of application (p=0.015) (Table 4).
The mean MDR of the patients with eye disorders was statistically
significantly higher than that of the patients with other disorders;
the mean MDRs were 92.82 ± 4.50 and 87.92 ± 8.27, respectively
(p=0.001). The number of patients without SSI was significantly higher
in rural areas than in urban areas (85%, p<0.001). No statistical significance was detected in terms of the other parameters (Table 5). The
sociodemographic and economic characteristics of the patients who
were blind and visually impaired are shown in table 6. Seventy-nine
percent of the blind patients were from rural areas, and 88% of the
blind patients had no regular follow-up. Nearly 64% of the blind
patients were women.
Of the 199 patients, 60 (30%) had ophthalmologic conditions
or diseases. Thirty-four (57%) had applied to the disability board
because of eye disease and 22% because of neurological disorders.
Forty-three of the 199 patients (22%) were blind or visually impaired.
The mean age of the blind or visually impaired patients was 81.4 ±
6.9 years. Among the blind and visually impaired patients, the rate
of those with SSI was significantly higher in women (75%; p=0.037)
and patients from urban areas (73%; p=0.043). The follow-up rate
was significantly lower in women (p=0.025).
DISCUSSION
Aging is a natural process, and the increased rates of age-related
diseases due to this increase in life expectancy are currently an important public health issue. Individuals aged 65 years or older now
comprise 14.7%, 12.5%, and 13% of the whole population of the
Netherlands, Australia, and the USA, respectively(18). While the current
population aged 65 years or older is 5.9 million (approximately 8%) in
Turkey, it has been extrapolated to reach over 8.5 million (approximately 10%) in 10 years’ time(19). According to data released in 2011, there
are 30,318 patients aged over 65 years receiving disability benefits
who are severely disabled(15). The individuals aged 65 years or older
who received care services at home or special care centers constitute
6.6%, 6.0%, and 3.5% of the total population in the Netherlands, Australia, and the USA, respectively(18).
In the present study, we noticed that ophthalmology is among
the first three major disciplines related to severe disability. Globally,
there are 32 million blind people and 153 million people with visual
impairment who are 50 years old or older. In Europe, there are 3000
blind people and 25,500 people with visual impairment per one million
people(12). The burden of visual impairment is greatest amongst those
50 years of age and older. Globally, 84.6% of blind people and 77.5% of
visually impaired people are in these age groups(13). A study from the
Netherlands reported prevalence rates in 2008 of 2.4% for blindness
and 7.8% for visual impairment in people aged 65 years and over(20).
The prevalence of blindness in adult individuals has been assessed as
varying between 0.5% and 3% in different studies(21,22).
In our study, we found that the major causes for blindness and visual
impairment were cataract, glaucoma, AMD, retinal detachment, and
neovascular glaucoma, in descending order. Pascolini and Mariotti
reviewed studies on this topic and found that cataract (51%) was the
most common cause of blindness(12).
Moreover, cataract has been found to be the most common cause
of blindness in various population-based studies. However, the cau-
Table 2. Percentages of patients with eye diseases, visual impairment, and blindness in different medical specialties
Patients
Patients with eye diseases
Medical specialty
N
%
N
%
DR
Endocrinology
01
00.5
01
01.7
17
Physical medicine and rehabilitation
29
14.6
02
03.3
28
Visual impairment
N
%
1
10
Chest diseases
09
04.5
03
05.0
28
1
10
Ophthalmology
34
17.1
34
56.7
84
2
20
Hematology
01
00.5
00
0
1
10
Cardiology
10
05.0
02
03.3
40
Ear nose throat
04
02.0
01
01.7
35
Nephrology
06
03.0
01
01.7
35
1
10
Neurology
94
47.2
13
21.7
20
4
40
Oncology
06
03.0
01
01.7
35
Psychiatry
04
02.0
01
01.7
36
Urology
01
00.5
01
01.7
36
N= number; DR= mean disability rate from eye diseases.
26
Blindness
N
%
32
97
01
03
Kıvanç SA, et al.
Table 3. Ocular diseases causing visual impairment and blindness
Patients with eye diseases
N
Ocular diseases
Blindness
%
N
Visual impairment
%
N
%
11
50.0
Lens-related diseases
Cataract
46
38.4
17
24.0
Aphakia
01
00.8
01
01.4
Total
47
39.2
18
25.4
11
50.0
01
04.5
01
04.5
08
36.4
02
009.1
10
45.5
Cornea-related diseases
Corneal leucoma
03
02.5
02
02.8
Corneal dystrophies
02
01.7
02
02.8
Bullous keratopathy
01
00.8
01
01.4
Total
06
05.0
05
07.0
14
11.7
14
19.7
Glaucoma-related diseases
Glaucoma
Neovascular glaucoma
07
05.8
07
10.0
Total
21
17.5
21
29.7
Retina-related diseases
Age-related macular degeneration
19
15.8
05
07.0
Retinal detachment
07
05.8
07
09.9
Degenerative myopia
06
05.0
05
07.0
Diabetic retinopathy
04
03.3
Macular dystrophies
02
01.7
02
02.8
Retinitis pigmentosa
02
01.7
02
02.8
Total
40
33.3
21
29.5
Optic atrophy
03
02.5
03
04.2
Phthisis bulbi
02
01.7
02
02.8
Exenteration
01
00.8
01
01.4
Total
06
05.0
06
08.4
Optic nerve-and globe-related diseases
Table 4. Associations of social security status, place of residence, regular follow-up, and gender with age, disability rates, and vision
Place of residence
Regular follow-up
Gender
Age (Years)
TBDR (%)
DR (%)
Right visual acuity (logMAR)
Left visual acuity (logMAR)
mean ± SD
mean ± SD
mean ± SD
mean ± SD
mean ± SD
Rural
79.54 ± 7.09
88.87 ± 7.89
57.54 ± 31.98
1.19 ± 1.1
1.10 ± 0.92
Urban
78.68 ± 6.48
88.46 ± 8.24
64.67 ± 26.88
1.52 ± 0.9
1.59 ± 1.01
P value
0.432
0.749
0.48
0.386
0.154
SSI
78.85 ± 6.88
88.93 ± 8.05
61.03 ± 30.62
1.45 ± 1.14
1.32 ± 1.05
No-SSI
79.85 ± 6.97
88.54 ± 7.90
56.76 ± 31.68
1.06 ± 0.95
1.11 ± 0.85
P value
0.308
0.734
0.597
0.218
0.47
Yes
77.27 ± 6.18
88.55 ± 8.11
48.70 ± 36.60
1.06 ± 1.02
0.76 ± 1.12
1.29 ± 0.92
No
79.99 ± 7.04
88.82 ± 7.95
61.02 ± 29.69
1.31 ± 1.07
P value
0.015
0.832
0.254
0.544
0.21
Women
79.29 ± 6.88
88.26 ± 8.48
64.91 ± 29.21
1.50 ± 1.11
1.47 ± 1.05
Men
79.31 ± 7.03
89.58 ± 7.00
51.70 ± 31.99
1.01 ± 0.96
0.91 ± 0.73
P value
0.988
0.261
0.1
0.125
0.056
TBDR= total body disability rate; DR= disability rate from ophthalmologic conditions; SD= standard deviation; SSI= social security insurance; No-SSI= no social security insurance;
logMAR= logarithm of the minimum angle of resolution.
ses of blindness and its prevalence vary in countries depending on
their levels of economic development and even within different regions of the same country(13,14,23,24). A study on Latin American countries
reported that unoperated cataract is the main cause of blindness(22). In
the Barbados eye study, the most common causes of blindness were,
in descending order, cataract (58.3%), glaucoma (14.3%), diabetic
retinopathy (8.7%), optic atrophy (7.1%), and AMD (2.4%)(23). Cataract
is also the main cause of blindness in Paraguay(24). In several studies
27
Table 5. Interrelationships of social security status, place of residence, regular follow-up, and gender
Place of residence
Rural
Place of residence
Rural
SSI
No-SSI
Yes
Gender
No
Women
Men
%
N
%
N
%
N
%
N
%
N
%
N
%
N
%
143
100.0
00
0
67
046.9
76
053.1
32
022.4
111
077.6
88
061.5
55
038.5
0
56
100.0
43
076.8
13
023.2
19
033.9
037
066.1
37
066.1
19
033.9
Urban
0
N/A
0.000
0.093
0.552
SSI
67
060.9
43
039.1
110
100.0
00
0
29
026.4
081
073.6
73
066.4
37
033.6
No-SSI
76
085.4
13
014.6
0
0
89
100.0
22
024.7
067
075.3
52
058.4
37
041.6
P value
0.000
Regular follow-up
Gender
Urban
N
P value
Patients with regular hospital
follow-up
N/A
0.792
0.249
Yes
32
062.7
19
037.3
29
056.9
22
043.1
51
100.0
000
0
29
056.9
22
043.1
No
111
75.0
37
25.0
81
054.7
67
045.3
0
0
148
100.0
96
064.9
52
035.1
Pvalue
0.093
Women
88
070.4
37
029.6
73
058.4
52
041.6
29
023.2
096
076.8
125
100.0
0
0
Men
55
074.3
19
025.7
37
050.0
37
50.0
22
029.7
052
070.3
0
0
74
100.0
P value
0.552
0.792
N/A
0.249
0.308
0.308
N/A
N/A= not available; N= number; SSI= social security insurance; No-SSI= no social security insurance.
Table 6. Comparison of blind patients with visually impaired patients according to their sociodemographic characteristics
SSI
Place of residence
No-SSI
Urban
Regular follow-up
Rural
Yes
Gender
No
Men
Women
N
%
N
%
N
%
N
%
N
%
N
%
N
%
N
%
Visual impairment
06
60.0
04
40.0
4
40.0
06
60.0
0
0
10
100.0
06
60.0
04
40.0
Blindness
17
51.5
16
48.5
7
21.2
26
78.8
4
12.1
29
087.9
12
36.4
21
63.6
P value
0.801
0.715
0.248
0.184
N= number; SSI= social security insurance; No-SSI= no social security insurance.
Table 7. Comparison of blind or visually impaired patients with other severely disabled patients in terms of place of residence
Place of residence
Rural
N
SSI
Regular follow-up
No-SSI
Yes
Gender
No
N
R%
C%
N
R%
C%
N
R%
C%
N
R%
032
74.4 22.4
11
25.6 19.6
23
53.5 20.9
20
46.5 22.5
04
09.3 07.8
039
90.7 26.4
Others
111
71.2 77.6
45
28.8 80.4
87
55.8 79.1
69
44.2 77.5
47
30.1 92.2
109
69.9 73.6
P value
0.848
0.863
0.005
C%
N
R%
Women
C%
Blind or visually
impaired patients
R%
SSI Status
Urban
C%
N
Men
R% C%
N
R% C%
025 58.1 20
18
41.9 24.3
100 64.1 80
56
35.9 75.7
0.481
N= number; R%= row percentage; C%= column percentage; SSI= social security insurance; No-SSI= no social security insurance.
performed in European countries and the USA, which are places with
high life expectancy, the most common cause of visual impairment
has been shown to be AMD(25,26). In a study conducted in 2008 the
Netherlands, the main cause of blindness was macular degeneration,
followed by cataract, refractive errors, glaucoma, and diabetic retinopathy(18). In the present study, we studied severely disabled elderly
patients, and our study was not population based, as the aforementioned studies were; therefore, we were not able to compare our results
with those from the previous studies.
In Turkey, there are more than 400,000 visually impaired individuals
according to data from 2002. Of these, 48,500 (11.8%) individuals
were blind, while 162,000 (39%) individuals had visual impairment. In
Eastern Turkey, of 35,000 visually impaired, 9400 (26.7%) individuals
were blind, and 11,000 (31.1%) individuals had visual impairment,
whereas in industrialized and developed regions of Western Turkey,
13% were blind, and 34% had visual impairment. Forty-nine percent
28
of the visually impaired in Eastern Turkey and 33% in Western Turkey
did not undergo treatment for their visual impairment(14). Our study
was performed by retrospective analysis of two years of data from
the disability board of a tertiary hospital in Eastern Turkey. Seven
percent of the disabled were over 65 years old, and were classed as
severely disabled. Thirty percent of these patients had ophthalmologic diseases, and 17% were identified as being severely disabled
due to ophthalmologic diseases. In a study that assessed blindness
globally, the largest proportion of blind people resided in South Asia,
followed by East Asia and Southeast Asia. The prevalence of blindness
varied from 0.1% in the high-income North America region to 0.7%
in the North Africa and Middle East regions. Moreover, the prevalence of blindness among older adults was greater than 4% in Western
Sub-Saharan Africa, Eastern Sub-Saharan Africa, South Asia, North Africa, and the Middle East. The prevalence of blindness was lowest in
high-income regions, with percentages of 0.4% or lower(13,27).
Kıvanç SA, et al.
In the Netherlands, an estimated 311,000 people are visually impaired, and the visual loss is thought to be treatable or preventable in
174,000 (56%) of these people(18). The most common preventable and
treatable cause of blindness throughout the world is cataract, and
this is particularly true in developing countries. When cataracts are
left untreated, the relatives of the patients, and eventually, society as
a whole, face economic and moral burdens(13). It has been calculated
that blindness and visual impairment constitute a financial burden of
15-73 billion US dollars per year(28,29).
According to the data from the TSI, 42.4% of all the disabled people
in Turkey have a disability rate of 70% or more. The percentages of
disabled people living in urban areas, aged 65 years and over, and
who are females constitute 62.4%, 15.2%, and 41.4%, respectively, out
of all the disabled people in Turkey(14). Apart from the official data of
Turkey, in our study, 27% of the individuals who received the severely
disabled rating for ophthalmologic reasons came from urban areas,
and 73% came from rural areas. Additionally, 79% of the blind patients
came from rural areas, and the patients living in rural areas had significantly lower rates of having SSI. Health access and utilization of eye
care services may be influenced by various sociodemographic factors
such as age, sex, and education level(30). In our study, we found that
having SSI was associated with patients’ place of residence. Patients
with no SSI have to pay their own health expenses when they seek
medical care in tertiary centers if they are not referred officially by a
local physician, which may be an obstacle to health services. Therefore,
the place of residence as a sociodemographic factor might have
affected health access in our study, particularly in blind patients. In
our study, we noted a higher rate of females than males aged over 65
years who were classed as severely disabled due to blindness; further,
females had significantly lower rates of follow-up. Thus, gender
affects health access. In all regions worldwide, women have a higher
age-standardized prevalence of vision impairment and blindness
than men(13). Globally, 4.2% of males and 5.3% of females aged over 70
years are blind, and 18.8% of males and 20.9% of females aged over 70
years are visually impaired,(13) suggesting lower accessibility to health
for women compared with that for men. Multivariate analysis showed
that patients who were severely disabled due to their ophthalmological conditions were less likely to visit hospitals than the other severely
disabled patients. Compatible with this finding, it was shown that
elderly people with visual impairment and/or blindness have participation restrictions and activity loss that are associated with functional
and cognitive decline(6-10).
In conclusion, blindness gives rise to severe disability and constitutes a large proportion of the diseases that lead to severe disability.
The most common ophthalmologic diseases that cause severe disability are cataract, glaucoma, and AMD. Sociodemographic factors
that may affect the accessibility to health services of visually impaired
and blind people include their place of residence and gender. Finally,
visually impaired and blind people are more likely to have lower
follow-up rates than other severely disabled people.
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29
Original Article
Intrastromal corneal ring segments delay corneal grafting in patients
with keratoconus
Segmentos de anéis intracorneanos protelam o transplante de córnea em pacientes com ceratocone
luiz arthur f. BEniz1, GuStavo h. QuEiroz1, carloS f. QuEiroz1, wanESSa l. lopES1, lEiSEr f. MoraES1, joSé BEniz1
ABSTRACT
RESUMO
Purpose: To assess the impact of intrastromal corneal ring segments (ICRS) as
a surgical alternative to corneal grafting in patients with keratoconus who were
scheduled for a corneal transplant.
Methods: This single-surgeon, single-center, retrospective, observational case
series study included 19 eyes of 18 patients (mean age, 23.36 ± 6.22 years) with a
confirmed diagnosis of keratoconus. These patients were enrolled from the State
of Goiás, Brazil corneal graft waiting list. Following extensive pre-operative testing,
including the measurement of best-corrected visual acuity (BCVA), applanation
tonometry, biomicroscopy, funduscopy, pachymetry, and corneal topography,
patients were implanted with Keraring® ICRS. Patients underwent clinical examination at postoperative days 1, 7, 30, 90, and 180 and were examined again 2
years following surgery.
Results: At the 2-year cut-off following ICRS implantation (mean follow-up, 28.72
± 4.71 months), there was a statistically significant improvement in BCVA (logMAR)
from 0.59 ± 0.35 preoperatively to 0.35 ± 0.45 postoperatively (p<0.01). Three of
19 eyes (15.8%) still required keratoplasty. In the remaining patients (84.2%), BCVA
was managed with spectacles (52.6%) or contact lenses (31.6%). One patient developed infectious keratitis, requiring removal of ICR at the first postoperative visit.
Conclusion: ICRS implantation may be a surgical alternative to keratoplasty in
patients with keratoconus. This procedure may delay or even eliminate the need
for keratoplasty in such patients.
Objetivo: Avaliar o impacto do implante de anéis corneanos intraestromais como
alternativa cirúrgica à ceratoplastia, em pacientes com ceratocone previamente
inscritos na fila de espera para transplante de córnea.
Métodos: Este estudo unicêntrico, retrospectivo, observacional analisou prontuários de 19 olhos de 18 pacientes (idade média de 23,36 ± 6,22) com diagnóstico de
ceratocone, incluídos na lista de espera para transplante de córnea do estado de
Goiás, Brasil. Após realização de exame oftalmológico completo pré-operatório, incluindo acuidade visual (AV) corrigida, tonometria de aplanação, biomicroscopia,
fundoscopia, paquimetria e topografia corneana, os pacientes foram submetidos a
cirurgia para implante de anel intracorneano Keraring®. Os mesmos foram submetidos a exame oftalmológico no 1o, 7o, 30o, 90o, 180o dias de pós-operatório, e também
após 2 anos da cirurgia.
Resultado: Após a visita final de 2 anos de acompanhamento (média de seguimento
de 28,72 ± 4,71 meses), houve melhora estatisticamente significativa da AV corrigida
(logMAR): 0,59 ± 0,35 no pré-operatório para 0,35 ± 0,45 do pós-operatório (p<0,01).
Três dos 19 olhos (15,8%) permaneceram com a indicação de ceratoplastia. A conduta
para os demais (84,2%) foi correção óptica com óculos (52,6%) ou lente de contato
(31,6%). Um paciente evoluiu com ceratite infecciosa no pós-operatório, tendo seus
anéis removidos.
Conclusão: O implante de anéis intraestromais mostrou ser uma alternativa eficaz ao
transplante de córnea nesta série de casos. Esse procedimento pode ajudar a retardar
ou eliminar a necessidade de indicação de ceratoplastia em pacientes com ceratocone.
Keywords: Keratoconus; Corneal transplantation; Corneal stroma; Eye banking;
Visual acuity
Descritores: Ceratocone; Transplante de córnea; Banco de olhos; Estroma corneano;
Acuidade visual
INTRODUCTION
crobial keratitis(4,5). Moreover, visual rehabilitation or recovery of visual
acuity following transplantation may be slow and unsatisfactory.
There is a growing interest in treatment options that may delay or
defer corneal grafting, including the use of intrastromal corneal ring
segments (ICRS)(6).
Originally used to correct mild-to-moderate myopia, ICRS exert
an ‘‘arc-shortening” effect on the corneal lamellae, thus reducing
steepening of the central cornea(3). This decreases refractive errors
and improves corneal surface regularity. Moreover, there is evidence
to suggest that implanting an ICRS may delay the requirement for
penetrating keratoplasty(7-9).
There are several commercially available ICRS that vary with regard
to curvature, width, and zone of implantation(3). One such ICRS is the
Keraring (Mediphacos, Belo Horizonte, Brazil), a small, arc-like segment
made of polymethyl methacrylate. It is characterized by a unique pris-
Keratoconus is a common, non-inflammatory, progressive corneal disorder with a typical onset in early adulthood(1). Keratoconus
that is characterized by thinning and protrusion of the central cornea
frequently leads to a mild-to-severe decrease in best-corrected visual
acuity (BCVA). Loss of visual acuity can be improved with contact lenses or spectacles in the early stages of the disease; however, patients
may eventually require corneal grafting as their condition progresses.
Keratoconus is the single most common reason for keratoplasty in
the developed world(1-3).
Penetrating keratoplasty is associated with a high success rate and
continues to play an important role in keratoconus management.
However, it is also associated with significant complications, including immunological rejection, secondary cataract, glaucoma, and mi-
Submitted for publication: February 20, 2015
1
Centro de Referência em Oftalmologia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
interest to disclosure.
Corresponding author: José Beniz Neto. Av. T-2, no 401- Goiânia, GO - 74210-010 - Brazil
Approved by the following research ethics committee: Hospital das Clínicas, Universidade Federal
de Goiás (219.191).
30
http://dx.doi.org/10.5935/0004-2749.20160009
Beniz LAF, et al.
matic design that flattens the cornea and reduces the incidence of
glare and halos. Several clinical studies have demonstrated their efficacy in improving visual function, reducing the magnitude of corneal
astigmatism, and flattening the central corneal surface(10-14). Although
previous studies have evaluated ICRS efficacy in patients who were
intolerant to rigid contact lenses (and therefore potential candidates
for a corneal transplant)(15-17), to the best of our knowledge, there
are no published data regarding Keraring ICRS efficacy in patients
with keratoconus who were already scheduled for penetrating keratoplasty. Consequently, we performed a small case series study to
determine whether Keraring ICRS implantation might represent a
surgical alternative to corneal grafting in patients with keratoconus
who were awaiting penetrating keratoplasty.
