Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

margins; these may be mistakenly diagnosed as retinoblastoma. Another striking feature of astrocytic hamartomas is the characteristic nodular calcification that may give a mulberry appearance that has also been likened to fish eggs or tapioca (Fig. 8-15). The calcification seen in retinoblastoma is usually dull and chalky white as opposed to the more glistening yellow, nodular calcification that is seen with astrocytic hamartomas. Dilated, tortuous retinal feeder vessels are a more common feature of retinoblastomas than of astrocytic hamartomas.22

Diagnosis of astrocytic hamartomas is usually made on the basis of the ophthalmoscopic appearance and associated findings of tuberous sclerosis. Fluorescein angiography reveals varying degrees of vascularity within and on the surface of the tumor. There is an invariable leakage of dye from the tumor vessels late in the angiogram, which may pool within the cystic areas of the tumor. Echography is helpful for larger tumors but is of little value with smaller tumors.

Histopathologically, the tumors are composed of welldifferentiated, spindle-shaped fibrous astrocytes with round or oval nuclei and abundant eosinophilic cytoplasm. Some authors have stressed the importance of the vascular component of these lesions, which may suggest a link between these typically glial

FIGURE 8-15. Retinal astrocytoma with calcifications appearing like “tapioca.”

tumors and the retinal capillary hemangiomas seen in von Hippel–Lindau syndrome.3 The calcification seen clinically has been verified histopathologically. The most common retinal finding in tuberous sclerosis is usually reported to be a flat, hypopigmented macule which appears similar to ash leaf spots on the skin, however a large British study found this punchedout lesion in only 39% of patients, compared to a flat translucent hamartoma in 70%. “Mulberry” lesions were found in 55%.18a Mutations of the TSC1 and TSC2 genes cause tuberous sclerosis.11a

NEUROFIBROMATOSIS

Neurofibromatosis is a syndrome with skin, neurological, and ophthalmic manifestations and is discussed more fully elsewhere in this volume. The most common ocular features are the iris Lisch nodules (probably nevi), neurofibromas of the eyelids, large corneal nerves, and optic nerve gliomas and meningiomas.

The most frequent retinal lesion seen with neurofibromatosis is an astrocytic hamartoma, although these occur less frequently than in patients with tuberous sclerosis. The astrocytic hamartomas seen in both phakomatoses are identical clinically and histologically. Additional retinal findings include myelinated nerve fibers. Multifocal congenital hypertrophy of the RPE (bear tracks) probably occurs more frequently in association with neurofibromatosis than in the general population.14 Additionally combined hamartomas of the RPE and retina have been described in patients with neurofibromatosis, lending support to the idea that the combined hamartomas may be developmental in origin.10

Choroidal lesions similar to iris Lisch nodules have been described. Histopathologically, these hamartomas are probably nevi. Malignant melanomas are also more common in patients with neurofibromatosis and may be related to the greater number of nevi.25 Additionally, some patients have thickened long ciliary nerves (neurilemoma) or may have diffuse thickening of the uveal tract (neurofibroma), which is probably caused by proliferation of neurons and Schwann cells of the ciliary nerves. Choroidal neurofibromas and neurilemomas occur more frequently in neurofibromatosis than in the general population, with the former tumor occurring in approximately 35% to 50% of patients.

Acknowledgments. Revision of this chapter was supported in part by the Georgia Lions Children’s Eyecare Center.

References

1.Augsburger JJ, Schroeder RP, Terito CL, Gamel JW, Shields JA. Clinical parameters predictive of enlargement of choroidal melanocytic lesions. Br J Ophthalmol 1989;74:911–917.

2.Baker–Griffith AE, McDonald PR, Green WR. Malignant melanoma arising in a choroidal magnocellular nevus. Can J Ophthalmol 1976; 11:140–146.

3.Barsky WB, Wolter JR. The retinal lesions of tuberous schlerosis: angiomatous hamartoma? J Pediatr Ophthalmol 1971;8:261– 265.

4.Duke JR, Maumenee AE. An unusual tumor of the retinal pigment epithelium in an eye with early open angle glaucoma. Am J Ophthalmol 1959;47:311–317.

5.Folk JC, Weingeist TA, Coonan P. The treatment of serous macular detachment secondary to choroidal melanomas and nevi. Ophthalmology 1989;96:547–551.

