Retinopathy of prematurity (ROP), also called retrolental fibroplasia (RLF) and Terry syndrome, is a disease of the
eye
Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...
affecting
prematurely born babies generally having received
neonatal intensive care
A neonatal intensive care unit (NICU), also known as an intensive care nursery (ICN), is an intensive care unit (ICU) specializing in the care of ill or premature newborn infants. Neonatal refers to the first 28 days of life. Neonatal care, as kn ...
, in which
oxygen therapy
Oxygen therapy, also known as supplemental oxygen, is the use of oxygen as medical treatment. Acute indications for therapy include hypoxemia (low blood oxygen levels), carbon monoxide toxicity and cluster headache. It may also be prophylactica ...
is used due to the premature development of their lungs. It is thought to be caused by disorganized growth of
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
l
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s which may result in
scar
A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a na ...
ring and
retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...
. ROP can be mild and may resolve spontaneously, but it may lead to
blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment†...
in serious cases. Thus, all preterm babies are at risk for ROP, and very low birth-weight is an additional risk factor. Both
oxygen toxicity
Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen () at increased partial pressures. Severe cases can result in cell damage and death, with effects most often seen in the central nervous system, lu ...
and relative
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
can contribute to the development of ROP.
Causes
By the fourth month of pregnancy, the fetal retina has begun to develop vascularization. Such formation of blood vessels appears to be very sensitive to the amount of oxygen supplied, either naturally or artificially. In rare cases ROP has been found in some patients with a mutation in the NDP gene, which is normally associated with the more damaging
Norrie disease
Norrie disease is a rare disease and genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the ''Norrin cystine knot growth factor (NDP)'' gene, which is located on the X chromosome. In ...
.
Risk factors
Various risk factors contribute to the development of ROP. They are:
* Prematurity
* High exposure to oxygen
* Low birth weight
* Various types of infections
* Cardiac defects
* Anaemia
* Low vitamin E level
Pathophysiology
During development, blood vessels grow from the central part of the retina outwards. This process is completed a few weeks before the normal time of delivery. However, in
premature babies
Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...
it is incomplete. If blood vessels grow normally, ROP does not occur. If the vessels grow and branch abnormally the baby develops ROP. These abnormal blood vessels may grow up from the plane of the retina and may bleed inside the eye. When the blood and abnormal vessels are reabsorbed, it may give rise to multiple ''band like'' membranes which can pull up the retina, causing detachment of the retina and eventually blindness before 6 months.
Normally, maturation of the retina proceeds ''in utero'', and at term, the
medial portion (Nasal retina) of the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
is fully vascularized, while the
lateral
Lateral is a geometric term of location which may refer to:
Healthcare
*Lateral (anatomy), an anatomical direction
*Lateral cricoarytenoid muscle
*Lateral release (surgery), a surgical procedure on the side of a kneecap
Phonetics
*Lateral cons ...
portion (Temporal retina) is only incompletely vascularized.
The normal growth of the blood vessels is directed to relatively low-oxygen areas of the retina, but the vessels remain in the plane of the retina and do not grow into the
vitreous humor
The vitreous body (''vitreous'' meaning "glass-like"; , ) is the clear gel that fills the space between the lens and the retina of the eyeball (the vitreous chamber) in humans and other vertebrates. It is often referred to as the vitreous humor ...
. If excess oxygen is given, normal blood vessels degrade and cease to develop. When the excess oxygen environment is removed, the blood vessels rapidly begin forming again and grow into the vitreous humor of the eye from the retina.
The key disease element in ROP is fibrovascular proliferation. This is growth of abnormal new vessels; this may regress, but frequently progresses. Associated with the growth of these new vessels is fibrous tissue (scar tissue) that may contract to cause retinal detachment. Multiple factors can determine whether the disease progresses, including overall health, birth weight, the stage of ROP at initial diagnosis, and the presence or absence of "plus disease". Supplemental
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
exposure, while a
risk factor
In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection.
Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
, is not the main risk factor for development of this disease. Restricting supplemental oxygen use reduces the rate of ROP, but may raise the risk of other
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
-related systemic complications, including death.
Patients with ROP, particularly those who have developed severe disease needing treatment are at greater risk for
strabismus
Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...
,
glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
,
cataracts
A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
and shortsightedness (
myopia
Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...
) later in life and should be examined yearly to help prevent or detect and treat these conditions.
Diagnosis
The stages of ROP disease have been defined by the International Classification of Retinopathy of Prematurity (ICROP).
In older patients, the appearance of the disease is less well described but includes the residua of the ICROP stages as well as secondary retinal responses.
International classification
The system used for describing the findings of active ROP is entitled ''The International Classification of Retinopathy of Prematurity (ICROP)''. ICROP uses a number of parameters to describe the disease. They are location (zone) of the disease, the circumferential extent of the disease based on the clock hours, the severity (stage) of the disease and the presence or absence of "Plus Disease". Each aspect of the classification has a technical definition. This classification was used for the major clinical trials. It was revised in 2005.
The zones are centered on the optic nerve. ZoneI is the posterior zone of the retina, defined as the circle with a radius extending from the optic nerve to double the distance to the macula. ZoneII is an annulus with the inner border defined by zoneI and the outer border defined by the radius defined as the distance from the optic nerve to the nasal ora serrata. ZoneIII is the residual temporal crescent of the retina.
The circumferential extent of the disease is described in segments as if the top of the eye were 12 on the face of an analog clock, e.g. stage1 from 4:00 to 7:00. (The extent is a bit less important since the treatment indications from the Early Treatment for ROP.)
The Stages describe the ophthalmoscopic findings at the junction between the vascularized and avascular retina.
* Stage 1 is a faint demarcation line.
* Stage 2 is an elevated ridge.
* Stage 3 is extraretinal fibrovascular tissue.
* Stage 4 is sub-total retinal detachment.
* Stage 5 is total retinal detachment.
Plus disease
Plus disease can be present as a major complicating factor at any stage. It is characterised by:
* Significant level of vascular dilation and
tortuosity
Tortuosity is widely used as a critical parameter to predict transport properties of porous media, such as rocks and soils. But unlike other standard microstructural properties, the concept of tortuosity is vague with multiple definitions and vari ...
observed at the posterior retinal arterioles. This reflects the increase of blood flow through the retina.
* Vitreous haze and anterior chamber haze
* Iris vascular engorgement
*
Persistent tunica vasculosa lentis
Persistent tunica vasculosa lentis is a congenital ocular anomaly. It is a form of persistent hyperplastic primary vitreous (PHPV).
It is a developmental disorder of the vitreous. It is usually unilateral and first noticed in the neonatal perio ...
or immature blood vessels growing over the lens which also restrict the dilatation of the pupils.
Differential diagnosis
The most difficult aspect of the differential diagnosis may arise from the similarity of two other diseases:
*
Familial exudative vitreoretinopathy
Familial exudative vitreoretinopathy (FEVR, pronounced as fever) is a genetic disorder affecting the growth and development of blood vessels in the retina of the eye. This disease can lead to visual impairment and sometimes complete blindness in o ...
which is a genetic disorder that also disrupts the retinal vascularization in full-term infants.
*
Persistent fetal vasculature syndrome
Persistent hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature (PFV), is a rare congenital developmental anomaly of the eye that results following failure of the embryological, primary vitreous and hyaloid vasculature ...
also known as
persistent hyperplastic primary vitreous
Persistent hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature (PFV), is a rare congenital developmental anomaly of the eye that results following failure of the embryological, primary vitreous and hyaloid vasculature ...
that can cause a traction
retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...
difficult to differentiate but typically unilateral.
Screening
Almost all infants with ROP have a gestational age of 31 weeks or less (regardless of birth weight) or a birth weight of 1250 g (2.76 lbs) or less; these indications are generally used to decide whether a baby should be screened for ROP, but some centres, especially in developing countrie
extend birth weight screening criteria to 1500 g (3.3 lbs).