METHODS
We conducted a retrospective observational case series study
on the basis of an analysis of records of patients included in the State
of Goiás corneal graft waiting list. These patients underwent Keraring ICRS implantation as a potential alternative to keratoplasty. All
procedures were performed by the same surgeon at the Centro de
Referência em Oftalmologia UFG, Goiânia, Brazil between June and
December 2008. Written informed consent was obtained prior to
study and data collection.
The study included 18 patients (19 eyes) with a mean age of
23.36 ± 6.22 years and with keratoconus varying from Grade II to IV
(Amsler-Krumeich scale). Patients were included if they had evidence
of topographical alteration that was compatible with keratoconus, a
minimal corneal thickness of 380 µm, low BCVA with spectacles, and
intolerance to contact lenses. Exclusion criteria included topographic
curves over 70 D, apical opacity, and external ocular infection. Baseline
characteristics of the patients are summarized in table 1.
Prior to ICRS implantation, all patients underwent a detailed preoperative clinical assessment, including the measurement of BCVA
(logMAR), applanation tonometry, biomicroscopy, fundoscopy, pachymetry, and corneal topography. Patients were postoperatively
evaluated for BCVA.
ICRS selection was based on the Mediphacos nomogram for the
Keraring® calculation system (Belo Horizonte, Brazil). All surgeries were
performed on an outpatient basis under topical anesthesia (5 mg/mL
proxymetacaine HCl and 5% povidone iodine). The ICRS tunnel was
manually created. The center of the visual axis on the cornea was
marked, and an initial perpendicular corneal incision was made at the
5-7-mm zone with an adequate depth for each case. This was followed
by radio intrastromal channelization. Appropriate ICRS was finally
placed inside the corneal tunnels.
Following the procedure, patients were administered Maxitrol® eye
drops (Alcon Laboratories, Brazil) every 2 h for 2 weeks, followed by
Florate® (Alcon Laboratories, Brazil) four times daily, also for 2 weeks.
Postoperative outcomes were evaluated at postoperative days 1,
7, 30, 90, 180, and eventually 2 years following implantation. BCVA was
measured and biomicroscopy and applanation tonometry were performed at each follow-up visit, whereas fundoscopy was performed
at the 6-month follow-up visit. The effectiveness of ICRS in terms of
preventing corneal grafting was evaluated at the 2-year follow-up
visit.
RESULTS
Pre- and postoperative BCVA (logMAR) data of each patient are
displayed in table 2. Mean preoperative BCVA was 0.59 ± 0.35. At the
2-year cut-off point following ICRS implantation (mean follow-up,
28.72 ± 4.71 months), mean BCVA was 0.35 ± 0.45 (Figure 1). This improvement in BCVA was statistically significant (p<0.01). One patient
developed infectious keratitis on postoperative day 1. Consequently,
this patient had his corneal rings removed, and his data excluded
from the statistical analysis of BCVA. The patient subsequently underwent corneal grafting.
At the 2-year cut-off point, 3/19 eyes (15.8%) were still considered
candidates for penetrating keratoplasty because they did not achieve
significant corneal applanation or regularity. However, the remaining
patients (84.2%) maintained BCVA with spectacles (52.6% patients)
or contact lenses (31.6% patients). Apart from one case of infectious
keratitis, no other relevant complications occurred.
DISCUSSION
Although initially approved by the US Food and Drug Administration as a treatment for myopia, ICRS has become a mainstay in managing keratoconus. Since Colin et al. first reported regarding the use of
ICRS in keratoconus more than a decade ago(7), a plethora of studies
have demonstrated their ability to effectively reduce refractive errors
and safely improve corneal surface regularity. While there is also
increasing evidence to suggest that ICRS may delay the requirement
for penetrating keratoplasty(5,18), published evidence describing ICRS
effects in patients with keratoconus already scheduled to undergo
penetrating keratoplasty is limited.
Table 1. Patient characteristics
N (%)
No patients
18
Gender
Female
12*
Male
6
No of eyes
19
Right eyes
09
Left eyes
10
Age (years)
Mean
23.36 e 6.22
Range
14-32
*= one female was subject to bilateral implantation with ICRS.
Table 2. BCVA (logMAR) pre- and post-ICRS implantation
Eye
Preoperative BCVA
Postoperative BCVA*
01
0.15
0.15
02
0.53
0.30
03
0.30
1.00
04
1.00
0.30
05
0.70
0.22
06
0.70
0.53
07
0.30
0.14
08
0.70
0
09
1.60
1.80
10
0.40
0.15
11
0.27
0
12
0.40
0.53
13
0.82
0.70
14
0.10
0.10
15
0.70
0.15
16
0.70
0.04
17
0.40
0.04
18
0.40
0.20
*= two-year cut-off point (mean follow-up, 28.72 ± 4.71 months); NB= one of 19 eyes
included in the study was excluded from BCVA statistics.
31
Intrastromal corneal ring segments delay corneal grafting in patients with keratoconus
improved from 0.07 ± 0.07 preoperatively to 0.6 ± 0.26 postoperatively, whereas mean BCVA changed from 0.4 ± 0.15 preoperatively to
0.9 ± 0.29 postoperatively(20).
Although data from our small study suggests that ICRS may be a
surgical alternative to keratoplasty in some patients with keratoconus, longer-term follow-up is required to determine for how long ICRS
adequately maintain BCVA and whether patients for whom ICRS implantation was effective will eventually require penetrating keratoplasty.
CONCLUSION
The results indicate that ICRS implantation may delay or even
eliminate the requirement for corneal grafting in a group of patients
with keratoconus who awaited keratoplasty.
REFERENCES
*= two-year cut-off point (mean follow-up, 28.72 ± 4.71 months).
NB= one of 19 eyes included in the study was excluded from analysis of BCVA data.
Figure 1. Change in BCVA (logMAR) following ICRS implantation.
The results of our case series of 18 patients (19 eyes) who awaited
corneal grafting suggest that ICRS may be an efficacious alternative
to penetrating keratoplasty. At the 2-year data cut-off point, we noted
that 84% eyes maintained BCVA with spectacles (52.6%) or contact
lenses (31.6%), whereas 3/19 eyes (15.8%) still required keratoplasty
because they did not achieve significant corneal applanation or
regularity.
Data from a previously published, one-year, 50-eye study demonstrated that Keraring ICRS implantation improved both uncorrected visual acuity and BCVA in patients with keratoconus (17). Similarly,
in a 35-eye study, Coimbra et al. demonstrated that Keraring ICRS improved visual acuity and topographic data in patients with secondary
corneal ectasia at a 3-month postoperative follow-up(11). However, to
the best of our knowledge, no reports on the use of Keraring ICRS as
a treatment for patients who have already been triaged for corneal
transplantation are available. Consequently, it is somewhat difficult
to discuss our findings within the context of others. However, there
is a comparative case study of 76 eyes with advanced keratoconus.
These patients received either ICRS implantation or deep anterior lamellar keratoplasty. ICRS effected a statistically significant increase in
visual acuity (corrected and uncorrected distance visual acuity) from
baseline to postoperative 24 months (p<0.001)(19). Similarly, data from
a study by El-Husseiny et al., which included 20 eyes of 16 patients,
revealed that ICRS (Intacs, Addition Technology, Inc, Sunnyvale, CA)
provided a viable alternative to early penetrating keratoplasty for
patients with keratoconus having a clear central cornea and a history
of contact lens intolerance. Specifically, the data revealed that after
6 months of follow-up, the mean uncorrected distance visual acuity
32
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follow-up of Intacs in keratoconus. Am J Ophthalmol. 2007;143(2):236-44.
17. Coskunseven E, Kymionis GD, Tsiklis NS, Atun S, Arslan E, Jankov MR, et al. One-year
results of intrastromal corneal ring segment implantation (KeraRing) using femtosecond laser in patients with keratoconus. Am J Ophthalmol. 2008;145(5):775-9.
18. Ertan A, Colin J. Intracorneal rings for keratoconus and keratectasia. J Cataract Refract
Surg. 2007;33(7):1303-14.
19. Ozertürk Y, Sari ES, Kubaloglu A, Koytak A, Piñero D, Akyol S. Comparison of deep
anterior lamellar keratoplasty and intrastromal corneal ring segment implantation in
advanced keratoconus. J Cataract Refract Surg. 2012;38(2):324-32.
20. El-Husseiny M, Tsintarakis T, Eppig T, Langenbucher A, Seitz B. [Intacs intracorneal ring
segments in keratoconus]. Ophthalmologe. 2013;110(9):823-6. German.
Original Article
Effects of prostaglandin analogs on blood flow velocity and resistance in the
ophthalmic artery of rabbits
Efeitos dos análogos da prostaglandina na velocidade do fluxo sanguíneo e resistência na
artéria oftálmica de coelhos
aMália turnEr Giannico1, lEandro liMa1, Gillian c. Shaw2, hEloiSa h. a. ruSS3, tildE rodriGuES froES1, faBiano Montiani-fErrEira1
ABSTRACT
RESUMO
Purpose: The aim of this study was to investigate the effects of prostaglandin
analogs on blood flow in the ophthalmic artery of clinically healthy rabbits.
Methods: Fifty-five clinically healthy New Zealand white rabbits were divided
into six groups, and the left eyes were treated for four weeks with the preservative
benzalkonium chloride (BAK) only or a topical formulation of different prostaglandin analogs (bimatoprost BAK, tafluprost BAK-free, travoprost BAK, travoprost
POLYQUAD, and latanoprost BAK). Color Doppler imaging was performed before
and after the treatments. The mean values of the peak systolic velocity (PSV) and
end diastolic velocity and the resistive index (RI) were calculated. Statistical analysis
was performed to compare the differences pre- and post-treatment for each drug
and post-treatment among the drugs.
Results: The prostaglandin analogs did not affect PSV. Bimatoprost BAK, travoprost
POLYQUAD, and latanoprost BAK did not change RI. Tafluprost BAK-free and travoprost BAK therapy resulted in similar reductions in RI. No significant differences
pre- and post-treatment were found when BAK was administered alone.
Conclusion: The prostaglandin analogs tafluprost BAK-free and travoprost BAK
improved blood flow in the ophthalmic artery in healthy New Zealand white
rabbits, which suggests that these drugs enhance the prevention of the progression the progression of glaucoma.
Objetivo: O objetivo deste estudo foi investigar os efeitos dos análogos da prostaglandina (PGAs) no fluxo sanguíneo da artéria oftálmica em coelhos.
Métodos: Cinquenta e cinco coelhos da raça Nova Zelândia clinicamente saudáveis
foram divididos em seis grupos para tratamento com formulação tópica de diferentes
APGs (bimatoprosta BAK, tafluprosta BAK-free, travoprosta BAK, travoprosta POLYQUAD
e latanoprosta BAK) e formulações contendo apenas o conservante cloreto de benzalcônio (BAK). Foi realizada ultrassonografia com Doppler antes e após os tratamentos.
Os valores do pico da velocidade sistólica (PSV) e da velocidade diastólica final foram
obtidos e o índice de resistência (RI) foi então calculado. A análise estatística foi realizada para comparar as diferenças entre cada droga no pré e pós-tratamento, além
das diferenças no pós-tratamento entre as drogas.
Resultados: Estes colírios PGAs não afetaram o PSV. A bimatoprosta com o conservante
BAK, travoprosta com o conservante POLYQUAD e latanoprosta com o conservante
BAK não alteraram o RI. Já o tratamento com tafluprosta sem conservante (BAK-free)
e travoprosta com o conservante BAK promoveram redução similar dos valores do RI.
Não houve diferença significativa na comparação entre valores pré e pós-tratamento
quando BAK foi administrado isoladamente.
Conclusão: Os PGAs tafluprosta BAK-free e travoprosta BAK melhoraram o fluxo sanguíneo na artéria oftálmica em coelhos da raça Nova Zelândia sugerindo que estes
medicamentos possam contribuir na prevenção da progressão do glaucoma.
Keywords: Color Doppler imaging; Orbital hemodynamics; Glaucoma; Oryctolagus cuniculus
Descritores: Doppler colorido; Hemodinâmica orbital; Glaucoma; Oryctolagus
cuniculus
INTRODUCTION
Glaucoma is a multifactorial disease characterized by progressive
optic neuropathy with loss of visual field. Historically, elevated intraocular pressure (IOP) is regarded as the primary cause of glaucomatous
optic nerve damage; however, there is now evidence that other factors are involved in the pathogenesis of glaucoma, such as changes
in blood flow, perfusion, and oxygen delivery(1). There is compelling
accumulated evidence supporting the theory that decreased ocular
blood flow contributes to glaucomatous optic neuropathy(1,2). In a
model of optic nerve injury, it was demonstrated that alterations of
perfusion and oxygen delivery to the retinal ganglion cells may significantly contribute to vision loss(3). Therefore, detailed hemodynamic
evaluation of the orbital circulation is needed to better understand
this complex disorder.
The hemodynamics of orbital blood vessels can be quantified
by color Doppler imaging (CDI), which allows estimations of velocity and resistance to blood flow in unanesthetized subjects. This
method has been widely used to study these blood flow parameters
in retrobulbar blood vessels in humans and animals(4-8). The Doppler
waveform represents changes in the velocity of the blood flow during
the cardiac cycle, and deflections in the late systolic [peak systolic
velocity (PSV)] or early diastolic flow [end diastolic velocity (EDV)]
are characteristic of high resistance arterial blood flow waveforms(6,9).
The resistive index (RI), also known as the Pourcelot ratio, is calculated
1
2
3
Universidade Federal do Paraná, Curitiba, PR, Brazil.
Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Instituto Graefe de Oftalmologia, Curitiba, PR, Brazil.
http://dx.doi.org/10.5935/0004-2749.20160010
Corresponding author: Amália T. Giannico. Rua dos Funcionários, 1.540 - Curitiba, PR - 80035-050 Brazil - E-mail: [email protected]
Approved by the following research ethics committee: Universidade Federal do Paraná, protocol
#011/2011.
33
from the blood flow velocities. This index, expressed by the formula
[(PSV - EDV) / PSV], indicates the downstream resistance in arteries
(ranging from 0 to 1, where 0 is no resistance and 1 is the maximum
resistance)(9). CDI research has shown that through increased RI,
retrobulbar blood flow is reduced in patients with glaucoma and that
there may be a predictive value for the progression of the disease(10,11).
A high RI value correlates with an increase in vascular resistance,
leading to decreased perfusion, which may in turn contribute to
glaucomatous optic neuropathy(2,5,7,9,12,13).
Prostaglandin analogs (PGAs) are IOP-lowering agents commonly
prescribed in glaucoma treatment. PGAs act primarily by enhancing
uveoscleral outflow of aqueous humor; however, PGAs also appear to
act on the trabecular meshwork to facilitate aqueous humor outflow
through the conventional outflow pathway(14).
The majority of topical treatments for elevated IOP contain a
preservative, the most common of which is benzalkonium chloride
(BAK), a quaternary ammonium salt. Chronic exposure to BAK has
been associated with symptoms of ocular discomfort attributed to
BAK-induced instability of the tear film, reduced density of superficial epithelial cells, disruption of corneal epithelial barrier function,
and conjunctival inflammation(15,16). These undesirable effects may
be reversible in glaucoma patients who are switched to BAK-free
medications(15). BAK is absorbed and accumulates in ocular structures
involved in glaucoma pathogenesis, but the potential effects of preservatives in the vasculature of the eye are unknown(17).
Considering the growing evidence supporting a vascular pathogenesis for glaucoma, a decrease in blood flow could potentially
accelerate disease development. Therefore, in addition to their IOPlowering capabilities, these medications may be detrimental or
beneficial to ocular hemodynamics. The purpose of this investigation
was to examine the potential effects of topical solutions of PGAs with
and without preservatives on the blood flow of the ophthalmic artery
(OA) in clinically healthy rabbits.
METHODS
ANIMALS
The investigation was carried out using 55 clinically healthy, sixmonth-old New Zealand white rabbits (Oryctolagus cuniculus), with
32 females and 23 males weighing 2.2 kg to 3.0 kg. The animals were
selected randomly from a commercial breeder. All procedures using
live rabbits were conducted in accordance with the Federal University of Parana’s Animal Use Committee (Curitiba city, Paraná state, Brazil)
and with the ARVO Statement for the Use of Animals in Ophthalmic
and Vision Research.
The rabbits were housed under a 12:12 hour light: dark cycle for
one week prior to and for the duration of the study. Food and water
were given ad libitum, and the humidity (70%) and temperature
(22.5°C) were controlled.
Physical examinations were performed before the ocular examinations to exclude animals with any indications of systemic disease.
Rabbits with evidence of ocular or systemic diseases were excluded
from this research. To avoid inter-investigator discrepancies, the same
masked investigator performed the CDI, and another investigator,
who was not masked, instilled the eye drops.
TREATMENTS
The rabbits received a number from one to 55 and were then
divided into six groups using the randomized function in Microsoft
Office Excel (Microsoft Office 2007 for Windows). The left eyes were
treated daily for four weeks with one drop of topical PGA eye drops
applied to the conjunctival fornix. The ophthalmic drugs and numbers of females and males are listed in table 1.
COLOR DOPPLER IMAGING
CDI was performed before and after the treatment with eye drops
using an ultrasound system (MyLab 30; Esaote, Genova, Italy) equipped with a 12-MHz linear ultrasound transducer. The animals were
not anesthetized, and the eye and orbit were imaged with the
animal in sternal recumbency. All CDI examinations were performed
by the same two people, one of whom restrained the rabbit, while
the other performed the imaging. Ultrasound gel was applied to the
dorsal region and to the zygomatic arch, and the transducer was
gently positioned with minimal pressure in the horizontal plane after
instillation of one drop of topical anesthesia (tetracaine ophthalmic
drops, Anestalcon®, Alcon). The long axis of the transducer was held
horizontally between the lateral and medial canthus with the marker
pointing nasally (Figure 1A).
We used the muscular cone and power Doppler mode to determine the relative position of the OA. After the detection of the
blood flow by the power Doppler, the spectral Doppler sampling
volume was placed in the center of the imaged vessel. The OA is
readily identifiable by its characteristic dicrotic notch in the Doppler
waveform associated with the closure of the aortic valve(5). The ultrasound beam and the OA were parallel, and the sample volume was
set at 1 mm inside the vessel (Figure 1B). The mean values of PSV
and EDV from three pulse waveforms were calculated (Figure 1B),
and the RI of the blood flow was calculated using the formula
[(PSV - EDV) / PSV].
Table 1. Prostaglandin analog eye drops, commercial names, manufacturers, and numbers of female and male New Zealand white rabbits
Animals
Antiglaucomatous eye drops
Commercial name
Manufacturer
Female
Male
Bimatoprost 0.03%BAK
Lumigan
Allergan Indústria Farmacêutica Ltda.
Guarulhos, SP, Brazil
5
5
Tafluprost 0.0015%BAK-FREE
Saflutan
Merck Sharp & Dohme Ltda.,
Guarulhos, SP, Brazil
6
4
Travoprost 0.004%BAK
Travatan*
Alcon Laboratórios do Brasil Ltda.
São Paulo, SP, Brazil
5
5
Travoprost 0.004%POLYQUAD
Travatan*
Alcon Laboratórios do Brasil Ltda.
7
3
Xalatan
Pfizer Indústria Farmacêutica
6
4
BAK
Benzalkonium chloride 0.01%, “Ophthalmos” Ophthalmic Pharmaceuticals Manipulation
3
2
Latanoprost 0.005%BAK
Control solutionBAK
*= there is no difference in the commercial name between the eye drops TravatanBAK and TravatanPOLYQUAD.
BAK= benzalkonium chloride.
34
Giannico AT, et al.
The Shapiro-Wilk normality test demonstrated that the data
errors were normally distributed. The data were statistically analyzed
using the computer software StatView (SAS Institute, Cary, NC, USA).
ANOVA was used to compare the pre-treatment results to show that
the groups were homogeneous. Paired t-tests were used to compare
the potential differences between pre- and post-treatment results for
each drug, and the Tukey-Kramer post hoc test was used to compare
potential post-treatment differences among the drugs. P-values of
<0.05 were considered to be statistically significant.
RESULTS
The means and standard deviations of the pre- and post-treatment
values for RI, PSV, and EDV are presented in table 2. PSV and EDV are
expressed in centimeters per second (cm/s), whereas RI has no units.
No significant differences were found in the pre-treatment PSV,
EDV, and RI of the left eye of all the rabbits (P>0.05), showing that these
parameters were homogeneous amongst the groups before treatment.
No significant differences were found between pre- and posttreatment PSV or EDV in all the animal groups nor for the pre- and
post-treatment RI in the rabbits that received bimatoprost BAK, travoprost POLYQUAD, or latanoprost BAK (P>0.05) (Table 2). However,
A
eyes that received tafluprost BAK-free and travoprost BAK exhibited
a significant RI decrease after treatment (P=0.003 and P=0.005, respectively) (Table 2). This decrease in RI was similar in magnitude for
the two drugs because the post-treatment values in the eyes that
received tafluprost BAK-free and travoprost BAK were not significantly different (P=0.6264).
DISCUSSION
In general, prostaglandins play an important role in the local regulation of blood flow, and both endogenous prostaglandins as well
as PGAs can have potent vasodilator effects(18). Previous experiments,
both in human and animal models, have reported how PGAs may
affect ocular blood flow. Depending on the drug or formulation used,
PGAs have been reported to increase, decrease, or not affect ocular
blood flow. However, the reports are conflicting, with opposing results in some cases(19,20).
