Hypoplasia Marjorie
A.
of the
Optic
Nerve
Mosier, MD; Marc F. Lieberman, MD; W. Richard Green, MD; David L. Knox, MD
Premorbid ophthalmoscopic and histopathologic findings were correlated in a case of bilateral optic nerve hypoplasia in
9-month-old infant with bilateral hydranThe double-ring sign was due to an extension of retina and retinal pigment epithelium (RPE) over the outer portion of the lamina cribrosa. The outer ring was the junction between sclera and lamina cribrosa, and the inner ring was the termination of the RPE. The center of the inner ring was the hypoplastic nerve head, which appeared whitish because of fibroglial tissue surrounding the central retinal vessels where they entered the optic nerve head. We speculate that an in utero vascular insult, after the third month of development, led to cystic cavitation of the anterior cerebral hemispheres, with subsequent retrograde degeneration of developing retinal ganglion cells. a
encephaly.
(Arch Ophthalmol 96:1437-1442, 1978)
is available in cases with major extraocular anomalies. Absence of retinal ganglion cells, the nerve fiber layer, and nerve fibers within the optic nerve have been described in otherwise normal eyes in patients with osteogenesis imperfecta,1" hy¬ dranencephaly,2"22 and anencephaly.21"2" Only one of these reports described the appearance of the disc. In that case there were multifocal retinal pigmentation and widespread retinal atrophy, probably repre¬ senting additional congenital de¬ fects.2" This report gives the clinical and postmortem findings in the case of a patient with hydranencephaly whose only ocular anomalies were hypoplastic optic nerves. We advance a histo¬ pathologic explanation of the double-
ring sign2 (peripapillary halo) is
hypoplasia Opticgenital malformation, increasingly nerve
a con¬
once con¬
sidered
rare
but
now
recognized.'"7 There is no correlated description, however, of both the clin¬
ical appearance of the fundus and the
histopathologic findings
in
an
Accepted
for publication Nov 9, 1977. From the Eye Pathology Laboratory, Wilmer Institute, and Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore. Dr Mosier is currently with the Department of Ophthalmology, University of California, Irvine.
Reprint requests Eye Pathology Laboratory, Hopkins Hospital, 600 N Wolfe St, Balti(Dr Green). to
Johns
more, MD 21205
secondary optic atrophy resulting from areas of cerebral destruction by the hydranencephaly.
other¬
wise normal eye. In most of the reported cases, there are no other ocular or systemic abnormalities, and no histologie studies have been done in those affected eyes.8"18 Histologie description of hypoplasia
seen
with this condition. We also discuss the possible mechanisms of hypopla¬ sia, proposing a sequence of in utero
REPORT OF A CASE Clinical Findings This boy was the Rh-positive product of 40-week gestation in an Rh-negative mother. Delivery was complicated by premature rupture of membranes followed by precipitate labor. The birth weight was 3.3 kg. The one-minute Apgar score was nine. The results of the infant's serologie test for syphilis were negative; titers to cytomegalo virus, toxoplasmosis, and ru¬ bella obtained at 15 weeks of age were negative; the herpes simplex titer was a
1:16. At 2 months of age, he was referred for evaluation because of suspected blindness. Examination showed a well-formed infant
who was active and moderately irritable. The head had a slightly increased anteroposterior diameter. It transilluminated brightly except in the occipital and midsagittal areas. The eye movements were wandering, with some horizontal nystag¬ mus. Setting-sun eyes were noted. There were no following movements or blink to bright light. The pupils were 4 mm and round. There was no direct or consensual reaction to light, but both pupils moved with blinking. The media were clear. Both eyes showed the typical double-ring sign of the optic nerve head. The right optic disc appeared one-half normal size, with a large distinct area of hyperpigmentation from 9 to 12 o'clock in the peripapillary cuff or halo (the "double-ring" sign, Fig 1). The left optic disc had a similar appearance but with less prominent pigmentation in the halo zone (Fig 2). Foveal light reflexes were absent bilaterally. Retinal vessels appeared normal. The fundus was hypopigmented with a distinct choroidal pattern (Fig 1 and 2). When examined at 3'/2 months of age, the child had a greatly enlarged head circum¬ ference and a generalized depression of motor activity and reflexes. The doll's-eyes sign was also absent. A ventricular aspi¬ rate showed lymphoid mononuelear cells and some cells of uncertain origin. Chroma¬ tograph}' of urine amino acids showed no abnormalities. X-ray films of the skull and an echogram were normal. An EEG showed an almost flat tracing over the right frontal area, suggesting an extensive lesion of the anterior cortex. A ventriculogram showed two large communicating cavities. There was no evidence of a cortical mantle except oecipitally. At this time, a shunt was placed between the cerebral ventricular and peritoneal cavities. Five months later the patient died, at the age of 9 months, from fulmi¬ nant
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meningoperitonitis.
Pathologic Findings On
opening the cranial cavity,
an
exten-
sive to
purulent meningeal exúdate was
seen
the entire visible surface of the brain. Brain weight was 740 gm. Large, bilateral, fluid-filled cysts with trans¬ parent membranes replaced the frontal, parietal, and superior aspect of the tempo¬ ral lobes (Fig 3). A thin strip of cortex in the anterior midline, lateral to the superior sagittal sinus, was preserved. The fornix and corpus callosum could be seen through the collapsed cysts. The occipital cortex, cerebellum, and brain stem were well developed and grossly normal in ap¬ pearance. The carotid arteries were of normal size and patency; the circle of Willis was likewise unremarkable. Microscopically, the walls of the mem¬ branous cysts were of meningeal origin, without ependymal elements. Immediately adjacent cortex showed surface gliosis and focal abnormalities of sulcation (polymicrogyria). Elsewhere, however, the cytologie development of the brain was quite normal, including the occipital and inferior cover
temporal cortex, cerebellum, posterior diencephalon, brain stem, and cranial other than nerve II. The intracranial optic nerves and chiasm appeared small and slightly discolored. No other systemic abnormalities were found at nerves
autopsy. Gross examination of the eyes showed normal globes, but optic nerves of inappro¬ priately small diameter: 2 mm rather than the 3 to 4 mm expected at this age. After sectioning, the globes revealed macroscopically normal anterior structures and normal retinas with Lange's folds. The peripapillary pigmented lesions seen on ophthalmoscopy were visible. On microscopic examination, both right and left eyes showed the same pathologic findings. The retinas were remarkable for the total absence of ganglion cell and nerve fiber layers in contrast to the preservation of normal inner-nuclear, outer-plexiform, and photoreceptor cell layers (Fig 4). Otherwise, the macula, choriocapillaris, and choroid appeared normal. Although clinically albinotic, the fundus showed normal cuboidal retinal pigment epithe¬ lium (RPE) with a modest number of
typical pigment granules. The optic nerve head showed an extraor¬ dinary aberration. Normally the retina stops at the junction of sclera and lamina cribrosa, where axons arch through the papilla toward the chiasm. The retinaalong with the RPE, Bruch's membrane, and a modest choriocapillaris-traversed the outer one third of the inner surface of the lamina cribrosa in all meridians (Fig 5). This allowed passage for the central retinal vessels in only the central one third of the lamina cribrosa. The junction between the
sclera and lamina cribrosa was abrupt and normal in appearance (Fig 6). Retinal pigment epithelium extending over the lamina cribrosa area was darkly pigmented in some areas (Fig 7). Bleaching with potassium permanganate disclosed that these areas of hyperpigmentation were due to a single layer containing an increased number of RPE cells (Fig 8) as compared with other areas such as the area centralis (Fig 9). The pigment granules in the RPE cells in these areas of hyperpig¬ mentation were normal (Fig 10). The intrascleral foramen and lamina cribrosa were normal in their dimensions. No traces of neural tissue in the papilla could be detected by histological stains: VerhoeffVan Gieson for connective tissue, Luxol fast blue for myelin, and Bodian stains for axons (performed by David Bodian, MD). Hölzer stains for glia showed a monotonous glial proliferation in the compressed lami¬ na cribrosa. Anteriorly, the "choroidal" lamina cribrosa was appropriately poor in connective tissue and dominated by glia, but tightly sandwiched. The "scierai" lamina cribrosa was deficient in the thick, "robust" collagen lamellae normally seen, which were replaced in large part by a wispy reticulin-rich network. Cross sec¬ tions of the optic nerve showed narrowing of the interseptal spaces, with no nerve fibers or myelin. The double-ring appearance of the optic disc observed clinically is explained by the foregoing histopathologic findings. The outer portion of the ring was the junction between sclera and lamina cribrosa where choroid was discontinuous. Retina and RPF extended over the outer portion of the lamina cribrosa. The inner ring (central zone) or "hypoplasic nerve head" was delin¬ eated by termination of RPE that was crowded and darker at that margin. The whitish appearance of the central zone was due to glial and connective tissue surround¬ ing the central retinal vessels.