6.Ganley JP, Comstock GW. Benign nevi and malignant melanomas of the choroid. Am J Ophthalmol 1973;76:19–25.

7.Gass JDM. An unusual tumor of the pigment epithelium and retina simulating choroidal melanoma and retinoblastoma. Trans Am Ophthalmol Soc 1973;71:171–183.

8.Gass JDM. Problems in the differential diagnosis of choroidal nevi and malignant melanomas: the XXXIII Edward Jackson Memorial Lecture. Am J Ophthalmol 1977;83:299–323.

9.Gass JDM. New observations concerning choroidal osteomas. Int Ophthalmol 1979;1:71–84.

10.Gass JDM. Discussion of: Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology 1984;91:1615.

11.Hale PN, Allen PA, Straatsma BR. Benign melanomas (nevi) of the choroid and ciliary body. Arch Ophthalmol 1965;74:532–538.

11a. Hodges A, et al. Pathologic mutations in TSC1 and TSC2. Hum Molec Genet 2001;10(25):2899–2905.

12.Joffe L, Shields JA, Osher R, Gass JDM. Clinical follow-up studies of melanocytomas of the optic disc. Ophthalmology 1979;86:1067– 1078.

13.Lambert HM, Sipperley JO, Shore JW, Dieckert JP, Evans R, Lowd DK. Linear nevus sebaceous syndrome. Ophthalmology 1987;94: 278–282.

14.Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis. Incidence of iris hamartoma. Ophthalmology 1981;88:348–354.

15.McDonald HR, Abrams GW, Burke JM, Neuwirth J. Clinicopathologic results of vitreous surgery for epiretinal membranes in

patients with combined retinal and retinal pigment epithelial hamartomas. Am J Ophthalmol 1976;100:227–231.

16. Munden PM, Sobol WM, Weingeist TA. Ocular findings in Turcot Syndrome (glioma-polyposis).Ophthalmology 1991;98:111–114.

16a. Naseripour M et al. Pseudohypopyon of orange pigment overlying a stable choroidal nevus. Am J Ophthalmol 2001;132(3):416–417.

17.Noble KG. Bilateral choroidal osteoma in three siblings. Am J Ophthalmol 1990;109:656–660.

18.Purcell JJ, Shields JA. Hypertrophy with hyperpigmentation of the retinal pigment epithelium. Arch Ophthalmol 1975;93:1122–1126.

18a. Rowley SA et al. Ophthalmic manifestations of tuberous sclerosis: a population based study. BJO 2001;85(4):420–423.

19.Schachat AP, Shields JA, Fine SL, et al., and The Macula Society Research Committee. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology 1984;91:1609–1614.

20.Schachat AP, Glaser BM. Retinal hamartoma, acquired retinoschisis, and retinal hole. Am J Ophthalmol 1985;99:604–605.

20a. Scott RJ, et al. Familial Adenomatous Polyposis: more evidence for disease diversity and genetic heterogeneity. Gut 2001;48(4):508–514.

21.Shields JA, Shields CL, Eagle RG, Lieb WE, Stern S. Malignant melanoma associated with melanocytoma of the optic disc. Ophthalmology 1990;97:225–230.

22.Shields JA, Shields CL. Intraocular tumors. Philadelphia: Saunders, 1992:432.

22a. Shields C, Shields J. Clinical features of small choroidal melanoma. Curr Opin Ophthalmol 2002;13(3):135–141.

23.Sivalingam A, Shields CL, Shields JA, et al. Idiopathic sclerochoroidal calcification. Ophthalmology 1991;98:720–724.

24.Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner’s syndrome. N Engl J Med 1987;316:661–667.

25.Wiznia RA, Freedman JE, Mancini AD, Shields JA. Malignant melanoma of the choroid in neurofibromatosis. Am J Ophthalmol 1978;86:684–687.

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The first hurdle is the rarity issue. The argument goes like this: “Retinoblastoma is so rare, that I (the pediatrician) will see only 2 to 3 cases in my 30 years of practice. Are you telling me I must screen 25,000 to 35,000 infants to find those 2 to 3 cases early?” The response to that argument is simple. Well-child care is all about screening and prevention.