Any premature baby with severe illness in perinatal period (Respiratory distress syndrome, sepsis, blood transfusion, Intra ventricular haemorrhage, apnoeic episodes, etc.) may also be offered ROP screening.
Timing
Retinal examination with scleral depression is generally recommended for patients born before 30–32 weeks
gestation
Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregna ...
, or 4–6 weeks of life, whichever is later. It is then repeated every 1–3 weeks until vascularization is complete (or until disease progression mandates treatment).
Procedure
Following
pupillary dilation
Pupillary response is a physiological response that varies the size of the pupil, via the optic and oculomotor cranial nerve.
A constriction response (miosis), is the narrowing of the pupil, which may be caused by scleral buckles or drugs such a ...
using eye drops, the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
is examined using a special lighted instrument (an
indirect ophthalmoscope). The peripheral portions of the retina are sometimes pushed into view using
scleral depression. Examination of the retina of a premature infant is performed to determine how far the retinal blood vessels have grown (the zone), and whether or not the vessels are growing flat along the wall of the eye (the stage). Once the vessels have grown into zoneIII (see below) it is usually safe to discharge the child from further screening for ROP. The stage of ROP refers to the character of the leading edge of growing retinal blood vessels (at the vascular-avascular border).
Monitoring
In order to allow timely intervention, a system of monitoring is undertaken for infants at risk of developing ROP. These monitoring protocols differ geographically because the definition of high-risk is not uniform or perfectly defined. In the USA the consensus statement of experts is informed by data derived by clinical trials and published in Pediatrics 2006. They included infants with birthweights under 1500 grams or under 30 weeks gestation in most cases. The first examination should take place within the first 4 weeks of birth, and regular, weekly examination is required until it is clear that the eyes are not going to develop disease needing treatment, or one or both eyes develop disease requiring treatment. Treatment should be administered within a 48 hours, as the condition can progress rapidly.
Management
Treatment
![Human eye cross section scleral buckle](https://upload.wikimedia.org/wikipedia/commons/4/43/Human_eye_cross_section_scleral_buckle.svg)
* Peripheral retinal ablation is the mainstay of ROP treatment. The destruction of the avascular retina is performed with a solid state
laser photocoagulation
Laser coagulation or laser photocoagulation surgery is used to treat a number of eye diseases and has become widely used in recent decades. During the procedure, a laser is used to finely cauterize ocular blood vessels to attempt to bring about var ...
device, as these are easily portable to the operating room or
neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
ICU.
Cryotherapy
Cryotherapy, sometimes known as cold therapy, is the local or general use of low temperatures in medical therapy. Cryotherapy may be used to treat a variety of tissue lesions. The most prominent use of the term refers to the surgical treatment, s ...
, an earlier technique in which regional retinal destruction was done using a probe to freeze the desired areas, has also been evaluated in multi-center clinical trials as an effective modality for prevention and treatment of ROP. However, when laser treatment is available, cryotherapy is no longer preferred for routine avascular retinal ablation in premature babies, due to the side effects of inflammation and lid swelling. Furthermore, recent trials have shown that treatment at an earlier stage of the disease gives better results.
*
Scleral buckling
A scleral buckle is one of several ophthalmologic procedures that can be used to repair a retinal detachment. Retinal detachments are usually caused by retinal tears, and a scleral buckle can be used to close the retinal break, both for acute an ...
and/or
vitrectomy
Vitrectomy is a surgery to remove some or all of the vitreous humor from the eye.
Anterior vitrectomy entails removing small portions of the vitreous humor from the front structures of the eye—often because these are tangled in an intraocular ...
surgery may be considered for severe ROP (stages4 and5) for eyes that progress to
retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...
. Few centers in the world specialize in this surgery, because of its attendant surgical risks and generally poor outcomes.
