Lieukokoria literally means white pupil and is generally interpreted as being pathologic by the medical observer, regardless of the cause. Because it is not normal, and is viewed in such an ominous light, further investigation is required.
When a pediatrician examines a child he often shines a white light into the patient's eyes along the pupillary axis and observes the color of the reflected light filling the pupillary space. Normally the ingoing beam passes through clear cornea, aqueous humor, pupil, lens, vitreous and retina to strike the vascular choroid. Because of its high degree of vascularity the beam of light picks up the red color and is reflected out of the eye. taking a reverse path through the same structures to exit through the pupil and the cornea as an observed "normal red reflex. " Such an observation is comforting, but should not be relied upon as a guarantee of a normal eye examination. Any lesion not directly in the path of the ingoing beam would not interfere with the formation of a red reflex, and hence would be left undiagnosed. Such serious conditions as tumors, retinal detachments, retinal hemorrhages, intraocular formed bodies and many others may be missed.
Most ominous among the causes of leukokoria is the potential diagnosis of a retinoblastoma, a fatal malignancy if left undiagnosed. Table I lists the causes of leukokoria.
Cataracts are still the most common cause of leukokoria. A cataract represents any opacity of the crystalline lens of the eye. The lens is formed from surface ectoderm cells of the developing fetus. Having invaginated and separated from the surface, a spherical developing lens is present. The posterior fibers elongate and fill the lens. The anterior fiber cells continue to divide and elongate on the surface to lay down layer upon layer of new lens material in a fusiform-shaped cell, this process continuingthroughout life. Any physical or chemical agent that damages these cells may cause an opacity, or cataract to develop. This varies from a contusion injury to radiation and from chemicals and medicines to infections and inherited causes.1 LeFevre and Merlen estimate an observed incidence of 0.04% of cataracts noticed on casual inspections at birth.2 An incidence of 1 1 cataracts in 2500 live births was noted in a study of newborns (0.44%). Ina series of children treated with total parenteral nutrition, an incidence of slightly less than 1% was recorded (unpublished data, 1982). This latter finding has since been observed by others.3
Table 2 lists some causes of congenital cataracts. It is important to note that 50% to 60% of cataracts in children are idiopathic. Put in another way, approximately half of these cases have diagnosable and potentially treatable causes. For this reason, if for none other, it behooves the practitioner to examine these patients in conjunction with other pediatric specialists- ophthalmologists, endocrinologists, nephrologists, geneticists, etc.
ETIOLOGY OF LEUKOKORIA
PERSISTENT HYPERPLASTIC PRIMARY VITREOUS
The vitreous humor (or jelly) of the eye is formed in three successive phases - primary, secondary and tertiary. The primary vitreous is formed during the first and second months of embryogenesis and originates from ectodermal and mesodermal cells in the cavity of the optic cup. Us structure includes both vessels and fibrillar strands. This causes it to be less optically clear than its successor in the normal eye, the secondary vitreous. This secondary vitreous represents the vitreous, as we usually refer to it. in a mature eye. The tertiary vitreous is formed as the suspensory zonules of the lens.
If the primary vitreous fails to regress and allow the secondary vitreous to fill the cavity, the entity of a persistent hyperplastic primary vitreous (PHPV) is present. PHPV is usually present at birth in full-term infants, is unilateral 90% of the time and presents as a retrolental white fibrovascular mass a leukokoria (Figure I ). Only with the aid that the slit lamp microscope affords can a PHPV be differentiated from other causes of leukokoria. If viewed closely as the disease progresses, the finger-like processes of the peripherally located ciliary body can be seen being pulled into the center of the fibrovascular mass, directly behind the lens. This is a most helpful diagnostic point. As the fibrovascular tissue extends into the lens through a posterior defect, the lens itself may become opaque, thus causing a secondary cataract. It is important to note that PHPV is most often unilateral, in a small eye. and present at birth. When bilateral, PHPV has been associated with trisomy 13-15.4
Figure 1. Persistent hyperplastic primary vitreous.