COMMENT
Optic nerve hypoplasia occurs as an
isolated disorder, both unilaterally and bilaterally.'-'8 It is also found in association with extraocular anoma¬ lies,'"-'2 most commonly in the CNS. These may be major defects—such as
hydranencephaly
or
anencephaly—or
circumscribed lesions compatible with continued development of the patient, such as septo-optic dysplasia with endocrine dysfunction.2"-12 Ge¬ netic information suggesting a mode of inheritance is sparse. These hypoplasias probably do not constitute a more
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homogeneous group, so that conclu¬ sions regarding hereditary pattern cannot be made."
Optic nerve hypoplasia is of clinical importance for two reasons: (1) it is a marker for a static pathologic condi¬ tion,1 and (2) it can be an unrecognized cause of decreased visual acuity and strabismus.2-'ls Persons with optic nerve hypoplasia may have varying loss of visual acuity.3 Visual field defects may also be present, including binasal811 and bitemporal" defects, small arcuate defects,11 altitudinal hemianopsia,' and centrocecal scotomas."
The diagnosis of hypoplasia of the optic disc is facilitated by recognition of the "double-ring sign," whose histopathologic characteristics are de¬ scribed above. Ophthalmoscopy may reveal a normal retinal vasculature, but a diminution or absence of the foveal light reflex, probably as a result of thinning of the perifoveal retina.18 Afferent pupillary defects are often present. Small optic canals on roentgenography have also been reported,'"'"' as have cases of associated aniridia.6 Apparent blindness in an infant, as in our case, or strabismus in an older child, may be the initial
complaint. The findings
in our case correspond with those described in the German literature by Kreibig of a newborn infant with osteogenesis imperfecta whose eyes at autopsy showed loss of the tertiary retinal neuron and nerve fiber layer, but with continuous pig¬ ment epithelium and retina overlying the optic stalk.1" The same observa¬ tions have been made in an anencephalic embryo'7 and in infants with anencephaly in which absence or marked reduction of retinal ganglion cells and their processes is the rule.'-'"'26 Similar histopathologic findings have been described in rodents,i8:i" cats,'"" and dogs.'2 Eyes with other anomalies have shown similar patterns. In an eye thought to have optic hypoplasia that was later removed because of acute glaucoma, the coexistence of patho¬ logic cupping of the optic disc with retinal atrophy, with sparse ganglion cells and optic nerve fibers, with pigmentary degeneration, and with
marked
gliosis
was
noted.41
The
sequence of disease in that eye is not
clear. In another patient, hydranen¬ cephaly was associated with absence of ganglion cells and paucity of nerve fibers.41 In that case, however, there were also abnormalities of very atten¬ uated retinal vessels and pronounced retinal gliosis and distortion. Hypoplasia of the optic nerve is one in a clinical spectrum of congenital anomalies involving the disc.7 The cause of the defect is not known, nor is it clear that the types of embryogenesis of all the observed cases are related. An ideal etiologic hypothesis should account for both the CNS and
Fig 1—Ophthalmoscopic, double-ring ap¬ pearance of optic nerve head, OD. Hyperpigmentation of RPE is present in outer ring zone from 9 to 12 o'clock.
retinal abnormalities
290).
in
our
The most widely held explanation of optic nerve hypoplasia is primary failure of differentiation of retinal ganglion cells.* This postulated apla¬ sia is believed to occur on or before the 17 mm stage of embryonic develop¬ ment. No mechanism for this failure
has been proposed. The assumption of some defect of development residing in the ganglion cells alone is made on the basis of the histologie findings. Another conceivable primary patho¬ genesis may be the failure of ganglion
cell development because of impaired induction of differentiation. Based on the paradigm of selected central neurons failing to mature when deprived of normal subcortical inner¬ vation,45·46 such a mechanism could explain ganglion cell hypoplasia if a retrograde version of the process were assumed. Another theoretical expla¬ nation might involve an exaggeration of the developmentally normal event
*References 1, 2, 4, 10, 12-16, 18, 30, 43.
appearance of optic head, OS. Darker RPE is present in
Fig 2.—Double-ring nerve
at 2 o'clock and
outer
zone
inner
ring ("hypoplastic
Fig 4.—Parafoveal area OD shows total absence of ganglion cell and nerve fiber layers. Inner plexiform layer and remainder of retina have a normal appearance (hematoxylin-eosin, original magnification
seen
case.
highlights the head").
Fig 3.—Collapsed bilateral large cyst involving frontal, parietal, and superior portion
of
temporal lobes.
nerve
5.—Section through center of optic disc OS shows junction of sclera and lamina cribrosa (large arrows) delineating outer ring and extension of retina and RPE over outer one third of lamina cribrosa on both sides. Termination of retina and RPE (short arrows) marks inner ring or hypoplastic nerve head (PAS, original
Fig
magnification
40).
