Clinical Symptoms

• Decreased vision in one or both eyes.

Clinical Signs

• Reduced best-corrected visual acuity in one or both eyes in the absence of ocular disease and in the presence of an amblyogenic factor.
• Abnormal contour interaction (crowding phenomenon) in the amblyopic eye.
• Eccentric fixation (usually associated with strabismic amblyopia).
• Decreased contrast sensitivity in the amblyopic eye.
• Binocular suppression of the amblyopic eye.
• Reduced accommodative response in the amblyopic eye.
• Mild afferent pupillary defects have also been reported in some severely amblyopic eyes.

Demographics

Amblyopia occurs in 2% to 4% of the general population. Amblyopia is the most common visual disability in children, with approximately 120,000 children diagnosed per year in the United States. Amblyopia is the leading cause of monocular vision loss in the 20- to 70-year age group.

Significant History

• A history of “lazy eye,” misaligned eyes, uncorrected ametropia, extraocular muscle surgery, occlusion therapy, or other vision therapy may be elicited.

Ancillary Tests

A thorough eye examination is indicated with particular attention to best-corrected visual acuity, binocularity, cycloplegic retinoscopy/refraction, and ocular health. Visuoscopy is a useful ancillary test to determine the presence or absence of eccentric fixation.

The Treatment

Strabismic Amblyopia

Isoametropic Amblyopia

• Optical correction of ametropia based on cycloplegic retinoscopy/refraction.
• Follow up in approximately 4 weeks.
• If necessary, make any changes to the prescription.
• Follow every 4 to 6 months to monitor acuity improvement.
• Patching or penalization is necessary only in cases of asymmetric aided acuity.

Anisometropic Amblyopia

• Optical correction of ametropia based on cycloplegic retinoscopy/refraction.
• Part-time, direct, full occlusion for 2 to 6 h/d for mild to moderate amblyopia, with the possible need for increased hours for deep amblyopia.
• Penalization with 1% atropine may be used instead of traditional occlusion for mild to moderate amblyopia.
• Active monocular visual activities for 30 to 60 min/d while occluded. Once visual acuity in the amblyopic eye reaches 20/40–50, consider the addition of binocular vision therapy to break down remaining suppression.
• Follow up every 4 to 6 weeks.

Deprivation Amblyopia

• Remove the obstruction of the visual axis promptly, ideally within 2 months of onset.
• Correct any significant ametropia or aphakia.
• Part-time, direct, full occlusion for 2 to 6 h/d for mild to moderate amblyopia, with the possible need for increased hours for deep amblyopia.
• Penalization with 1% atropine may be used instead of traditional occlusion for mild to moderate amblyopia.
• Active monocular visual activities for 30 to 60 min/d while occluded.
• Follow up every 4 to 6 weeks.

Esodeviations

Suzanne M. Wickum

ICD-9: 378.00—ESOTROPIA, UNSPECIFIED

ICD-9: 378.01—ESOTROPIA, MONOCULAR

ICD-9: 378.02—ESOTROPIA, MONOCULAR WITH “A” PATTERN

ICD-9: 378.03—ESOTROPIA, MONOCULAR WITH “V” PATTERN

ICD-9: 378.04—ESOTROPIA, MONOCULAR WITH OTHER NONCOMITANCY

ICD-9: 378.05—ESOTROPIA, ALTERNATING

ICD-9: 378.06—ESOTROPIA, ALTERNATING WITH “A” PATTERN

ICD-9: 378.07—ESOTROPIA, ALTERNATING WITH “V” PATTERN

ICD-9: 378.08—ESOTROPIA, ALTERNATING WITH OTHER NONCOMITANCY

ICD-9: 378.21—ESOTROPIA, INTERMITTENT, UNILATERAL

ICD-9: 378.22—ESOTROPIA, INTERMITTENT, ALTERNATING

ICD-9: 378.35—ESOTROPIA, WITH ACCOMMODATIVE COMPONENT

     THE DISEASE

Pathophysiology

Esodeviations present with an intermittent or constant inward eye turn resulting in convergent visual axes.