In the work presented here, both tafluprost BAK-free and travoprost BAK significantly reduced the RI of the OA in rabbits. This decrease in RI can be interpreted as a beneficial effect on ocular blood
flow. In primates, chronic optic nerve ischemia has been shown to
induce retinal ganglion cell loss independently of high IOP(3). Consequently, this reduction of the RI of the OA could also be helpful in
glaucoma treatment, by potentially preventing retinal ganglion cell
B
PSV= peak systolic velocity; EDV= end diastolic velocity.
Figure 1. (A) Image of a New Zealand white rabbit during the ultrasound exam. The transducer was positioned in the
horizontal plane, with the long axis of the transducer held parallel with a line connecting the medial and lateral canthus,
and the marker pointing nasally. (B) The top panel shows an image of retrobulbar color Doppler imaging and pulse
waveform with dicrotic notches showing blood flow velocities in a rabbit’s ophthalmic artery. Blood flow toward the
ultrasound transducer was encoded in red by the power Doppler mode. The ophthalmic artery was detected and the
spectral Doppler sampling volume (gate of 1 mm) was placed in the center and parallel to the imaged vessel (arrow).
The bottom panel is a pulse waveform showing relative blood flow velocities.
Table 2. Results of retrobulbar blood flow velocity (cm/s) and resistive index pre- and post-treatment with prostaglandin analog eye drops as measured with color Doppler imaging in the ophthalmic artery of New Zealand white rabbits
PSV
EDV
RI
Pre
Post
P-value
Pre
Post
P-value
Pre
Post
P-value
BimatoprostBAK
31.19 ± 4.88
34.89 ± 07.17
0.194
08.21 ± 2.89
09.94 ± 3.38
0.234
0.74 ± 0.08
0.74 ± 0.10
0.941
TafluprostBAK-FREE
36.64 ± 5.50
30.03 ± 08.92
0.061
09.80 ± 2.81
11.22 ± 4.71
0.424
0.73 ± 0.07
0.63 ± 0.07
0.003*
TravoprostBAK
29.21 ± 5.79
31.91 ± 11.14
0.548
08.49 ± 3.45
13.62 ± 6.55
0.066
0.71 ± 0.09
0.59 ± 0.07
0.005*
TravoprostPOLYQUAD
34.81 ± 9.34
33.01 ± 10.44
0.689
09.68 ± 3.46
10.48 ± 5.29
0.694
0.72 ± 0.05
0.68 ± 0.09
0.244
LatanoprostBAK
34.57 ± 6.23
30.07 ± 08.57
0.196
10.94 ± 3.51
09.20 ± 4.73
0.362
0.69 ± 0.06
0.70 ± 0.06
0.551
Control solutionBAK
33.88 ± 7.37
34.26 ± 11.95
0.953
08.10 ± 1.67
09.10 ± 2.84
0.517
0.75 ± 0.07
0.73 ± 0.04
0.552
Antiglaucomatous eye drops
Values are the mean ± standard deviation.
PSV= peak systolic velocity; EDV= end diastolic velocity; RI= resistive index; BAK= benzalkonium chloride.
*= P<0.05, paired t-test between pre- and post-treatment results.
35
death. Although these two formulations decreased the RI to similar
extents, other factors need to be considered when choosing which
one to prescribe, such as which one is more effective for decreasing
IOP and, in this specific case, whether the presence of a preservative is
detrimental to each patient in question. The presence of preservatives
in topical antiglaucoma drug formulations is currently under scrutiny(21). Chronic exposure to the preservative BAK has been associated
with ocular discomfort, causing changes in the tear film, cornea (including the corneal epithelium), and conjunctiva(15,16).
No effects on CDI parameters were found for topical bimatoprost
BAK, travoprost POLYQUAD, or latanoprost BAK. Some research has
also revealed no changes in the blood flow in the OA in humans and
rabbits in response to PGAs, although some PGAs show good results
in other vascular beds, such as on the optic nerve head and in the
central retinal artery(20,22-24). Nevertheless, our research showed that
the results with travoprost are controversial. Interestingly, formulation of this drug with two different preservatives showed disparate
results, and more studies are needed to confirm the effect of this
drug on RI. Other research groups have shown that travoprost is
effective for improving blood flow, as found in the present study with
travoprost BAK(25-27). Further, in the present research, travoprost with
BAK as a preservative significantly decreased RI, while travoprost with
POLYQUAD did not; therefore, the preservative BAK may have some
effect in this instance. Little is known about the long-term effects of
different preservatives concerning their penetration and distribution
in the eye, but it is recognized that BAK is itself absorbed and accumulates in ocular surface structures as well as in deeper structures
involved in glaucoma(17). Interestingly, our findings suggest that the
combination of PGA with BAK decreases RI, ultimately improving ocular blood flow. Despite this RI alteration observed in the travoprost
with BAK group, no significant decreases in RI were found in the other
groups receiving drugs preserved with BAK or groups receiving only
BAK. It is possible that BAK specifically and synergistically enhances
the effect of travoprost by an as-yet-unknown mechanism. Nevertheless, some investigators have argued that eye drops formulated with
preservatives other than BAK or with no preservatives demonstrate
little or no ocular toxicity, and may always be preferred(28).
Few studies have evaluated the effect of tafluprost on ocular circulation. In the present study, a significant decrease was found in the
RI of the OA of rabbits, and similar results have also been found in the
optic nerve and retinal circulation in rabbits, cats, and humans (27,29,30).
In the present study, both eyes were analyzed, but the eye drops
were instilled in only one of the eyes. The main advantage of using
the fellow eye as a control is that the experimental eye and the
control eye are both in the same animal, therefore allowing direct
comparison, balancing out any variations of the treatment and control groups.
A limitation of our study is that no glaucomatous eyes were evaluated. Healthy eyes, without increased IOP, may facilitate changes in
Doppler parameters. Thus, we suggest that further studies be carried
out in rabbits with induced glaucoma to assess whether the changes
would be similar to those found in the present study.
Our study reveals the effect of different PGAs used to treat glaucoma on OA blood flow in healthy New Zealand white rabbits. Further
studies on human patients and patients with glaucoma (humans and
animals) are necessary to establish the effects of each treatment and
to assess whether improvement of retrobulbar blood flow enhance
the prevention of the progression of this disease.
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Original Article
Characterization of cryopreserved primary human corneal endothelial cells cultured
in human serum-supplemented media
Caracterização de células endoteliais corneanas humanas primárias criopreservadas cultivadas em
meio suplementado com soro humano
lucaS MonfErrari MontEiro vianna1,2,3, hao-donG li1, jEffrEy d. holiMan4, chriStophEr StoEGEr4, ruBEnS BElfort jr.2, alBErt S. jun1
ABSTRACT
RESUMO
Purpose: To compare cryopreserved human corneal endothelial cells (HCECs)
grown in human serum-supplemented media (HS-SM) with cryopreserved HCECs
grown in fetal bovine serum-supplemented media (FBS-SM).
Methods: Three pairs of human corneas from donors aged 8, 28, and 31 years
were obtained from the eye bank. From each pair, one cornea was used to start a
HCEC culture using HS-SM; the other cornea was grown in FBS-SM. On reaching
confluence, the six cell populations were frozen using 10% dimethyl sulfoxidecontaining medium. Thawed cells grown in HS-SM were compared with those
grown in FBS-SM with respect to morphology, growth curves, immunohistochemistry, real time-reverse transcriptase polymerase chain reaction (RT-PCR)
for endothelial cell markers, and detachment time.
Results: No difference in morphology was observed for cells grown in the two
media before or after cryopreservation. By growth curves, cell counts after thawing
were similar in both media, with a slight trend toward higher cell counts in FBS-SM.
Cells grown in both the media demonstrated a similar expression of endothelial cell
markers when assessed by immunohistochemistry, although HCEC marker gene
expression was higher in cells grown in HS-SM than in those grown in FBS-SM as
assessed by RT-PCR. With FBS-SM, there was a tendency of longer detachment
time and lower cell passages.
Conclusions: HS-SM was similar to FBS-SM for cryopreservation of cultured HCECs
as assessed by analysis of cell morphology, proliferation, and protein expression,
although marker gene expression was higher in cells grown in HS-SM than in those
grown in FBS-SM. Detachment time was longer with FBS-SM and in lower passages.
Objetivo: Comparar células endoteliais de córnea humana (HCECs) criopreserva das e cultivadas em meio suplementado com soro humano (HS-SM) com HCEC
criopreservadas e cultivadas em meio suplementado com soro bovino fetal (FBS-SM).
Métodos: Três pares de córneas humanas de doadores com 8, 28 e 31 anos de idade
foram obtidos do banco de olhos e, de cada par, uma córnea foi utilizado para iniciar
uma cultura com HS-SM e outra com FBS-SM. Ao atingir a confluência, as populações
de células foram congeladas utilizando-se dimetil-sulfóxido 10% no respectivo meio
de cultura. Após descongeladas, as células cultivadas em HS-SM foram comparados
com as cultivadas em FBS-SM por meio de morfologia, curva de crescimento, imuno-histoquímica, reação em cadeia de Reação em cadeia da polimerase da transcrição
reversa em tempo real (RT-PCR) para marcadores de células endoteliais e tempo de
descolamento.
Resultado: Não foram observadas diferenças morfológicas antes ou após a criopreservação. Curva de crescimento mostrou contagens celulares semelhantes em ambos
os meios, com discreta tendência para um maior número em FBS-SM. As células cultivadas em ambos os meios mostraram expressão semelhante de marcadores celulares
endoteliais quando avaliadas por imuno-histoquímica, embora a expressão genética de
marcadores para HCEC tenha sido maior em HS-SM quando avaliado por RT-PCR. Houve
uma tendência de maior tempo de descolamento com FBS-SM e passagens iniciais.
Conclusões: HS-SM foi semelhante ao FBS-SM na criopreservação de HCEC cultivadas
in vitro quando avaliadas por morfologia celular, proliferação celular e expressão
proteica, embora a expressão genética de marcadores endoteliais tenha sido maior em
células cultivadas em HS-SM quando comparadas a células cultivadas em FBS-SM. O
tempo de descolamento foi maior quando utilizado FBS-SM e em passagens iniciais.
Keywords: Cryopreservation; Cornea; Endothelium, Corneal; Cell culture techniques;
Culture media
Descritores: Criopreservação; Córnea; Endotélio corneano; Técnicas de cultura de células; Meios de cultura
INTRODUCTION
Since Stocker et al.(1) established a human corneal endothelial cell
(HCEC) culture, the potential for cell therapy to treat corneal endothelial dysfunction using HCECs has demonstrated continuous
development(2-8). The limitations associated with this therapy can
be basically divided into two major areas: those related to culturing
the cells, such as proliferation, cellular senescence, and fibroblastic
transformation and those related to the logistics and techniques for
transplanting the cells(2-8).
Regarding the first area, we recently published an article demonstrating the applicability of human serum-supplemented medium
(HS-SM) as an alternative to fetal bovine serum-supplemented media (FBS-SM), suggesting potential advantages of a medium with
fewer animal-derived components(9). Regarding the second area, the
cryopreservation of both corneas for transplantation(10) and cultured
HCEC using a standard medium (FBS-SM) have been already demonstrated(11) and could potentially improve the logistics related
to the distribution of cultured HCECs for clinical use. The purpose
Submitted for publication: July 24, 2015
1
2
3
4
Cornea and Anterior Segment Service, The Wilmer Eye Institute, Johns Hopkins University, Baltimore
(MD), USA.
Ophhtalmology and Vision Science Department, Escola Paulista de Medicina, Universidade Federal
de São Paulo, São Paulo, SP, Brazil.
Ophthalmology Department, Hospital Universitário Pedro Ernesto, Universidade Estadual do Rio
de Janeiro, Rio de Janeiro, RJ, Brazil.
Lions VisionGift, Portland, OR, USA.
http://dx.doi.org/10.5935/0004-2749.20160011
Corresponding author: Lucas Monferrari Monteiro Vianna. Rua Botucatu, 821 - São Paulo, SP 04023-900 - Brazil - E-mail: [email protected]
37
of this study is to determine the ability of HCECs grown in HS-SM to
be cryopreserved and maintain their characteristics compared with
cryopreserved cells grown in FBS-SM.
METHODS
This study adhered to the tenets of the Declaration of Helsinki.
Materials were obtained from the following sources: serum-free
medium (OptiMEM I), Dulbecco phosphate-buffered saline, Hank’s
balanced salt solution (HBSS), gentamicin, trypsin-EDTA, and goat serum (Gibco BRL/Life Technologies, Rockville, MD); mouse submaxillary
gland nerve growth factor (NGF), human epidermal growth factor
(hEGF), and bovine pituitary extract (BPE) (Biomedical Technologies, Stoughton, MA); FBS (Hyclone, Logan, UT); heat-inactivated
human serum (HS, Valley Biomedical, Winchester, VA); ascorbic acid,
chondroitin sulfate, calcium chloride, 0.02% ethylene diamine tetra
acetic acid (EDTA) solution, and antibiotic/antimycotic solution (Sigma,
St. Louis, MO); cell attachment reagent (FNC Coating Mix; Athena
Environmental Sciences Inc., Baltimore, MD); dimethyl sulfoxide
(DMSO) (Mediatech Inc, Manassas, VA); rabbit polyclonal antibody
to ZO-1 (Invitrogen, Camarillo, CA); mouse monoclonal antibody to
Na+/K+-ATPase alpha 1 subunit (Santa Cruz Biotechnology, Dallas,
TX); mouse monoclonal antibody to glypican 4 (GPC4) and donkey
serum (Novus Biologicals, Littletown, CO); AlexaFluor 488 donkey
anti-mouse IgG (Life Technologies, Eugene, OR); AlexaFluor 555 goat
anti-mouse IgG and Hoechst nuclear staining (Molecular Probes,
Eugene, OR); and eight-well glass chamber slides (Laboratory-Tek,
Nunc, Rochester, NY).
HUMAN CORNEAL ENDOTHELIAL CELL CULTURE
Three pairs of human corneas from donors aged 8, 28, and 31 years
(referred to as donor 1, 2, and 3, respectively) were obtained from Lions
VisionGift (Portland, OR) and the Alabama Eye Bank (Birmingham,
AL). Donors had died from trauma, cardiomyopathy, and pneumonia, respectively, and death-to-preservation time was 4, 6, and 8 h,
respectively. Standard eye bank protocols for informed consent and
protection of donor confidentiality were used. Donor corneas were
unsuitable for transplantation. Standard serologies for infectious
agents were negative for the three donors. Primary cultures were
initiated within 2-10 days of preservation in Optisol-GS.
CULTURE MEDIA
FBS-SM was previously described in a study(12) and was used in our
laboratory(11) and comprised serum-free medium (OptiMEM-I), 8%
FBS, 5 ng/mL hEGF, 20 ng/mL NGF, 100 mcg/mL BPE, 20 mcg/mL
ascorbic acid, 200 mg/L calcium chloride, 0.08% chondroitin sulfate,
50 mcg/mL gentamicin, and antibiotic/antimycotic solution (diluted
1/100). HS-SM was described in our previous study(9) and comprised
the same components as FBS-SM, with the exception that 8% FBS
was replaced with 8% HS. The concentration of serum (both in FBS
and HS) that was used to culture cells in glass chamber slides was
doubled to 16%.
re-suspended in the respective medium. Isolated cells and pieces of
DM were plated in a 6-well tissue culture plate that was pre-coated
with undiluted cell attachment reagent (FNC Coating Mix). Initial
plating density (P0) was variable and depended on the number of
cells recovered from each DM. Overall, we would estimate the initial
plating density as being between 100-200 cells/mm2 (approximately
104 to 2 × 104 cells/well of a 6-well plate). Cultures were then incubated at 37°C in a humidified 5% CO2 incubator, and the medium was
changed every other day.
CRYOPRESERVATION OF HCECS
At the day when the primary cultures [passage (P) 0] reached confluence, cells were trypsinized and re-suspended in their respective
culture media (HS- or FBS-SM). They were then gently centrifuged
and re-suspended in freezing medium comprising 90% initial medium and 10% DMSO. The cells were then slowly frozen overnight
in an isopropanol bath freezing container at -80°C and subsequently
transferred to liquid nitrogen. For recovery from cryopreservation,
all cells were thawed at different time points (1, 2, and 3 months for
donor 1, 2 and 3, respectively) in a water bath at 37°C, and the cells
were promptly re-suspended drop-by-drop with their respective
pre-warmed culture medium. The cells were then centrifuged,
washed, and re-suspended in the culture medium to remove residual
DMSO and were plated on pre-coated standard tissue culture plates
(each cell population was seeded in two wells of a 6 well-plate). Subsequently, cells were passaged (P1-P5) on the day when they reached
confluence, except for those used for immunofluorescence, which
were maintained for 3 additional days after reaching confluence. To
identify each cell population at each time point, the cells were named
according to the passage by which they had been generated (e.g.,
P1 cells originated from the first passage). To enhance the understanding of the methodology, the process is shown in figure 1.
REAL TIME-REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION
For each donor and medium, total RNA was extracted from confluent cultures in a single well of a 6-well plate at passage 2 (as described in Figure 1) using a commercially available kit (RNeasy Mini
Kit; Qiagen, Valencia, CA) and stored at -80°C. The concentration
and purity of the isolated RNA were determined using a NanoDrop
instrument (Thermo Fisher Scientific Inc., Waltham, MA). Complementary DNA (cDNA) was obtained using the commercially available
High Capacity RNA-to-cDNA™ kit (Life Technologies) and was stored
at -20°C. Polymerase chain reaction (PCR) was conducted in a StepOne-
ISOLATION AND GROWTH OF HCECS
HCEC populations were established according to published methods(12). Corneas were removed from corneal preservation media
(Optisol-GS, Bausch & Lomb Inc., Rochester, New York), and Descemet
membranes (DM) with intact endothelium were peeled. From each
pair of corneas, one DM was used to initiate an HCEC culture with
HS-SM and the other DM was grown with FBS-SM, comprising a total
of six cell populations. DM was placed in either FBS- or HS-SM for 24 h
at 37°C under 5% CO2. Next, the tissues were incubated in 0.02%
EDTA for 1 h at 37°C to loosen cell-to-cell junctions and were manually
disrupted by a passage through a pipette. The dissociated cells
were centrifuged at 3000 rpm for 5 min, and the pellet was gently
38
P= passage; FBS-SM= fetal bovine serum-supplemented media; HS-SM= human serum-supplemented
media; RT-PCR= real time-polymerase chain reaction.
Figure 1. Flow chart of HCEC passaging and cell use.
Vianna LMM, et al.
Plus Real Time PCR System (Life Technologies) with the prepared
cDNA and commercially available TaqMan primer-probe sets (Life
Technologies), targeting 1) ZO-1, tight junction protein 1 (TJP1); Na+/
K+-ATPase, Na+/K+ transporting, alpha 1 polypeptide (ATP1A1); and
GPC4. Gene expression was assessed by the comparative CT (∆∆CT)
method with β-actin as the normalizing gene. Assays were performed in triplicates for all samples.
IMMUNOHISTOCHEMISTRY
For immunohistochemical analysis, cells were grown (using 16%
serum-supplemented media) in chamber slides that were pre-coated
with FNC Coating Mix, fixed in 4% paraformaldehyde for 15 min, and
treated with 0.1% Triton X-100 for 10 min at room temperature.
Non-specific binding was blocked by incubating cells in 10% donkey
or goat serum for 1 h before incubation overnight at 4°C with the
primary antibodies (all 1:100, ZO-1, Na+/K+-ATPase, and GPC4). Secondary staining was performed with secondary antibodies (1:500) for
1 h at room temperature, and cells were counterstained with Hoechst
nuclear staining (1:2500). Cells were analyzed using a Zeiss LSM 510
Meta Confocal Microscope (Carl Zeiss, Berlin, Germany).
GROWTH CURVE
As shown in figure 1, 30,000 cells for each donor and medium were
recovered from P2 and were used to seed 5,000 cells in five different
wells of a 24-well plate (for counting on days 1, 2, 3, 5, and 7) and in
one well of a 6-well plate (for counting on day 10). Thus, each well
contained the same number of cells at different densities depending
on the size of the well in which they were placed. At specified times,
on plating (days 1, 2, 3, 5, 7, and 10), cells were trypsinized and
counted using a microscope (IMT-2, Olympus, Tokyo, Japan) and a
hemocytometer (Hausser Scientific, Horsham, PA). Three counts were
performed in triplicates for each well, and the results were averaged
to construct the growth curve.
could be initially observed for both FBS- and HS-SM at P5 (Figure 2).
No difference in morphology could be observed at P0, P1, P5 or at
any other passages for cells grown in the two media before or after
cryopreservation.
GROWTH CHARACTERISTICS
The time from initial plating (P0) to confluence was 7, 17, and 14
days for donor 1, 2, and 3, respectively, when grown in FBS-SM and 5,
15, and 14 days, respectively, when grown in HS. For subsequent passages, times were slightly different between cell populations when
comparing FBS- and HS-SM for a given passage and cell population.
Using growth curves, cell counts after thawing were similar for FBS- and
HS-SM from days 1 to 10, with a slight trend toward higher cell counts
in FBS-SM (Figure 3).
IMMUNOFLUORESCENCE AND REAL TIME-PCR
Cells grown in both FBS- and HS-SM demonstrated similar staining
of functional (ZO-1 and Na+/K+-ATPase) and endothelial cell (GPC4)
markers when assessed by immunohistochemistry (Figure 4). Negative
controls using only secondary antibodies AlexaFluor 488 and 555
demonstrated no staining (Figure 4). When assessed by real time
(RT)-PCR, gene expression of HCEC markers was higher in HS-SM than
in FBS-SM: TJP1 (1.3-fold, P=0.083), ATP1A1 (two fold, P=0.031), and
GPC4 (3-fold, P=0.064) (Figure 5).