Most pediatricians already screen for retinoblastoma. Currently they either perform, or know that they need to perform, the pupillary red-reflex exam. As a result, the proposed change in practice patterns to include pupil dilation as part of well-child care does not add a single step to the physical examination that is already a part of the well-child visit. The current practice of performing the pupillary red-reflex exam with an undilated pupil is like listening for a heart murmur without a stethoscope; it is hardly worth the trouble.

It is true that retinoblastoma is rare, affecting at most only 1 in 12,000 infants. However, if the incidence of retinoblastoma is combined with congenital cataracts, the other major treatable congenital developmental anomaly of the eye, intraocular pathology that can be treated successfully before the end of the third month of life would be found in 1 of every 750 infants screened. To put these numbers in perspective, the incidence of congenital heart disease is about 1 in 500 live births; congenital dislocation of the hip affects 1 in 1,000 infants. A major reason neonatal well-child examinations exist is to screen for both these developmental disorders because early diagnosis and treatment is essential for the well-being of the child. During the 1- or 2-month well-child visit, pediatricians accurately listen for faint heart murmurs and competently manipulate the hip joint for evidence of a congenital dislocation. They do not, as yet, adequately screen for treatable intraocular pathology.

The second hurdle to achieving practice pattern changes that encourage dilation of the pupil in the primary care office relates to their personal past experience screening for intraocular pathology with an undilated pupil. Most pediatricians received little medical school training in ophthalmology and feel unprepared to screen for intraocular pathology. They all, however, know that the red-reflex examination is the best way to screen for retinoblastoma. They are generally now uncomfortable, however, with the routine results they get from the undilated red-reflex screen. The pupil is so small, often 2 mm or less, that the data from the test are inconclusive. The rationale for checking the “eyes normal” box is that because the

disease is rare, the chances of being right are very high. Unfortunately, the chances of overlooking the presence of a large intraocular tumor are also high.

The third hurdle to the concept of pupil dilation in the primary care office is the misperceived burden that a single instillation of a mydriatric drop would impose on the doctor, office staff, and office routine. Poorly or misremembered information from medical school mixed with past personal experience contributes to this problem. Examples of misremembered information include (1) dilating the pupils causes glaucoma; (2) dilating the pupil takes three instillations of drops 5 min apart and then a wait of 30 min; (3) holding down a child to put in dilating drops requires three or four office staff members and totally disrupts the office routine; (4) dilating the pupils requires more work from the pediatrician that will not be separately reimbursed; and (5) dilating the pupils will obscure critical information that could be gathered from the pupil exam before dilation.

Each of the five misremembered “facts” about pupil dilation commonly used by those opposed to the use of dilation as a part of the 1- or 2-month well-baby examination is pure myth.

1.Pupillary dilation causes glaucoma in older adults with narrow anterior chambers, not in infants. Iatrogenic glaucoma has not been a concern or a finding in the hundreds of thousands of tiny infants dilated for ROP screening in the last decade.

2.A single instillation of a single agent, 1% tropicamide, gives 5 to 6 mm of dilation at 20 min, more than adequate for red-reflex screening

3.Three or four people might be required to hold down a 3- or 4-year-old to put in eye drops, but the subjects of our interest are newborn infants no more than 1 to 2 months old. When they are placed supine to be weighed, the nurse makes a “lake” of 2 to 3 drops of tropicamide over the inner edge of the lid fissure. If the “lake” wets the lashes to the lateral edge of the fissure and excess runs down the temple toward the ear, the drop is “in.” There is no need or benefit of holding the lids open. If the drop does not get “in” immediately, gentle manipulation of the upper lid with the thumb on the brow will accomplish the trick. Holding the infant down is not necessary.

4.Dilating the pupil as part of the well-baby examination requires no extra effort on the part of the pediatrician. In fact,

CHAPTER 9: RETINOBLASTOMA & OTHER MALIGNANT INTRAOCULAR TUMORS 249

pediatricians who have been doing this routinely in their practice for more than 8 years report that except that they now get a wonderfully informative red-reflex examination on virtually every baby, they are not consciously aware of the mechanics of the dilation process. They always performed the red-reflex examination. The only difference is that now they get useful information.2

5. Drops are not instilled during the first examination of the child by the pediatrician, which usually occurs before discharge from the hospital. Significant anisocoria or papillary pathology would be noted on that exam.