Etiology

Innervational, accommodative, genetic, and environmental factors play a role in the development of esotropia.

The Patient

Clinical Symptoms

• Patients may report diplopia, asthenopia, and/or blurred vision.

Esotropia Classification and Characteristics

Infantile Esotropia

• Clinical characteristics: Onset occurs between birth and 6 months of age. Esotropia is constant, comitant (A or V patterns may be present), moderate to large magnitude (30 to 70 prism diopters), and cross-fixation is common. The accommodative-convergence accommodation (AC/A) ratio is usually normal. Ametropia is skewed toward low hyperopia. Sensory adaptations are present in 35% to 72% of cases. Dissociated vertical deviation is present in 50% to 75% of cases. Overaction of the inferior oblique muscle is present in 68% of cases. Latent or manifest-latent nystagmus is found in 25% to 52% of cases.

Accommodative Esotropia

Refractive Accommodative Esotropia

Nonrefractive Accommodative Esotropia

• Clinical characteristics: The characteristics are the same as refractive accommodative esotropia with a few exceptions. The AC/A ratio in this case is high, and thus the near angle is larger than distance. The average ametropia is +2.25 D, but any refractive error can be found. The etiology in this case is the high AC/A ratio; therefore, esotropia typically responds to plus lenses at near.

Partially Accommodative Esotropia

• Clinical characteristics: The characteristics are the same as refractive accommodative esotropia with a few exceptions. Esotropia is constant; therefore, sensory adaptations are likely. The AC/A ratio is normal or high. Typically, there is moderate to high hyperopia present. Esotropia magnitude decreases, but is not eliminated, with the hyperopic correction.

Nonaccommodative Acquired Esotropia

• Clinical characteristics: Onset occurs after 6 months of age. Esotropia is typically constant, comitant (A or V patterns may be present), and of moderate to large magnitude (20 to 70 prism diopters), and sensory adaptations may occur. Often, some amount of hyperopia is present. Causes include idiopathic, decompensated esophoria; disruption of fusion by occlusion; physical/emotional stress; and rarely CNS pathology.

Basic Esotropia

• This is the most common subcategory. The AC/A ratio is normal. The refractive error is usually insignificant.

Divergence Insufficiency Esotropia

• The AC/A ratio is low, and thus the distance magnitude is greater than near. Divergence paralysis, which originates from a midbrain lesion, must be ruled out. Divergence paralysis initially presents as a noncomitant esotropia that shows spread of comitancy.

Acute Esotropia

• Diplopia is likely. Some patients may close or wink one eye to alleviate the diplopia.

Sensory Esotropia

• Onset may occur at any age. Deviation is constant, comitant, and unilateral, and the magnitude is often variable. The strabismus is secondary to significantly reduced visual acuity, resulting in a sensory obstacle to fusion. Visually depriving factors may include uncorrected anisometropia, ptosis, corneal opacities, cataracts, optic nerve lesions, or retinal lesions. Sensory esotropia is as frequent as sensory exotropia in children under 6 years of age; however, sensory exotropia predominates in older children and adults.

Microtropia

Clinical Characteristics

Incomitant Esotropia

Abducens Nerve Palsy (Sixth Cranial Nerve Palsy)

Exodeviations

Suzanne M. Wickum

ICD-9: 378.10—EXOTROPIA, UNSPECIFIED

ICD-9: 378.11—EXOTROPIA, MONOCULAR

ICD-9: 378.12—EXOTROPIA, MONOCULAR WITH ‘A’ PATTERN

ICD-9: 378.13—EXOTROPIA, MONOCULAR WITH ‘V’ PATTERN

ICD-9: 378.14—EXOTROPIA, MONOCULAR WITH OTHER NONCOMITANCY

ICD-9: 378.15—EXOTROPIA, ALTERNATING

ICD-9: 378.16—EXOTROPIA, ALTERNATING WITH ‘A’ PATTERN

ICD-9: 378.17—EXOTROPIA, ALTERNATING WITH ‘V’ PATTERN

ICD-9: 378.18—EXOTROPIA, ALTERNATING WITH OTHER NONCOMITANCY

ICD-9: 378.23—EXOTROPIA, INTERMITTENT, UNILATERAL

ICD-9: 378.24—EXOTROPIA, INTERMITTENT, ALTERNATING

     THE DISEASE

Pathophysiology

Exodeviations present as an intermittent or constant outward eye turn resulting in divergent visual axes. Deviation often begins as an exophoria and over time becomes an intermittent exotropia. When left untreated, an intermittent exotropia may progress to a constant exotropia.

