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Clinicopathologic Correlation of Microphthalmos with Cyst
CLINICOPATHOLOGIC CORRELATION O F MICROPHTHALMOS WITH CYST G E O R G E O. W A R I N G III, M.D., Davis,
AND A L A N M. R O T H ,
M.D.
California AND
MERLYN
M.
RODRIGUES,
Philadelphia,
M.D.
Pennsylvania
Microphthalmos with cyst and congen ital cystic eye result from defects in the closure of the embryonic fissure and in vagination of the optic vesicle, respec tively. These abnormalities vary in their clinical presentation and are often misdiagnosed. We illustrate this clinical vari ation in three patients and give histopathologic findings in four of the eyes. CASE REPORTS Case 1—On Sept. 24, 1964, a white infant boy weighing 3,420 g (7 lb, 7 oz) was born after an uncomplicated delivery at 36 weeks' gestation as a double footling breech with assistance under local anesthesia. The mother was a 21-year-old gravida 2, para 1, healthy woman who had neither serious illness nor significant drug ingestion during preg nancy. The one-minute Apgar score was 8, but respiratory and cardiac arrest occurred at three min utes. The infant was resuscitated and transferred to the Sacramento Medical Ccenter. General physical examination revealed mild microcephaly (head cir cumference, 34 cm); severe bilateral cleft lip and palate with absent philtrum; microphallus with left hydrocele; decreased neurologic tone; and hyperconvex fingernails on short stubby fingers. Skull x-ray films showed slight microcephaly with a se vere midline facial deformity. Karyotype was nor mal. The eyelids were normal, but the orbits appeared small (Fig. 1, top). In the right orbit, there was no visible globe, but palpation of the mucous membrane-lined socket revealed a slight fullness.
From the Departments of Ophthalmology (Drs. Waring and Roth) and Pathology (Dr. Roth), Univer sity of California, Davis, California; and the Depart ment of Pathology, Wills Eye Hospital, Philadel phia, Pennsylvania (Dr. Rodrigues). Presented in part at the annual meeting of the Western Section of the Association for Research in Vision and Ophthalmology, Portland, Oregon, Sept. 19, 1975. Reprint requests to George O. Waring, M.D., Department of Ophthalmology, U.C.D. Professional Building, 4301 "X" St., Rm. 251, Sacramento, CA 95817.
Fig. 1 (Waring, Roth, and Rodrigues). Three pa tients with micropthalmos with cyst. Top, Case 1. Right: congenital cystic eye. Left: microphthalmos with inferior orbital cyst producing protuberant darkly colored lower eyelid. Center, Case 2. Right: microphthalmos with finger counting vision. Left: microphthalmos with inferior orbital cyst not appar ent on inspection (outlined). Bottom, Case 3. Bilat eral microphthalmos with superior orbital cyst. Right: cyst protrudes between eyelids. Left: cyst shrunken by multiple aspirations.
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A-scan ultrasonography of the right orbit demon strated a cystic structure. On the left side, an easily palpable, slightly firm mass distended the bluish lower eyelid. A dusky-colored mucous membrane lined the orbit and there were no visible normal ocular structures. A-scan ultrasonography produced multiple orbital echoes without clearly defined structure. The child was transferred to a convalescent home at age 4 weeks, where he was fed by gavage because of the severe cleft palate. At 4 months of age, he died after aspiration pneumonitis. The orbital contents were completely removed at autopsy. P A T H O L O G I C D E S C R I P T I O N — T h e right orbit contained a 19 x 14 x 11-mm cyst attached to orbital fat. The cyst wall was thin with inner trabeculations and the lumen contained serous yellow fluid. Mi croscopically, the cyst wall consisted of collagenous connective tissue resembling sciera lined by, and often interdigitated with, a neuroectodermal layer of variable thickness. The neuroectodermal lining stained positive for fibroglia with phosphotungstic acid-hematoxylin, and con tained scattered hemosiderin deposits (Fig. 2). There were no recognizable ocu lar structures or cartilage.
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The left orbit contained a small dis torted eye, 10.5 mm in diameter. A firm 6-mm mass was attached to the equatorial sciera and merged imperceptibly with or bital fat. Neurosensory retina and pig ment epithelium extended through a scierai defect into the mass. The anterior segment showed total peripheral anterior uveal synechiae. Microscopically, con junctiva covered the cornea with absence of corneal epithelium and Bowman's membrane. Endothelial cells were pres ent without Descemet's membrane. The iris and ciliary body were composed of loose mesenchymal stroma lined posteri orly by pigment epithelial layers. The iris sphincter, dilator, and ciliary muscles were absent. There was no angle differen tiation. The lens adhered to detached reti na posteriorly and was diffusely cataractous with some retained cell nuclei in the nuclear zone. The choroid appeared nor mal, but the retinal pigment epithelium was diffusely irregular in size and pig mentation with absence of Bruch's mem-
Fig. 2 (Waring, Roth, and Rodrigues). Case 1. Right congenital cystic eye showing neuroepithelial inner lining (n), collagenous outer layer (c), and orbital fat (f). There was no organoid differentiation (hematoxylin and eosin, x l ) .