PHPV has come to be held as a surgically treatable condition if seen and diagnosed early, before retraction of the fibrous mass causes irreparable damage to the internal eye. If one delays too long, surgery is no longer effective, and the eye is lost. Modern-day microsurgical techniques allow excision of the fibrovascular retrolental membrane and return of a clear pupillary opening. Once removed, PHPV does not recur.
RETROLENTAL FIBROPLASIA (RLF)
Retrolental fibroplasia remains in our midst today just as it has since first described by Terry in 1 942/ At that time it was confused with retinal dysplasia, a condition which it may mimic in later stages. In the early 1940s the use of high concentrations of oxygen to treat premature infants and newborns with respiratory difficulty became generally accepted. In the following decades, increasing numbers of children were noted who had developed a gray-white vascularized retrolental membrane who had been born prematurely and exposed to high oxygen concentrations. A significant percentage of these children became visually impaired. In the 1950s it was estimated that 50% of those children below the age of seven who had been institutionalized for blindness had retrolental fibroplasia. Since then, many studies have been completed implicating oxygen as a causative or contributing agent in the development of RLF. This led to the belief that high oxygen concentrations, the duration of its administration and the degree of prematurity were all related in causing this devastating condition. Further research, however, has brought to light that the situation is not quite so simple. Cases have been documented in which retrolental fibroplasia developed in full-term infants who had received no oxygen therapy.
Anatomically, retrolental fibroplasia passes through three basic stages- an initial vascular stage, a second stage of regression or possibly a third phase of cicatrical distortion of the internal eye. In the first stage, blood vessels initially constrict and may in two or three weeks become irreversibly constricted. This is a very difficult sign to see clinically, though physiologically it does occur. Many children have been observed in intensive care nurseries while under high oxygen therapy and no vascular changes could be seen using indirect ophthalmoscopy. A more clinically noticeable sign is the sequential phase of the retinal vascular dilatation ( Figure 2). This is prominent first in the periphery of the retina and usually occurs following longer periods of stress. The retinal arteries may become dilated and demonstrate a more tortuous serpentine path. New vessel growth, neovascularization, is seen to develop in the peripheral retina. The surrounding retina becomes grey and hazy. Fine vascular strands proliferate from the retina, growing into the vitreous body proper. Here they detract from the avascular optical clarity of the structure. As these vessels continue to grow, several findings become manifest. These new vessels are very delicate and easily ruptured, causing both retinal and vitreous hemorrhage. Blood is irritating and ultimately leads to a reactive fibrosis. As this Fibrous tissue contracts with time, increased traction may be placed upon the retina and on other surrounding blood vessels. A detached retina may occur, or more blood vessels may be sheared, worsening the hemorrhage and adding to the vicious cycle. The retinal vessels growing in the periphery, once thought to represent a "brush border" of neovascularization, are now realized to be a patent mesenchymomal channel, on the periphery of which is nonvascularized poorlv developed retina ( Figure 3).
Figure 2. Retrolental fibroplasia-vascular tortuosity.
Once the active phase is begun, there are no absolute clues which allow prediction of its final outcome. It is possible, and usually is the case, that the active phase becomes stabilized. This is then referred to as a regressed stage. The fact that the active stage may continue, even though such classically inciting agents as oxygen are discontinued, lends credence to the belief that other factors are involved. Approximately one-third of patients do not progress beyond the active phase, and one-third do not progress past the regressive stage. Those patients developing severe and rapid changes early in the disease process are more likely to progress to an end stage scarred and distorted retina. Such a case has been observed to occur over a ten-day period in a severely ill premature infant.
The third and most destructive stage is a cicatrical stage revealing a pale fundus with blood vessels of reduced caliber and having lost their normal arched pathway.