* Intravitreal injection of
bevacizumab
Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, l ...
(
Avastin
Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (Intravenous therapy, intravenous) and use ...
) has been reported as a supportive measure in aggressive posterior retinopathy of prematurity. In a 2011 clinical trial comparing bevacizumab with conventional laser therapy, intravitreal bevacizumab monotherapy showed a significant benefit for zoneI but not zoneII disease when used to treat infants with stage3+ retinopathy of prematurity. Potential benefits of intravitreal Avastin injection over laser therapy include: reduction in level of anesthesia required, preservation of viable peripheral retina, and, possibly, reduced incidence of subsequent high refractive error. However, the safety of this new treatment has not yet been established in terms of ocular complications as well as systemic complications. The latter are theoretically possible, as the active ingredient of bevacizumab not only blocks the development of abnormal blood vessels in the eye but may also prevent the normal development ofother tissues such as the lung and kidney. A 2018 Cochrane review also examined the effectiveness of
Anti-vascular Endothelial Growth Factor Drugs and their use for ROP.
* Oral propranolol is being evaluated for counteracting the progression of ROP, but safety is a concern. A prospective randomized trial in which pre-term newborns were randomized to receiving oral propranolol with standard treatment or standard treatment alone found that oral propranolol showed a 48% relative risk reduction for progression to stage3, 58% reduction for progression to stage3 plus, and 100% reduction for progression to stage4. Furthermore, there was a 52% relative risk reduction for the need for laser treatment or intravitreal bevacizumab. However 19% of the newborns experienced serious adverse effects including hypotension and bradycardia. A study in a mouse model of human ROP has shown that beta-blockade is protective against retinal angiogenesis and ameliorate blood-retinal barrier dysfunction.
Follow up
* Once diagnosed with ROP lifelong follow up (yearly) is performed in some centers. In others, only children treated for ROP are followed yearly.
* Follow up after laser or anti-VEGF treatment is individualized.
* Follow up of premature children (with or without ROP) is varying among centers and countries, mirroring the diverse states of health care system in different countries.
Prognosis
Stages 1 and 2 do not lead to blindness. However, they can progress to the more severe stages. Threshold disease is defined as disease that has a 50% likelihood of progressing to retinal detachment. Threshold disease is considered to be present when stage3 ROP is present in either zoneI or zoneII, with at least five continuous or eight total clock hours of disease, and the presence of ''plus'' disease. Progression to stage4 (partial retinal detachment), or to stage5 (total retinal detachment), will result in substantial or total loss of vision for the infant.
*
Refractive error
Refractive error, also known as refraction error, is a problem with focus (optics), focusing light accurately on the retina due to the shape of the human eye, eye and or cornea. The most common types of refractive error are myopia, near-sightedne ...
s including
myopia
Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...
(most common)
*
Squint
Squinting is the action of looking at something with partially closed eyes.
Squinting is most often practiced by people who suffer from refractive errors of the eye who either do not have or are not using their glasses. Squinting helps momentari ...
*
Amblyopia
Amblyopia, also called lazy eye, is a disorder of sight in which the brain fails to fully process input from one eye and over time favors the other eye. It results in decreased vision in an eye that typically appears normal in other aspects. Amb ...
*
Retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blin ...
, traction of the retina and
blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment†...
*
Glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
*Impairments in
visual acuity
Visual acuity (VA) commonly refers to the clarity of vision, but technically rates an examinee's ability to recognize small details with precision. Visual acuity is dependent on optical and neural factors, i.e. (1) the sharpness of the retinal ...
,
contrast sensitivity
Contrast is the contradiction in luminance or colour that makes an object (or its representation in an image or display) distinguishable. In visual perception of the real world, contrast is determined by the difference in the colour and brightn ...
,
visual field
The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments". Or simply, visual field can be defined as the entire area that can be seen when an eye is fixed straight at a point ...