MORPHOLOGY ASSESSMENT (PHASE CONTRAST MICROSCOPY)
A phase-contrast microscope with a digital camera (ProgResC5,
Jenoptik, Jena, Germany) was used to image confluent cells for each
donor, media, and passage from P0 to P5 to document morphology
data. The well was randomly placed under the microscope, and images were taken at 20× magnification from each passage.
DETACHMENT TIME ASSESSMENT
For each donor, the medium was aspirated, and cells were washed
with HBSS, with the same amount of trypsin solution being added to
all plates, at each passage. A standard amount of tapping was applied
to the plate every 30 s to facilitate detachment. The time taken for
complete cell detachment was counted for each of the media. If the
detachment period amounted to 5 min and complete detachment
was not achieved, cells were mechanically detached by adding media
using a pipette.
STATISTICS
A two-tailed Mann-Whitney U test was performed to compare
detachment times. For gene expression, probability (P) values were
generated using ∆∆CT mode of the Expression Suite Software (Life
Technologies). P values of <0.05 were considered statistically significant.
RESULTS
MORPHOLOGY
Typical endothelial-cell polygonal morphology was observed
for cells grown in both FBS- and HS-SM at passage 1 (P1) for all three
pairs of cell populations, and a typical spindle-shape transformation
Figure 2. Phase-contrast images of confluent passage 0 (before cryopreservation) and
passages 1 and 5 (after cryopreservation) HCECs cultured in fetal bovine serum-supplemented medium (FBS-SM) and human serum-supplemented medium (HS-SM). Similar
cell morphologies were observed for the two media for the same cell populations and
passages. All pictures were taken using 20× magnification. Scale bar=200 μm.
39
DETACHMENT TIME
All cell populations from both the media reached the maximum
time allowed for detachment from P0 to P1; thus, there was no difference between the populations at these passages. However, for P2
and for all subsequent passages, there was a trend toward longer
detachment time with FBS-SM and lower passages (Figure 6), with
statistical significance for passages 4 (P=0.0268), 5 (P=0.0279), and 6
(P=0.0098).
DISCUSSION
The development in surgical treatment of corneal endothelial
diseases, with progressive thinning of grafts and its related advantages(13,14), leads us to conclude that transplantation with cultured en-
Figure 3. Ten-day growth curve comparing cells cultured in fetal bovine serum-supplemented medium and human serum-supplemented medium starting at passage 2. On days
1, 2, 3, 5, and 7 counts were obtained for cells seeded in a 24-well plate; at day 10, counts
for cells seeded in a 6-well plate were obtained. Error bars represent standard deviations.
*= P<0.05.
Figure 5. RT-PCR of tight junction protein 1 (TJP1); ATPase, Na+/K+ transporting, alpha
1 polypeptide (ATP1A1); and glypican 4 (GPC4) of passage-2 HCECs cultured in media
with fetal bovine serum (FBS-SM) and human serum (HS-SM). FBS-SM is presented as
the reference (RQ=1).
*= P<0.05.
Figure 6. Average detachment time of all cell populations from passage 1 (P1) to passage
6 (P6), comparing cells cultured in FBS-SM and HS-SM. Maximum time allowed to detach
was 5 min. Error bars represent standard deviations.
Figure 4. Immunostaining for zonula occludens-1 (ZO-1), sodium-potassium ATPase (Na+/K+-ATPase), and glypican 4 (GPC4) of confluent
passage-2 HCECs cultured in media with fetal bovine serum (FBS-SM) or human serum (HS-SM). Staining for ZO-1 is from the 31-year-old
donor; Na+/K+-ATPase and Negative Control [secondary antibodies AlexaFluor 488 (above) and 555 (below) only] from the 8-year-old donor,
and GPC4 from the 31-year-old donor. Scale bars=50 micrometers.
40
Vianna LMM, et al.
dothelial cells may represent the next advance in this field(2-9). Animal
studies have demonstrated promising results(15,16). An important issue
that may arise if this approach becomes feasible is cell maintenance
and distribution to surgeons. Cryopreservation can mitigate these
issues with some additional advantages, such as the long-term preservation of the endothelial cell source(5). We have recently demonstrated that human serum can be used as a supplement for HCEC
culture, conferring the added advantage of a medium with a lower
content of animal derivatives. In this study we demonstrated the
ability of HCECs grown in HS-SM to be cryopreserved and maintain
their characteristics by comparing them with cells grown in FBS-SM.
No evident difference in morphology of the cells could be observed
when comparing FBS- and HS-SM cultures from P0 to P5 across all
cell populations studied. Growth rates were also similar between
the two media using passage-2 cultures, with a slight trend toward
higher cell counts in FBS-SM. Both FBS- and HS-SM demonstrated
similar immunostaining for functional (ZO-1 and Na+/K+-ATPase)
and endothelial cell (GPC4) markers of passage-2 cultures. However,
HCEC marker gene expression was higher in HS-SM when assessed by
RT-PCR. The impact of this finding on the suitability of cryopreserved
HCECs grown in HS-SM for use in cell therapy is unclear and warrants
further study with an expanded number of cell populations and
markers. Further testing should include physiological assays, such
as the use of an Ussing chamber(17), to determine any differences in
the pumping activity of HCECs grown in FBS- and HS-SM with and
without cryopreservation.
Unpublished observations during our previous study(9) have demonstrated that cells grown in HS-SM detach faster than those grown
in FBS-SM. Similarly, in this study, we observed a tendency of longer
detachment time with FBS-SM and lower passages. Moreover, we observed that when cells are plated in glass chamber slides with HS-SM
(8% as standard), they can spontaneously detach even with the use
of a cell-attachment reagent, which does not occur when 16% HS-SM
or 8% FBS-SM is used. Further studies are warranted to establish the
cause of this finding and its potential clinical implications.
In summary, we demonstrated that on cryopreservation, HS-SM
was similar to FBS-SM for HCEC culture as assessed by comparison
of cell morphology, proliferation, and protein expression, although
marker gene expression by RT-PCR was higher in HS-SM-based cultures than in FBS-SM-based cultures. Detachment time was longer with
FBS-SM and lower passages. To establish the relevance of our findings
with regard to the potential clinical use of cryopreserved HCECs cultured in HS-SM, follow-up studies should be conducted that which
would further contribute to the progress toward the ultimate goal of
endothelial cell therapy.
ACKNOWLEDGMENTS
The authors acknowledge the Brazilian government CAPES
Foundation and State University of Rio de Janeiro for supporting Dr.
Vianna’s research fellowship, Norman Barker, MS, for assistance with
the figures, and Lions VisionGift (Portland, OR) and the Alabama Eye
Bank (Birmingham, AL) for providing corneas.
REFERENCES
1. Stocker FW, Eiring A, Georgiade R, Georgiade N. A tissue culture technique for growing
corneal epithelial, stromal, and endothelial tissues separately. Am J Ophthalmol. 1958;
46(5 Part 2):294-8.
2. Okumura N, Kinoshita S, Koizumi N. Cell-based approach for treatment of corneal
endothelial dysfunction. Cornea. 2014;33 Suppl 11:S37-41.
3. Engelmann K, Bednarz J, Valtink M. Prospects for endothelial transplantation. Exp Eye
Res. 2004;78(3):573-8.
4. Joyce NC. Proliferative capacity of the corneal endothelium. Prog Retin Eye Res. 2003;
22(3):359-89.
5. Proulx S, Brunette I. Methods being developed for preparation, delivery and transplantation of a tissue-engineered corneal endothelium. Exp Eye Res. 2012;95(1):68-75.
6. Koizumi N, Okumura N, Kinoshita S. Development of new therapeutic modalities for
corneal endothelial disease focused on the proliferation of corneal endothelial cells
using animal models. Exp Eye Res. 2012;95(1):60-7.
7. Joyce NC. Proliferative capacity of corneal endothelial cells. Exp Eye Res. 2012;95(1):
16-23.
8. Peh GS, Beuerman RW, Colman A, Tan DT, Mehta JS. Human corneal endothelial cell
expansion for corneal endothelium transplantation: an overview. Transplantation.
2011;91(8):811-9.
9. Vianna LM, Kallay L, Toyono T, Belfort R Jr, Holiman JD, Jun AS.se of human serum for
human corneal endothelial cell culture. Br J Ophthalmol. 2014;0:1-5.
10. Brunette I, Le François M, Tremblay MC, Guertin MC. Corneal transplant tolerance of
cryopreservation. Cornea. 2001;20(6):590-6.
11. Suh LH, Zhang C, Chuck RS, Stark WJ, Naylor S, Binley K, Chakravarti S, Jun AS. Cryopreservation and lentiviral-mediated genetic modification of human primary cultured
corneal endothelial cells. Invest Ophthalmol Vis Sci. 2007;48(7):3056-61.
12. Zhu C, Joyce NC. Proliferative response of corneal endothelial cells from young and
older donors. Invest Ophthalmol Vis Sci. 2004;45(6):1743-51.
13. Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEK-the thinner
the better? Curr Opin Ophthalmol. 2009;20(4):299-307.
14. Ple-Plakon PA, Shtein RM. Trends in corneal transplantation: indications and techniques.
Curr Opin Ophthalmol. 2014;25(4):300-5.
15. Koizumi N, Sakamoto Y, Okumura N, Tsuchiya H, Torii R, Cooper LJ, Ban Y, Tanioka H,
Kinoshita S. Cultivated corneal endothelial transplantation in a primate: possible future
clinical application in corneal endothelial regenerative medicine. Cornea. 2008;27 Suppl
1:S48-55.
16. Mimura T, Yamagami S, Usui T, Seiichi, Honda N, Amano S. Necessary prone position
time for human corneal endothelial precursor transplantation in a rabbit endothelial
deficiency model. Curr Eye Res. 2007;32(7-8):617-23.
17. Bonanno JA, Giasson C. Intracellular pH regulation in fresh and cultured bovine corneal
endothelium. I. Na+/H+ exchange in the absence and presence of HCO3-. Invest
41
Case Report
Contact lens fitting in a patient with Alport syndrome and posterior polymorphous
corneal dystrophy: a case report
Adaptação de lentes de contato em paciente com síndrome de Alport e distrofia polimorfa posterior:
relato de caso
juliana Maria da Silva roSa1, MarcElo vicEntE dE andradE SoBrinho1, céSar lipEnEr1
ABSTRACT
Alport Syndrome is a hereditary disease that is caused by a gene mutation and
affects the production of collagen in basement membranes; this condition causes
hemorrhagic nephritis associated with deafness and ocular changes. The X-linked
form of this disease is the most common and mainly affects males. Typical ocular
findings are dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy. Some cases involving polymorphous corneal dystrophy
and corneal ectasia have been previously described. Here we present a case report
of a 33-year-old female with Alport syndrome, posterior polymorphous corneal
dystrophy, and irregular astigmatism, whose visual acuity improved with a rigid
gas permeable contact lens.
Keywords: Collagen diseases; Nephritis, hereditary; Corneal dystrophies, hereditary/etiology; Contact lenses
RESUMO
A síndrome de Alport é descrita como uma doença hereditária que afeta um gene
relacionado à produção de colágeno das membranas basais causando nefrite
hemorrágica associada com surdez e alterações oculares. A forma ligada ao X é
a mais comum e afeta principalmente homens. Os achados oculares típicos são
retinopatia em ponto-mancha, lenticone anterior e distrofia polimorfa posterior.
Alguns casos foram descritos de associação entre a distrofia polimorfa posterior e
ectasia corneana. Nós apresentamos um caso de paciente do sexo feminino, 33 anos,
diagnóstico de síndrome de Alport, distrofia polimorfa posterior e astigmatismo
irregular, que apresenta melhora da acuidade visual após adaptação com lentes de
contato rígidas gás permeáveis.
Descritores: Doenças do colágeno; Nefrite hereditária; Distrofias hereditárias da córnea/etiologia; Lentes de contato
INTRODUCTION
Arthur Alport first published his description of a triad of symptoms in a family with hereditary congenital hemorrhagic nephritis,
deafness, and ocular changes in 1927. To this day, Alport syndrome
may still inevitably leads to end-stage renal disease and the need
for renal replacement therapy, starting in young adulthood(¹). Alport
syndrome has a prevalence of 1 in 5,000, and 85% of patients have
the X-linked form, which mainly affects males. The typical ocular
associations are a dot-and-fleck retinopathy that occurs in approximately 85% of affected adult males, anterior lenticonus that occurs
in approximately 25%, and the rare posterior polymorphous corneal
dystrophy (PPCD). The retinopathy and anterior lenticonus do not
usually appear during childhood but tend to worsen with time so
that the retinal lesions are often present at the onset of renal failure;
the anterior lenticonus develops later. The presence of anterior lenticonus or posterior polymorphous corneal dystrophy in any individual
is highly suggestive for the diagnosis of Alport syndrome. Additional
ocular features described in X-linked Alport syndrome include other
corneal dystrophies, microcornea, arcus juvenilis, iris atrophy, cataracts, spontaneous lens rupture, spherophakia, posterior lenticonus,
a poor macular reflex, fluorescein angiogram hyperfluorescence,
electrooculogram and electroretinogram abnormalities, and retinal
pigmentation. All mutations that have been detected to date in
X-linked Alport syndrome have affected the COL4A5 gene, which en-
codes the alpha-5 chain of type IV collagen. This protein plays a role
in the basement membranes of the glomerulus, cochlea, retina, lens
capsule, and cornea, resulting in abnormal ultrastructures(2).
Accepted for publication: February 6, 2015
1
Setor de Lentes de Contato e Refração, Universidade Federal de São Paulo (UNIFESP) - São Paulo,
SP - Brazil.
CASE REPORT
RCBL, a 33-year-old female, with previously diagnosed Alport syndrome, was referred to the contact lenses sector complaining of poor
vision in OU. She had presented chronic renal failure (two kidney
transplantations), and had undergone cataract surgery in both eyes
one year ago due to anterior lenticonus (Figure 1-3).
Ophthalmological examination denoted bilateral posterior polymorphous dystrophy (PPD), intraocular lenses that were in the bag
in both eyes, as well as multiple perimacular changes on fundoscopy
(dot-and-fleck retinopathy). Her refraction was OD: -7.00 -1.00 @ 180
(VA: 0.30 - LogMAR) and OS: -3.25 -4,00 @ 125 (VA: 0.40 - logMAR). Her
corneal topography showed an irregular astigmatism with superior
steepening in both eyes (Figure 4).
After comprehensive ophthalmological examination and rigid
gas permeable contact lens fitting, we were able to improve her
visual acuity to 0.18 in OD and 0.30 in OS (logMAR). The prescribed
contact lens had the following parameters:
t 0%4QIFSJDBM#BTF$VSWF%%JPQUSJDQPXFS%%JBNFter: 9.4 mm.
t 044QIFSJDBM#BTF$VSWF%%JPQUSJDQPXFS%%JBNFter: 9.4 mm.
Corresponding author: Juliana Maria da Silva Rosa. Avenida João Carlos Machado, 455/202 - Rio
de Janeiro, RJ - 22620-081 - Brazil - E-mail: [email protected]
Approved by the following research ethics committee: UNIFESP - number 871432.
42
http://dx.doi.org/10.5935/0004-2749.20160012
Rosa JMS, et al.
Figure 1. Anterior lenticonus - picture before cataract surgery.
Figure 4. Corneal topography, after cataract surgery, shows irregular astigmatism with
superior steepening OU.
Figure 2. Anterior lenticonus in OD before cataract surgery.
tinopathy (85%), and PPCD(3). Aldave et al suggested that there was
a gene (ZEB1) involved in keratocyte function that may play a role in
both the corneal stromal and endothelial development and function.
The identification of abnormally steep corneal curvatures in 37% of all
individuals with PPCD and in 86% of affected individuals with PPCD
secondary to ZEB1 mutations confirms this association(4). Many genetically determined corneal dystrophies can occur in association with
keratoconus including PPCD, lattice dystrophy, granular dystrophy,
and Fuchs endothelial dystrophy. The association with so many corneal dystrophies and ocular abnormalities implies either a similarity in
the underlying genetic defect or a tightly-linked network of interacting proteins, with a final common developmental pathway(5). PPCD
and keratoconus share a potential common area of involvement (the
posterior corneal surface, specifically Descemet’s membrane) and/
or an underlying commonality for the pathophysiology of corneal
dystrophies. A recent paper characterized the cornea in patients
with PPCD and demonstrated that the topographic parameters were
significantly steeper but had no clinical or topographical evidence of
keratoconus. The authors accumulated a cohort of patients who presented between 1982 and 2004 with a mean topographic simulated
keratometry reading of 52.21 D, ranging from 46.47 D to 59.86 D, with
no slit lamp or topographic findings suggestive of keratoconus(6). In
this particular case, our patient had Alport Syndrome, PPCD, irregular
astigmatism with superior steepening in both eyes; however, her
visual acuity was improved with rigid gas permeable (RGP) scleral
CLs despite other findings.
REFERENCES
Figure 3. Anterior lenticonus OS - picture before cataract surgery.
DISCUSSION
The main features of Alport Syndrome are kidney failure, hearing
loss, and ocular features, such as anterior lenticonus (15%-25% of
patients, and may also be associated with cataract), dot-and-fleck re-
1. Kruegel J, Rubel D, Gross O. Alport syndrome-insights from basic and clinical research.
Nat Rev Nephrol. 2013;9(3):170-8.
2. Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. 1997;18(4):161-73.
3. Xu JM, Zhang SS, Zhang Q, Zhou YM, Zhu CH, Ge J, Wang L. Ocular Manifestations of
Alport Syndrome. Int J Ophthalmol. 2010;3(2):149-51.
4. Aldave AJ, Ann LB, Frausto RF, Nguyen CK, Yu F, Raber IM. Classification of Posterior Polymorphous Corneal Dystrophy as a Corneal Ectatic Disorder Following Confirmation
of Associated Significant Corneal Steepening. JAMA Ophthalmol. 2013;131(12):1583-90.
5. Gasset AR, Zimmerman TJ. Posterior polymorphous dystrophy associated with keratoconus. Am J Ophthalmol. 1974;78:535-7.
6. Raber IM, Fintelmann R, Chhabra S, Ribeiro MP, Eagle RC Jr, Orlin SE. Posterior polymorphous dystrophy associated with nonkeratoconic steep corneal curvatures. Cornea.
2011;30:1120-4.
43
Case Report
Aniridia after blunt trauma and presumed wound dehiscence in a pseudophakic eye
Aniridia após trauma contuso e deiscência presumida da incisão em um olho pseudofácico
kyEonG hwan kiM1,2, wan Soo kiM1,2
ABSTRACT
RESUMO
This was a report about a pseudophakic patient who experienced isolated total
aniridia without damage to other intraocular structures following blunt trauma
to the eye. This patient had a history of uneventful cataract surgery using a small
clear corneal incision (CCI). This 71-year-old male presented at our clinic with glare
in his left eye. He reported that he had fallen down while drunk and struck his
left eye against a stone on the road 15 days earlier. He had undergone cataract
surgery on his left eye nine months before the accident at another eye clinic.
Slit-lamp examination showed total aniridia in his left eye, but there was no
hyphema or cells in the anterior chamber. The intraocular lens in his left eye was
stable, without decentration, dislocation, or zonular dehiscence and remained
in an intact capsular bag. Review of the medical records from the surgical clinic
at which he had undergone cataract surgery indicated no specific findings for
any intraocular structure including the iris. He had previously undergone an
uneventful phacoemulsification for his left eye through a 2.2 mm CCI, followed by
the implantation of a single piece acrylic intraocular lens inside an intact capsular
bag. This report showed that small-sized CCIs can be opened postoperatively by
trauma and that this can result in isolated total aniridia without damage to other
intraocular structures.
Relatamos um paciente com história de cirurgia de catarata sem intercorrências
usando uma pequena incisão na córnea clara (CCI), que apresentou aniridia total
isolada, sem danos a outras estruturas intraoculares, após trauma contuso no olho.
Um homem de 71 anos de idade apresentou-se em nossa clínica referindo brilho no
olho esquerdo. Ele relatou que, 15 dias antes, havia caído enquanto estava bêbado e
atingiu seu olho esquerdo contra uma pedra na estrada. Ele havia passado por uma
cirurgia de catarata no olho esquerdo, nove meses antes do acidente em outro serviço.
Exame de lâmpada de fenda mostrou aniridia total de olho esquerdo, sem hifema
ou células na câmara anterior. A lente intraocular no olho esquerdo ficou estável,
com o saco capsular restante intacto, sem descentralização, luxação ou deiscência
zonular. O exame dos registros médicos do serviço em que ele havia se submetido
a uma cirurgia de catarata não mostraram relatos específicos a qualquer estrutura
intraocular, incluindo a íris. O olho esquerdo fora submetido à facoemulsificação sem
complicações, através de um CCI de 2,2 mm, seguido pela implantação de uma lente
intraocular acrílica peça única dentro do saco capsular intacto. Este relatório mostra
que, mesmo pequenas CCIs podem ser abertas no pós-operatório por trauma e que isso
pode resultar em aniridia total isolada, sem danos a outras estruturas intraoculares.
Keywords: Aniridia; Phacoemulsification; Eye injuries; Cornea; Wound and injuries;
Case reports
Descriotres: Aniridia; Facoemulsificação; Traumatismos oculares; Córnea; Ferimentos
e lesões; Relatos de casos
INTRODUCTION
The advances in cataract surgery have made small, self-sealing clear
corneal incisions (CCIs) a standard surgical technique. Furthermore,
a study using cadaveric eyes showed that this type of incision was
highly stable under substantial external pressure(1). Here we describe
a patient with a history of uneventful cataract surgery using a small
CCI who experienced isolated total aniridia, without damage to other
intraocular structures after blunt trauma to the eye.
in each eye and an intraocular pressure of 18 mmHg, as measured by
Goldmann applanation tonometry. There was no bruising or edema
in the periorbital area. Slit-lamp examination showed total aniridia in
his left eye, but there was no hyphema or cells in the anterior chamber.