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of "morphogenetic degeneration."47 In the earliest differentiation of the rat optic nerve, for example, bionecrosis of neuroepithelial cells at the border zone between optic stalk and retina is necessary for further development of the optic cup.48 The relevance of these findings, however, to clinically ob¬ served optic nerve hypoplasia remains unclear. The explanation of a specific ganglion cell toxic agent, such as quin¬ ine,'7 has also been advanced. For several reasons, primary failure of differentiation of ganglion cells is an unlikely cause of optic nerve hypo¬ plasia. Since ganglion cells, amacrine
cells, and horizontal cells form from common precursors, it is unlikely that injury to the stem cells could affect only one of the differentiated cell types. When this optic anomaly is
associated with other brain deforma¬ tions, there is no one central lesion corresponding to defects of retinal third-order neurons alone. In experi¬ mental studies of the effects of intrauterine injury on the develop¬ ment of the mammalian eye, various kinds of tissue malformations devel¬ op, but not the isolated absence of a single cell type.4"""'"" A more attractive hypothesis, that
Fig 6.—Higher power of junction (arrow) between sclera (S) and lamina cribrosa (LC). Retinal pigment epithelium (arrowhead) and retina extend over outer portion of lamina cribrosa (PAS, original magnification
optic nerve hypoplasia is caused by secondary degeneration of ganglion
cells and their fibers, has received little attention.21·28•·17·52 This would involve well-known patterns of reac¬ tion of nerve tissue to injury and could account for the selective loss of one kind of retinal cell. Assuming that the ocular and corti¬ cal pathologic findings of our case are a reflection of a single process, let us specify the nature and possible causes of our patient's lesions. Coherent speculation on the sequence of second¬ ary optic atrophy can then be made. The CNS anomaly in our case falls
Fig 7.—Darkly pigmented RPE (arrow) over lamina cribrosa in superior temporal area of outer ring area of right optic nerve head (PAS, original magnification 525).
200).
RPE in same area as described in Fig 7. Number of RPE cells is greatly increased (bleached for 15
Fig 8.—Partially bleached
minutes) (hematoxylin-eosin, original magnification
900).
Fig 9.—Area centralis OD shows normal concentration of RPE cells (hematoxylin-eosin, original magnification 900).
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ture."54
Fig 10.—Higher power of RPE over lamina cribrosa in area described in Fig 7. Pigment granules have a normal appearance. These granules are small and have a lancet shape (arrow). Choriocapillaris (asterisk) is also present overlying the lamina cribrosa (hema¬ toxylin-eosin, original magnification 1,450). into the spectrum of cystic disorders, which include hydranencephaly, porencephaly, and schizencephaly. All are
congenital, circumscribed, hemispher¬
ic defects occurring in utero, with minimal scarring and demonstrating various degrees of developmental dis¬ turbances in adjacent cytoarchitecture (polymicrogyria and subcortical heterotopia).51"'4 These anomalies con¬ trast with encephaloclastic lesions that occur at term or postnatally, destroy cortical tissue with only reac¬ tive changes in adjacent tissues, and form irregular defects with shaggy cystic walls.'1 Although schizencepha¬ ly has been postulated to be the result of early focal aplasia of the hemi¬ spheric walls,"'5 it is frequently indis¬ tinguishable from porencephaly. Both lesions have cystic membranes com¬ posed of both glial and ependymal elements.54 On the other hand, the hydranencephalic membrane is only glial, without ventricular rem¬ nants."'"57 The brain in our case was hydranencephalic, the result of an early insult to the embryo or fetus. The actual pathogenesis of these in utero cystic processes is rarely demon¬ strable. Vascular dysfunction is an
especially appealing explanation for those cases of porencephaly or hy¬ dranencephaly that, like ours, show
circumscribed defects in the neural territory supplied by the internal carotid arteries and their branches, sparing the inferior temporal and occipital lobes.5' "'"58 Structural defects of the carotids—such as agenesis or prenatal obstruction-are rarely seen.5' However, functional disorders of perfusion—such as ischemia from placental abruption, carotid kinking, or transient vasculitis—may be in¬ volved.54 Interestingly enough, a mon¬ key born eight weeks after partial placental abruption showed gross cys¬ tic disruption of the CNS, but only absence of ganglion cells in an other¬ wise intact retina.59 Notwithstanding the attractiveness of a theoretical circulatory insult, a multitude of other causes have been invoked for these cystic defects: fetal infection with toxoplasmosis or cy-
tomegalovirus,5' prenatal hyperther¬ mia,"" in utero irradiation,'" and
others. Whether or not these various causes share a common pathogenetic mechanism, such as vascular insuffi¬ ciency, remains a "matter of conjee-
Whatever the origin of the CNS defect in our patient, it is a funda¬ mental tenet of teratology that the timing of the prenatal injury is criti¬ cally related to the degree and type of disorder. Hydranencephaly is thought to occur after the 12th week of devel¬ opment.51 Since the brain's major venous drainage system is developed by the 80 mm stage (12 weeks),51 and was intact in our case, it is likely that the responsible insult occurred after the third month. The optic nerve does not develop until after the seventh week; as noted microscopically, intrascleral dimensions of the nerve were normal in our material. Given the prolonged period of retinal ganglion cell differentiation—from the 12 mm to 170 mm stage (22 weeks)"2—an insult during the second trimester could account for both the hydranen¬ cephaly and postulated retrograde degeneration of retinal axons. Hence, the interface of papilla and retina would have disappeared while retinal growth proceeded. The hypertrophy and hyperplasia of the RPE over the lamina cribrosa may be the reactive markers of axonal death. An intriguing sidelight of a vascu¬ lar hypothesis is that, in adults with anterior ischemie optic neuropathy, variable defects in acuity, visual fields, and ocular laterality are also
Although optic nerve hypoplasia probably not a homogeneous set of
seen.
is
disorders,
some
cases
may reflect utero with
secondary optic atrophy in
the localization in time and site of injury determining the extent of visual impairment. For example, binasal field defects alone may reflect the later development of uncrossed fibers.28 Similarly, unilateral cases of optic nerve hypoplasia may reflect a discrete prechiasmal insult during development. If the exogenous injury is extensive and early enough, gross extraocular defects (such as the hydranencephaly in our case) may appear. This study was supported in part by research grant EYO 1684-02 (Dr Mosier) and 1 ROÍ EY 168-01 (Dr Green) from the National Eye Insti¬ tute.
Barbara W. Hudson, MD, Rosewood State referred the
Hospital, Owings Mills, Md, patient.