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brane. The retina showed some differen tiation into layers, but was diffusely atrophie with extensive cystoid degenera tion. Some solid areas of glial tissue were present and retinal tissue was adherentto the posterior lens capsule. No rosette for mation was seen. This gliotic retina and hyperplastic retinal pigment epithelium lined the lips of the scierai coloboma and extended a short distance into an attached cyst. The cyst wall was composed of fibrovascular tissue resembling sciera and was lined by gliotic neuroepithelial tissue containing pseudorosettes. Neuropathologic examination revealed a shortened cribriform plate. The soft palate constituted the floor of the sella turcica. The 500-g unfixed brain mani fested anteroposterior elongation of the cerebral hemispheres, relative hypoplasia of temporal lobes, and a complex anoma lous gyral pattern in the frontal and pariental lobes. No olfactory bulbs, optic nerves, or optic chiasm were visible. The corpus callosum consisted of a shelf of white matter protruding from the medial surface of each hemisphere without evi dence of interhemispheric connection. No anterior commissure, optic tracts, or lateral geniculate bodies were identified on coronal sections. The cerebellar vermis was hypoplastic. There was a de creased amount of white matter, and it was incompletely myelinated in the cere brum and cerebellum. Case 2—A 5-year-old boy was seen at Wills Eye Hospital in July 1973 because of bilateral, con genially small eyes. Surgery of the left lower eye lid had been performed previously, apparently for entropion. A left preauricular skin tag was pres ent. The child had no known systemic abnormal ities. Visual acuity was R.E.: finger counting at 5 feet, and L.E.: no light perception. The right eye was microphthalmic (Fig. 1, center). The horizontal cor nea! diameter was 8 mm with superior and inferior scleralization. A persistent pupillary membrane and a small inferonasal iris coloboma were present. Ophthalmoscopic examination appeared normal. Mucous membrane lined the anterior left orbit. On eyelid retraction, a small pigmented mass resem-
NOVEMBER, 1976
bling an eyeball was seen deep in the orbital recess. A moderately firm, 2-cm mass was palpated through the lower eyelid but was not apparent on inspection. The clinical diagnosis was right microphthalmos with iris coloboma and left microphthalmos with orbital cyst. To facilitate fitting a cosmetic prosthesis in the left orbit, the cyst and microphthalmic eye were surgically excised. After a lateral canthotomy, a small eyeball was identified superiorally. A large cyst was attached to the eyeball and filled the inferior orbit. This ruptured near the end of the dissection, releasing a clear yellowish serous fluid. PATHOLOGIC
DESCRIPTION—The
eye
measured 11 x 9 x 12 mm and the cyst, 48 x 38 mm (Fig. 3). Grossly, the sciera showed a posterior inferior coloboma ex tending into the attached cyst. Micro scopically, the cornea was covered by stratified squamous epithelium without Bowman's membrane. The anterior stroma showed avascular scarring. Descemet's membrane and the endothelium were intact. The chamber angle, iris, and ciliary body appeared normal. The large lens was posteriorly displaced, adhered to the retina, and showed a homogeneous eosinophilic cortex without recognizable fiber arrangement. Remnants of the tunica vasculosa lentis were present posteriorly. The partially detached retina was com posed predominantly of disorganized
Fig. 3 (Waring, Roth, and Rodrigues). Case 2. Gross specimen of left eye. Microphthalmic eye on left attached to large cyst on right. Rule calibrated in millimeters (x0.5).
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glial tissue with focal areas showing a lamellar pattern of neurons and rod and cone cells. Posteriorly, the retina was at tached to a mass of glial tissue that ex tended into the attached cyst (Fig. 4). The retinal pigment epithelium, Bruch's membrane, and choroid extended through the coloboma and terminated abruptly a short distance into the cyst. The thick sciera continued posteriorly to surround the cyst which was lined by a variably thick layer of glial tissue (Fig. 5) with rare rosette formation. Case 3—A 10-month-old white boy was admitted to Wills Eye Hospital on June 8, 1973. The mother had rubella in the fourth month of pregnancy. The child was born prematurely weighing 1,680 g (3 lb, 12 oz). Multiple aspirations of bilateral orbital cysts had been performed. The child exhibited mental retardation and poor muscle tone, but had no other systemic abnormalities. Visual acuity was R.E.: light perception, and L.E.: no light perception (Fig. 1, bottom). The microph thalmic right eye was displaced inferonsally in the orbit. The clear cornea was about 6 mm in diameter and the anterior chamber and iris were normal. A thin, bluish cyst measured 4 cm in diameter, pro truded from beneath the right upper eyelid, and transilluminated easily. There was distortion of the left eyelids from previous surgery. On the left a
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small scarred microphthalmic globe was displaced inferonasally and no cyst could be palpated. Scarred conjunctiva lined the eyelids and globe. Aspiration of the right cyst removed about 10 ml of clear yellow fluid and allowed the microph thalmic globe to return to a more central position (Fig. 6). The cyst gradually enlarged over the next few months and protruded between the eyelids. It collapsed after a second aspiration, but subsequent ly became distended. On March 20, 1974, the cyst was surgically excised and ruptured during the dissection. There was no direct connection between the cyst and the globe. HlSTOPATHOLOGIC
DESCRIPTION—
The cyst wall consisted of an outer layer of vascularized fibroadipose tissue with scattered foci of hypoplastic neuroglial tissue on the inner surface. DISCUSSION
The clinician should suspect microphthalmos with cyst in an individual with a small eye associated with a visible or palpable mass behind the lower eyelid. Since true anophthalmia is rare, cases without clinically detectable ocular struc tures in the orbit are more likely to have either a congenital cystic eye or microphthalmos with cyst. 1 - 5 Orbital ultrasound
Fig. 4 (Waring, Roth, and Rodrigues). Case 2. Left eye. Microphthalmic globe (m) with dislocated cataractous lens, gliotic tissue (g) filling large choroidal and scierai coloboma, and two-layered cyst (c) (ruptured posteriorly). Arrow indicates area shown in Figure 5 (hematoxylin and eosin, x l ) .