Etiology

Innervational, mechanical/anatomic, and multifactorial genetic inheritance patterns have all been implicated in the development of exotropia.

The Patient

Clinical Symptoms

• Patients may complain of asthenopia, squinting, photophobia, unilateral eye closure, diplopia, and/or blurred vision.

Exotropia Classification and Characteristics

Primary Comitant Exotropia

Clinical Characteristics

Infantile Exotropia

Clinical Characteristics

• A rare type of exotropia occurring in approximately 1/30,000 births. Onset occurs between birth and 6 months of age. Deviation is constant, moderate to large (30 to 90 prism diopters), and comitant with possible A or V patterns if superior or inferior oblique overactions are present. Sensory adaptations are likely. Infantile exotropia may occur in otherwise healthy infants but is typically associated with other ocular disorders, neurologic disease, craniofacial syndromes, and genetic syndromes.

Sensory Exotropia

Clinical Characteristics

• Onset may occur at any age. Deviation is constant, unilateral, and comitant, and the magnitude is often variable. The strabismus is secondary to significantly reduced visual acuity, resulting in a sensory obstacle to fusion. Visually depriving factors may include uncorrected anisometropia, ptosis, corneal opacities, cataracts, optic nerve lesions, or retinal lesions. Sensory exotropia is as frequent as sensory esotropia in children under 6 years of age; however, sensory exotropia predominates in older children and adults.

Oculomotor Nerve Palsy (Third Cranial Nerve Palsy)

Clinical Characteristics

Ancillary Tests

A thorough ocular examination is indicated in all strabismic patients. Careful refractive error and visual acuity measurements should be performed to evaluate for amblyopia. Visuoscopy can be utilized to measure eccentric fixation. Measurement of the exotropia including frequency, laterality, magnitude, and comitancy is essential. Evaluation of ocular motility and near point of convergence is necessary. In cases of intermittent exotropia, base-out (compensating) vergence ranges should be measured, and sensory-motor fusion should be assessed (Worth-dot/stereopsis). Subjective assessment of the deviation is performed with tests such as Maddox rod and Bagolini lenses. The subjective angle of deviation is then compared to the objective angle of deviation to determine the presence/absence of anomalous correspondence. Cycloplegic retinoscopy/refraction is recommended in all strabismic patients. A thorough ocular health examination is necessary to rule out causes of sensory deprivation.

The Treatment

• For all classifications of exotropia, the initial treatment should include correcting significant refractive error and treating amblyopia.
• Minus lenses may be used full-time as a passive therapy for young children or may be utilized during vision therapy sessions for older children and adults.
• Relieving or correcting prism (base-in) may be used as an individual treatment or may be combined with vision therapy.
• Vision therapy can be utilized in some cases of exotropia. The therapy begins by increasing the patient’s gross convergence ability, thus normalizing the near point of convergence. Next, sensory-motor fusion is trained with the goal of expanding the patient’s positive fusional vergence range so as to compensate for the exotropia. Therapy techniques that enhance diplopia awareness and break suppression are recommended.
• Surgery is utilized in moderate- to large-angle exotropia. In cases of intermittent exotropia, many surgeons recommend that surgery be delayed until 4 years of age, unless the frequency of the exotropia is increasing. In the case of constant exotropia, surgery should be performed much earlier.
• Utilizing vision therapy before and/or after surgery improves the chances for functional binocular vision.
• For cases of sensory exotropia, the treatment is different. First, the underlying cause of the reduced acuity must be addressed. Any significant ametropia should be corrected, and all patients should be given protective glasses for full-time wear. If superimposed amblyopia is suspected, treatment should be implemented. If improved ocular alignment is desired, strabismus surgery may be performed.