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References 1. Edwards WC, Layden WE: Optic nerve Am J Ophthalmol 70:950-959, 1970. 2. Walton DS, Robb RM: Optic nerve hypoplasia. Arch Ophthalmol 84:572-578, 1970. 3. Gardner HB, Irvine AR: Optic nerve hypoplasia with good visual acuity. Arch Ophthalmol 88:255-258, 1972. 4. Billson FA: The clinical significance of optic nerve hypoplasia. Trans Ophthalmol Soc NZ 25:179-180, 1973. 5. Krzystkowa K, Mirkiewicz-Sieradzka B, Bryk E: Dysplasia of the optic disk. Klin Oczna 43:731-735, 1973. 6. Layman PR: Optic nerve hypoplasia in aniridia, in Smith JL, Glaser JS (eds): Neurophthalmology: Symposium of the University of Miami and the Bascom Palmer Eye Institute. St Louis, CV Mosby Co, 1973, chap 2, vol 7, pp 10-13. 7. Jensen PE, Kalina RE: Congenital anomalies of the optic disk. Am J Ophthalmol 82:27-31, 1976. 8. Schwarz 0: Ein Fall von mangelhafter Bildung (Hypoplasie) beider Sehnerven. Albrecht von Graefes Arch Klin Ophthalmol 90:326-328, 1915. 9. Cords R: Einseitige Kleinheit der Papille. Klin Mbl Augenheilk 71:414-418, 1923. 10. Scheie HG, Adler FH: Aplasia of the optic nerve. Arch Ophthalmol 26:61-70, 1941. 11. Missiroli G: Una nuova sindrome congenita a carattere famigliare: Ipoplasia del nervo ottico ed emianopsia binasale. Boll Ocul 26:683-698, 1947. 12. Jerome B, Forster HW: Congenital hypoplasia (partial aplasia) of the optic nerve. Arch Ophthalmol 39:669-672, 1948. 13. Boyce DC. Hypoplasia of the optic nerve. Am J Ophthalmol 34:888-889, 1951. 14. Smith HE: Aplasia of the optic nerve: Report of three cases. Am J Ophthalmol 37:498\x=req-\ 504, 1954. 15. Kytila J, Miettinen P: On bilateral aplasia of the optic nerve. Acta Ophthalmol 39:416-419, 1961. 16. Somerville F: Uniocular aplasia of the optic nerve. Br J Ophthalmol 46:51-55, 1962. 17. McKinna AJ: Quinine induced hypoplasia of the optic nerve. Can J Ophthalmol 1:261-266, 1966. 18. Ewald RA: Unilateral hypoplasia of the optic nerve. Am J Ophthalmol 63:763-767, 1967. 19. Kreibig W: \l=U"\berAplasie and Hypoplasie der Papilla nervi optici. Klin Mbl Augenheilk 135:212-223, 1959. 20. Crome L, Sylvester PE: Hydranencephaly (hydrencephaly). Arch Dis Child 33:235-245, 1958. 21. Manschot WA: Eye findings in hydranencephaly. Ophthalmologica 162:151-159, 1971. 22. Muir CS: Hydranencephaly and allied disorders. Arch Dis Child 34:231-246, 1959. 23. Rosenbaum S: Beitrage zur Aplasie des Nervus opticus. Z Augenheilk 7:200-213, 1902. 24. Mayou MS: The condition of the retina and
hypoplasia.
optic
nerves
in
anencephaly.
Trans
Ophthalmol
Soc UK 24:150-161, 1904. 25. Walsh FB: Clinical Neuro-ophthalmology. Baltimore, Williams and Wilkins, 1947, p 429. 26. Lindenberg R, Walsh FB, Sacks JG: Neuro-
Vision. Philadelphia, Lea and pp 72-73. 27. Leber T: Ueber anomale Formen der Retinitis pigmentosa. Albrecht von Graefes Arch Klin Ophthalmol 17:314-341, 1871. 28. Ellenberger C Jr, Runyan TE: Holoprosencephaly with hypoplasia of the optic nerves, dwarfism and agenesis of the septum pellucidum. Am J Ophthalmol 70:960-967, 1970. 29. Hoyt WF, Kaplan SL, Grumbach MM, et al:
pathology of Febiger, 1973,
Septo-optic dysplasia and pituitary dwarfism. Lancet 1:893-894, 1970. 30. Brook CG, Sanders MD, Hoare RD: Septooptic dysplasia. Br Med J 3:811-813, 1972. 31. Ellenberger C: Septo-optic dysplasia. Br Med J 4:552, 1972. 32. Harris RJ, Haas L: Septo-optic dysplasia with growth hormone deficiency (deMorsier syndrome). Arch Dis Child 47:973-976, 1972. 33. Glaser J: Heredeofamilial disorders of the optic nerve Goldberg M (ed): Genetic and Metabolic Eye Disease. Boston, Little Brown & Co, 1974, chap 19, pp 463-486. 34. Seeley RL, Smith JL: Visual field defects in optic nerve hypoplasia. Am J Ophthalmol 73:882-889, 1972. 35. Boynton JR, Pheasant TR, Levine MR: Hypoplastic optic nerves studied with B-scan ultrasonography and axial tomography of the optic canals. Can J Ophthalmol 10:473-481, 1975. 36. Layman PR, Anderson DR, Flynn JT: Frequent occurrence of hypoplastic optic disks in patients with aniridia. Am J Ophthalmol 77:513\x=req-\ 516, 1974. 37. Mann I: Developmental Abnormalities of the Eye. London, Cambridge University Press, 1957, pp 50-55. 38. Brueckner R: Spaltlampenmikroskopie and Ophthalmoskopie am Auge von Ratte und Maus. Doc Ophthalmol 5-6:452-554, 1951. 39. Bein HJ: \l=U"\bervererbliche Aplasie des Sehnerven bei der Maus. Ophthalmologica 113:12\x=req-\ 37, 1947. 40. Zeeman WPC, Tumbelaka R: Das zentrale und periphere optische System bei einer kongenital blinden Katze. Albrecht von Graefes Arch Klin Ophthalmol 91:242-263, 1916. 41. Szymanski M: Les alterations retiniennes dansl'oeil d'un chat prive de papille. Bull Soc Ophthalmol Fr 39:265-272, 1926. 42. Saunders LZ, Rubin LF: Ophthalmic Pathology of Animals. New York, S Harger, 1975, pp 155-158. 43. Whinery RD, Blodi FC: Hypoplasia of the optic nerve: A clinical and histopathologic correlation. Trans Am Acad Ophthalmol Otolaryngol 67:733-738, 1963. 44. Hill K, Cogan DG, Dodge PR: Ocular signs associated with hydraencephaly. Am J Ophthal-
Downloaded From: http://archopht.jamanetwork.com/ by a Michigan State University User on 06/14/2015
mol 51:267-275, 1961. 45. Mottet K: The effect of the removal of somatopleur on the development of motor and sensory neurons in the spinal cord and ganglia. J Comp Neurol 96:519-553, 1952. 46. Black DD: Study of an atypical cerebral cortex. J Comp Neurol 23:351-369, 1913. 47. Kuwabara T, Weidman TA: Development of the prenatal rat retina. Invest Ophthalmol 13:725-739, 1974. 48. Kuwabara T: Development of the optic nerve of the rat. Invest Ophthalmol 14:732-745, 1975. 49. Hicks SP: Mechanism of radiation anencephaly, anophthalmia, and pituitary anomalies: Repair in the mammalian embryo. Arch Pathol 57:363-378, 1954. 50. Hicks SP, D'Amato CJ: Effects of radiation on the developing embryo and fetus, in Progress in Gynecology. New York, Grune and Stratton, 1963, vol 4, pp 65, 70. 51. Silverstein AM, Parshall CJ, Osburn BI, et al: An experimental virus-induced retinal dysplasia in the fetal lamb. Am J Ophthalmol 72:22-34, 1971. 52. Andersen SR, Bro-Rasmussen F, Tygstrup I: Anencephaly related to ocular development and malformation. Am J Ophthalmol 64:559-566, 1967. 53. Halsey JH, Allen N, Chamberlin HR: The morphogenesis of hydranencephaly. J Neurol Sci 12:187-217, 1971. 54. Friede RL: Developmental Neuropathology. New York, Springer-Verlag, 1975, pp 102-122. 55. Yakovlev PI, Wadsworth RC: Schizencephalies: A study of the congenital clefts in the cerebral mantle: Part II. J Neuropathol Exp Neurol 5:169-206, 1946. 56. Escourolle R, Poirier J: Manual of Basic Neuropathology. Philadelphia, WB Saunders Co, 1973, pp 173-174. 57. Tedeschi CG (ed): Neuropathology: Methods and Diagnosis. Boston, Little Brown & Co, 1970, p 603. 58. Lindenberg R, Swanson PD: Infantile hydranencephaly: A report of five cases of infarction of both cerebral hemispheres in infancy. Brain 90:839-850, 1967. 59. Myers RE: Cystic brain alteration after incomplete placental abruption in monkey. Arch Neurol 21:133-141, 1969. 60. Hartley WJ, Alexander G, Edward MJ: Brain cavitation and micrencephaly in lambs
exposed
to
prenatal hyperthermia. Teratology
9:299-304, 1974.