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Fig. 5 (Waring, Roth, and Rodrigues). Area of cyst wall shown by arrow in Figure 4. N indicates neuroepithelial inner lining resembling retina; C, collagenous outer layer resembling sciera (hematoxylin and eosin, x80).
is valuable in demonstrating rudimentary ocular and cystic structures in difficult cases. The clinical manifestations of microphthalmos with cyst are variable (Fig. 1). This nonheritable condition some times has a familial occurrence. 2 There is no predisposition for sex or laterality. Among 74 cases, Natanson 3 found 23 on the right side, 22 on the left side, and 20 bilaterally. No definite association with systemic abnormalities has been detected, although central nervous system defects 4,5 (Cases 1 and 3), such as meningoencephalocoele 6 and hydrocephalus, 3 and cardiac, 3,5,7 urogenital 4,5 (Case 1), fa cial 4 - 7 (Case 1), and skeletal 4 abnormali-
Fig. 6 (Waring, Roth, and Rodrigues). Case 3. Right eye. After aspiration of superior cyst, microphthalmic globe assumed a more central position. Cyst enlarged again and was excised, leaving a cosmetically acceptable globe.
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ties may occur. Natanson 3 found systemic anomalies in only eight of 74 cases. In most cases the eyelids are normal. Ehlers 8 found ten instances of microphthalmos with cyst among 15 cryptophthalmic eyes in which the globe was care fully described. The microphthalmic eye is often ob scured within the orbit by conjunctival folds or by a large cyst. Extreme retrac tion of the eyelids sometimes reveals uveal pigmentation that indicates the lo cation of the eye (Cases 2 and 3). Aspira tion 9 (Case 3) or excision 10 of the cyst may reveal a microphthalmic eye. Size of the cystic component varies. It may be small enough to escape clinical detection (Case 2) and, in cases of extreme microphthalmos, may lead to the misdiagnosis of anophthalmia. 1 1 , 1 2 The cyst usually produces a bluish bulge in the lower eyelid, is moderately firm on palpa tion, and may be visible through the con junctiva where it transilluminates easily (Case 1). In the extreme, the cyst pro trudes grotesquely between the eye lids 6 , 9 ' 1 1 (Case 3). It is usually located in the inferior orbit (Cases 1 and 2) since the embryonic fissure from which it develops is located inferiorly. However, the cyst is present beneath the upper eyelid in about 6% of cases 3,13 (Case 3), either because it is large enough to extend around the globe superiorly or because it arose from an atypical superior coloboma. A congen ital cystic eye frequently has protrusion of the upper eyelid, 14 but in our Case 1, the cyst was not apparent clinically. Histopathologically, the cyst is a twolayered structure. The inner layer is com posed of gliotic neuroretinal tissue 1 that may show retinal architecture, 7 · 10 photoreceptor differentiation, or rosette forma tion. 13 It may proliferate profusely enough to fill the fibrous capsule. 1 5 The outer layer consists of vascularized con nective tissue and occasionally contains cartilage. 5 ' 1 5 - 1 7
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While the structure of the cyst is mo notonously predictable, the microphthal mic eye presents a wide spectrum of ab normal development. 3 · 5 ' 1 5 The anterior segment may appear nearly normal (Case 1), may have recognizable anomalous structures such as hypoiridia and iridocorneal adhesions 7 (Case 2), or may dis play marked derangement. The lens is often large, dislocated, and cataractous, 1 while the vitreous body is usually fibrotic and vascularized. The retina may show focal preservation of its architecture, but is usually disorganized, gliotic, detached, and folded. 1 · 2,5 The retinal pigment epi thelium and choroid frequently extend through the mouth of the scierai colobo ma a short distance into the cyst, but they do not line the cyst wall 1 5 (Cases 1 and 2). The findings on the contralateral side vary (Fig. 1); the other orbit may contain a congenital cystic eye (Case 2), microph thalmos with cyst (Case 3), a microph thalmic eye with vision (Case 1), or a normal eye. 2 ' 12 The congenital cystic eye (Case 1) is histopathologically similar to the cystic portion of microphthalmos with cyst. i4,i6,i7 S i n c e t n e optic vesicle has not invaginated, no anterior segment struc tures are present, although an abortive attempt at invagination may produce nonattachment of the retina and a lens rem nant. 17 Connections between the cyst and the central nervous system occur rarely. 1 ' 18 The optic stalk apparently develops enough to obliterate its cavity and to prevent leakage of cerebrospinal fluid after excision of the cyst. The yellow fluid within the cyst resembles cerebrospinal fluid in its glucose, protein, and chloride concentrations. 6 Confusion with orbital meningoencephaloceles is unusual, since these often increase in size with crying and demonstrate defects in the posterior or medial orbit on roentgenographic ex amination.
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Case 1 showed anomalies in the forma tion of median structures of the brain (agenesis of the corpus callosum), the face (bilateral cleft lip and palate), and the eyes (failure of embryonic fissure clo sure). Agenesis of the corpus callosum is associated with ocular anomalies in about 25% of cases. 19 The pathogenesis of microphthal mos with cyst was demonstrated by von Szily 20 in rabbits, where autosomal-dominant inheritance can occur. In humans, the embryonic fissure forms during the invagination of the optic vesicle and optic stalk at the 5- to 8-mm stage of gestation. 21 The fissure allows the hyaloid vascular system to enter the future vitreous cavity and the sprouting nerve fibers to grow from the retina to the lateral geniculate body. The embryonic fissure begins to close centrally at about the 8-mm stage and fuses both posteriorly and anteriorly by the 20-mm stage. Improper fusion of the lips of the fissure may produce a defect in the neuroectodermal and uveal tissues, manifesting as a typical coloboma consisting of a layer of sciera lined by a thin membrane of maldeveloped neuroectoderm. Proliferation of the neuroectoderm at the lips of the persistent embry onic fissure may form a cyst, the cavity of which is continuous with the space be tween the two layers of the optic cup 2 0 (Fig. 7). The cyst sometimes originates from the optic nerve. 9 Four morphologic variations are then possible. 3 · 22 If both sides of the embryon ic fissure proliferate, two separate cysts in communication with the future subretinal space result. 23 If only one lip of the fis sure proliferates, a single cyst occurs. 12 Fusion of the two cysts at each lip of the fissure results in a uniocular cyst with a cavity continuous with the future subre tinal space (Cases 1 and 2). If the wall of the cyst separating the vitreous cavity from the future subretinal space is absent,
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Fig. 7 (Waring, Roth, and Rodrigues). Probable mechanism of formation of microphthalmos with cyst is proliferation of the inner neuroectodermal layer at the edge of the embryonic fissure. Cyst is originally continuous with the space between the two layers of the optic cup.