Strabismus Syndromes

Suzanne M. Wickum

ICD-9: 378.71—DUANE RETRACTION SYNDROME

ICD-9: 378.61—BROWN’S SYNDROME

ICD-9: 352.6—MOBIUS SYNDROME

ICD-9: 378.62—EYE MUSCLE FIBROSIS

DUANE RETRACTION SYNDROME (DRS)

     THE DISEASE

Pathophysiology

Etiology

Although there have been many theories regarding the etiology of DRS, the most widely accepted theory involves innervational and central nervous system anomalies. It has been found that the abducens nucleus and nerve are absent or hypoplastic, resulting in limited or absent abduction. Additionally, there is anomalous innervation of the lateral rectus muscle by branches of the oculomotor nerve.

Most cases of DRS are sporadic; however, familial cases have been reported to occur in 5% to 23% of patients. The inheritance pattern is autosomal dominant with incomplete penetrance and variable expressivity. Since DRS is associated with a 10 to 20 times increase in frequency of other congenital ocular and nonocular anomalies, there is speculation that a teratogenic event may take place somewhere between the 4th and 10th week of gestation in sporadic cases.

The Patient

Clinical Symptoms

Because of the young age at diagnosis, the patient will not be symptomatic; however, the parents may report that the child has an eye turn, abnormal face turn, and/or abnormal eye movements.

Clinical Signs

DRS is divided into three categories. Each type has the common characteristics of globe retraction and narrowing of the palpebral fissure on adduction, as well as upshoots or downshoots on attempted adduction.

DRS type I characteristics: Esotropia or heterophoria are common in primary gaze, but exotropia is possible. There is marked limitation of abduction with no/minimal limitation of adduction. The child may adopt a face turn in the direction of the abduction deficit in order to maintain binocularity.

DRS type II characteristics: Exotropia is frequently observed in primary gaze. There is marked limitation of adduction with no/minimal limitation of abduction. The child may adopt a face turn in the direction of the adduction deficit in order to maintain binocularity.

DRS type III characteristics: Exotropia is frequently observed in primary gaze. There is combined limitation of abduction and adduction. Face turns are variable.

Demographics

Duane retraction syndrome is the most common of all congenital oculomotor anomalies and accounts for 1% to 4% of strabismus cases. While there is no racial predilection, there is a slight preponderance for females (55% to 60% of cases). The left eye is affected in approximately 60% of cases, the right eye in 22%, and bilateral in 18%. DRS type I is the most common (78%), followed by DRS type III (15%) and DRS type II (7%).

Significant History

• Age of onset
• Positive family history of ocular motility restriction/strabismus
• Presence of diplopia (DRS patients rarely report diplopia)

Ancillary Tests

The Treatment

Surgery is utilized to improve unacceptable face turns, correct significant ocular misalignment in primary gaze, reduce severe globe retraction, and improve the appearance of upshoots and downshoots. It must be stressed that surgery may improve, but will not eliminate, the abnormal eye movements. For patients who are not good surgical candidates but who have asthenopia, vision therapy and/or prism can be beneficial.

BROWN’S SYNDROME (SUPERIOR OBLIQUE TENDON SHEATH SYNDROME)

     THE DISEASE

Pathophysiology

Brown’s syndrome is typically a congenital ocular motility disorder, although acquired forms are possible. The syndrome is primarily characterized by deficient elevation in adduction.

Etiology

In congenital Brown’s syndrome, the motility deficiency is constant and not likely to resolve. The motility deficiency is a result of a short or inelastic superior oblique tendon or because of a limitation of the tendon to slide through the pulley-like trochlea. Most cases of congenital Brown’s syndrome are sporadic; however, familial cases have been reported. The inheritance pattern is autosomal dominant with incomplete penetrance and variable expressivity.

In acquired Brown’s syndrome, the motility deficiency may be constant or intermittent and may resolve over time. This syndrome may be caused by surgical procedures including strabismus surgery, sinus surgery, blepharoplasty, and scleral buckling. Brown’s syndrome is also associated with inflammatory disorders such as rheumatoid arthritis, sinusitis, and metastasis in the area of the trochlea. Trauma may also give rise to Brown’s syndrome.