61. Norman RM: Malformations of the nervous system, birth injury and diseases of early life, in Greenfield's Neuropathology. London, Edward Arnold, 1963, pp 324-440. 62. Mann I: The Development of the Human Eye. London, British Medical Association, 1964, pp 68-149.
A.
of the
Optic
Nerve
Mosier, MD; Marc F. Lieberman, MD; W. Richard Green, MD; David L. Knox, MD
Premorbid ophthalmoscopic and histopathologic findings were correlated in a case of bilateral optic nerve hypoplasia in
9-month-old infant with bilateral hydranThe double-ring sign was due to an extension of retina and retinal pigment epithelium (RPE) over the outer portion of the lamina cribrosa. The outer ring was the junction between sclera and lamina cribrosa, and the inner ring was the termination of the RPE. The center of the inner ring was the hypoplastic nerve head, which appeared whitish because of fibroglial tissue surrounding the central retinal vessels where they entered the optic nerve head. We speculate that an in utero vascular insult, after the third month of development, led to cystic cavitation of the anterior cerebral hemispheres, with subsequent retrograde degeneration of developing retinal ganglion cells. a
encephaly.
(Arch Ophthalmol 96:1437-1442, 1978)
is available in cases with major extraocular anomalies. Absence of retinal ganglion cells, the nerve fiber layer, and nerve fibers within the optic nerve have been described in otherwise normal eyes in patients with osteogenesis imperfecta,1" hy¬ dranencephaly,2"22 and anencephaly.21"2" Only one of these reports described the appearance of the disc. In that case there were multifocal retinal pigmentation and widespread retinal atrophy, probably repre¬ senting additional congenital de¬ fects.2" This report gives the clinical and postmortem findings in the case of a patient with hydranencephaly whose only ocular anomalies were hypoplastic optic nerves. We advance a histo¬ pathologic explanation of the double-
ring sign2 (peripapillary halo) is
hypoplasia Opticgenital malformation, increasingly nerve
a con¬
once con¬
sidered
rare
but
now
recognized.'"7 There is no correlated description, however, of both the clin¬
ical appearance of the fundus and the
histopathologic findings
in
an
Accepted
for publication Nov 9, 1977. From the Eye Pathology Laboratory, Wilmer Institute, and Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore. Dr Mosier is currently with the Department of Ophthalmology, University of California, Irvine.
Reprint requests Eye Pathology Laboratory, Hopkins Hospital, 600 N Wolfe St, Balti(Dr Green). to
Johns
more, MD 21205
secondary optic atrophy resulting from areas of cerebral destruction by the hydranencephaly.
other¬
wise normal eye. In most of the reported cases, there are no other ocular or systemic abnormalities, and no histologie studies have been done in those affected eyes.8"18 Histologie description of hypoplasia
seen
with this condition. We also discuss the possible mechanisms of hypopla¬ sia, proposing a sequence of in utero
REPORT OF A CASE Clinical Findings This boy was the Rh-positive product of 40-week gestation in an Rh-negative mother. Delivery was complicated by premature rupture of membranes followed by precipitate labor. The birth weight was 3.3 kg. The one-minute Apgar score was nine. The results of the infant's serologie test for syphilis were negative; titers to cytomegalo virus, toxoplasmosis, and ru¬ bella obtained at 15 weeks of age were negative; the herpes simplex titer was a
1:16. At 2 months of age, he was referred for evaluation because of suspected blindness. Examination showed a well-formed infant
who was active and moderately irritable. The head had a slightly increased anteroposterior diameter. It transilluminated brightly except in the occipital and midsagittal areas. The eye movements were wandering, with some horizontal nystag¬ mus. Setting-sun eyes were noted. There were no following movements or blink to bright light. The pupils were 4 mm and round. There was no direct or consensual reaction to light, but both pupils moved with blinking. The media were clear. Both eyes showed the typical double-ring sign of the optic nerve head. The right optic disc appeared one-half normal size, with a large distinct area of hyperpigmentation from 9 to 12 o'clock in the peripapillary cuff or halo (the "double-ring" sign, Fig 1). The left optic disc had a similar appearance but with less prominent pigmentation in the halo zone (Fig 2). Foveal light reflexes were absent bilaterally. Retinal vessels appeared normal. The fundus was hypopigmented with a distinct choroidal pattern (Fig 1 and 2). When examined at 3'/2 months of age, the child had a greatly enlarged head circum¬ ference and a generalized depression of motor activity and reflexes. The doll's-eyes sign was also absent. A ventricular aspi¬ rate showed lymphoid mononuelear cells and some cells of uncertain origin. Chroma¬ tograph}' of urine amino acids showed no abnormalities. X-ray films of the skull and an echogram were normal. An EEG showed an almost flat tracing over the right frontal area, suggesting an extensive lesion of the anterior cortex. A ventriculogram showed two large communicating cavities. There was no evidence of a cortical mantle except oecipitally. At this time, a shunt was placed between the cerebral ventricular and peritoneal cavities. Five months later the patient died, at the age of 9 months, from fulmi¬ nant
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meningoperitonitis.