, convergence, and
accommodation
Epidemiology
ROP prevalence varies, from 5 to 8% in developed countries with adequate neonatological facilities, to up to 30% in middle-income developing countries.
There is increasing evidence that ROP and blindness due to ROP are now public health problems in the middle income countries of Latin America, Eastern Europe and the more advanced economies in South East Asia and the Middle east region. In these countries ROP is often the most common cause of blindness in children.
ROP is highly likely to become an increasing problem in India, China and other countries in Asia as these countries expand the provision of services for premature infants.
There is also evidence that the population of premature infants at risk of severe ROP varies depending on the level of neonatal intensive care being provided.
[ In countries with high development indices and very low neonatal mortality rates (e.g. North America, Western Europe), severe ROP is generally limited to extremely preterm infants i.e. those weighing less than 1 kg (2.2 lbs) at birth. At the other end of the development spectrum, countries with very low development indices and very high neonatal mortality rates (e.g. much of subSaharan Africa) ROP is rare as most premature babies do not have access to neonatal intensive care and so do not survive. Countries with moderate development indices are improving access to neonatal intensive care, and in these settings bigger, more mature babies are also at risk of severe ROP as neonatal care may be suboptimal. These findings have two main implications: firstly, much can be done in countries with moderate development indices to improve neonatal care, to reduce the risk of severe ROP in bigger babies and increase survival of extremely preterm infants, and secondly, in these settings bigger more mature babies need to be included in ROP programs and examined regularly so as to detect those babies developing ROP requiring treatment.
In 2012, the World Health Organization published data on rates of preterm birth and the number of premature babies born in different regions of the world. This report contained three main findings:
* Premature birth has many different causes, and prevention is challenging,
* Prematurity is the most common cause of neonatal death in many countries, totaling as many as 1 million infants annually due to complications of preterm birth, and
* the number of preterm births is currently estimated to be 15 million, and increasing.
]
History
This disease was first described in a premature baby in 1942 as reported by Theodore L. Terry. Between 1941 and 1953, over 12,000 babies worldwide were affected by it. However, Dr Kate Isabel Campbell (1889-1986), a specialist in children's diseases, was actually responsible in 1951 for proving the link between retrolental fibroplasia (a blindness in premature babies) and oxygen levels in humidicribs.
Soul musician Stevie Wonder
Stevland Hardaway Morris ( Judkins; May 13, 1950), known professionally as Stevie Wonder, is an American singer-songwriter, who is credited as a pioneer and influence by musicians across a range of genres that include rhythm and blues, Pop musi ...
, actor Tom Sullivan, and jazz singer Diane Schuur
Diane Joan Schuur (born December 10, 1953), nicknamed "Deedles", is an American jazz singer and pianist. As of 2015, Schuur had released 23 albums, and had extended her jazz repertoire to include essences of Latin, gospel, pop and country music ...
are a few famous people who have the disease. The first case of the epidemic was seen on St. Valentine's Day in 1941 when a premature baby in Boston was diagnosed. Cases were then seen all over the world and the cause was, at that point, unknown. By 1951 a clear link between incidence and affluence became clear: many cases were seen in developed countries with organized and well-funded health care. Two British scientists suggested that it was oxygen toxicity that caused the disease. Babies born prematurely in such affluent areas were treated in incubators which had artificially high levels of oxygen. Studies on rats made this cause seem more likely, but the link was eventually confirmed by a controversial study undertaken by American pediatricians. The study involved two groups of babies. Some given the usual oxygen concentrations in their incubators, while the other group had "curtailed" oxygen levels. The latter group was shown to have a lower incidence of the disease. As a result, oxygen levels in incubators were lowered and consequently, the epidemic was halted. Each case of ROP avoided by withholding oxygen "may have cost some 16 deaths".
References
External links
Retinopathy of Prematurity
Resource Guide from the National Eye Institute (NEI).
World ROP Congress
Archives of the International Conferences on ROP.
{{Eye pathology
Blindness
Disorders of choroid and retina
Neonatology
Preterm birth