The intraocular lens in his left eye was stable without decentration,
dislocation, or zonular dehiscence and remained in an intact capsular
bag (Figure 1). A Seidel test was negative, but the deposition of a few
granules of iris pigment was observed in the CCI wound. Other than
the CCI wound, there was no evidence of open wounds throughout
the entire cornea and sclera. Gonioscopy and fundus examination
revealed no iris remnants or tissues suspected of being iris (Figure 2).
His right eye was completely normal.
Examination of the medical records from the clinic at which he
had undergone cataract surgery showed no specific findings for any
intraocular structure including the iris. He had previously undergone
an uneventful phacoemulsification of his left eye through a 2.2 mm
CCI, followed by the implantation of a single piece acrylic intraocular
lens (IOL) (Akreos Adapt; Bausch & Lomb Inc., Rochester, NY, USA)
inside an intact capsular bag.
He did not come for his scheduled follow-up visits for 5 months
after his initial visit. However, he reported negligible dazzling and
CASE REPORT
A 71-year-old male presented at our clinic with dazzling in his left
eye. He reported that he had fallen down 15 days earlier while drunk
and struck his left eye against a stone on the road. For about 10 days
following this incident, he had slightly blurred vision and dazzling
in his left eye but no other specific symptoms. Although his vision
had improved considerably without treatment, the residual dazzling
prompted his visit to the hospital. He had undergone cataract surgery
on his left and right eyes 9 and 15 months before the accident, respectively, at another eye clinic. At examination, he had 20/20 vision
1
2
Department of Ophthalmology, Haeundae Paik Hospital, Busan, South Korea.
Department of Ophthalmology, Inje University College of Medicine, Busan, South Korea.
44
Corresponding author: Wan Soo Kim. Department of Ophthalmology. Haeundae Paik Hospital - Inje
University College of Medicine - Busan - South Korea - E-mail: [email protected]
http://dx.doi.org/10.5935/0004-2749.20160013
Kim KH, et al.
Figure 1. Anterior segment photo showing total aniridia with an intact ciliary
body, intraocular lens, and capsular bag.
Figure 2. Gonioscopic examination showing total aniridia with an intact ciliary body and
no iris remnant.
denied the need for treatment during a telephone interview that
encouraged a follow-up visit.
DISCUSSION
There have been few reported cases of total aniridia caused by blunt
trauma in pseudophakic patients who have undergone phacoemulsification using a CCI since the first report in a patient with a 4.0-mm
sized incision and the implantation of a multipiece IOL(2). Although
a previous report had described total aniridia in patients who had
undergone implantation of a single piece IOL into an intact capsular
bag(3), our case was unique in that the wound size (2.2 mm) was the
smallest to be reported till date and there was no damage to the
zonules, capsular bag, or IOL despite the single piece design of the
latter. Furthermore, to our knowledge, this was the first such case in
an Asian patient. In addition, our patient was distinguished by his
initially mild symptoms and symptom alleviation within 5 months
following the blunt trauma.
The mechanism underlying isolated total aniridia following blunt
trauma remains to be fully understood. According to one hypothesis,
the significant increase in pressure caused by the blunt trauma could
reopen the previous corneal incisional wound, inducing a complete
iris avulsion and its expulsion through the wound. In this situation,
the small incision may function as a release valve, preventing global
rupture(2). However, another hypothesis is that the disinserted iris
remains within the eye and is phagocytosed by macrophages and/or
trabecular meshwork cells, as shown by the presence on UBM imaging of echogenic particles at the anatomic position of the iris(4). This
second hypothesis was formulated based on the observation of the
phagocytic properties of the iris and trabecular meshwork in animal
experiments; however, since the disinserted iris is an immunological
self-material and considering the immunologic privileges of intraocular structures, it seems unlikely that inflammatory reactions, including
phagocytosis, associated with a disinserted iris would be sufficient to
absorb all structures within the 1 week in their case report. Furthermore, our patient initially presented with mild symptoms, allowing him to
delay his initial visit to the hospital for 2 weeks. This suggested that any
hyphema or inflammation in the anterior chamber was insignificant
after the trauma. This finding, together with the deposition of some
iris pigment within the CCI wound, strengthened the hypothesis that
the disinserted iris was expelled through the wound.
This report demonstrated that even small sized CCIs can be opened postoperatively by trauma and that this can result in isolated
total aniridia without damage to other intraocular structures.
REFERENCES
1. Ernest PH, Fenzl R, Lavery KT, Sensoli A. Relative stability of clear corneal incisions in a
cadaver eye model. J Cataract Refract Surg. 1995;21(1):39-42.
2. Ball J, Caesar R, Choudhuri D. Mystery of the vanishing iris. J Cataract Refract Surg. 2002;
28(1):180-1.
3. Oltra EZ, Chow CC, Lunde MW. Bilateral traumatic expulsive aniridia after phacoemulsification. Middle East Afr J Ophthalmol. 2012;19(3):334-6.
4. Parmeggiani F, Mantovani E, Costagliola C, Campa C, Steindler P. Total aniridia after
nonperforating trauma of a pseudophakic eye: ultrasound biomicroscopic findings.
J Ultrasound Med. 2007;26(12):1795-7.
45
Case Report
Using thermography for an obstruction of the lower lacrimal system
Utilização da termografia de uma obstrução da via lacrimal baixa
Marco antonio dE caMpoS Machado1, joão aMaro fErrari Silva1, MarcoS lEal BrioSchi2, norMa allEMann1
ABSTRACT
RESUMO
Obstructions in the lacrimal pathways quite often require accurate and reliable
image scanning for confirmation and documentation. Infrared thermal imaging,
known as thermography, is a resource that complements diagnosis; it does not
require touching the patient or applying contrast materials and has been used in
various medical procedures for decades. However, there have been few studies
in the literature about its use in ophthalmology. In this paper, the authors have
presented a case of dacryocystitis where the obstruction of the lacrimal punctum
was so acute that conventional dacryocystography could not be used. The authors
have successfully reported the use of thermography as a complementary propaedeutic and will discuss the method they used.
As obstruções de vias lacrimais muitas vezes necessitam de exames de imagem precisos
e confiáveis para confirmação e documentação diagnóstica. A imagem térmica por
infravermelho, conhecida como termografia, é um recurso complementar diagnóstico
sem contato e sem contraste, utilizada há décadas em diversas aplicações médicas.
Porém, ainda são poucos os estudos na literatura sobre seu uso na oftalmologia. Neste
trabalho os autores apresentam um caso de dacriocistite com obstrução dos pontos
lacrimais onde não foi possível utilizar a técnica convencional de dacrioscistografia
relatando o uso com sucesso da termografia como propedêutica complementar e
discutem o método.
Keywords: Thermography/methods; Dacryocystitis/diagnosis; Case reports
Descriotres: Termografia/métodos; Dacriocistite/diagnóstico; Relatos de casos
INTRODUCTION
Temperature is an important health indicator and can be assessed using the wavelength of the infrared rays between 700 nm and
100,000 nm that are released by the human body as heat(1). The human body reflects its surface temperature because it is an excellent
infrared energy emitter(2).
Thermography is a diagnostic imaging method that can capture
and record the heat emitted from the body surface, allowing both
non-invasive and safe investigation(3,4). The thermography diagnostic
method is based on the detection of infrared images that are emitted
from the patient’s body surface in real time. A thermographic camera
captures the infrared radiation emission patterns, which are invisible
to the naked eye and imperceptible to touch, and translates them
into information encrypted in colors that can help to detect changes
in normal patients(4).
In this report, we have demonstrated the recurrent acute inflammatory process in a case of lower tear obstruction and the use of
thermal imaging.
was referred to the Lacrimal System Service at the Department of
Ophthalmology.
Ectoscopic evaluation revealed a substantial tumefaction of the
lacrimal sac area and an apparent occlusion of both the upper and
lower tear puncta in the right eye, which was probably related to
the radioiodine therapy. Dacryocystography is typically the standard
procedure for diagnosing this type of obstruction, but was contraindicated in this case. In order to evaluate the nasolacrimal duct,
infrared thermography was used as a complementary propaedeutic.
The examination was performed with a thermal camera T650 sc
model (FLIR Systems Inc., Portland, USA), which promoted high definition images (620 × 420 pixels) with high sensitivity and allowed the
detection of differences at 0.03°C in tissue temperature (Figure 1). The
patient was positioned in front of the camera, which was placed on a
support 80 cm away from the lacrimal sac area.
The room temperature was maintained at 23°C throughout the
evaluation and the images were captured 15 min after the temperature of the patient’s face matched the temperature of the environment (thermalization). One drop of saline solution (sodium chloride
0.9%) cooled to 18°C had been previously applied to both eyes; a
sequence of thermographic images was then shot with the eyes
open 3 s after a blink. Care was taken not to allow excessive saline
solution to run onto her face, thus preventing any thermal artifact
from interfering with the local thermographic images. The camera
allowed image magnification of up to eight times and fusion of the
thermal and visual images in 3D mode, with optimal heat contrast
that corresponded with the photographic image.
The thermographic image captured hypo-radiation in the area
corresponding to the dilatation of the right lacrimal sac and appeared
as a blue coloration (Figures 2 A and 2 B). The hypo-radiation obser-
CASE REPORT
A 56-year-old woman (MAS) visited the Ophthalmology Emergency
Room with a complaint of epiphora and swelling in the lacrimal sac
region of the right eye. She had experienced the same symptoms on
two previous occasions at an interval of 3 years and had been treated
with systemic antibiotics. The patient had undergone radioiodine
therapy for 6 months at the same institution due to thyroid carcinoma associated with a thyroid nodular goiter and follicular adenoma.
It was first believed to be an acute case of dacryocystitis. After the
prescription of 500 mg of cephalexine, 4 times a day for 7 days, she
Submitted for publication: September 29, 2014
Accepted for publication: March 11, 2015
1
2
Department of Opthalmology and Visual Sciences, Escola Paulista de Medicina (EPM), Universidade
Federal de São Paulo (UNIFESP).
Termologia Clínica e Termografia, School of Medicine, Universidade de São Paulo (USP).
46
Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of interest
to disclose.
Corresponding author: Norma Allemann. Rua Olimpíadas, 134, cj. 51 - São Paulo, SP - 04551-000 Brazil - E-mail: [email protected]
http://dx.doi.org/10.5935/0004-2749.20160014
Machado MAC, et al.
Figure 1. Thermographic camera, T650 sc model (FLIR Systems Inc., Portland, USA)
that is used for diagnostic thermography examinations with 620 × 420 pixel
definition, and that is capable of detecting differences in temperature with
0.03°C sensitivity.
A
B
Figure 2. A) Thermographic image of the patient’s face, showing inflammation around
the lacrimal sac of the right eye that reached the lower eyelid that was observed as a
bluish warm halo (hyper-radiation); this corresponded to hyper-radiation or local heating,
which was not observed in the lacrimal sac of the left eye. B) Magnified image of 2A,
showing blue coloration where the dilatation of the lacrimal sac indicated local edema
from chronic inflammation (hypo-radiation).
ved in the thermography image could be associated with the degree
of edema caused by tissue inflammation. The same bluish image was
not captured in the area corresponding to the left lacrimal sac. After
a dynamic examination that included the instillation of cooled drops
in the eyes, the left normal eye presented with lacrimal sac cooling
with bluish coloration. No local cooling was observed in the right
lacrimal sac.
Diagnosed with chronic dacryocystitis, the patient was referred
for surgical intervention with an external right dacryocystorhinostomy, which included the surgical opening of the upper and lower
ipsilateral lacrimal puncta.
DISCUSSION
First described by Raflo et al. in 1982, the use of thermal imaging
for the lacrimal system is an investigative method without known
side effects(5). Unlike the dacryocystography exam, there is no need to
touch the patient or to use a contrast substance. This allows for safer
and faster assessment of the drainage system, with a higher degree
of patient cooperation.
Blood flow is the major mechanism of heat transfer in the human
body(5) and thermography can use images to document the effects
on the microcirculation and vasomotor activity involved in the inflammatory process as well as in superficial tumors(6).
Thermal imaging of the lacrimal drainage allows confirmation
and assessment of the degree of tissue inflammation. The thermographic images are compared to determine the bilateral asymmetry of the
thermal capture and the hyper-radiation or heat. In cases of acute
dacryocystitis crises, the finding of the thermal imaging will be a hyper-radiation of the lacrimal sac(7). Even when relying on an apparatus
that had lower definition than that described in this case, Rosenstock
et al. found a sensitivity of 42% and a specificity of 60%(8) for the detection of inflammatory processes in the lacrimal drainage system. In
the case presented, the static thermal image highlighted a chronic
inflammation of the lacrimal sac that already contained edema; this
appeared bluish (cold) in the thermographic examination.
In this case, the dynamic examination using the cold drop was
crucial. The lacrimal sac has an average diameter of 1.5 cm and is
located in the tear sac at a distance of approximately 0.5 cm from the
skin; these factors allow medical thermography to provide a reliable
thermal evaluation(9). Cooling of the medial corner of the orbits is
the expected normal response to the instillation test of cooled drops(4).
When no local cooling is observed, it is identified as a pathologic finding, and may suggest the existence of an obstruction.
The clinical presentation of a lacrimal obstruction in the reported
case may have been due to radioiodine therapy for thyroid carcinoma. This association has been described in the literature(10), or combined with other conditions that jointly acted to produce lacrimal
obstruction.
In the present case, we chose to use the thermography method
due to the presence of a tumefaction in the lacrimal sac area that
could preclude cannulation in dacryocystography. This method also
had the advantage of avoiding additional radiation exposure, lowering
cost, and improving ease of use compared to radiologic methods
such as computed tomography (CT) and magnetic resonance imaging (MRI). In the event there was any suspicion of a possible invasion
of the lacrimal system by a neoplastic process, CT or MRI scans would
be mandatory.
Thermography is a non-contact diagnostic technique that does
not require the use of radiation and that provides objective evidence about the permeability of the lacrimal drainage system. This information is particularly useful when there is clinical suspicion of
inflammation.
REFERENCES
1. Hardly JD. The radiating power of human skin in the infrared. Am J Physiol. 1939;127:
454-62.
2. Hagblad J, Folke M, Lindén M. Long term monitoring of blood flow at multiple depths observations of changes. Stud Health Technol Inform. 2012;117:107-12.
3. Farid KJ, Winkelman C, Rizkala A, Jones K. Using temperature of pressure-related
intact discolored areas of skin to detect deep tissue injury: an observational, retrospective, correlational study. Ostomy Wound Manage. 2012;58(8):20-31.
4. Brioschi ML, Teixeira MJ, Yeng LT, Silva FM. Manual de termografia médica São Paulo:
Editora Andreoli; 2012.
5. Raflo GT, Chart P, Hurwitz JJ. Thermographic evaluation of lacrimal drainage system.
Ophthalmic Surg. 1982;13(2):119-24.
6. Anbar M. Hyperthermia of the cancerous breast: analysis of mechanism. Cancer Lett.
1994;84(1):23-9.
7. Hinton P, Hurwitz JJ, Chart PL. Liquid crystal contact thermography and lacrimal tract
inflammation: a preliminary report. Can J Ophthalmol. 1984;19(4):176-7.
8. Rosenstock T, Chart P, Hurwitz JJ. Inflammation of the lacrimal drainage system-assessment by thermography. Ophthalmic Surg. 1983;14(3):229-37.
9. Fayet B, Racy E, Assouline M, Zerbib M. Surgical anatomy of the lacrimal fossa A prospective computed tomodensitometry scan analysis. Ophthalmology. 2005;112(6):
1119-28.
10. Fonseca FL, Lunardelli P, Matayoshi S. Obstruction of lacrimal system associated with
radioiodine therapy of thyroid carcinoma. Arq Bras Oftalmol. 2012;75(2):97-100.
47
Case Report
Choroidal melanoma recurrence after episcleral brachytherapy and transpupillary
thermotherapy
Recorrência melanoma de coroide após a braquiterapia episcleral e termoterapia transpupilar
yrBani lantiGua-dorvillE1, Maria antonia Saornil1, ciro García-alvarEz1, ElEna García-laGarto2
ABSTRACT
RESUMO
A 68-year-old man diagnosed with choroidal melanoma (CM) in the right eye
underwent treatment with episcleral brachytherapy (I125) and transpupillary thermotherapy. Ultrasound, computed tomography, and magnetic resonance imaging
were performed and revealed ocular recurrence of CM. Treatment with extended
enucleation was performed. Macroscopic and microscopic examinations revealed
extraocular extension and malignant cells, respectively. Immunohistochemistry
demonstrated tumoral Melan-A and HMB-45 expression. No cytogenic abnormalities
were detected with fluorescence in situ hybridization of tumor cells using probes
against chromosomes 3q27 and 8q24. The patient underwent adjuvant external
beam radiotherapy for treatment of residual tumor tissue. This case represents
the first reported case of recurrent CM with no cytogenetic abnormalities and the
absence of metastatic disease, despite a number of the poorest prognostic factors.
Um homem de 68 anos de idade com diagnóstico de melanoma de coroide no olho
direito foi submetido a tratamento com braquiterapia episcleral (I125) e termoterapia
transpupilar. Ultrassonografia, tomografia computadorizada e ressonância magnética
foram realizadas para avaliar a presença de recorrência ocular ou doença sistêmica.
Enucleação ampliada foi realizada para tratar a recorrência ocular. O exame macroscópico e microscópico revelou o tipo de célula tumoral e a extensão extraocular.
Colorações por Melan-A e HMB-45 foram realizadas. A fluorescência por hibridização
in situ com sondas para os cromossomos 3q27 e 8q24 não mostraram anormalidades
citogenéticas. O paciente foi submetido a radioterapia externa adjuvante para o tratamento de tumor residual orbitário. Este caso representa a o primeiro relato de paciente
sem anomalias citogenéticas e sem doença metastática, apesar de demonstrar alguns
dos mais pobres fatores prognósticos.
Keywords: Choroid neoplasms; Melanoma; Neoplasm recurrence, local; Brachytherapy; Case reports
Descritores: Neoplasias da coroide; Melanoma; recidiva local de neoplasia; Braquiterapia; Relatos de casos
INTRODUCTION
Extraocular extension of choroidal melanoma (CM) is the primary
presentation in 2.5-28% of cases of CM. Extraocular extension of CM
as a secondary presentation is even more rare and occurs following
the failure of conservative treatment (e.g., brachytherapy, radiotherapy, surgical resection, and transpupillary thermotherapy [TTT])(1).
Massive orbital invasion, reported in 0.5% of cases, occurs rarely with
small CM lesions(1). Massive orbital invasion has been reported as a
strong negative prognostic factor with a 5-year survival rate of less
than 11% due to increased risk of metastatic disease(2).
Herein, we describe an unusual case of CM presenting with minimal intraocular recurrence and massive orbital spread following
conservative treatment.
after initial diagnosis due to proptosis and decreased visual acuity of
the right eye. Upon examination, proptosis of the right eye was observed with limitation of up-gaze and adduction (Figure 1 A). Fundus
examination revealed a pigmented nodular lesion. Ultrasonography
revealed a choroidal mass consistent with recurrent melanoma and
a large extraocular shadow with extraocular extension (Figure 1 B).
Computed tomography and magnetic resonance imaging demonstrated an extraocular mass involving the optic nerve and inferior and
inner rectus muscles (Figure 1 C and D). There was no evidence of
systemic disease with liver test or ultrasonography. Extended enucleation was performed. Macroscopic examination revealed a chorioretinal scar, pigmented nodules, an amelanotic mass surrounding the
optic disc, and a retroocular pigmented multinodular tumor measuring 25 mm x 19 mm (Figure 2 A). Light microscopy demonstrated
that the tumor was composed of epithelioid cells found to express
Melan A and HMB45 by immunohistochemical analysis. The tumor
was found to have infiltrated the emissary channels and optic nerve
and reached the retroocular space where wide areas of necrosis were
observed with presumed tumoral tissue occupying the orbit (Figure
2 B-D). Fluorescence in situ hybridization analysis of the tumor with
probes against chromosomes 3q27 and 8q24 found no cytogenetic
abnormalities.
CASE REPORT
We report the case of a 68-year-old man diagnosed with CM (9.9 mm
base x 2.9 mm height) of the right eye (located at the superior
temporal edge) initially treated at another hospital with episcleral
brachytherapy (I125) and TTT. The initial therapeutic outcome was
favorable; i.e., tumor regression on ultrasound was observed after six
months of treatment. The patient was referred to our institution 2 years
Accepted for publication: April 18, 2015
1
2
Ophthalmology Department (Ocular oncology unit), Hospital Clínico Universitario de Valladolid,
Valladolid, Spain.
Pathology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
48
Corresponding author: Yrbani Lantigua Dorville. Ophthalmology Department, Hospital Clínico
Universitario de Valladolid - R. Ramón y Cajal 3 - Valladolid - 47005 - Spain
http://dx.doi.org/10.5935/0004-2749.20160015
Lantigua-Dorville Y, et al.
A
C
B
D
Figure 1. Clinical and imaging findings. (A) Right eye proptosis and limited up-gaze.
(B-D) magnetic resonance imaging studies demonstrating recurrence (B), extraocular
extension, and superior and inner rectus muscle involvement of the right eye (C), and a
small intraocular mass (arrow) with extraocular extension (D).
A
B
C
D
sequently, the patient underwent adjuvant external beam radiotherapy to treat the residual tumor and had no signs of local recurrence
or metastatic disease at 18 months of follow-up.