Pathologic Findings On
opening the cranial cavity,
an
exten-
sive to
purulent meningeal exúdate was
seen
the entire visible surface of the brain. Brain weight was 740 gm. Large, bilateral, fluid-filled cysts with trans¬ parent membranes replaced the frontal, parietal, and superior aspect of the tempo¬ ral lobes (Fig 3). A thin strip of cortex in the anterior midline, lateral to the superior sagittal sinus, was preserved. The fornix and corpus callosum could be seen through the collapsed cysts. The occipital cortex, cerebellum, and brain stem were well developed and grossly normal in ap¬ pearance. The carotid arteries were of normal size and patency; the circle of Willis was likewise unremarkable. Microscopically, the walls of the mem¬ branous cysts were of meningeal origin, without ependymal elements. Immediately adjacent cortex showed surface gliosis and focal abnormalities of sulcation (polymicrogyria). Elsewhere, however, the cytologie development of the brain was quite normal, including the occipital and inferior cover
temporal cortex, cerebellum, posterior diencephalon, brain stem, and cranial other than nerve II. The intracranial optic nerves and chiasm appeared small and slightly discolored. No other systemic abnormalities were found at nerves
autopsy. Gross examination of the eyes showed normal globes, but optic nerves of inappro¬ priately small diameter: 2 mm rather than the 3 to 4 mm expected at this age. After sectioning, the globes revealed macroscopically normal anterior structures and normal retinas with Lange's folds. The peripapillary pigmented lesions seen on ophthalmoscopy were visible. On microscopic examination, both right and left eyes showed the same pathologic findings. The retinas were remarkable for the total absence of ganglion cell and nerve fiber layers in contrast to the preservation of normal inner-nuclear, outer-plexiform, and photoreceptor cell layers (Fig 4). Otherwise, the macula, choriocapillaris, and choroid appeared normal. Although clinically albinotic, the fundus showed normal cuboidal retinal pigment epithe¬ lium (RPE) with a modest number of
typical pigment granules. The optic nerve head showed an extraor¬ dinary aberration. Normally the retina stops at the junction of sclera and lamina cribrosa, where axons arch through the papilla toward the chiasm. The retinaalong with the RPE, Bruch's membrane, and a modest choriocapillaris-traversed the outer one third of the inner surface of the lamina cribrosa in all meridians (Fig 5). This allowed passage for the central retinal vessels in only the central one third of the lamina cribrosa. The junction between the
sclera and lamina cribrosa was abrupt and normal in appearance (Fig 6). Retinal pigment epithelium extending over the lamina cribrosa area was darkly pigmented in some areas (Fig 7). Bleaching with potassium permanganate disclosed that these areas of hyperpigmentation were due to a single layer containing an increased number of RPE cells (Fig 8) as compared with other areas such as the area centralis (Fig 9). The pigment granules in the RPE cells in these areas of hyperpig¬ mentation were normal (Fig 10). The intrascleral foramen and lamina cribrosa were normal in their dimensions. No traces of neural tissue in the papilla could be detected by histological stains: VerhoeffVan Gieson for connective tissue, Luxol fast blue for myelin, and Bodian stains for axons (performed by David Bodian, MD). Hölzer stains for glia showed a monotonous glial proliferation in the compressed lami¬ na cribrosa. Anteriorly, the "choroidal" lamina cribrosa was appropriately poor in connective tissue and dominated by glia, but tightly sandwiched. The "scierai" lamina cribrosa was deficient in the thick, "robust" collagen lamellae normally seen, which were replaced in large part by a wispy reticulin-rich network. Cross sec¬ tions of the optic nerve showed narrowing of the interseptal spaces, with no nerve fibers or myelin. The double-ring appearance of the optic disc observed clinically is explained by the foregoing histopathologic findings. The outer portion of the ring was the junction between sclera and lamina cribrosa where choroid was discontinuous. Retina and RPF extended over the outer portion of the lamina cribrosa. The inner ring (central zone) or "hypoplasic nerve head" was delin¬ eated by termination of RPE that was crowded and darker at that margin. The whitish appearance of the central zone was due to glial and connective tissue surround¬ ing the central retinal vessels.
COMMENT
Optic nerve hypoplasia occurs as an
isolated disorder, both unilaterally and bilaterally.'-'8 It is also found in association with extraocular anoma¬ lies,'"-'2 most commonly in the CNS. These may be major defects—such as
hydranencephaly
or
anencephaly—or
circumscribed lesions compatible with continued development of the patient, such as septo-optic dysplasia with endocrine dysfunction.2"-12 Ge¬ netic information suggesting a mode of inheritance is sparse. These hypoplasias probably do not constitute a more
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homogeneous group, so that conclu¬ sions regarding hereditary pattern cannot be made."
Optic nerve hypoplasia is of clinical importance for two reasons: (1) it is a marker for a static pathologic condi¬ tion,1 and (2) it can be an unrecognized cause of decreased visual acuity and strabismus.2-'ls Persons with optic nerve hypoplasia may have varying loss of visual acuity.3 Visual field defects may also be present, including binasal811 and bitemporal" defects, small arcuate defects,11 altitudinal hemianopsia,' and centrocecal scotomas."
The diagnosis of hypoplasia of the optic disc is facilitated by recognition of the "double-ring sign," whose histopathologic characteristics are de¬ scribed above. Ophthalmoscopy may reveal a normal retinal vasculature, but a diminution or absence of the foveal light reflex, probably as a result of thinning of the perifoveal retina.18 Afferent pupillary defects are often present. Small optic canals on roentgenography have also been reported,'"'"' as have cases of associated aniridia.6 Apparent blindness in an infant, as in our case, or strabismus in an older child, may be the initial
complaint. The findings
in our case correspond with those described in the German literature by Kreibig of a newborn infant with osteogenesis imperfecta whose eyes at autopsy showed loss of the tertiary retinal neuron and nerve fiber layer, but with continuous pig¬ ment epithelium and retina overlying the optic stalk.1" The same observa¬ tions have been made in an anencephalic embryo'7 and in infants with anencephaly in which absence or marked reduction of retinal ganglion cells and their processes is the rule.'-'"'26 Similar histopathologic findings have been described in rodents,i8:i" cats,'"" and dogs.'2 Eyes with other anomalies have shown similar patterns. In an eye thought to have optic hypoplasia that was later removed because of acute glaucoma, the coexistence of patho¬ logic cupping of the optic disc with retinal atrophy, with sparse ganglion cells and optic nerve fibers, with pigmentary degeneration, and with
marked
gliosis
was
noted.41
The
sequence of disease in that eye is not
clear. In another patient, hydranen¬ cephaly was associated with absence of ganglion cells and paucity of nerve fibers.41 In that case, however, there were also abnormalities of very atten¬ uated retinal vessels and pronounced retinal gliosis and distortion. Hypoplasia of the optic nerve is one in a clinical spectrum of congenital anomalies involving the disc.7 The cause of the defect is not known, nor is it clear that the types of embryogenesis of all the observed cases are related. An ideal etiologic hypothesis should account for both the CNS and
Fig 1—Ophthalmoscopic, double-ring ap¬ pearance of optic nerve head, OD. Hyperpigmentation of RPE is present in outer ring zone from 9 to 12 o'clock.
retinal abnormalities
290).
in
our
The most widely held explanation of optic nerve hypoplasia is primary failure of differentiation of retinal ganglion cells.* This postulated apla¬ sia is believed to occur on or before the 17 mm stage of embryonic develop¬ ment. No mechanism for this failure
has been proposed. The assumption of some defect of development residing in the ganglion cells alone is made on the basis of the histologie findings. Another conceivable primary patho¬ genesis may be the failure of ganglion
cell development because of impaired induction of differentiation. Based on the paradigm of selected central neurons failing to mature when deprived of normal subcortical inner¬ vation,45·46 such a mechanism could explain ganglion cell hypoplasia if a retrograde version of the process were assumed. Another theoretical expla¬ nation might involve an exaggeration of the developmentally normal event
*References 1, 2, 4, 10, 12-16, 18, 30, 43.
appearance of optic head, OS. Darker RPE is present in
Fig 2.—Double-ring nerve
at 2 o'clock and
outer
zone
inner
ring ("hypoplastic
Fig 4.—Parafoveal area OD shows total absence of ganglion cell and nerve fiber layers. Inner plexiform layer and remainder of retina have a normal appearance (hematoxylin-eosin, original magnification
seen
case.
highlights the head").