the cyst communicates directly with the vitreous cavity. 15 Aspiration of the cyst is the simplest management and, while the cyst usually recurs 6 (Case 3, right eye; Fig. 6), repeat ed aspiration sometimes produces perma nent disappearance 9 (Case 3, left eye). Excision of the cyst alone is possible if there is minimal attachment to the globe, and may leave a cosmetically acceptable eye 1 3 (Case 3, right eye). Removal of the eye and cyst usually necessitates orbital or eyelid reconstruction for prosthetic fit ting. 1 SUMMARY
Three patients had microphthalmos with cyst in one orbit and contralateral congenital cystic eye, microphthalmos alone, or microphthalmos with cyst. Four eyes were examined histopathologically. The microphthalmie eye demonstrated a spectrum of anterior segment abnormali ties, retinal disorganization and gliosis, and a choroidal and scierai coloboma. The cyst connected to the coloboma con sisted of an outer fibrovascular layer and inner gliotic neuroectodermal layer. The cyst probably originated from proliféra-
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tion of neuroectodermal tissue at the edge of a persistently open embryonic fissure. Treatment consisted of multiple aspira tions of the cyst, excision of the cyst alone, and excision of both the microphthalmic eye and cyst. ACKNOWLEDGMENT
Joseph Flanagan, M.D., allowed us to report Case 3.
REFERENCES 1. Kok-van Alphen, C. C , Manschot, W. A., Frederiks, E., and van Beusekom, G. T.: Microphthalmus and orbital cyst. Ophthalmologica 167:389, 1973. 2. Makley, T. A., Jr., and Battles, M.: Microphthalmos with cyst. Report on two cases in the same family. Survey Ophthalmol. 13:200, 1969. 3. Natanson, L.: Über Mikrophthalmus and Anophthalmus congenitus mit serösen Orbitopalpebralcysten. Albrecht von Graefe's Arch. Ophthal mol. 67:185, 1908. 4. von Hippel, E.: Über die Beziehungen von Mikrophthalmus mit Unterlidcyste zu allgemeinen Missbildungen, besonders zum Lindauschen Symptomenkomplex. Albrecht von Graefe's Arch. Ophthalmol. 132:25, 1934. 5. Yanoff, M., Ballian, L. R., and Niederer, B. S.: Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am. J. Ophthalmol. 70:391,1970. 6. Ladenheim, J., and Metrick, S.: Congenital microphthalmos with cyst formation. Am. J. Ophthalmol. 41:1059, 1956. 7. Arstikaitis, M.: A case report of bilateral mi crophthalmos with cysts. Arch. Ophthalmol. 82:480, 1969. 8. Ehlers, N.: Cryptophthalmos with orbitopalpebral cyst and microphthalmos (report of a bilateral case). Acta Ophthalmol. 44:84, 1966. 9. Kleberger, E., and Stolowsky, R. B.: Eine aussergewöhnlich grosse Orbitalzyste mit mächtiger
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Erweiterung der knöchernen Orbita. Klin. Monantsbl. Augenheilkd. 133:218, 1958. 10. Briggs, R. M., Chase, R. A., and Dellaporta, A.: Unilateral congenital orbital cyst with microph thalmos. Plastic Reconstr. Surg. 41:376, 1968. 11. Lim, G., and Bejec, L. C : Congenital cystic microphthalmos. Philippine J. Ophthalmol. 5:93, 1973. 12. Weyman, M. F.: Microphthalmos with cyst formation. Am. J. Ophthalmol. 8:214, 1925. 13. May, C. H., and Holden, W. A.: A case of microphthalmos with upper-lid cyst. Arch. Ophthal mol. 35:424, 1906. 14. Dollfus, M. A., Marx, P., Langlois, J., Clem ent, J. C , and Forthomme, J.: Congenital cystic eyeball. Am. J. Ophthalmol. 66:504, 1968. 15. Treacher-Collins, E.: Microphthalmos with cystic protrusion from the globe. Trans. Ophthal mol. Soc. U. K. 17:254, 1897. 16. Helveston, E. M., Malone, E., Jr., and Lashmet, M. H.: Congenital cystic eye. Arch. Ophthal mol. 84:622, 1970. 17. Taylor, S. J., and Treacher-Collins, E.: Con genially malformed cystic eye. Trans. Ophthalmol. Soc. U. K. 26:177, 1906. 18. Bonner, J., and Ide, C. H.: Astrocytoma of the optic nerve and chiasm associated with micro phthalmos and orbital cyst. Br. J. Ophthalmol. 58: 828, 1974. 19. Saraux, H., Biais, B., and Chatellier, P.: Anomalies oculaires et malformations des structures médianes du cerveau antérieur. Ann. Oculistique 202:241, 1969. 20. von Szily, A.: Die Ontogenese der idiotypischen (erbbildlichen) Spaltbildungen des Auges, des Mikrophthalmus und der Orbitalcysten. Zeitschr. Anat. 74:1, 1934. 21. O'Rahilly, R.: The early development of the eye in staged human embryos. Contrib. Embryology 38:1, 1966. 22. Mann, I.: Developmental Abnormalities of the Eye, 2nd ed. Philadelphia, J. B. Lippincott Co., 1957, pp. 79-94. 23. Baylis, H., Bartlett, R., and Cies, W.: Re construction of the lower lid in congenital microph thalmos and anophthalmos. Ophthalmic Surg. 6:36, 1975.