DISCUSSION
Secondary extraocular extension following conservative treatment
of CM is extremely rare(3) and usually small in size. Historically, this
presentation has been associated with surgical resection and TTT
without adjuvant brachytherapy thought to result in insufficient
elimination of tumor margins and intrascleral tumor cells. Combined
plaque radiotherapy and TTT has been shown to provide excellent
control of intraocular tumors. Shields et al.(3) and Bartlema et al.(4)
reviewed 270 and 50 cases, respectively, and found recurrence rates
at 5 years after treatment of up to 3%. However, neither study found
any cases of extraocular extension. In the present case, brachytherapy
was initially performed with a 2 mm tumor margin resulting in diffuse
recurrence that extended to the orbit through emissary channels
surrounding the optic nerve. The extra ocular lesion had grown substantially larger than the intraocular lesion during the postoperative
period. Recurrence in this case may be attributable to incomplete
prior treatment of tumor margins allowing residual tumor regrowth.
However, extraocular spread has been shown to be strongly associated with the histological and cytogenetic features of the index
tumor(5). In the present case, several of the poorest CM prognostic
factors were present including disease recurrence, massive orbital
invasion, and epithelioid tumor cell type, which tend to occur with
cytogenetic abnormalities, such as monosomy of chromosome 3
and polysomy of chromosome 8, associated with more aggressive
melanoma, greater risk of metastases, and decreased survival. However, no cytogenetic abnormalities or signs of metastatic disease were
observed at 18 months of follow-up.
To our knowledge, this is the first reported case of CM with
minimal intraocular recurrence and massive extraocular extension
following combination treatment with TTT and episcleral brachytherapy. Moreover, cytogenetic abnormalities and metastatic disease
were not identified in this case despite the presence of several of the
poorest CM prognostic factors.
REFERENCES
Figure 2. Histopathological and inmunohistochemical findings. (A and B) Macroscopic
and lower magnification examination demonstrated a large retroocular pigmented
multinodular tumor enveloping the optic nerve. Intraocular pigmented nodules were
observed with an amelanotic mass enveloping the optic disc. (C) Border of the treated
choroid area with extensive fibrosis and tumor recurrence (H&E x40). (D) Tumor samples
from the intraocular recurrence and extraocular extension were found to be composed
of small epithelioid cells (H&E x400).
The final diagnosis was recurrence of CM with massive extraocular extension and presumed residual tissue occupying the orbit. Con-
1. Blanco G. Diagnosis and treatment of orbital invasion in uveal melanoma. Can J Ophthalmol. 2004;39(4):388-96.
2. Coupland SE, Campbell I, Damato BE. Routes of extraocular extension of uveal melanoma. Risk factors an influence on survival probability. Ophthalmology. 2008;115(10):
1778-85.
3. Shields CL, Carter J, Shields JA, Chao A, Krema H, Materin M, et al. Combined plaque
radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor
control and treatment complications in 270 consecutives patients. Arch Ophthalmol.
2002;120(7):933-40.
4. Bartlema YM, Oosterhuis JA, Journée-De Korver JG, Tjho-Heslinga RE, Keunen JE. Combined plaque radiotherapy and transpupillary thermotherapy in choroidal melanoma:
5 years’ experience. Br J Ophthalmol. 2003;87(11):1370-3.
5. Damato B, Duke C, Coupland SE, Hiscott P, Smith PA, Campbell I, et al. Cytogenetics of
uveal melanoma: a 7-year clinical experience. Ophthalmology. 2007;114(10):1921-35.
49
Case Report
Early post-LASIK flap amputation in the treatment of aggressive, branching keratitis:
a case report
Amputação precoce de pedículo de LASIK para o tratamento de ceratite ramificada agressiva: relato de caso
john au1, thoMaS plESEc1, karolinnE rocha2, williaM duppS jr.1, ronald kruEGEr1
ABSTRACT
RESUMO
Infectious keratitis is rare following laser vision correction. We present a case of
aggressive fungal keratitis caused by Aspergillus flavus, following laser in situ
keratomileusis (LASIK) in the setting of a unique environmental risk factor. We
describe the key features of the acute case presentation, which guided empirical
medical and surgical treatment, resulting in the most favorable outcome found
in the literature, to date.
Ceratites infecciosas são raras após a correção da visão a laser. Apresentamos um
relato de caso de uma ceratite fúngica agressivo por Aspergillus flavus, após ceratomileuse a laser “in situ” (LASIK) em situação peculiar de fator de risco ambiental. Nós
descrevemos as principais características da apresentação caso agudo, que orientou
tratamento médico e cirúrgico empírico, demonstrando resultado mais favorável do
que o encontrado na literatura até o momento.
Keywords: Keratomileusis, laser in situ/adverse effects; Keratitis/etiology
Descritores: Ceratomileuse assistida por excimer laser in situ/efeitos adversos; Ceratite/
etiologia
INTRODUCTION
Infectious keratitis following laser vision correction is uncommon(1,2).
The estimated incidence as reported by the 2008 American Society
of Cataract and Refractive Surgery (ASCRS) survey was 19 of 20,941
eyes (0.09%). The most commonly cultured organism in this series
was methicillin-resistant Staphylococcus aureus. One case was confirmed to be caused by a fungal infection(1). We wish to share our
experience with a case of Aspergillus flavus keratitis following laser in
situ keratomileusis (LASIK), in association with a potential environmental risk factor.
CASE REPORT
A 24-year-old female with low myopia was treated with wavefront-optimized femtosecond-LASIK on the WaveLight FS-200 and
Allegretto Eye-Q laser platform (Alcon, Fort Worth, TX, USA). Her initial
manifest refraction was -1.25 D sphere in both eyes. Central corneal
thickness was 508 µm in OD and 505 µm in OS, as measured with
ultrasound pachymetry. The remainder of her ophthalmic examination and corneal tomography were normal. Her history included
prior right V1 dermatome herpes zoster without ophthalmic involvement. The LASIK procedure was uneventful, and she was started on
ciprofloxacin 0.3% (Ciloxan®) and dexamethasone 0.1% drops four
times daily. On postoperative day 1, the uncorrected distance visual
acuity (UDVA) was 20/15 in each eye, and the ophthalmic exam was
unremarkable.
On postoperative day 2, the patient experienced severe pain,
photophobia, and decreased vision in the right eye. UDVA was 20/50
in the right eye and 20/15 in the left eye. Ophthalmic exam with a slit
lamp revealed a dense, branching, feathery infiltrate within the flap
Submitted for publication: December 11, 2014
1
2
Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, OH.
Medical University of South Carolina, Storm Eye Institute.
50
interface of the right eye (Figure 1). Given this appearance, the clinical
suspicion for fungal keratitis was high.
The patient provided informed consent, and was immediately
taken to the operating room for flap-lift, culture, irrigation of the flap
interface, and potential flap amputation. The flap was lifted and a
gelatinous branching infiltrate was observed, extending superficially
into the flap and posteriorly into the stromal bed. After bacterial and
fungal culture samples were obtained, the interface was extensively
irrigated with a balanced salt solution. The infiltrate penetrated into
the flap stroma, and because of the rapid progression (<24 h) of
fungal keratitis, a decision was made to amputate the flap. Hourly
topical fortified tobramycin (13.5 mg/ml), vancomycin (25 mg/ml),
and voriconazole (1%) were immediately started. Although the infiltrate was clearly in the flap interface and not involving the overlying
epithelium, 1 g of oral valacyclovir three times daily was also started
for 10 days because of the patient’s history of right V1 herpes zoster.
Prednisolone therapy was discontinued.
The infiltrate remained prominent on the day following flap
amputation. The patient was followed-up very closely for the first 3
weeks postflap amputation. Four days postflap amputation, UDVA
was 20/100-1. The infiltrate was improving and the epithelium had
healed approximately 85% over the stromal bed (Figure 2 A). Bacterial cultures from the samples taken during flap amputation were
negative. Nine days after these were taken, fungal cultures showed
A. flavus growth. Histopathology of the flap showed fungal elements
within the undersurface of the flap stroma (Figure 3). Fungal sensitivities were requested and hourly topical voriconazole was continued,
while the fortified vancomycin and tobramycin were tapered. On
day 11 postflap amputation, UDVA in the right eye had improved to
20/40. Photography (Figure 2 B) and corneal SD-OCT (Figure 4) were
Corresponding author: John Au. 3.501 Jamboree Road #1.100 - Newport Beach, CA 92660
http://dx.doi.org/10.5935/0004-2749.20160016
Au J, et al.
repeated at that time. Antifungal sensitivity testing confirmed that
voriconazole was appropriate for the isolated strain (Table 1).
After 3 weeks of hourly voriconazole, UDVA had improved to
20/25 (-2) in the right eye. The manifest refraction was -0.50 D sphere
with a corrected distance visual acuity of 20/20-3. Voriconazole was
tapered and prednisolone acetate was slowly added in an attempt
to decrease corneal haze. At 5 months postoperatively, UDVA was
20/15 in the right eye. Ophthalmic exam at that time showed a persistent but improved 1+ corneal haze. She has not required further
intervention to date.
DISCUSSION
A review of the literature shows a generally poor outcome for
post-LASIK Aspergillus keratitis(2-4). Of the published cases, one required a penetrating keratoplasty(2); another resulted in corneal perforation, requiring glue patching(3); and the third resulted in a final pinhole vision of 20/40(4). Our case demonstrated an aggressive nature of A.
flavus keratitis, which resulted in lifting of the flap and irrigation of the
Figure 1. The day 2 postoperative appearance of branching feathery interface
infiltrate
A
B
Figure 3. Histology of the amputated corneal flap showing fungal elements in the stroma
(black arrows).
Figure 4. A day 11 postflap amputation SD-OCT image showing dense central hyper-reflectivity, representing the residual infiltrate and surrounding haze. Reepithelialization
is noted.
Table 1. The minimum inhibitory concentration (MIC) of antifungal
agents for use against Aspergillus flavus cultured in this patient
Antifungal agent
Figure 2. A) The day 2 postflap amputation slit lamp appearance with reformation of dense feathery infiltrate. B) The day 11 postflap amputation slit lamp
appearance showing improvement of the infiltrate with decreasing density.
MIC (µg/ml)
Amphotericin B
2
Natamycin
32
Fluconazole
>64
Itraconazole
1
Posaconazole
>0.5
Voriconazole
1
51
Early post-LASIK flap amputation in the treatment of aggressive, branching keratitis: a case report
interface, as well as complete amputation of the flap. Ultimately, this
decision in conjunction with proper empirical medical intervention
has allowed for a remarkably good visual result for our patient.
During the week prior to this case, a new wall was built within the
refractive suite waiting area, which was not directly connected with
the laser suite. However, on the day prior to the case, construction
workers had removed some ceiling tiles in the laser suite, in preparation for the upcoming construction and removal of an internal wall.
It is well established in the literature that construction is a risk
factor for aerosolized dissemination of spore-forming organisms
including fungi(5-9). Several cases and outbreaks of Aspergillus in association with hospital construction have been described, resulting in
pulmonary aspergillosis in immunocompromised patients. Primarily,
A. flavus and A. fumigatus are the responsible organisms in these
cases(6-9). A prior outbreak of Aspergillus endophthalmitis has been
described in association with hospital construction(5). To the best of
our knowledge, this is the first reported case of post-LASIK A. flavus
keratitis with construction in the laser suite as a potential risk factor.
Although the presentation of this patient was early for fungal
infection, the steroids administered to the patient could have
allowed for a more rapid progression of the fungal infection. In addition, we considered that the recent construction in the laser suite
could have released fungal organisms. We also considered bacterial,
including mycobacterial, and herpetic etiologies. Given the rapid
progression, the possibility of bacterial infection remained reasonably high. Therefore, fortified antibiotics were prescribed on an hourly
basis from the day of flap amputation until the cultures proved fungal
etiology. Atypical mycobacterium should always be considered in
LASIK-related infections. However, these infections typically present
weeks after the procedure. Finally, we empirically treated the patient
for herpetic disease as well because she had a history of herpes
zoster. The location of the infiltrate was within the flap interface and
not intraepithelial; this led us to favor a fungal or bacterial etiology
over a herpetic one.
One valuable clinical lesson gained from this experience is to
avoid surgical cases in the setting of recent construction. We are unaware of a specific recommended time period to wait to perform further refractive surgery following such construction events. It is encouraged to cover or move equipment prior to construction. In addition,
after construction is complete, a thorough cleaning of all dust-covered
surfaces in the area is necessary prior to any further surgery.
52
A second equally important lesson focuses on trusting clinical
judgment based upon physical findings in the absence of more definitive data (i.e., cultures). The initial clinical appearance must guide
therapy when more definitive data is lacking. Based on the earliest
finding on slit lamp exam, we surmised that flap amputation was indicated, which ultimately led to a good rather than poor postoperative
outcome. Several considerations led to this decision: 1) Penetration
of the antibiotics and antifungal medication to the infiltrate would
be improved. 2) The patient had a low myopic correction with robust
residual stromal bed thickness for possible future refractive treatment.
3) The flap was created with a femtosecond laser; therefore, it had a
uniform planar shape when amputated, allowing for minimal refractive change when compared with a meniscus-shaped microkeratome
flap. These factors, along with prompt, appropriate medical therapy,
contributed to this most favorable reported outcome in post-LASIK
fungal keratitis.
ACKNOWLEDGMENTS
Thank you to University of Texas Health Science Center at San Antonio, Department of Pathology for antifungal susceptibility testing.
REFERENCES
1. Solomon R, Donnenfeld ED, Holland EJ, Yoo SH, Daya S, Güell JL, Mah FS, Scoper SV,
Kim T. Microbial keratitis trends following refractive surgery: Results of the ASCRS
Infectious keratitis survey and comparisons with prior ASCRS surveys of infectious
keratitis following keratorefractive procedures. J Cataract Refract Surg. 2011;37(7):
1343-50.
2. Sridhar M, Garg P, Bansal A, Gopinathan U, Aspergillus flavus Keratitis After Laser in Situ
Keratomileusis. Am J Ophthalmol. 2000;129(6):802-4
3. Kuo I, Margolis T, Cevallos V, Hwang D, Aspergillus fumigatus Keratitis After Laser In
Situ Keratomileusis. Cornea. 2001;20(3):342-4.
4. Sun Y, Jain A, Ta C, Aspergillus fumigatus keratitis following laser in situ keratomileusis.
J Cataract and Refract Surg. 2007;33(10):1806-7.
5. Tabbara KF, al Jabarti AL. Hospital construction-associated outbreak of ocular aspergillosis after cataract surgery. Ophthalmology. 1998;105(3):522-6.
6. Krasinski K, Holzman RS, Hanna B, Greco MA, Graff M, Bhogal M. Nosocomial fungal
infection during hospital renovation. Infect Control. 1985;6(7):278-82.
7. Arnow PM, Andersen RL, Mainous PD, Smith EJ. Pulmonary aspergillosis during hospital renovation. Am Rev Respir Dis. 1978;118(1):49-53.
8. Vonberg RP, Gastmeier P. Nosocomial aspergillosis in outbreak settings. J Hosp Infect.
2006;63(3):246-54.
9. Lentino JR, Rosenkranz MA, Michaels JA, Kurup VP, Rose HD, Rytel MW. Nosocomial
aspergillosis: a retrospective review of airborne disease secondary to road construction
and contaminated air conditioners. Am J Epidemiol. 1982;116(3):430-7.
Case Report
Combinação de fixação transescleral de prótese de íris artificial com lente intraocular
uzEyir GunEnc1, taylan ozturk1, Gul arikan1, MahMut kaya1
ABSTRACT
RESUMO
Post-traumatic aniridia combined with aphakia may be seen after globe injury. Aside
from esthetic aspects, partial or total loss of the iris tissue may also be related to
various degrees of glare and photophobia. Such patients suffer from severe visual
impairment secondary to aphakia. Herein we describe a novel surgical technique
for the management of an aphakic eye with traumatic aniridia for a patient who
underwent transscleral fixation of a custom-tailored artificial iris prosthesis combined with a rigid intraocular lens (IOL). Tight suturing of the IOL haptic eyelets on
the silicone iris prosthesis and fixation of such a complex to the scleral wall may
provide excellent cosmetic and functional outcomes in aphakic eyes with aniridia.
Aniridia pós-traumática combinada com afacia pode ser observada após lesões do
globo ocular. Além do ponto de vista estético, a perda parcial ou total do tecido da
íris também pode estar relacionada com vários graus de ofuscamento e fotofobia.
Estes pacientes sofrem de deficiência visual grave secundária a afacia. Relata-se
uma técnica cirúrgica inovadora para tratamento de um olho com afacia associada
à aniridia traumática que foi submetido à fixação transescleral de uma prótese de
íris artificial feita sob medida combinada com uma lente intraocular rígida (IOL). A
sutura das alças da IOL sobre a prótese iriana de silicone, e a fixação desse complexo
na parede escleral podem proporcionar excelente resultado estético e funcional em
olhos afácicos com aniridia.
Keywords: Aniridia; Aphakia; Postcataract; Cataract extraction; Iris/injuries; Eye injuries; Lens implantation, Intraocular; Prosthesis design
Descritores: Aniridia; Afacia pós-catarata; Extração de catarata; Íris/lesões; Traumatismos oculares; Implante de lentes intraocular; Desenho de prótese
INTRODUCTION
Post-traumatic iris defects combined with crystalline lens abnormalities are among the major complications of globe injuries. Pupillary defects may cause glare and photophobia to various degrees;
however, traumatic aniridia may lead to severe visual deterioration.
Because corneal endothelial cell density is reduced in eyes with a traumatic cataract, every surgical trauma entails a potential risk of aggravating corneal decompensation(1-3). After custom-tailored iris prosthesis became available for ocular implantation, some authors have
described a combined surgical approach for treating aphakia and
aniridia with haptic fixation of an intraocular lens (IOL) on artificial iris
implants prior to intraocular placement(4,5). Herein we describe a new
surgical technique for simultaneously treating aniridia and aphakia.
A sclerally sutured rigid IOL was first fixated on a custom-tailored
ar tificial iris prosthesis by both of its haptics, after which intraocular
implantation was performed by suturing IOL to the scleral wall.
crylate (PMMA) IOL (CZ70BD; Alcon Laboratories, Fort Worth, TX, USA)
with the implantation of a custom-tailored artificial iris prosthesis
(Dr. Schmidt Intraocularlinsen GmbH, HumanOptics AG, Erlangen,
Germany) was scheduled for simultaneously treating aniridia and
aphakia. In order to match the color of the healthy iris, a custom-tailored artificial iris prosthesis was produced.
Under topical anesthesia, two conjunctival peritomies were made
at the 3 and 9 o’clock meridians before performing a superior 7.0-mm
clear corneal incision. Subsequently, an ophthalmic viscosurgical
device (OVD) was injected to protect the corneal endothelium. After
hitching the 9-0 polypropylene looped-sutures with a long-curved
needle (PC-9; Alcon Surgical, Fort Worth, TX, USA) to the haptic
eyelets of PMMA IOL, both pairs of such needles passed through
the periphery of the artificial iris prosthesis (Figure 1 A). The haptics
were tightly attached to the back of the iris implant. Next, IOL and
artificial iris complex were ab-internally fixed to the scleral wall at
the 3 and 9 o’clock meridians, approximately 1 mm posterior to the
limbus. After passing the needles through the marked scleral points,
IOL and the artificial iris complex were implanted. The complex was
retracted to be stabilized and well-centered after the withdrawal of
both needles through the pars plana. Polypropylene sutures were
tied to the sclera, and the suture knots were buried into the sclera
at both sides. To ensure placement within the sclera, the suture end
and knot were buried into the created scleral tunnel using a PC-9
needle after knotting the suture onto itself. The artificial iris did not
interfere with this process because there was no knot between the
CASE REPORT
A 56-year-old otherwise healthy female had experienced total iris
emanation and crystalline lens luxation secondary to a blunt trauma
to her left eye. She had previously undergone lensectomy and pars
plana vitrectomy at another center. A complete ophthalmologic examination revealed a clear cornea with a normal fundus and a visual
acuity of 20/20 with +12.0 diopters correction in the affected eye. The
combined transscleral fixation of a single-piece polymethylmetha-
Submitted for publication: December 9, 2014
Accepted publication: March 18, 2015
1
Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey.
Corresponding author: Taylan Ozturk. Albatros-9, 152, Daire: 26 - Mavisehir, Karsiyaka - 35540,
Izmir - Turkey - E-mail: [email protected]
http://dx.doi.org/10.5935/0004-2749.20160017
53
artificial iris and ciliary body. The corneal incision was sutured with
a 10-0 non-absorbable nylon suture, and OVD was gently removed
from the anterior chamber. The conjunctiva was subsequently closed
with 80 polyglactin 910 (Vicryl®, Ethicon Inc) sutures (Figure 1 B). The
patient was satisfied with the cosmetic appearance from the early
postoperative period (Figure 2). Over the first postoperative week, the
patient had no complaints of any persisting glare and photophobia,
and visual acuity was found to be 20/20 with -0.50 diopters of astigmatism in her left eye.
DISCUSSION
Iris defects combined with aphakia are serious problems frequently encountered after globe injuries. Aside from esthetic aspects, partial or total loss of iris tissue may also be related to various degrees
of glare, photophobia, and visual impairment. In patients with major
A
iris defects, an artificial iris prosthesis provides satisfactory anterior
segment reconstruction with a remarkable functional outcome(3-10).