The Patient

Clinical Symptoms

Patients may complain of pain or tenderness in between their eyes (in the area of the trochlea), especially during up gaze movements. Some patients may also report an audible “clicking” noise as they look up. Additionally, patients may complain of diplopia, particularly in up gaze.

Clinical Signs

There is limitation or absence of elevation in adduction with normal/near normal elevation in midline and abduction. Hypotropia of the involved eye may be found in primary gaze. Divergence occurs in up gaze, causing a V-pattern deviation. Downshoots on adduction are possible. There is minimal or no superior oblique overaction of the ipsilateral eye. Patients may adopt a compensatory chin-up head posture to preserve binocularity and/or eliminate diplopia.

Demographics

Brown’s syndrome occurs in less than 1% of strabismus patients. It has been estimated to occur in 1/20,000 live births. This condition does not show any gender or racial predilection. Brown’s syndrome is found unilaterally in 90% of cases and bilaterally in 10% of cases.

Significant History

Ancillary Tests

Evaluation of ocular misalignment, abnormal head posture, range of extraocular motility, and observation of downshoots are important. Additionally, forced ductions are useful in confirming the restrictive nature of this syndrome.

The Treatment

In many cases of Brown’s syndrome, observation and patient/parent education are all that are necessary. This is particularly true in mild cases with preserved binocularity in primary gaze and without an anomalous head posture. Indications for surgical intervention include hypotropia present in primary gaze, significant anomalous head posture, and/or unacceptable downshoots of the involved eye. In inflammatory cases, steroids administered orally or locally are useful.

MOBIUS SYNDROME

     THE DISEASE

Pathophysiology

Mobius’ syndrome consists of congenital facial diplegia and bilateral abducens nerve palsies. Systemic abnormalities and other cranial nerve palsies may also be present.

Etiology

The exact pathogenesis of Mobius syndrome is uncertain; however, the timing of the syndrome seems to be well defined. A pathologic insult takes place during the first trimester, typically between the fourth to sixth week of gestation, when the cranial nerve nuclei are undergoing rapid development. Trauma, illness, and maternal ingestion of certain medications have been associated with this syndrome. In more recent years, a vascular etiology of Mobius syndrome has been implicated. The vascular insult leads to hypoxia and ischemia of the cranial nerve nuclei.

While the majority of Mobius syndrome cases are sporadic, there have been case reports of pedigrees demonstrating autosomal dominant, autosomal recessive, and X-linked inheritance.

The Patient

Clinical Symptoms

Symptoms present in infancy and include difficulty sucking, excessive drooling, lack of facial expression, and lagophthalmos. Parents may also report crossed eyes and tracking problems.

Clinical Signs

Common ocular signs include esotropia, bilateral abduction deficits, lagophthalmos, and exposure keratitis. Additional ocular or orbital signs have been noted, including hypertelorism, epicanthal folds, small palpebral fissures, ptosis, and entropion. Abnormalities of the extremities, swallowing and speech difficulties, craniofacial abnormalities, defective brachial musculature, tongue hypoplasia, and mental retardation have all been reported as well.

Demographics

Mobius syndrome is very rare. No racial or gender predilections have been reported.

Significant History

• Trouble with sucking/feeding
• Eyes partially open when sleeping
• Presence of photophobia
• Problems with facial expression

A complete eye examination is necessary, with special attention to eye alignment, extraocular motility, lagophthalmos, and exposure keratitis. When esotropia is present, one must also evaluate the patient for amblyopia. Because of the frequently associated systemic anomalies, the patient should also have a complete physical examination with a pediatrician.

The Treatment

Ocular management includes correcting significant refractive error, providing therapy for amblyopia, considering strabismus surgery when significant esotropia is present, and treating keratitis associated with lagophthalmos. A pediatrician should manage any systemic anomalies.

CONGENITAL FIBROSIS OF THE EXTRAOCULAR MUSCLES (CFEOM)

     THE DISEASE

Pathophysiology

CFEOM is a rare disorder characterized by congenital restrictive ophthalmoplegia.