AND A L A N M. R O T H ,
M.D.
California AND
MERLYN
M.
RODRIGUES,
Philadelphia,
M.D.
Pennsylvania
Microphthalmos with cyst and congen ital cystic eye result from defects in the closure of the embryonic fissure and in vagination of the optic vesicle, respec tively. These abnormalities vary in their clinical presentation and are often misdiagnosed. We illustrate this clinical vari ation in three patients and give histopathologic findings in four of the eyes. CASE REPORTS Case 1—On Sept. 24, 1964, a white infant boy weighing 3,420 g (7 lb, 7 oz) was born after an uncomplicated delivery at 36 weeks' gestation as a double footling breech with assistance under local anesthesia. The mother was a 21-year-old gravida 2, para 1, healthy woman who had neither serious illness nor significant drug ingestion during preg nancy. The one-minute Apgar score was 8, but respiratory and cardiac arrest occurred at three min utes. The infant was resuscitated and transferred to the Sacramento Medical Ccenter. General physical examination revealed mild microcephaly (head cir cumference, 34 cm); severe bilateral cleft lip and palate with absent philtrum; microphallus with left hydrocele; decreased neurologic tone; and hyperconvex fingernails on short stubby fingers. Skull x-ray films showed slight microcephaly with a se vere midline facial deformity. Karyotype was nor mal. The eyelids were normal, but the orbits appeared small (Fig. 1, top). In the right orbit, there was no visible globe, but palpation of the mucous membrane-lined socket revealed a slight fullness.
From the Departments of Ophthalmology (Drs. Waring and Roth) and Pathology (Dr. Roth), Univer sity of California, Davis, California; and the Depart ment of Pathology, Wills Eye Hospital, Philadel phia, Pennsylvania (Dr. Rodrigues). Presented in part at the annual meeting of the Western Section of the Association for Research in Vision and Ophthalmology, Portland, Oregon, Sept. 19, 1975. Reprint requests to George O. Waring, M.D., Department of Ophthalmology, U.C.D. Professional Building, 4301 "X" St., Rm. 251, Sacramento, CA 95817.
Fig. 1 (Waring, Roth, and Rodrigues). Three pa tients with micropthalmos with cyst. Top, Case 1. Right: congenital cystic eye. Left: microphthalmos with inferior orbital cyst producing protuberant darkly colored lower eyelid. Center, Case 2. Right: microphthalmos with finger counting vision. Left: microphthalmos with inferior orbital cyst not appar ent on inspection (outlined). Bottom, Case 3. Bilat eral microphthalmos with superior orbital cyst. Right: cyst protrudes between eyelids. Left: cyst shrunken by multiple aspirations.
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A-scan ultrasonography of the right orbit demon strated a cystic structure. On the left side, an easily palpable, slightly firm mass distended the bluish lower eyelid. A dusky-colored mucous membrane lined the orbit and there were no visible normal ocular structures. A-scan ultrasonography produced multiple orbital echoes without clearly defined structure. The child was transferred to a convalescent home at age 4 weeks, where he was fed by gavage because of the severe cleft palate. At 4 months of age, he died after aspiration pneumonitis. The orbital contents were completely removed at autopsy. P A T H O L O G I C D E S C R I P T I O N — T h e right orbit contained a 19 x 14 x 11-mm cyst attached to orbital fat. The cyst wall was thin with inner trabeculations and the lumen contained serous yellow fluid. Mi croscopically, the cyst wall consisted of collagenous connective tissue resembling sciera lined by, and often interdigitated with, a neuroectodermal layer of variable thickness. The neuroectodermal lining stained positive for fibroglia with phosphotungstic acid-hematoxylin, and con tained scattered hemosiderin deposits (Fig. 2). There were no recognizable ocu lar structures or cartilage.
715
The left orbit contained a small dis torted eye, 10.5 mm in diameter. A firm 6-mm mass was attached to the equatorial sciera and merged imperceptibly with or bital fat. Neurosensory retina and pig ment epithelium extended through a scierai defect into the mass. The anterior segment showed total peripheral anterior uveal synechiae. Microscopically, con junctiva covered the cornea with absence of corneal epithelium and Bowman's membrane. Endothelial cells were pres ent without Descemet's membrane. The iris and ciliary body were composed of loose mesenchymal stroma lined posteri orly by pigment epithelial layers. The iris sphincter, dilator, and ciliary muscles were absent. There was no angle differen tiation. The lens adhered to detached reti na posteriorly and was diffusely cataractous with some retained cell nuclei in the nuclear zone. The choroid appeared nor mal, but the retinal pigment epithelium was diffusely irregular in size and pig mentation with absence of Bruch's mem-
Fig. 2 (Waring, Roth, and Rodrigues). Case 1. Right congenital cystic eye showing neuroepithelial inner lining (n), collagenous outer layer (c), and orbital fat (f). There was no organoid differentiation (hematoxylin and eosin, x l ) .