There are scattered areas of irregular pigmentation, and a residual myopia is often found. Areas of neovascular tufts are commonly seen, surrounding the optic nerve head, as well as in other areas. As these contract, with fibrosis, they exert traction on the retina and cause retinal folds to develop, extending to the optic nerve, ie, a dragged retina (Figure 4). Detachment of the retina is common, the underlying space being filled with fluid and fibrous tissue. The end stage is not at all diagnostic of retrolental fibroplasia and care should be exerted before the patient is so labeled, as other causes such as uveitis, persistent hyperplastic primary vitreous, retinal dysplasia, congenital retinal folds, trauma, severe intraocular hemorrhage or intraocular infections may lead to a similar end stage pathologic picture.
Those persons charged with caring for ill neonates at this point are wise to have an experienced pediatric ophthalmologist examine the eyes of these children. If no pathology is present, the documentation of a structurally normal eye is important. This not only adds to the comfort of the stressed parents, but aids in the prevention of future, ill-founded litigation. If pathology is present, this information should be brought to both the parents and the other physicians involved in caring for the child. Appropriate aids should be instituted. For some time, the problem of retrolental fibroplasia was viewed as possibly being tied to retinal vascular oxidation. Following Johnson's article.6 children with retrolental fibroplasia were in 1976 treated with large doses of Vitamin E. We believed at that time, and continue to hold as others do, that Vitamin E therapy seems to have a mollifying effect upon the disease state.
Retinal dysplasia is generally ranked as the fourth leading cause of leukokoria. It is a developmental anomaly, usually present at birth. The condition is characterized by a familial tendency, bilateralism, and association with systemic changes.
ETIOLOGY OF CATARACTS IN CHILDREN
Generally, the eyes appear small and may even be ranked as microphthalmic. The lens may be cataractous but is usually clear. This permits visualization of the retrolental fibrovascular membrane, which may be mistaken for retrolental fibroplasia. Indeed, in the end stage the two conditions are look-alikes ^one a congenital condition totally unrelated to any therapy, the other a topic of great concern to a pediatrician caring for ill neonates. Developmentally, this condition comes from an infolding of the inner layers of the retina, which also proliferate to form a series of interconnecting tubes. This dysgenesis is associated with a fibrosis of the retina, which may be extensive. Other ocular anomalies - including optic nerve hyplasia, glaucoma, and colobomas may be seen. Changes in the central nervous, respiratory, and cardiovascular svstems mav also be seen.
A retinoblastoma is a tumor arising from the inner layers of the retinal tissue (Figure 5). While it is only the fifth most common cause of leukokoria, it certainly is the most foreboding. Left unattended or undiagnosed, it is generally fatal. The tumor is highly malignant, occurs in one of every 14.000 to 23.000 live births, and has no predilection for sex or race. It is the most frequent ocular malignancy of childhood and second to malignant melanoma as the most common malignant ocular tumor of man. Although the disease is congenital, the average age at diagnosis is 13 months. Recognition and rapid treatment are imperative at this time; otherwise, a tumor whose multifocal tendency is well known may have time to metastasize. Again, early examination of the infant plays a diagnostic, preventive, and therapeutic role.
No cause has been described for retinoblastoma. A genetic influence is suggested, as 69c to 8% of cases are inherited (92% to 949c are spontaneous). The possibility of an embryonic cell rest is also entertained. Associated chromosomal disorders. D-group deletion syndromes being the most common, have been described with retinoblastomas.
Knowledge of the type of tumor is important when it comes to genetic counseling. Generally:
Figure 3. Retrolental fibroplasia-peripheral changes.
* Normal parents having one affected child have a 4% to 59c chance of having another affected child.
* Phenotypically normal parents who have had two affected children are at a 50% risk for each additional child to be a/ /îw/ a carrier and a 40% to 50% risk that each child will have the tumor.
* An affected person who has survived a proven inherited retinoblastoma will have a 50% chance that each of his offspring will be affected.
* A person surviving a sporadic tumor will have a 259c chance that each of his offspring will be affected.
* The parents and all siblings of an affected person should be examined carefully and repeatedly.
* A parent with bilateral retinoblastomas has a 509¿ chance of passing the tumor on to one child.
* A parent with unilateral multifocal retinoblastoma has a 50% chance of passing the tumor on to one child, the residual falling to 15% if the parent's tumor is unifocal.