Various implants have been developed for the treatment of aphakia
with aniridia. Some authors reported on effective and safe surgical
intervention with Morcher black-diaphragm IOL (Morcher 67F BDI,
Morcher GmBH, Stuttgart, Germany) for the treatment of both total
or partial aniridia in aphakic cases(6,7). The Ophtec iris reconstruction
lens with the color options of brown, blue, and green (Ophtec USA,
Boca Raton, FL, USA) has also been reported to provide better cosmetic outcomes as well as remarkable visual improvement(8,9). In cases
with partial iris defects, intraocular implantation of the Artisan iris
reconstruction implant (Ophtec, Groningen, The Netherlands) may
be chosen for cosmetic and functional improvement. Such a device
can be attached to the remaining iris tissue at its periphery; however,
an optical lens system enabling various dioptric powers is placed in
its center(10). A custom-tailored artificial iris prosthesis provides a much
B
Figure 1. (A) Haptics of a single-piece polymethylmethacrylate (PMMA) intraocular lens (IOL) were tightly attached to the back
of the iris implant using 9-0 polypropylene looped-sutures with a long-curved needle (PC-9; Alcon Surgical). (B) Operated eye
at the end of the surgery.
A
B
C
Figure 2. Operated eye at postoperative day one (A) and after first week (B). Acceptable cosmetic appearance of the left eye (C).
54
Gunenc U, et al.
better cosmetic outcome because it is produced according to the
exact iris color of the fellow eye. Because the management of aphakia
is not possible with such artificial iris implants, the transscleral fixation
of IOL has to be scheduled in aphakic eyes with a lack of a sufficient
capsular support. Hence, many authors have published an excellent
visual prognosis with transsclerally fixated IOLs in aphakic cases
without any capsular support(2-5). In order to reduce the risk of both
corneal decompensation and macular edema, transscleral fixation of
a standard IOL in combination with a custom-tailored artificial iris prosthesis in the same surgical session has been published very recently
in cases with concomitant aniridia and aphakia(4,5). Forlini et al. fixed a
monopiece foldable IOL centrally on the back side of the artificial iris
prosthesis(4), and Spitzer et al. reported on the implantation of such a
custom-tailored prosthesis combined with a three-piece foldable IOL
through a superior corneoscleral tunnel with a length of 5 mm(5). However, we used PMMA IOL that was tightly sutured onto the back side
of the artificial iris prosthesis with 9-0 polypropylene looped-sutures
in its haptic eyelets in order to provide the best fixation. Although a
major disadvantage of such a procedure was the necessity of extended corneal incision, a visual acuity of 20/20 with -0.50 diopters of
astigmatic correction in the affected eye was achieved only one week
after the operation.
Herein we presented a novel surgical technique for managing an
aphakic case with traumatic aniridia undergoing transscleral fixation
of a Dr. Schmidt custom-tailored artificial iris prosthesis combined
with PMMA IOL. Suturation of the IOL haptics on the artificial iris
prosthesis and the transscleral fixation of this complex to the scleral
wall provide a good cosmetic and functional outcome in aphakic
cases with aniridia.
REFERENCES
1. Yeniad B, Corum I, Ozgun C. The effects of blunt trauma and cataract surgery on corneal
endothelial cell density. Middle East Afr J Ophthalmol. 2010;17(4):354-8. Comment in:
Middle East Afr J Ophthalmol. 2012;19(2):269-70; author reply 270.
2. Lockington D, Ali NQ, Al-Taie R, Patel DV, McGhee CN. Outcomes of scleral-sutured conventional and aniridia intraocular lens implantation performed in a university hospital
setting. J Cataract Refract Surg. 2014;40(4):609-17.
3. Hanumanthu S, Webb LA. Management of traumatic aniridia and aphakia with an iris
reconstruction implant. J Cataract Refract Surg. 2003;29(6):1236-8.
4. Forlini C, Forlini M, Rejdak R, Prokopiuk A, Levkina O, Bratu A, et al. Simultaneous
correction of post-traumatic aphakia and aniridia with the use of artificial iris and IOL
implantation. Graefes Arch Clin Exp Ophthalmol. 2013;251(3):667-75. Comment in: Graefes Arch Clin Exp Ophthalmol. 2013;251(10):2493-4. Graefes Arch Clin Exp Ophthalmol.
2013;251(10):2491.
5. Spitzer MS, Yoeruek E, Leitritz MA, Szurman P, Bartz-Schmidt KU. A new technique for
treating posttraumatic aniridia with aphakia: first results of haptic fixation of a foldable
intraocular lens on a foldable and custom-tailored iris prosthesis. Am J Ophthalmol.
2012;130(6):771-5.
6. Aslam SA, Wong SC, Ficker LA, MacLaren RE. Implantation of the black diaphragm
intraocular lens in congenital and traumatic aniridia. Ophthalmology. 2008;115(10):
1705-12.
7. Beltrame G, Salvetat ML, Chizzolini M, Driussi GB, Bussato P, Di Giorgio G, et al. Implantation of a black diaphragm intraocular lens in ten cases of post-traumatic aniridia. Eur J
Ophthalmol. 2003;13(1):62-8.
8. Price MO, Price FW Jr, Chang DF, Kelley K, Olson MD, Miller KM. Ophtec iris reconstruction
lens United States clinical trial phase I. Ophthalmology. 2004;111(10):1847-52.
9. Mashor RS, Bahar I, Kaiserman I, Berg AL, Slomovic A, Rootman DS. Combined penetrating keratoplasty and implantation of iris prosthesis intraocular lenses after ocular
trauma. J Cataract Refract Surg. 2011;37(3):582-7.
10. Smina ML, Odenthal MT, Gortzak-Moorstein N, Wenniger-Prick LJ, Völker-Dieben HJ. Implantation of the Artisan iris reconstruction intraocular lens in 5 children with aphakia
and partial aniridia caused by perforating ocular trauma. J AAPOS. 2008;12(3):268-72.
55
Review Article
A vitamina A e o olho: uma velha história em tempos modernos
jacQuElinE fErrEira fauStino1, alfrEdo riBEiro-Silva2, rodriGo faEda dalto1, MarcElo MartinS dE Souza1, joão MarcEllo fortES furtado1,
GutEMBErG dE MElo rocha3, Monica alvES4, Eduardo MElani rocha1
ABSTRACT
RESUMO
Clinical presentations associated with vitamin A deficiency persist in poor regions
globally with the same clinical features as those described centuries ago. However,
new forms of vitamin A deficiency affecting the eyes, which have become widespread, as a result of modern societal habits are of increasing concern. Ophthalmic
conditions related to vitamin A deficiency require the combined attention of
ophthalmologists, pediatricians, internists, dermatologists, and nutritionists due
to their potential severity and the diversity of causes. As the eyes and their adnexa
are particularly sensitive to vitamin A deficiency and excess, ocular disturbances
are often early indicators of vitamin A imbalance. The present review describes the
clinical manifestations of hypovitaminosis A with an emphasis on so-called modern
dietary disorders and multidisciplinary treatment approaches. The present review
also discusses the relationship between retinoic acid therapy and dry eye disease.
As apresentações clínicas associadas à deficiência de vitamina A persistem em regiões
pobres ao redor do mundo com os mesmos achados clínicos descritos há séculos.
No entanto, novas formas de problemas causados pela vitamina A afetam os olhos,
estão associados com os hábitos da sociedade moderna e tem causado preocupação.
Eles exigem a atenção dos oftalmologistas, pediatras, internistas, dermatologistas e
nutricionistas, devido à sua gravidade e diversidade de causas. Uma vez que os olhos
e seus anexos são órgãos muito sensíveis à deficiência e excesso de vitamina A, manifestações oculares podem ser indicadores precoces do desequilíbrio de vitamina A. Essa
revisão traz as manifestações clínicas de hipovitaminose A enfatizando os chamados
distúrbios dietéticos modernos e formas de abordagem multidisciplinar. E também traz
evidências sobre a relação entre a terapia com ácido retinóico e doença do olho seco.
Keywords: Vitamin A deficiency/complications; Eye manifestations; Bariatric surgery;
Blepharoplasty; Refractive surgical procedures; Xerophthalmia
Descritores: Deficiência de vitamina A/complicações; Manifestações oculares; Cirurgia
bariátrica; Blefaroplastia; Procedimentos cirúrgicos refrativos; Xeroftalmia
INTRODUCTION
Night blindness, xerophthalmia, Bitot’s spot, keratitis, and keratomalacia are well-known clinical manifestations of hypovitaminosis
A(1). However, this condition is classically related to food deprivation
associated with malabsorption syndrome resulting from poverty
and/or chronic disease(1-3).
The present review aims to inform health professionals of the
modern presentations, causes, associated systemic diseases, and risk
factors of hypovitaminosis A. The utility of retinoic acid application
for the treatment of skin diseases and dry eye is also discussed(4).
Herein, we present the clinical presentation of hypovitaminosis A
and discuss strategies for the investigation and treatment of the
causes and consequences of hypovitaminosis A and side effects of
the use of retinoic acid (a form of vitamin A) in dermatological and
oncological therapies.
chanisms were elucidated more recently. The causes of deficiencies
in the micronutrient vitamin A, the biochemical vitamin A pathway,
food sources of retinol (vitamin A) and its metabolites, and the physiological roles of vitamin A have only begun to be understood since
the 20th century(5-9) (Figure 1; Table 1).
Interestingly, one of the most complete and objective descriptions of the clinical manifestations of hypovitaminosis A was
published decades before the specific underlying cause was known
by the Brazilian ophthalmologist, Manoel da Gama Lobo, in 1865(10).
Dr. Gama Lobo reported four cases of children, all descendants of
slaves, with ocular disease who subsequently developed lung and
digestive disorders before ultimately dying. In this report, the disease was termed Ophthalmia Braziliana, and the clinical progression
was comprehensively detailed. Food deprivation was identified
and credited to the practice of extensive monoculture in the farms
of Southeast Brazil, in that century dedicated to the production of
coffee and sugar.
Dr. Gama Lobo attributed the signs and symptoms observed
in his patients to the poor diet of slaves and their descendants, a
problem that he never saw in his homeland to north of the country
HISTORY
The classical clinical presentation of the disease currently known
as vitamin A deficiency was first described in antique medical documents of the ancient Egyptian civilization, although underlying me-
Submitted for publication: September 8, 2015
1
2
3
4
Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de
Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Departamento de Patologia e Medicina Legal, Faculdade de Medicina de Ribeirão Preto, Universidade
de São Paulo, Ribeirão Preto, SP, Brazil.
Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São
Paulo, Ribeirão Preto, SP, Brazil.
Departamento de Oftalmologia e Otorrinolaringologia da Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil.
56
Funding: This study was supported by CAPES, CNPq, FAPESP, FAEPA, and NAP-FTO-USP.
Corresponding author: Eduardo Melani Rocha. Department of Ophthalmology, Otorhinolaryngology
and Head & Neck Surgery, School of Medicine at Ribeirao Preto, University of Sao Paulo. Av.
Bandeirantes, 3.900 - Ribeirão Preto, SP - 14049-900 - Brazil - E-mail: [email protected]
http://dx.doi.org/10.5935/0004-2749.20160018
Faustino JF, et al.
where agriculture production was dedicated to local consumption
and therefore more variable and abundant. At the end of his report,
Dr. Gama Lobo called the attention of legislators to the need for
laws aimed at preventing the sequence of problems he outlined. His
paper was published in Portuguese and in German but is relatively
unknown to the majority of the medical community, although it is
now freely available online(11,12).
Recent epidemiologic data from Brazil in a study population of
3,499 children aged between 6 and 59 months and 5,698 women
aged between 15 and 49 years revealed that hypovitaminosis A is
present in all five regions of Brazil with a prevalence of 17.4% and
12.3% among children and women, respectively (13). The highest
prevalence was found to be in urban areas and the northeastern and
southeastern regions of the country.
CLASSIC DISEASE
The typical medical scenarios leading to hypovitaminosis A are
low food intake, intestinal parasitosis, malabsorption syndromes, and
diets containing low amounts of vitamin A (Figure 2).
Hypovitaminosis A is classically caused by food deprivation. It is
present in rural areas and the peripheries of large cities in South Asia,
Africa, and Latin America, and the poor communities of large cities
of developed countries(14-17). The most vulnerable individuals are children and pregnant women. The prevalence of hypovitaminosis A can
reach 50% in children under 6 years of age in certain areas(18). Laboratory confirmation of the diagnosis of hypovitaminosis A is defined
as a serum retinol level <0.3 mg/l or 0.7 µM(19).
Figure 1. Metabolic steps underlying vitamin A deficiency from the dietary level to target cells.
In addition to ocular problems, hypovitaminosis A also predisposes individuals to retarded growth, infertility, congenital malformations, infections, and early mortality(18,20). The issue of vitamin A deficiency in these populations, distributed in more than 45 countries,
has been the target of international preventive programs of vitamin
A supplementation and periodic evaluation(16,18,19).
Individuals suffering from food deprivation and malabsorption
are often infected with intestinal parasite diseases, such as Ascaris
lumbricoides and Ancilostomides, Giardia lamblia, which may aggravate the inflammatory background and the signs and symptoms of
hypovitaminosis A(21-24).
Other well-known causes of vitamin A deficiency can be grouped
into conditions associated with malabsorption syndrome. The treatments of several diseases that cause digestive disturbances and/or
absorption of lipids and vitamin A have improved in recent decades
leading to increased life expectancy and improved the clinical control of hypovitaminosis A allowing the majority of patients to lead
a normal life. However, the majority of these patients will develop
xerophthalmia (the specific term for hypovitaminosis A-related dry
eye), which may progress to more severe ocular damage and other
clinical manifestations of vitamin A depletion(25-27).
Acquired diseases associated with malabsorption syndrome known
to cause hypovitaminosis A include chronic pancreatitis caused by
chronic alcoholism, liver and pancreas autoimmunity, Crohn’s disease,
and ulcerative colitis, among other diseases affecting the digestive
system(28).
Congenital diseases associated with malabsorption syndrome and
hypovitaminosis A include cystic fibrosis and short bowel syndrome,
among other genetic diseases that may impair intestinal vitamin A
absorption in individuals with normal or high oral intake of retinoid
and carotenoids(2,29,30).
The fourth group of conditions that classically cause hypovitaminosis A is those that may initially lead to malabsorption syndrome but
later progresses to impaired hepatic storage of vitamin A. Biliary cirrhosis, chronic hepatitis, and chronic cirrhosis caused by toxic agents,
viruses, and other causes may lead to hypovitaminosis A and should
be screened for and treated by parenteral vitamin A supplementation
according to body mass index and level of vitamin A deficiency(31).
MODERN DISEASES ASSOCIATED WITH HYPOVITAMINOSIS A
In recent decades, the conditions known to induce hypovitaminosis A have been classified into four groups. Despite their varying
prevalence, such conditions should be carefully considered by
ophthalmologists during routine clinical practice.
Modern causes of hypovitaminosis A that may also lead to xerophthalmia and other eye diseases and cause blindness are shown
in (Figure 2 and Table 2) and comprising voluntary ingestion of low
vitamin A diets or restrictive diets (e.g., vegetarian or cafeteria diets),
psychiatric eating disorders (e.g., anorexia and bulimia), bariatric
Table 1. Vitamin A nomenclature
Name
Group
Characteristics
Retinoids
Vitamin A and natural or synthetic derivate
Similar chemical polyenes and polar end groups
Carotenes
α-Carotene, β-carotene, γ-carotene, and the xanthophyll β-cryptoxanthin
Β-ionine rings
Vitamin A
Group of lipophilic nutritional compounds
Essential and broad effects on chordate animal bodies
Provitamin A
Carotenes and retinyl esters
Dietary and pharmaceutical sources of vitamin A
Retinoic acid
Metabolite of vitamin A
Transcription factor binding to cell nuclear receptors
Retinal
Form of vitamin A
Essential for vision function
Retinol
Form of vitamin A
Growth and development functions
Tretinoin
All trans retinoic acid
Pharmaceutical formulas
1 IU of vitamin A = 0.3 μg retinol = 0.34 μg retinil acetate = 0.6 μg β-carotene.
57
surgeries mimicking malabsorption syndrome, and chronic diseases
that affect organs involved in vitamin A digestion or clearance (e.g.,
Sjögren’s syndrome and kidney failure).
Restrictive diets resulting from dietary behaviors may lead to
a status of hypovitaminosis A and the consequences mentioned
above. Diets adopted in conjunction with drugs to reduce appetite,
diets with monotonous ingredients, and diets with limited sources of
animal ingredients containing retinol and beta carotene (meat and
Figure 2. Classic and modern causes of hypovitaminosis A.
dairy products such as milk, eggs, and their derivatives) are typically
followed in the belief they will offer better control or prevention of
certain diseases or improve general health(32-35).
Exclusively vegetarian diets particularly put children and pregnant
woman at increased risk of hypovitaminosis A as the conversion of
beta carotenes present in vegetables to retinol is limited during digestion and the availability of vitamin A for absorption and hepatic
storage is <20% of dietary vitamin A content(1).
The so-called cafeteria diet or competitive food, based on refreshing sodas and industrialized food, is predominantly composed
of carbohydrates and lipids of vegetal source and provides insufficient amounts of dietary vitamin A. Accordingly, such diets could be considered causes of hypovitaminosis A and associated ocular problems
in patients with excessive habits related to these diets(36).
The second group of causes of hypovitaminosis A includes the
psychiatric eating disorders, anorexia, and bulimia nervosa, recognized as major, growing health problems with severe clinical complications, and high mortality. Both can cause hypovitaminosis A due
to chronic dietary disturbances. The complexity of such conditions
must be recognized in the context of early signs of xerophthalmia
and should be managed in parallel with psychiatric specialists(37,38).
Bariatric techniques for the treatment of obesity include jejunoileal bypass and stomach reduction to induce weight loss by malabsorbtive and restrictive mechanisms(39-41). Patients require vitamin supplementation following these procedures; however, a recent study
in Brazil demonstrated that even before bariatric surgery a relative
amount of patients already have hypovitaminosis A, and that this prevalence increases 30 and 180 days after the procedure(42). In patients
with no compliance for a period of weeks or months, ophthalmologists may evaluate the initial manifestations of hypovitaminosis A.
Special attention should be paid to patients undergoing oculoplastic
or refractive surgeries as their nutritional status may be subclinical
Table 2. Major causes of hypovitaminosis A and diagnosis guidelines
Major causes of deficiency of vitamin A
Description
Primary deficiency
Low dietary intake of vitamin A
Food source: liver beef, damascus, spinach, cabbage, milk, carrot, and butter
Diagnosis: food intake history, liver function, and vitamin A serum levels
Restrictive and monotonous diets
Restricted intake of sources of vitamin A and consumption of the same group of food for many months
Eating disorders: psychiatric, cafeteria diet, and vegetarian
Diagnosis: food intake history. Physical signs. Blood vitamin A levels
Malabsorption syndrome
Reduction in uptake and mucosa transport of digested nutrients to the blood stream
Diagnosis: diarrhea, steatorrhea, weight loss, anemia, hyperkeratosis, and acrodermatitis. Blood examination to check
pancreas and liver function. Stool analysis (fat, parasites)
Bariatric surgery
Surgery to treat obesity and associated diseases is divided into restrictive, disabsorptive, and mixed techniques and
often mimics malabsorption syndrome
Diagnosis: surgical history, use of vitamin supplements, bowel habits. Food intake history. Physical signs. Blood levels
of vitamin A. Stool analysis (fat)
Short bowel syndrome
Mesenteric vascular disease typically caused by congenital obstruction, thrombosis, and other diseases requiring
bowel resection
Diagnosis: diarrhea, fatigue. Blood levels of vitamin A. Stool analysis (fat)
Liver failure
Loss of liver digestive and storage functions due to alcohol toxicity, virus infection, or other causes. Malabsorption
mechanisms and signs may be present.
Diagnosis: blood levels of liver enzymes and vitamin A, virus serology. Stool analysis (fat)
Chronic pancreatitis
Loss of pancreas exocrine function affecting digestion. Malabsorption mechanisms and signs may be present
Diagnosis: blood levels of pancreas enzymes and vitamin A. Stool analysis (fat)
Cystic fibrosis
Inherited disease affecting chloride channels leading to exocrine gland dysfunction. Malabsorption mechanisms and
signs may be present
Diagnosis: low weight gain in infancy, progressive malnutrition, chronic cough with hypersecretion, chronic sinusitis,
biliary cirrhosis, diabetes, respiratory infections and infertility. Sodium and chloride levels in sweat
Salivary and deglutition diseases
Swallowing problems due to xerostomia, tooth problems, and/or muscular deglutition dysfunction. Example: Sjögren’s
syndrome
Diagnosis: oral and dental examination and salivary flow rate
58
Faustino JF, et al.
and cause disturbances in ocular surface homeostasis and wound
healing leading to poor outcomes and serious ocular complications(40).
Patients with the above-mentioned conditions may share a number
of characteristics including individual concern and anxiety regarding
body image, health, and satisfaction with food consumption.
The fourth class of modern causes of hypovitaminosis A that may
contribute to or worsen ocular surface diseases is the chronic disease
leading to chronic impairment of the organs involved in digestion
and clearance of vitamin A metabolites (Figure 1). Although the
majority of these diseases are not new, improvements in therapeutic
approach have allowed affected patients to lead longer and more active lives. Similarly, vitamin A deficiency may be neglected in patients
receiving frequent healthcare.
Within this group, the diseases causing severe dry mouth, such
as head and neck radiotherapy and Sjögren’s syndrome, may limit
deglutition and digestion and impose dietary restrictions that may
lead to hypovitaminosis A(43,44). Therefore, dietary habits and vitamin
A levels should be evaluated in patients presenting the diseases described above and ocular surface complications. Although patients
commonly present with dry eye disease associated with these conditions, the clinical picture may be aggravated by hypovitaminosis A.
Renal failure and hemodialysis are associated with dry eye disease
and ocular surface changes in diabetic and nondiabetic patients(45,46).
There is currently controversy regarding lower vitamin A levels in
such patients as renal failure reduced the reliability of traditional methods of measuring vitamin A levels. However, lower blood vitamin
A levels have been shown to be associated with higher morbidity and
mortality in these patient populations(47,48). Recently, a case of night
blindness and compatible retinal changes was described in a hemodialysis patient with apparent normal levels of serum retinol that
were corrected with retinol palmitate treatment(49).