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brane. The retina showed some differen tiation into layers, but was diffusely atrophie with extensive cystoid degenera tion. Some solid areas of glial tissue were present and retinal tissue was adherentto the posterior lens capsule. No rosette for mation was seen. This gliotic retina and hyperplastic retinal pigment epithelium lined the lips of the scierai coloboma and extended a short distance into an attached cyst. The cyst wall was composed of fibrovascular tissue resembling sciera and was lined by gliotic neuroepithelial tissue containing pseudorosettes. Neuropathologic examination revealed a shortened cribriform plate. The soft palate constituted the floor of the sella turcica. The 500-g unfixed brain mani fested anteroposterior elongation of the cerebral hemispheres, relative hypoplasia of temporal lobes, and a complex anoma lous gyral pattern in the frontal and pariental lobes. No olfactory bulbs, optic nerves, or optic chiasm were visible. The corpus callosum consisted of a shelf of white matter protruding from the medial surface of each hemisphere without evi dence of interhemispheric connection. No anterior commissure, optic tracts, or lateral geniculate bodies were identified on coronal sections. The cerebellar vermis was hypoplastic. There was a de creased amount of white matter, and it was incompletely myelinated in the cere brum and cerebellum. Case 2—A 5-year-old boy was seen at Wills Eye Hospital in July 1973 because of bilateral, con genially small eyes. Surgery of the left lower eye lid had been performed previously, apparently for entropion. A left preauricular skin tag was pres ent. The child had no known systemic abnormal ities. Visual acuity was R.E.: finger counting at 5 feet, and L.E.: no light perception. The right eye was microphthalmic (Fig. 1, center). The horizontal cor nea! diameter was 8 mm with superior and inferior scleralization. A persistent pupillary membrane and a small inferonasal iris coloboma were present. Ophthalmoscopic examination appeared normal. Mucous membrane lined the anterior left orbit. On eyelid retraction, a small pigmented mass resem-
NOVEMBER, 1976
bling an eyeball was seen deep in the orbital recess. A moderately firm, 2-cm mass was palpated through the lower eyelid but was not apparent on inspection. The clinical diagnosis was right microphthalmos with iris coloboma and left microphthalmos with orbital cyst. To facilitate fitting a cosmetic prosthesis in the left orbit, the cyst and microphthalmic eye were surgically excised. After a lateral canthotomy, a small eyeball was identified superiorally. A large cyst was attached to the eyeball and filled the inferior orbit. This ruptured near the end of the dissection, releasing a clear yellowish serous fluid. PATHOLOGIC
DESCRIPTION—The
eye
measured 11 x 9 x 12 mm and the cyst, 48 x 38 mm (Fig. 3). Grossly, the sciera showed a posterior inferior coloboma ex tending into the attached cyst. Micro scopically, the cornea was covered by stratified squamous epithelium without Bowman's membrane. The anterior stroma showed avascular scarring. Descemet's membrane and the endothelium were intact. The chamber angle, iris, and ciliary body appeared normal. The large lens was posteriorly displaced, adhered to the retina, and showed a homogeneous eosinophilic cortex without recognizable fiber arrangement. Remnants of the tunica vasculosa lentis were present posteriorly. The partially detached retina was com posed predominantly of disorganized
Fig. 3 (Waring, Roth, and Rodrigues). Case 2. Gross specimen of left eye. Microphthalmic eye on left attached to large cyst on right. Rule calibrated in millimeters (x0.5).
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glial tissue with focal areas showing a lamellar pattern of neurons and rod and cone cells. Posteriorly, the retina was at tached to a mass of glial tissue that ex tended into the attached cyst (Fig. 4). The retinal pigment epithelium, Bruch's membrane, and choroid extended through the coloboma and terminated abruptly a short distance into the cyst. The thick sciera continued posteriorly to surround the cyst which was lined by a variably thick layer of glial tissue (Fig. 5) with rare rosette formation. Case 3—A 10-month-old white boy was admitted to Wills Eye Hospital on June 8, 1973. The mother had rubella in the fourth month of pregnancy. The child was born prematurely weighing 1,680 g (3 lb, 12 oz). Multiple aspirations of bilateral orbital cysts had been performed. The child exhibited mental retardation and poor muscle tone, but had no other systemic abnormalities. Visual acuity was R.E.: light perception, and L.E.: no light perception (Fig. 1, bottom). The microph thalmic right eye was displaced inferonsally in the orbit. The clear cornea was about 6 mm in diameter and the anterior chamber and iris were normal. A thin, bluish cyst measured 4 cm in diameter, pro truded from beneath the right upper eyelid, and transilluminated easily. There was distortion of the left eyelids from previous surgery. On the left a
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small scarred microphthalmic globe was displaced inferonasally and no cyst could be palpated. Scarred conjunctiva lined the eyelids and globe. Aspiration of the right cyst removed about 10 ml of clear yellow fluid and allowed the microph thalmic globe to return to a more central position (Fig. 6). The cyst gradually enlarged over the next few months and protruded between the eyelids. It collapsed after a second aspiration, but subsequent ly became distended. On March 20, 1974, the cyst was surgically excised and ruptured during the dissection. There was no direct connection between the cyst and the globe. HlSTOPATHOLOGIC
DESCRIPTION—
The cyst wall consisted of an outer layer of vascularized fibroadipose tissue with scattered foci of hypoplastic neuroglial tissue on the inner surface. DISCUSSION
The clinician should suspect microphthalmos with cyst in an individual with a small eye associated with a visible or palpable mass behind the lower eyelid. Since true anophthalmia is rare, cases without clinically detectable ocular struc tures in the orbit are more likely to have either a congenital cystic eye or microphthalmos with cyst. 1 - 5 Orbital ultrasound
Fig. 4 (Waring, Roth, and Rodrigues). Case 2. Left eye. Microphthalmic globe (m) with dislocated cataractous lens, gliotic tissue (g) filling large choroidal and scierai coloboma, and two-layered cyst (c) (ruptured posteriorly). Arrow indicates area shown in Figure 5 (hematoxylin and eosin, x l ) .