* A phenotypically normal child born to a parent with bilateral retinoblastoma has a 19c chance of carrying the gene and a 0.5% chance of passing the disease on to any offspring.
* 5% of patients with retinoblastomas show multiple anomalies.
Clinically, there is great variability in the presenting characteristics of retinoblastomas. When the lesion is small, the patient may have decreased vision and or strabismus. Thus, a patient with an esotropia should be examined to rule out retinoblastoma. This should be more than a cursory examination, for. when small, a retinoblastoma may not cause leukokoria: if only an observation of a "white reflex" is depended on. the diagnosis can easily be missed.
As the tumor enlarges, the patient may develop other signs and symptoms. Glaucoma, photophobia, and ocular inflammation all have been reported. Even a collection of white blood cells (pus) in the anterior chamber, a hypopyon, is sometimes seen. X-rays of the orbit and skull may reveal intraocular calcification, as the tumor itself often calcifies (75%). If the mass has spread along the optic nerve, the foramina may show enlargement. Finding clumped retinoblastoma cells in a bone marrow aspirate is evidence of a very poor prognosis. Table 3 shows the Reese-Ellsworth system of classifying retinoblastomas. This system is important not only in diagnosis, but in evaluating those patients best served by certain modalities of treatment.
THE REESE-ELLSWORTH SYSTEM OF CLASSIFYING RETINOBLASTOMA
The treatment of retinoblastoma has changed significantly. Enucleation, while once viewed as the only treatment, is still retained in the armamentarium, but primarily for those patients who demonstrate on first examination large and advanced tumor growth. The overall aim of treatment is to protect vision to the greatest possible degree without endangering the patient's life. Currently a five-year survival rate of 92% for both unilateral and bilateral retinoblastomas is wellrecognized. The mainstay of treatment has been external beam radiation therapy. Over the past years lateral portal radiation has been extremely successful with a total of 4.000 rad being given over a four-week course. Factors such as patient's age. location of tumor, size of tumor and whether or not a multifocal presentation is observed, determine whether or not radiation therapy is to be employed. As a general rule, the younger the patient at the time of diagnosis, the greater the chance of a multifocal presentation for the retinoblastoma. Hence, youngereyes are generally not felt to be good candidates for enucleation and radiation therapy does play a frontline role. Tumors in the posterior one-half of the retina are also good candidates for radiation therapy. Tumors larger than four disc diameters are also treated with radiation therapy. Smaller tumors may be amenable to such ancillary treatments as diathermy, photocoagulation, cryotherapy or localized radioactive applications. Secondary non-ocular tumors do occur in patients with retinoblastoma. However, patients with unilateral retinoblastomas have not been noticed to develop these tumors following radiation therapy. These tumors primarily represent osteogenic sarcoma, the mortality from which is extremely high. Currently it is thought that these second tumors carry a greater risk of mortality than does the retinoblastoma itself.
Figure 4. Retrolental fibroplasia-dragged retina.
Colobomas are literally defects in ocular tissue. As the fetal eye is being formed, the fetal fissure may fail to close completely. This defect is usually inferior and may involve the iris, choroid, or retina. If the iris alone is involved, a tear-shaped pupil is seen with the apex inferiorly. If the retina and choroid are defective, various-size, usually single, areas are seen on fundus examination; these appear sharply demarcated and stark white (Figure 6). There may be scattered pigmentation in the periphery, but the overall appearance is entirely different from the scars of chorioretinitis, which shows multifocal irregular areas of fibrosis with pigment clumping. Histopathologically. the retina is absent or dysplastic. Areas of fibrosis are common. The sclera is thin. Colobomas may, if they involve large or strategic areas, damage vision. Because the choroid is removed, the white sclera reflects the incoming light as white hence a leukokoria.
There is no treatment of the condition per se. The patient is followed closely and given protection of the nondefective eye with safety glasses, and the best possible vision should be given to the damaged eye. This is an important point of preventive medicine. Any patient who has lost the vision or has defective vision in one eye should wear protective lens over the good eye, even if this lens has no power. It is not used to improve vision necessarily, but to protect the good eye from possible trauma.