Fig 3.—Collapsed bilateral large cyst involving frontal, parietal, and superior portion
of
temporal lobes.
nerve
5.—Section through center of optic disc OS shows junction of sclera and lamina cribrosa (large arrows) delineating outer ring and extension of retina and RPE over outer one third of lamina cribrosa on both sides. Termination of retina and RPE (short arrows) marks inner ring or hypoplastic nerve head (PAS, original
Fig
magnification
40).
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of "morphogenetic degeneration."47 In the earliest differentiation of the rat optic nerve, for example, bionecrosis of neuroepithelial cells at the border zone between optic stalk and retina is necessary for further development of the optic cup.48 The relevance of these findings, however, to clinically ob¬ served optic nerve hypoplasia remains unclear. The explanation of a specific ganglion cell toxic agent, such as quin¬ ine,'7 has also been advanced. For several reasons, primary failure of differentiation of ganglion cells is an unlikely cause of optic nerve hypo¬ plasia. Since ganglion cells, amacrine
cells, and horizontal cells form from common precursors, it is unlikely that injury to the stem cells could affect only one of the differentiated cell types. When this optic anomaly is
associated with other brain deforma¬ tions, there is no one central lesion corresponding to defects of retinal third-order neurons alone. In experi¬ mental studies of the effects of intrauterine injury on the develop¬ ment of the mammalian eye, various kinds of tissue malformations devel¬ op, but not the isolated absence of a single cell type.4"""'"" A more attractive hypothesis, that
Fig 6.—Higher power of junction (arrow) between sclera (S) and lamina cribrosa (LC). Retinal pigment epithelium (arrowhead) and retina extend over outer portion of lamina cribrosa (PAS, original magnification
optic nerve hypoplasia is caused by secondary degeneration of ganglion
cells and their fibers, has received little attention.21·28•·17·52 This would involve well-known patterns of reac¬ tion of nerve tissue to injury and could account for the selective loss of one kind of retinal cell. Assuming that the ocular and corti¬ cal pathologic findings of our case are a reflection of a single process, let us specify the nature and possible causes of our patient's lesions. Coherent speculation on the sequence of second¬ ary optic atrophy can then be made. The CNS anomaly in our case falls
Fig 7.—Darkly pigmented RPE (arrow) over lamina cribrosa in superior temporal area of outer ring area of right optic nerve head (PAS, original magnification 525).
200).
RPE in same area as described in Fig 7. Number of RPE cells is greatly increased (bleached for 15
Fig 8.—Partially bleached
minutes) (hematoxylin-eosin, original magnification
900).
Fig 9.—Area centralis OD shows normal concentration of RPE cells (hematoxylin-eosin, original magnification 900).
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ture."54
Fig 10.—Higher power of RPE over lamina cribrosa in area described in Fig 7. Pigment granules have a normal appearance. These granules are small and have a lancet shape (arrow). Choriocapillaris (asterisk) is also present overlying the lamina cribrosa (hema¬ toxylin-eosin, original magnification 1,450). into the spectrum of cystic disorders, which include hydranencephaly, porencephaly, and schizencephaly. All are
congenital, circumscribed, hemispher¬
ic defects occurring in utero, with minimal scarring and demonstrating various degrees of developmental dis¬ turbances in adjacent cytoarchitecture (polymicrogyria and subcortical heterotopia).51"'4 These anomalies con¬ trast with encephaloclastic lesions that occur at term or postnatally, destroy cortical tissue with only reac¬ tive changes in adjacent tissues, and form irregular defects with shaggy cystic walls.'1 Although schizencepha¬ ly has been postulated to be the result of early focal aplasia of the hemi¬ spheric walls,"'5 it is frequently indis¬ tinguishable from porencephaly. Both lesions have cystic membranes com¬ posed of both glial and ependymal elements.54 On the other hand, the hydranencephalic membrane is only glial, without ventricular rem¬ nants."'"57 The brain in our case was hydranencephalic, the result of an early insult to the embryo or fetus. The actual pathogenesis of these in utero cystic processes is rarely demon¬ strable. Vascular dysfunction is an
especially appealing explanation for those cases of porencephaly or hy¬ dranencephaly that, like ours, show
circumscribed defects in the neural territory supplied by the internal carotid arteries and their branches, sparing the inferior temporal and occipital lobes.5' "'"58 Structural defects of the carotids—such as agenesis or prenatal obstruction-are rarely seen.5' However, functional disorders of perfusion—such as ischemia from placental abruption, carotid kinking, or transient vasculitis—may be in¬ volved.54 Interestingly enough, a mon¬ key born eight weeks after partial placental abruption showed gross cys¬ tic disruption of the CNS, but only absence of ganglion cells in an other¬ wise intact retina.59 Notwithstanding the attractiveness of a theoretical circulatory insult, a multitude of other causes have been invoked for these cystic defects: fetal infection with toxoplasmosis or cy-
tomegalovirus,5' prenatal hyperther¬ mia,"" in utero irradiation,'" and
others. Whether or not these various causes share a common pathogenetic mechanism, such as vascular insuffi¬ ciency, remains a "matter of conjee-
Whatever the origin of the CNS defect in our patient, it is a funda¬ mental tenet of teratology that the timing of the prenatal injury is criti¬ cally related to the degree and type of disorder. Hydranencephaly is thought to occur after the 12th week of devel¬ opment.51 Since the brain's major venous drainage system is developed by the 80 mm stage (12 weeks),51 and was intact in our case, it is likely that the responsible insult occurred after the third month. The optic nerve does not develop until after the seventh week; as noted microscopically, intrascleral dimensions of the nerve were normal in our material. Given the prolonged period of retinal ganglion cell differentiation—from the 12 mm to 170 mm stage (22 weeks)"2—an insult during the second trimester could account for both the hydranen¬ cephaly and postulated retrograde degeneration of retinal axons. Hence, the interface of papilla and retina would have disappeared while retinal growth proceeded. The hypertrophy and hyperplasia of the RPE over the lamina cribrosa may be the reactive markers of axonal death. An intriguing sidelight of a vascu¬ lar hypothesis is that, in adults with anterior ischemie optic neuropathy, variable defects in acuity, visual fields, and ocular laterality are also
Although optic nerve hypoplasia probably not a homogeneous set of
seen.
is
disorders,
some
cases
may reflect utero with
secondary optic atrophy in
the localization in time and site of injury determining the extent of visual impairment. For example, binasal field defects alone may reflect the later development of uncrossed fibers.28 Similarly, unilateral cases of optic nerve hypoplasia may reflect a discrete prechiasmal insult during development. If the exogenous injury is extensive and early enough, gross extraocular defects (such as the hydranencephaly in our case) may appear. This study was supported in part by research grant EYO 1684-02 (Dr Mosier) and 1 ROÍ EY 168-01 (Dr Green) from the National Eye Insti¬ tute.