SIDE EFFECTS OF VITAMIN A MEDICAL USE
The utility of vitamin A topical eye drop administration in treating
dry eye has been comprehensively investigated(50,51). Vitamin A topical eye drops may also have utility in the treatment of skin diseases
and specific types of cancer including ocular surface neoplasia(52,53).
However, excessive vitamin A intake is known to induce gastric and
neural side effects such as abdominal and head pain, nausea, and
irritability(54,55). These symptoms may be aggravated by chronic use of
vitamin A eye drops and lead to the development of blurred vision and
pseudotumor cerebri(56-58). A clinical history of dry skin and mucosa,
nausea, and retinoic acid intake in meals or pharmaceutical formulations should inform suspicion of acute and chronic side effects or
consequences of excessive vitamin A dosing.
Recently, two publications reviewed the mechanisms underlying
the induction of meibomian gland dysfunction and dry eye symptoms
by systemic retinoic acid therapy for acne. The authors discussed
the effects of systemic and topical skin or ocular application of different forms and doses of vitamin A formulations. Moreover, it was
persistent meibomian gland dysfunction after systemic retinoic acid
discontinuation was reported(4,52).
CASE REPORTS
Case report 1: A 2-year-old boy presented with a history of consecutive episodes of hordeola affecting the upper and lower lids of
both eyes over the preceding 12 months. The patient had a history
of photophobia and crying without tears. Previous ocular treatment
included lubricants and antiallergic eye drops. The patient was an
only child with no other personal or family antecedents. His dietary
habits were based on soft drinks and junk food between meals with
deficient intake of meat, milk derivatives, vegetables, and fruits.
Swollen lids and hordeola affecting both eyes were observed on examination. He was able to fix and follow light projection with both eyes
but was unable to perform visual acuity testing. Slit lamp examination
demonstrated mild punctate keratitis and an epithelial defect in the
right cornea. The rest of the ocular examination was normal. His
body weight matched the 50th percentile for age and sex (12.7 kg);
however, his height was in the tenth percentile (84 cm). Laboratory
testing was requested and identified hypochromic and microcytic
anemia with low blood levels of iron and retinol (32.7 μg/dl and
0.20 mg/l, where the normal levels for children are 50-150 μg/dl
and 0.30-0.80 mg/l, respectively).
Clinical findings and laboratory testing indicated the chronic presence of hordeola, syndrome sicca, growth retardation, and anemia
were all consequences of a diet deficient in essential elements such
as vitamin A and iron (Fe). The diet was reoriented, and the child was
maintained under close observation by his pediatrician until clinical
signs improved fully.
Case report 2: A 71-year-old woman presented with decreased
vision and pain in the left eye (OS) for 20 days and a diagnosis of
corneal ulcer. She was receiving antibiotic and corticosteroids eye
drops at the time of presentation. She had previously undergone
cataract surgery in both eyes 2 months prior to this presentation.
Her medical history was noncontributive except for inappetence and
weight loss of approximately 10 kg over the preceding year. Her visual
acuity was 0.5 in her right eye (OD) and counting fingers at 1 m OS.
Biomicroscopic examination revealed conjunctiva hyperemia and a
1.5 mm by 2.5 mm corneal ulcer without secretion or infiltration. A
diagnosis of microbial keratitis was made, and eye drops were changed accordingly. During follow-up, she developed a corneal ulcer OD
and the ulcer in the OS worsened. Severe corneal punctate fluorescein staining and conjunctival Rose Bengal staining were observed
in both eyes. The Schirmer test without anesthesia was zero in both
eyes. Her salivary flow was 0.06 ml/min (normal values >0.1 ml/min;
Figure 3). Laboratory tests were positive for SSa and SSb (anti-Ro and
anti-La antibodies, respectively), and blood levels of vitamin A were
0.2 mg/l. A minor salivary gland biopsy demonstrated leukocyte infiltration with focal organization, ductal dilation, and extensive fibrosis
replacing acinar structures. The focus score was graded 4. During evaluations, the patient developed corneal melting OD and underwent
penetrant keratoplasty. The present findings indicated a diagnosis of
Sjögren’s syndrome aggravated by hypovitaminosis A. After a period
of corticosteroids and vitamin A therapy, her general and ocular
symptoms improved. Her case illustrates a delicate combination of
causes of sicca syndrome (Sjögren’s syndrome and hypovitaminosis
A) leading to a severe presentation. The extensive fibrosis of salivary
gland structures, almost completely replaced by fibrosis, may be a
consequence of concurrent disease and ageing (Figure 3 D).
Case report 3: A 22-year-old woman presented with ocular pain,
lid edema, and thick tearing for 5 months not improved by lubricants,
cyclosporine eye drops, or bandage contact lenses. She reported a
habit of mucous fishing. Her previous medical history included myopia, allergy, and acne vulgaris. She had been prescribed a 6-month
course of oral isotretinoin 6 years previously without side effects
and again 6 months prior to the current complaint. Examination
revealed skin scarring, meibomian gland dysfunction, and punctate
and filamentary keratitis that was worse OD (Figure 4). The tear film
breakup time was 3 s in both eyes and the tarsal conjunctiva presented papillary reaction. The Schirmer test without anesthesia was zero
in OD and 2 mm in OS, and her salivary flow rate was 0.033 ml/min.
Laboratory testing was negative for hormonal abnormalities, and
cystic fibrosis and her vitamin A blood levels were 0.4 mg/l. Tests for
autoimmune diseases were negative for SSa and SSb, rheumatoid
factor, and antinuclear antibody. Her condition was attributed to
a side effect of isotretinoin treatment that had persisted after an
18-month interruption of oral isotretinoin intake. Her case corroborates previous reports of vitamin A-induced dry eye and represents a
severe form of this condition that persisted after discontinuation of
the causative medication.
59
INVESTIGATION
Hypovitaminosis A should be suspected in all cases of night blindness,
ocular surface foreign body sensation, and photophobia without other
evident causes. Crying without tearing is another relevant symptom of
hypovitaminosis A. Recurrent hordeolum, meibomian gland dysfunction identified by gland dropout or inflammation with thickened lipid
secretion, corneal epithelial defect, conjunctiva metaplasia (where
Bitot’s spot is an advanced form and a hallmark), and diffuse punctate
keratitis also represent signs suspicious for hypovitaminosis A.
In all patients suspected to have hypovitaminosis A, a dietary intake
and nutritional habits enquiry must be conducted, with previously
validated evaluation models available. In children, investigations of
height and weight gain during the management period may also
have utility.
The utility of blood vitamin A levels measurements is broadly
accepted, and a classification system established by the World Health
Organization has defined low vitamin A levels as serum retinol concentrations <0.3 mg/l or 0.7 µM. There have been concerns regarding
A
B
C
D
the reliability of blood concentration measurements as the liver is
able to sustain normal levels even in extremely vitamin A-deficient
states(19,59,60).
Other blood tests including complete blood count, protein, albumin, micronutrients, electrolyte concentrations, and stool fat microscopy have all demonstrated utility in assessing vitamin A deficiency
severity. In addition, liver function tests, serology for hepatitis, and
sweat sodium chloride test values >60 mM may aid in distinguishing
between liver diseases and cystic fibrosis, respectively.
Ocular surface assessments may be performed with vital staining
and tear secretion measurements (fluorescein dye and Schirmer’s
test). Corneal and conjunctival impression cytology allows documentation of ocular surface epithelial metaplasia, square and speculate
cells morphology, reduced nuclear size, and the absence or paucity
of goblet cells on microscopy. Ocular surface assessments have demonstrated utility as simple and mildly invasive methods of recording and monitoring hypovitaminosis A in early xerophthalmia(61).
CONCLUSION
The major aim of treatment is to restore vitamin A levels in cases
of hypovitaminosis and reduce exposure in conditions associated
with side effects of oral or skin topical vitamin A use. Details regarding
dosage and administration routes are outside the scope of the present review, as they are dependent on the underlying cause, patient
characteristics, and severity of individual cases.
Healthcare professionals attending poor populations and patients with chronic malabsorption syndrome, hepatic, and other related diseases should be familiar with the classic causes of hypovitaminosis A. The modern causes of hypovitaminosis A do not have the
same magnitude in terms of prevalence but should be considered
by ophthalmologists in daily clinical practice. Hypovitaminosis A can
cause blindness and corneal opacity, but it is also an important cause
of morbidity and mortality.
Increased suspicion of hypovitaminosis A due to ocular surface
symptoms and signals should direct prompt investigation of nutritional
and digestive problems followed by interdisciplinary management
allowing early diagnosis and treatment of the causes and effects of
the majority of diseases related to hypovitaminosis A.
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Figure 3. A 71-year-old woman with bilateral corneal ulcers, weight loss, and features
of autoimmune disease affecting her hands. (A) Slit lamp examination demonstrating a
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of a minor salivary gland with leukocyte focal infiltration, ductal dilation, and extensive
fibrosis replacing acinar structures (200×). Her condition was attributed to a combination
of dryness caused by Sjögren’s syndrome and hypovitaminosis A.
A
B
C
Figure 4. A 22-year-old woman with skin scarring secondary to acne vulgaris (A). Her
meibomian glands were found to be dysfunctional (B), and her cornea has punctate
with evidence of filamentary keratitis (C). Her condition was attributed to systemic and
topical retinoic acid skin treatment.
60
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61
Preoperative usage of ultrasound
biomicroscopy in pediatric cataract
UBM is a non-invasive method that allows imaging of structural
details of the anterior segment and the lens. UBM could visualize
the epilens membrane and divulge the transparency of the lens.
Nevertheless, it is a great advantage to be able to differentiate the
membrane intraoperatively without damaging the anterior capsule.
Uso pré-operatório de biomicroscopia ultrassônica
em catarata pediátrica
Dear Editor:
I read the article “Epilens membrane simulating cataract in children
with uveitis: a report of three cases” by Paiva et al. with great interest(1).
Three cases were presented that were diagnosed as cataract secondary to uveitis but that were understood to have received treatment
for pupillary membrane intraoperatively. I congratulate the authors
for their attention and good management.
Cataract surgery is a radical operation in children(2) and may
cause quite a few complications; patients will also require follow-up
after operation. The indication for cataract surgery in children should
be evaluated carefully. Preoperative examination and imaging are
critical for deciding on whether to operate or not and to identifying
operation strategy. Ultrasound biomicroscopy (UBM) could be a good
imaging method to diagnose epilens membrane in these cases(3).
62
Arq Bras Oftalmol. 2016;79(1):62
Abdullah Kaya1
1
Department of Ophthalmology, Anittepe Military Dispensary, Cankaya, Ankara, Turkey.
Corresponding author: Abdullah Kaya. Anittepe Military Dispensary. Department of Ophthalmology
Cankaya, Ankara - Turkey - E-mail: [email protected]
REFERENCES
1. Paiva R, Nascimento H, Salomão G, Freitas L, Muccioli C, Belfort R Jr. Epilens membrane simulating cataract in children with uveitis: a report of three cases. Arq Bras Oftalmol.
2015;78(5):326-7.
2. Pavlović S. [Cataract surgery in children]. Med Pregl. 2000;53(5-6):257-61. Review.
Croatian.
3. Ünsal E, Eltutar K, Muftuoglu I, Akcetin TA, Acar Y. Ultrasound biomicroscopy in patients with unilateral pseudoexfoliation. Int J Ophthalmol. 2015;8(4):754-8.
http://dx.doi.org/10.5935/0004-2749.20160019
Zika virus-related hypertensive
iridocyclitis
Iridociclite hipertensiva associada à infecção por
Zika vírus
Dear Editor:
The epidemic of Zika virus infection in Brazil has lead to the description of new complications and manifestations such as Guillain-Barré
syndrome in adults and microcephaly in newborns(1,2). Zika virus is
a flavivirus transmitted to humans primarily through the bite of an
infected Aedes species mosquito(3). It was first isolated and described
in Africa, later spreading to Asia, Micronesia, Oceania, and to the
Americas(2).
It is thought that only 1 in 5 people infected with the Zika virus will
become symptomatic(3). The most common systemic manifestations
include: fever, arthralgia, malaise, and skin rash(4,5). More recently,
retinal abnormalities were described in children with microcephaly
attributed to Zika virus infection during pregnancy(6).
The purpose of this letter is to describe a case of bilateral hypertensive iridocyclitis attributed to Zika virus in an otherwise healthy
young male.
A 39-year-old male physician was clinically diagnosed with Zika
virus infection. This occurred in a neighborhood with an outbreak of
this disease. He presented with classic signs of fever, diffuse maculopapular rash, and severe arthralgia. Systemic work-up ruled out other
possible infectious such as Dengue, CMV, Herpes Simplex, Toxoplasmosis, Syphilis, Rubella, spondyloarthropathies, rheumatic diseases,
and systemic vasculitis.
One week after the systemic manifestations the patient complained of bilateral ocular discomfort for near tasks, blurry vision, and mild
redness. Best-corrected visual acuity was 20/40 in each eye. Slit-lamp
examination revealed moderate ciliary injection, mild anterior chamber
http://dx.doi.org/10.5935/0004-2749.20160020
reaction (1+ cells), and miosis in both eyes. Intraocular pressure (Goldmann applanation tonometry) was 40 and 28 mmHg in right and
left eyes, respectively.
He was treated with topical medications (steroids, cycloplegic
and hypotensive agents) for several weeks. This achieved improvement of visual acuity, lowering of intraocular pressure, and complete
resolution of symptoms.
Although no specific protein-chain reaction (PCR) for Zika virus
has been performed, it is very likely that this bilateral hypertensive iridocyclitis occurred secondary to Zika virus. Since it has been shown that
the virus penetrates the blood-brain and ocular barriers, many other
ocular findings (in addition to conjunctivitis and retinal abnormalities)
might be observed in the future. Physicians should be attentive to
ocular complaints when treating patients with Zika virus infection
and refer patients to a specialist for complete ocular examination.
Bruno M. Fontes1
Accepted for publication: January 18, 2016
1
Centro de Microcirurgia & Diagnóstico, Rio de Janeiro, RJ, Brazil.
Corresponding author: Bruno Machado Fontes. Av. Ataulfo de Paiva 135/1418 - Rio de Janeiro,
RJ - 22440-032 - Brazil - E-mail: [email protected]
REFERENCES
1. Fauci AS, Morens DM. Zika Virus in the Americas - Yet Another Arbovirus Threat. N Engl
J Med. 2016 Jan 13. (Epub ahead of print).
2. Zika virus outbreaks in the Americas. Wkly Epidemiol Rec. 2015 Nov 6;90(45):609-10
3. Marcondes CB, Ximenes MF. Zika virus in Brazil and the danger of infestation by Aedes
(Stegomyia) mosquitoes. Rev Soc Bras Med Trop. 2015 Dec 22 (Epub ahead of print).
4. Dyer O. Zika virus spreads across Americas as concerns mount over birth defects. BMJ.
Dec 23;351:h6983.
5. Triunfol M. A new mosquito-borne threat to pregnant women in Brazil. Lancet Infect
Dis. Published online: December 23, 2015.
6. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort Jr R. Zika virus in Brazil and macular
atrophy in a child with microcephaly. The Lancet, Vol. 387, No. 10015, p228. Published
online: January 7, 2016.
Arq Bras Oftalmol. 2016;79(1):63
63
Instructions Authors
INSTRUCTIONS TO AUTHORS
t4DPQFBOEQPMJDZ
t.FUIPET
t5ZQFTPG.BOVTDSJQUT
t&EJUPSJBM1SPDFTT
t.BOVTDSJQU1SFQBSBUJPO
ABO-ARQUIVOS BRASILEIROS DE OFTALMOLOGIA (ABO,
ISSN 0004-2749 - printed version and ISSN 1678-2925 - online version) is
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* Manuscripts containing speculative conclusions, unsubstantiated
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65
nuscript is 30 days after the authors are informed of the need to make
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It is recommended that authors follow the appropriate guideline
bellow before submitting your work:
t CONSORT (Controlled and randomized clinical trials)
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t PRISMA (Systematic reviews and meta-analyses)
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66
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Randomised Controlled Trial Number - ISRCTN, University Hospital
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abstract with no more than 150 words. Five keywords in English
listed by the National Library of Medicine (MeSH - Medical Subject
Headings).
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words. Unstructured abstract with no more than 150 words. Five
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Examples of references:
Journal Articles
Costa VP, Vasconcellos JP, Comegno PEC, José NK. O uso da mitomicina
C em cirurgia combinada. Arq Bras Oftalmol. 1999;62(5):577-80.
Books
Bicas HEA. Oftalmologia: fundamentos. São Paulo: Contexto; 1991.
Book Chapters
Gómez de Liaño F, Gómez de Liaño P, Gómez de Liaño R. Exploración
del niño estrábico. In: Horta-Barbosa P, editor. Estrabismo. Rio de
Janeiro: Cultura Médica; 1997. p. 47-72.
Annals
Höfling-Lima AL, Belfort R Jr. Infecção herpética do recém-nascido.
In: IV Congresso Brasileiro de Prevenção da Cegueira; 1980 Jul 28-30,
Belo Horizonte, Brasil. Anais. Belo Horizonte; 1980. v.2. p. 205-12.
Dissertations
Schor P. Idealização, desenho, construção e teste de um ceratômetro
cirúrgico quantitativo [dissertation]. São Paulo: Universidade Federal
de São Paulo; 1997.
Electronic Documents
Monteiro MLR, Scapolan HB. Constrição campimétrica causada por
vigabatrin. Arq Bras Oftalmol. [online journal]. 2000 [cited 2005
Jan 31]; 63(5): [about 4 p.]. Available at:http://www.scielo.br/scielo.
php?script=sci_arttext&pid=S0004-27492000000500012&lng=pt&
nrm=iso
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Before submitting their manuscript, authors should make sure
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□ Manuscript prepared in accordance with the instructions to
authors.
□ Maximum number of words, tables, figures, and references
according to the type of manuscript.
□ Title page including the clinical trial registration number is not
included in the main document
□ No figures and tables are included in the main document of
the manuscript.
□ All figures and tables were uploaded separately as supplementary documents.
□ Author Contribution Statement completed and saved as a
digital file to be sent as a supplementary document.
□ Form for Disclosure of Potential Conflicts of Interest of all
authors completed and saved as digital files to be sent as
supplementary documents.
□ Digital version of the report provided by the Institutional Review Board containing the approval of the project to be sent
as a supplementary document.
67
LIST OF WEBSITES
Authorship Principles according to the ICMJE
http://www.icmje.org/recommendations/browse/roles-andresponsibilities/defining-the-role-of-authors-and-contributors.html
Authors’ Participation Form
http://www.cbo.com.br/site/files/Formulario Contribuicao dos
Autores.pdf
CONSORT (Consolidated Standards of Reporting Trials)
http://www.consort-statement.org/consort-statement/
STARD (Standards for the Reporting of Diagnostic accuracy studies)
http://www.stard-statement.org/
PRISMA (Preferred Reporting Items for Systematic Reviews and
Meta-Analyses)
http://www.prisma-statement.org/index.htm
STROBE (Strengthening the Reporting of Observational studies
in Epidemiology)
http://www.strobe-statement.org/
Online interface for submission of manuscripts to ABO
http://www.scielo.br/ABO
International Committee of Medical Journal Editors (ICMJE)
http://www.icmje.org/
Uniform requirements for manuscripts submitted to biomedical
journals
http://www.nlm.nih.gov/bsd/uniform_requirements.html
%FDMBSBUJPOPG)FMTJOLJ
http://www.wma.net/en/30publications/10policies/b3/index.html
Principles of the Association for Research in Vision and Ophthalmology (ARVO)
http://www.arvo.org/About_ARVO/Policies/Statement_for_the_
Use_of_Animals_in_Ophthalmic_and_Visual_Research/
64/BUJPOBM*OTUJUVUFTPG)FBMUI
http://www.clinicaltrials.gov
"VTUSBMJBOBOE/FX;FBMBOE$MJOJDBM5SJBMT3FHJTUSZ
http://www.anzctr.org.au
International Standard Randomised Controlled Trial Number ISRCTN
http://isrctn.org/
6OJWFSTJUZ)PTQJUBM.FEJDBM*OGPSNBUJPO/FUXPSL$MJOJDBM5SJBMT
Registry - UMIN CTR
http://www.umin.ac.jp/ctr/index.htm
Nederlands Trial Register
http://www.trialregister.nl/trialreg/index.asp
Registros Brasileiros de Ensaios Clínicos
http://www.ensaiosclinicos.gov.br/
.F4).FEJDBM4VCKFDU)FBEJOHT
http://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh&term=
%F$4)FBMUI4DJFODFT,FZXPSETJO1PSUVHVFTF
http://decs.bvs.br/
Format suggested by the International Committee of Medical
Journal Editors (ICMJE)
http://www.nlm.nih.gov/bsd/uniform_requirements.html
List of Journal Indexed in Index Medicus
http://www.ncbi.nlm.nih.gov/journals
AMA Manual of Style 10th edition
http://www.amamanualofstyle.com/
8PSME"TTPDJBUJPOPG.FEJDBM&EJUPST$POøJDUPGJOUFSFTUJOQFFS
reviewed medical journals
http://www.wame.org/about/wame-editorial-on-coi
Protocols of the International Committee of Medical Journal
Editors (ICMJE)
http://www.icmje.org/recommendations/browse/publishing-andeditorial-issues/scientific-misconduct-expressions-of-concern-andretraction.html
Form for Disclosure of Potential Conflicts of Interest
http://www.icmje.org/coi_disclosure.pdf
Protocols of the Committee on Publication Ethics (COPE)
http://publicationethics.org/resources/flowcharts
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Zika virus‚ microcephaly and macular atrophy Zika virus and

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