Etiology

CFEOM is typically a familial disorder inherited in an autosomal dominant pattern with significant variability in expression; however, cases of autosomal recessive inheritance as well as sporadic cases have been reported. Original reports describe CFEOM as having a myogenic origin. More recent reports indicate a primary neurogenic etiology that leads to subsequent degeneration of muscle fibers.

The Patient

Clinical Symptoms

Because of the young age at diagnosis, the patient will not be symptomatic; however, parents will report that the child has abnormal eye movements, abnormal eye alignment, ptosis, and/or an abnormal head posture.

Clinical Signs

Traditionally, this syndrome has been divided into five categories based on slight clinical differences. The general fibrosis syndrome is characterized by bilateral restriction of all of the extraocular muscles. The inferior rectus shows greatest involvement, thus causing the eyes to be fixed approximately 20 to 30 degrees below midline. As a result of the bilateral hypotropic eye position combined with bilateral ptosis, the patient will adopt a chin-up head position. Congenital fibrosis of the inferior rectus with blepharoptosis is a variant of CFEOM in which the inferior rectus is affected with little to no involvement of the other extraocular muscles. In cases of strabismus fixus, the eyes are fixed in either an esotropic or exotropic position with severe limitation of horizontal eye movements. The vertical eye movements are usually intact. In contrast, cases of vertical retraction syndrome demonstrate severely impaired vertical eye movements with relatively intact horizontal movements. Lastly, a unilateral fixed globe characterizes congenital unilateral fibrosis.

More recently, a revised classification has been proposed based on the identification of three CFEOM genetic loci. Patients with CFEOM1, mapped to chromosome 12, have the features of general fibrosis syndrome as listed above. Cases with CFEOM2, mapped to chromosome 11, present with exotropic strabismus fixus. Patients with CFEOM3, mapped to chromosome 16, present with variable expression of ptosis and restrictive ophthalmoplegia.

Demographics

Significant History

• Age of onset
• Positive family history of similar ocular motility restrictions and ptosis

Ancillary Tests

Forced duction testing is useful in confirming the restrictive nature of this condition. Orbital imaging such as computed tomography or magnetic resonance imaging may be of benefit. Imaging studies may show extraocular muscle atrophy, abnormal insertion, or absence.

The Treatment

Treatment for CFEOM is primarily surgical; however, proper refractive correction and treatment of amblyopia should be done prior to surgical intervention.

Leukocoria

Suzanne M. Wickum

ICD-9: 360.44

     THE DISEASE

Pathophysiology

Leukocoria literally means white pupil. Leukocoria itself is not a specific diagnosis, but rather a clinical finding suggestive of intraocular pathology. When an ocular condition disrupts light from striking the retina, a whitish reflex, rather than the usual red, will be evident in the pupil.

Etiology

The Patient

Clinical Symptoms

Clinical symptoms will vary based on the specific etiology. Parents and/or the patient will complain of a white pupil and possibly reduced vision and/or an eye turn.

Clinical Signs

The clinical signs will vary based on the specific etiology. (See characteristics described earlier.)

Significant History

• Age of onset
• Prematurity and/or low birth weight (LBW)
• Metabolic disorders or other systemic disorders/syndromes
• Maternal infection during pregnancy
• Contact with puppies, eating dirt, or playing in a sandbox
• Positive family history of one of the conditions listed here

Ancillary Tests

Additional tests that may be useful in diagnosis include the following:

• B-scan ultrasound (cataract, PHPV, retinoblastoma, RD)
• Serum ELISA test (toxocariasis)
• Anterior chamber paracentesis (toxocariasis)
• Fluorescein angiography (Coats’ disease, retinoblastoma, ROP)
• CT scan and/or MRI of the orbits and brain (Coats’ disease, retinoblastoma)
• Systemic examination (retinoblastoma, congenital cataract)