Detachment of the retina describes a condition in which the two layers of primitive retina separate, the more superficial neural layer separating from the underlying pigment epithelium (Figure 7). Retinal detachment is often not a disease but an associated finding; as such, it may be seen in a variety of conditions, including myopia, diabetes, inflammations, trauma and tumors. If the underlying pathology is not identified, it is referred to as idiopathic. Retinal atrophy, holes or breaks allow fluid to collect under the retina and detach it. Fibrous bands in the vitreous pull the retina from its normal position. These bands may follow inflammation, hemorrhages, retrolental fibroplasia or congenital conditions.
Figure 5. Retinoblastoma.
When a retinal detachment does occur, the patient may complain of floaters or spots before his eyes. Flashes of light may signal stimulation of the retina as it detaches. Patients old enough to report it may describe a veil or cloud over part of the visual field or generalized reduced vision. Visual field testing is diagnostic. Ophthalmic examination of the total retina is difficult with a direct ophthalmoscope, and a small detachment could be overlooked. An examination with an indirect ophthalmoscope is preferred. The retina loses its pink color and appears gray and opaque and ballooned out; hence the leukokoria.
Any patient who has a retinal detachment warrants a detailed ophthalmic examination. Often treatment of the cause is more important, as in patients with a tumor or infection.
Treatment is variable and depends on the cause. It may entail the use of medicines, cryotherapy, diathermy, surgery, a laser, or combination of these.
Retinoschisis is similar to retinal detachment except that there is a splitting within the retina. The condition may be congenital or follow a variety of inflammations and other causes similar to those of retinal detachment. Signs and symptoms mimic those of a detachment.
CONGENITAL RETINAL FOLDS
Folds in the retina coursing from the optic disk to the inferior nasal quadrant differentiate this congenital condition from other causes of leukokoria. Inheritance is autosomal recessive.
Figure 6. Chorioretinal coloboma.
PERSISTENT PUPILLARY MEMBRANE
This fine fibrillar network, extending across the pupil, is often seen in premature infants and reflects a failure of regression of the vascular network usually covering the pupil. Unless extensive, it is a benign condition and requires no treatment.
Uveitis is an inflammation of the uveal tract and may include the iris, the ciliary body, or the choroid. The causes are legion but difficult to identify. Trauma, viral and bacterial infection, juvenile rheumatoid arthritis(and other collagen diseases), tumors, tuberculosis, sarcoidosis and syphilis are but a few. There may be cataractous lens changes, retrolental membrane formation, vitreous changes or retinal detachment as the cause of leukokoria. The patient may experience photophobia, reduction of vision, pain or ocular congestion. The treatment is aimed at the cause, if such can be identified. If not, treatment entails use of steroids to relieve the inflammation and the pain from ciliary body spasm with cycloplegia. Frequent examinations by the ophthalmologist are required.
Ophthalmitis, whether endophthalmitis (not involving the sclera) or panophthalmitis (including all ocular coats) (Figure 8). causes leukokoria by initiating cataracts, corneal opacities, pupillary or retrolental membranes, vitreous opacities (membranes or abscesses) or retinal detachment. The patient has pain, reduced vision, photophobia and systemic signs associated with the specific disease. Here etiology is important as a guide to specificity of treatment.
An exudative retinitis of Coats is a unilateral condition seen in male children, usually between the ages of eight months and eight years. Vision is reduced and, as in situations reducing vision in children, a strabismus is often seen. The fundus shows a detached retina and possible associated iritis, glaucoma or cataracts. The cause is unknown and there is no specific treatment.!
Figure 7. Retinal detachment.
In 1933, Norrie described a sex-linked recessive disorder characterized by bilateral blindness following severe retinal detachments, deafness and mental retardation. The condition is unusual and treatment is aimed at the symptoms.
OTHER OCULAR TUMORS
Other than retinoblastoma, ocular tumors of children are extremely rare. They may include hemangiomas (as in von Hippel-Findau disease) or astrocytomas (tuberous sclerosis) among others.