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Fig. 5 (Waring, Roth, and Rodrigues). Area of cyst wall shown by arrow in Figure 4. N indicates neuroepithelial inner lining resembling retina; C, collagenous outer layer resembling sciera (hematoxylin and eosin, x80).
is valuable in demonstrating rudimentary ocular and cystic structures in difficult cases. The clinical manifestations of microphthalmos with cyst are variable (Fig. 1). This nonheritable condition some times has a familial occurrence. 2 There is no predisposition for sex or laterality. Among 74 cases, Natanson 3 found 23 on the right side, 22 on the left side, and 20 bilaterally. No definite association with systemic abnormalities has been detected, although central nervous system defects 4,5 (Cases 1 and 3), such as meningoencephalocoele 6 and hydrocephalus, 3 and cardiac, 3,5,7 urogenital 4,5 (Case 1), fa cial 4 - 7 (Case 1), and skeletal 4 abnormali-
Fig. 6 (Waring, Roth, and Rodrigues). Case 3. Right eye. After aspiration of superior cyst, microphthalmic globe assumed a more central position. Cyst enlarged again and was excised, leaving a cosmetically acceptable globe.
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ties may occur. Natanson 3 found systemic anomalies in only eight of 74 cases. In most cases the eyelids are normal. Ehlers 8 found ten instances of microphthalmos with cyst among 15 cryptophthalmic eyes in which the globe was care fully described. The microphthalmic eye is often ob scured within the orbit by conjunctival folds or by a large cyst. Extreme retrac tion of the eyelids sometimes reveals uveal pigmentation that indicates the lo cation of the eye (Cases 2 and 3). Aspira tion 9 (Case 3) or excision 10 of the cyst may reveal a microphthalmic eye. Size of the cystic component varies. It may be small enough to escape clinical detection (Case 2) and, in cases of extreme microphthalmos, may lead to the misdiagnosis of anophthalmia. 1 1 , 1 2 The cyst usually produces a bluish bulge in the lower eyelid, is moderately firm on palpa tion, and may be visible through the con junctiva where it transilluminates easily (Case 1). In the extreme, the cyst pro trudes grotesquely between the eye lids 6 , 9 ' 1 1 (Case 3). It is usually located in the inferior orbit (Cases 1 and 2) since the embryonic fissure from which it develops is located inferiorly. However, the cyst is present beneath the upper eyelid in about 6% of cases 3,13 (Case 3), either because it is large enough to extend around the globe superiorly or because it arose from an atypical superior coloboma. A congen ital cystic eye frequently has protrusion of the upper eyelid, 14 but in our Case 1, the cyst was not apparent clinically. Histopathologically, the cyst is a twolayered structure. The inner layer is com posed of gliotic neuroretinal tissue 1 that may show retinal architecture, 7 · 10 photoreceptor differentiation, or rosette forma tion. 13 It may proliferate profusely enough to fill the fibrous capsule. 1 5 The outer layer consists of vascularized con nective tissue and occasionally contains cartilage. 5 ' 1 5 - 1 7
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While the structure of the cyst is mo notonously predictable, the microphthal mic eye presents a wide spectrum of ab normal development. 3 · 5 ' 1 5 The anterior segment may appear nearly normal (Case 1), may have recognizable anomalous structures such as hypoiridia and iridocorneal adhesions 7 (Case 2), or may dis play marked derangement. The lens is often large, dislocated, and cataractous, 1 while the vitreous body is usually fibrotic and vascularized. The retina may show focal preservation of its architecture, but is usually disorganized, gliotic, detached, and folded. 1 · 2,5 The retinal pigment epi thelium and choroid frequently extend through the mouth of the scierai colobo ma a short distance into the cyst, but they do not line the cyst wall 1 5 (Cases 1 and 2). The findings on the contralateral side vary (Fig. 1); the other orbit may contain a congenital cystic eye (Case 2), microph thalmos with cyst (Case 3), a microph thalmic eye with vision (Case 1), or a normal eye. 2 ' 12 The congenital cystic eye (Case 1) is histopathologically similar to the cystic portion of microphthalmos with cyst. i4,i6,i7 S i n c e t n e optic vesicle has not invaginated, no anterior segment struc tures are present, although an abortive attempt at invagination may produce nonattachment of the retina and a lens rem nant. 17 Connections between the cyst and the central nervous system occur rarely. 1 ' 18 The optic stalk apparently develops enough to obliterate its cavity and to prevent leakage of cerebrospinal fluid after excision of the cyst. The yellow fluid within the cyst resembles cerebrospinal fluid in its glucose, protein, and chloride concentrations. 6 Confusion with orbital meningoencephaloceles is unusual, since these often increase in size with crying and demonstrate defects in the posterior or medial orbit on roentgenographic ex amination.
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Case 1 showed anomalies in the forma tion of median structures of the brain (agenesis of the corpus callosum), the face (bilateral cleft lip and palate), and the eyes (failure of embryonic fissure clo sure). Agenesis of the corpus callosum is associated with ocular anomalies in about 25% of cases. 19 The pathogenesis of microphthal mos with cyst was demonstrated by von Szily 20 in rabbits, where autosomal-dominant inheritance can occur. In humans, the embryonic fissure forms during the invagination of the optic vesicle and optic stalk at the 5- to 8-mm stage of gestation. 21 The fissure allows the hyaloid vascular system to enter the future vitreous cavity and the sprouting nerve fibers to grow from the retina to the lateral geniculate body. The embryonic fissure begins to close centrally at about the 8-mm stage and fuses both posteriorly and anteriorly by the 20-mm stage. Improper fusion of the lips of the fissure may produce a defect in the neuroectodermal and uveal tissues, manifesting as a typical coloboma consisting of a layer of sciera lined by a thin membrane of maldeveloped neuroectoderm. Proliferation of the neuroectoderm at the lips of the persistent embry onic fissure may form a cyst, the cavity of which is continuous with the space be tween the two layers of the optic cup 2 0 (Fig. 7). The cyst sometimes originates from the optic nerve. 9 Four morphologic variations are then possible. 3 · 22 If both sides of the embryon ic fissure proliferate, two separate cysts in communication with the future subretinal space result. 23 If only one lip of the fis sure proliferates, a single cyst occurs. 12 Fusion of the two cysts at each lip of the fissure results in a uniocular cyst with a cavity continuous with the future subre tinal space (Cases 1 and 2). If the wall of the cyst separating the vitreous cavity from the future subretinal space is absent,
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Fig. 7 (Waring, Roth, and Rodrigues). Probable mechanism of formation of microphthalmos with cyst is proliferation of the inner neuroectodermal layer at the edge of the embryonic fissure. Cyst is originally continuous with the space between the two layers of the optic cup.