The Treatment

• Cataracts: Treat any underlying systemic/metabolic conditions. For visually significant cataracts, surgical intervention and aggressive visual rehabilitation are necessary.
• Retinoblastoma: Treatment options include enucleation, external-beam radiation, cryotherapy, laser photocoagulation, brachytherapy, thermotherapy, or chemotherapy.
• Coats’ disease: Laser photocoagulation and/or cryotherapy to the leaking vessels. Surgical intervention is necessary if an RD develops.
• PHPV: Treatment may include cataract extraction and possible fibrovascular vitreal membrane extraction. Aggressive visual rehabilitation should begin after surgery.
• ROP: Treatment options include laser photocoagulation and cryotherapy. Additional surgical intervention is necessary if an RD develops.
• Toxocariasis: Recommended treatment includes oral thiabendazole plus prednisone. Photocoagulation or cryocoagulation may be used to destroy the organism if it is outside the foveal area. Surgery is necessary if tractional RDs occur.
• RD: Laser, cryotherapy, scleral buckling, or vitrectomy is required.
• Coloboma of the retina and choroid: Specific treatment of the coloboma is not necessary; however, if an RD develops, surgical intervention is required.
• Myelinated nerve fiber: No treatment is needed for this benign condition.

Retinopathy of Prematurity

Suzanne M. Wickum

ICD-9: 362.21

     THE DISEASE

Retinopathy of prematurity (ROP) is a proliferative vasculopathy affecting premature and primarily low birth weight (LBW) infants. Complications include fibrovascular proliferation and scarring, retinal detachment (RD), vitreous hemorrhage, retinal dragging and macular distortion, leukocoria, myopia, strabismus, and vision impairment/blindness.

Pathophysiology

• ROP development has two phases:

Initial Phase

• Exposure to oxygen after premature birth causes marked constriction of the fragile new retinal vessels. This may represent exaggerated autoregulation, but it compromises retinal perfusion by inhibiting vascular endothelial growth factor (VEGF) and other necessary growth factors.
• VEGF paradox: It is required for normal function but plays an important role in the development of retinovascular disease. Different VEGF isoforms subserve different functions.
• VEGF properties: It stimulates angiogenesis, is a potent inducer of vascular permeability, and is proinflammatory. It is secreted by the retina and retinal pigment epithelium, with increased synthesis induced by ischemia. Conversely, hyperoxia inhibits VEGF synthesis. VEGF has high endothelial cell affinity.
• During the initial phase of ROP, the choroidal circulation plays an important role as, unlike the retinal vessels, the choroidal vessels lack autoregulation and do not constrict in response to elevated oxygen tension. As a result, oxygen moves from the choroidal to the retinal circulation, further aggravating the VEGF inhibition and obliteration of the immature retinal vessels. This may explain why excess oxygen administration exacerbates ROP early on.
• The initial downregulation of VEGF leads to irreversible capillary endothelial cell destruction in affected areas. This results in ischemia of the portion of the retina in the avascular zone and sets the stage for the second phase of ROP development.

Second Phase

• The second phase of ROP development is initiated by the increased metabolic demands of the neural elements of the retina at the same time that marked ischemia has developed in the avascular periphery.
• This results in a marked increase in VEGF production and its effects on angiogenesis and permeability. The severity of this response depends on the extent of avascular retina in any given eye.
• As there has been irreversible destruction of the normal vascular element at the leading edge of the developing retina, the huge upregulation in VEGF stimulates the formation of neovascularization. The growth of these vessels occurs in an uncontrolled fashion.
• This explains why supplemental oxygen may actually be beneficial in this phase, as the oxygen has a downregulating effect on VEGF.
• Selective VEGF blockade will likely play a role in future ROP treatment strategies.
• Cytotoxic effects of oxygen-induced free radicals also play a role in ROP, particularly in very low birth weight (VLBW) infants. Immature retinal vessels lack efficient antioxidative systems.
• If normal retinal vascularization has completed, the vessels are not susceptible to ROP.

Classification of ROP

• The International Classification of Retinopathy of Prematurity (ICROP) was developed in the early 1980s. The scheme is based on the posterior extent of the avascular retina (Zone) and the severity of the retinopathy (Stage). Another important component is the presence or absence of “plus” disease.

Zone