Trauma is discussed elsewhere in this issue and will be mentioned only superficially here. Injury may cause cataracts, vitreous hemorrhages, retinal detachment or chorioretinal degeneration. Whenever trauma is seen or suspected, the possibility of a battered child should be investigated.
MEDULLATED NERVE FIBERS
If myelination of the optic nerve extends beyond its normal termination at the optic disk, white feather-edged areas may be observed radiating from the nerve head. Blind spots may be noticed on visual-field examination (Figure 9). No treatment is required or possible.
The Block-Sulzberger Syndrome is a pigmentary dematosis inherited as an autosomal or sex-linked dominant trait and is present shortly after birth. A herpetiform dermatitis is followed by slate-gray cutaneous pigmentation in whorl-like patterns. Ocular anomalies include cataracts, optic atrophy, nystagmus and strabismus. A pigmentary change in the retina is also noted. Other systemic defects include those of the skeletal, cardiac, and central nervous systems.
Figure 8. Panophthalmitis.
Myopia in general is associated with an increased incidence of retinal detachment. High myopia is frequently accompanied by chorioretinal degeneration, which gives the retina a white appearance (Figure K)),
Glaucoma, meaning an increased intraocular pressure, is rare in children. The incidence is such that the practicing pediatrician may see only one case in 20 years; the average ophthalmologist sees one case in ten years. Congenital glaucoma often presents in the neonatal period with tearing and photophobia. The child finds it more comfortable to turn his face away from light. During the first three months of life, corneal clouding is often manifest. With this symptom alone, 607c of cases of congenital glaucoma are diagnosed before age six months. If the disease is not diagnosed and treated early, the eye will enlarge and become buphthalmic. The condition is believed to be autosomal recessive; however, a slight male preponderance is noted. Treatment is aimed at early diagnosis and combined medical and surgical care.
Examination of the eyes is an integral and important part of the total examination of the child. With modernday technology and awareness of the multiplicity of newborn eye diseases, failure to properly examine newborn eyes jeopardizes the overall health and performance of the individual. The eyes often serve as a window through which to see other systemic diseases, whether suspected or not. The observance of leukokoria alerts the examiner to an abnormality; however, the absence of leukokoria does not assure normality. Pediatric ophthalmic examination in the newborn period, including external as well as dilated indirect ophthalmoscopic examination serves as an aid to the pediatrician and to the patient by affording early diagnosis and treatment of observed abnormalities or by establishing the lack of ocular pathology. This latter is of importance also to prevent unwarranted legal entanglements.
Figure 9. Medullated nerve fibers.
Figure 10. High myopia.
1. Medical letter I 975: I8( ?5):63-64.
2. L.cFebvre G. Merlen J: I .a place de la rubeola et des autres facteurs infectieux ou toxiques survenus en cours de gestation dans la genese des malformations et dystrophies congénitales. Ann Paediatr I94K: 171:266-278.
3. McCormick AJ: Nutritional cataracts. Read before the American Academy of Pediatrics. Reno. Nevada. March 1977.
4. Kuhn BG: The differential diagnosis of cataracts in infancy and childhood. Am J Dis Child 1976: 130:184-192.
5. Terry TL: Fibroblastic overgrowth of persistent tunica vasculosa lentis in infants born prematurely. Studies in development and regression of hyaloid artery and tunica vasculosa lentis. Am J Ophthalmol 1942. 25:1409-1423.
6. Johnson L, Schaffer I). Boggs. TR Jr; The premature infant, vitamin E deficiency and retrolental fibroplasia. Am J Clin Nutr 1974: 27:1 158-1 173.
7. Catalano J I): Differential diagnosis of white pupil. Pediatr Ann 1977:6:90114.
ETIOLOGY OF LEUKOKORIA
ETIOLOGY OF CATARACTS IN CHILDREN
THE REESE-ELLSWORTH SYSTEM OF CLASSIFYING RETINOBLASTOMA