Finally, failure to recognize the signs of retinoblastoma early can often be blamed on poor communication between parents and pediatrician. Several factors contribute to this problem: (1) parents see the leukocoria and pediatricians generally do not (because of the small pupil); (2) pediatricians find it hard to believe that the parents or other lay family members can see signs of disease that they (the trained professionals) cannot; and

(3) parents accept reassurance from the pediatrician because they question their own observations of the abnormal white “glow” that is present only some times. When an irritated authority figure suggests that they might be imagining things and that they are overreacting, the parents often question the validity of their own observations and quietly acquiesce to the opinion of the professional.

Clinical Presentation

Any white or yellow lesion in the posterior segment of the eye in a child under 5 years of age should raise the possibility of retinoblastoma. This disease is highly curable in its early stages but can be fatal if the diagnosis is missed or delayed. When the fundus of a young child cannot be seen clearly for whatever reason, a CT scan or ocular ultrasound is essential to rule out the presence of intraocular calcium before surgically entering the eye.

Retinoblastoma rarely, if ever, causes pain and discomfort unless secondary glaucoma is present. Evidence that the child does not see well is nonexistent in unilateral disease where one eye is normal. Even in bilateral disease, it is rare for the macula in both eyes to be destroyed by the tumor, although in advanced disease this can happen.

Clinical signs of retinoblastoma relate to the tumor location, size, and color (Table 9-1). In the majority of cases, the diagnosis of retinoblastoma is straightforward. In a large majority of children with this disease, a parent or family member first notes the presence of a white pupillary reflection or reflex (leukocoria). A posterior pole tumor as small as 3 to 5 mm in diameter has the capacity to create leukocoria.

The term that parents use for the leukocoria observation is rarely the textbook-cited “cat’s eye.” Usually it is a “g” word, such as “gleam, glow, glare, or glint” (Fig. 9-1). Parents are often unsure of their observation because they see it only intermittently. It is most obvious near the end of the day when the light is low and the pupil dilates naturally. It is common for parents to seek brighter light for a better look. A combination of the child’s near pupillary reflex (from the parent’s face near the child) and the brighter light almost always defeats that effort, leaving the parent questioning their earlier observation.

In other infants, loss of binocularity and central vision in one eye because of a tumor in the macula is the reason that strabismus may be the first sign of the tumor. In the genetically predisposed individual in whom the tumor appears in the first few months of life, there seems to be a predilection for the posterior pole, most likely because of the number of dividing retinoblasts in the macula at this stage of retinal development. In any case, a macular tumor is likely to be in position to reflect incident light, and create leucocoria (see Fig. 9-1). It is rare for a retinoblastoma to be initially discovered during a dilated fundus exam done for an unrelated reason. However, we have found

TABLE 9-1. Differential Diagnosis of Leukocoria.

1.Retinoblastoma

2.Persistent hyperplastic primary vitreous (PHPV)

3.Cataract

4.Retinopathy of prematurity

5.Toxocariasis

6.Coloboma of choroid

7.Uveitis

8.Coats’ disease

9.Vitreous hemorrhage

10.Retinal dysplasia

11.Tumors other than retinoblastoma

12.Retinal detachment

13.Corneal opacity

14.Myelinated nerve fibers

CHAPTER 9: RETINOBLASTOMA & OTHER MALIGNANT INTRAOCULAR TUMORS 251

A

B

FIGURE 9-1A,B. Snapshots obtained from family of an 18-month-old child with unilateral retinoblastoma OS. (A) At 15 months of age, red reflexes are evident bilaterally. (B) At 17 months of age, leukocoria is obvious in the left eye. Old photographs can be helpful in dating the onset of leukocoria or strabismus.

three unsuspected retinoblastomas during routine screening for retinopathy of prematurity in at-risk infants.

Unfortunately, unless there is bilateral retinoblastoma in a parent, appropriate screening for retinoblastoma is rarely a part of well-child care. This unfortunate situation accounts for the average age of diagnosis of 12 months for sporadic new bilateral disease. The suspected diagnosis of retinoblastoma is confirmed when ophthalmoscopy reveals one or more nodular masses that appear creamy white. Tumors larger than 3 mm will have intralesional vascularization (Fig. 9-2). Atypical cases of