the cyst communicates directly with the vitreous cavity. 15 Aspiration of the cyst is the simplest management and, while the cyst usually recurs 6 (Case 3, right eye; Fig. 6), repeat ed aspiration sometimes produces perma nent disappearance 9 (Case 3, left eye). Excision of the cyst alone is possible if there is minimal attachment to the globe, and may leave a cosmetically acceptable eye 1 3 (Case 3, right eye). Removal of the eye and cyst usually necessitates orbital or eyelid reconstruction for prosthetic fit ting. 1 SUMMARY
Three patients had microphthalmos with cyst in one orbit and contralateral congenital cystic eye, microphthalmos alone, or microphthalmos with cyst. Four eyes were examined histopathologically. The microphthalmie eye demonstrated a spectrum of anterior segment abnormali ties, retinal disorganization and gliosis, and a choroidal and scierai coloboma. The cyst connected to the coloboma con sisted of an outer fibrovascular layer and inner gliotic neuroectodermal layer. The cyst probably originated from proliféra-
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tion of neuroectodermal tissue at the edge of a persistently open embryonic fissure. Treatment consisted of multiple aspira tions of the cyst, excision of the cyst alone, and excision of both the microphthalmic eye and cyst. ACKNOWLEDGMENT
Joseph Flanagan, M.D., allowed us to report Case 3.
REFERENCES 1. Kok-van Alphen, C. C , Manschot, W. A., Frederiks, E., and van Beusekom, G. T.: Microphthalmus and orbital cyst. Ophthalmologica 167:389, 1973. 2. Makley, T. A., Jr., and Battles, M.: Microphthalmos with cyst. Report on two cases in the same family. Survey Ophthalmol. 13:200, 1969. 3. Natanson, L.: Über Mikrophthalmus and Anophthalmus congenitus mit serösen Orbitopalpebralcysten. Albrecht von Graefe's Arch. Ophthal mol. 67:185, 1908. 4. von Hippel, E.: Über die Beziehungen von Mikrophthalmus mit Unterlidcyste zu allgemeinen Missbildungen, besonders zum Lindauschen Symptomenkomplex. Albrecht von Graefe's Arch. Ophthalmol. 132:25, 1934. 5. Yanoff, M., Ballian, L. R., and Niederer, B. S.: Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am. J. Ophthalmol. 70:391,1970. 6. Ladenheim, J., and Metrick, S.: Congenital microphthalmos with cyst formation. Am. J. Ophthalmol. 41:1059, 1956. 7. Arstikaitis, M.: A case report of bilateral mi crophthalmos with cysts. Arch. Ophthalmol. 82:480, 1969. 8. Ehlers, N.: Cryptophthalmos with orbitopalpebral cyst and microphthalmos (report of a bilateral case). Acta Ophthalmol. 44:84, 1966. 9. Kleberger, E., and Stolowsky, R. B.: Eine aussergewöhnlich grosse Orbitalzyste mit mächtiger
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Erweiterung der knöchernen Orbita. Klin. Monantsbl. Augenheilkd. 133:218, 1958. 10. Briggs, R. M., Chase, R. A., and Dellaporta, A.: Unilateral congenital orbital cyst with microph thalmos. Plastic Reconstr. Surg. 41:376, 1968. 11. Lim, G., and Bejec, L. C : Congenital cystic microphthalmos. Philippine J. Ophthalmol. 5:93, 1973. 12. Weyman, M. F.: Microphthalmos with cyst formation. Am. J. Ophthalmol. 8:214, 1925. 13. May, C. H., and Holden, W. A.: A case of microphthalmos with upper-lid cyst. Arch. Ophthal mol. 35:424, 1906. 14. Dollfus, M. A., Marx, P., Langlois, J., Clem ent, J. C , and Forthomme, J.: Congenital cystic eyeball. Am. J. Ophthalmol. 66:504, 1968. 15. Treacher-Collins, E.: Microphthalmos with cystic protrusion from the globe. Trans. Ophthal mol. Soc. U. K. 17:254, 1897. 16. Helveston, E. M., Malone, E., Jr., and Lashmet, M. H.: Congenital cystic eye. Arch. Ophthal mol. 84:622, 1970. 17. Taylor, S. J., and Treacher-Collins, E.: Con genially malformed cystic eye. Trans. Ophthalmol. Soc. U. K. 26:177, 1906. 18. Bonner, J., and Ide, C. H.: Astrocytoma of the optic nerve and chiasm associated with micro phthalmos and orbital cyst. Br. J. Ophthalmol. 58: 828, 1974. 19. Saraux, H., Biais, B., and Chatellier, P.: Anomalies oculaires et malformations des structures médianes du cerveau antérieur. Ann. Oculistique 202:241, 1969. 20. von Szily, A.: Die Ontogenese der idiotypischen (erbbildlichen) Spaltbildungen des Auges, des Mikrophthalmus und der Orbitalcysten. Zeitschr. Anat. 74:1, 1934. 21. O'Rahilly, R.: The early development of the eye in staged human embryos. Contrib. Embryology 38:1, 1966. 22. Mann, I.: Developmental Abnormalities of the Eye, 2nd ed. Philadelphia, J. B. Lippincott Co., 1957, pp. 79-94. 23. Baylis, H., Bartlett, R., and Cies, W.: Re construction of the lower lid in congenital microph thalmos and anophthalmos. Ophthalmic Surg. 6:36, 1975.