Barbara W. Hudson, MD, Rosewood State referred the
Hospital, Owings Mills, Md, patient.
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References 1. Edwards WC, Layden WE: Optic nerve Am J Ophthalmol 70:950-959, 1970. 2. Walton DS, Robb RM: Optic nerve hypoplasia. Arch Ophthalmol 84:572-578, 1970. 3. Gardner HB, Irvine AR: Optic nerve hypoplasia with good visual acuity. Arch Ophthalmol 88:255-258, 1972. 4. Billson FA: The clinical significance of optic nerve hypoplasia. Trans Ophthalmol Soc NZ 25:179-180, 1973. 5. Krzystkowa K, Mirkiewicz-Sieradzka B, Bryk E: Dysplasia of the optic disk. Klin Oczna 43:731-735, 1973. 6. Layman PR: Optic nerve hypoplasia in aniridia, in Smith JL, Glaser JS (eds): Neurophthalmology: Symposium of the University of Miami and the Bascom Palmer Eye Institute. St Louis, CV Mosby Co, 1973, chap 2, vol 7, pp 10-13. 7. Jensen PE, Kalina RE: Congenital anomalies of the optic disk. Am J Ophthalmol 82:27-31, 1976. 8. Schwarz 0: Ein Fall von mangelhafter Bildung (Hypoplasie) beider Sehnerven. Albrecht von Graefes Arch Klin Ophthalmol 90:326-328, 1915. 9. Cords R: Einseitige Kleinheit der Papille. Klin Mbl Augenheilk 71:414-418, 1923. 10. Scheie HG, Adler FH: Aplasia of the optic nerve. Arch Ophthalmol 26:61-70, 1941. 11. Missiroli G: Una nuova sindrome congenita a carattere famigliare: Ipoplasia del nervo ottico ed emianopsia binasale. Boll Ocul 26:683-698, 1947. 12. Jerome B, Forster HW: Congenital hypoplasia (partial aplasia) of the optic nerve. Arch Ophthalmol 39:669-672, 1948. 13. Boyce DC. Hypoplasia of the optic nerve. Am J Ophthalmol 34:888-889, 1951. 14. Smith HE: Aplasia of the optic nerve: Report of three cases. Am J Ophthalmol 37:498\x=req-\ 504, 1954. 15. Kytila J, Miettinen P: On bilateral aplasia of the optic nerve. Acta Ophthalmol 39:416-419, 1961. 16. Somerville F: Uniocular aplasia of the optic nerve. Br J Ophthalmol 46:51-55, 1962. 17. McKinna AJ: Quinine induced hypoplasia of the optic nerve. Can J Ophthalmol 1:261-266, 1966. 18. Ewald RA: Unilateral hypoplasia of the optic nerve. Am J Ophthalmol 63:763-767, 1967. 19. Kreibig W: \l=U"\berAplasie and Hypoplasie der Papilla nervi optici. Klin Mbl Augenheilk 135:212-223, 1959. 20. Crome L, Sylvester PE: Hydranencephaly (hydrencephaly). Arch Dis Child 33:235-245, 1958. 21. Manschot WA: Eye findings in hydranencephaly. Ophthalmologica 162:151-159, 1971. 22. Muir CS: Hydranencephaly and allied disorders. Arch Dis Child 34:231-246, 1959. 23. Rosenbaum S: Beitrage zur Aplasie des Nervus opticus. Z Augenheilk 7:200-213, 1902. 24. Mayou MS: The condition of the retina and
hypoplasia.
optic
nerves
in
anencephaly.
Trans
Ophthalmol
Soc UK 24:150-161, 1904. 25. Walsh FB: Clinical Neuro-ophthalmology. Baltimore, Williams and Wilkins, 1947, p 429. 26. Lindenberg R, Walsh FB, Sacks JG: Neuro-
Vision. Philadelphia, Lea and pp 72-73. 27. Leber T: Ueber anomale Formen der Retinitis pigmentosa. Albrecht von Graefes Arch Klin Ophthalmol 17:314-341, 1871. 28. Ellenberger C Jr, Runyan TE: Holoprosencephaly with hypoplasia of the optic nerves, dwarfism and agenesis of the septum pellucidum. Am J Ophthalmol 70:960-967, 1970. 29. Hoyt WF, Kaplan SL, Grumbach MM, et al:
pathology of Febiger, 1973,
Septo-optic dysplasia and pituitary dwarfism. Lancet 1:893-894, 1970. 30. Brook CG, Sanders MD, Hoare RD: Septooptic dysplasia. Br Med J 3:811-813, 1972. 31. Ellenberger C: Septo-optic dysplasia. Br Med J 4:552, 1972. 32. Harris RJ, Haas L: Septo-optic dysplasia with growth hormone deficiency (deMorsier syndrome). Arch Dis Child 47:973-976, 1972. 33. Glaser J: Heredeofamilial disorders of the optic nerve Goldberg M (ed): Genetic and Metabolic Eye Disease. Boston, Little Brown & Co, 1974, chap 19, pp 463-486. 34. Seeley RL, Smith JL: Visual field defects in optic nerve hypoplasia. Am J Ophthalmol 73:882-889, 1972. 35. Boynton JR, Pheasant TR, Levine MR: Hypoplastic optic nerves studied with B-scan ultrasonography and axial tomography of the optic canals. Can J Ophthalmol 10:473-481, 1975. 36. Layman PR, Anderson DR, Flynn JT: Frequent occurrence of hypoplastic optic disks in patients with aniridia. Am J Ophthalmol 77:513\x=req-\ 516, 1974. 37. Mann I: Developmental Abnormalities of the Eye. London, Cambridge University Press, 1957, pp 50-55. 38. Brueckner R: Spaltlampenmikroskopie and Ophthalmoskopie am Auge von Ratte und Maus. Doc Ophthalmol 5-6:452-554, 1951. 39. Bein HJ: \l=U"\bervererbliche Aplasie des Sehnerven bei der Maus. Ophthalmologica 113:12\x=req-\ 37, 1947. 40. Zeeman WPC, Tumbelaka R: Das zentrale und periphere optische System bei einer kongenital blinden Katze. Albrecht von Graefes Arch Klin Ophthalmol 91:242-263, 1916. 41. Szymanski M: Les alterations retiniennes dansl'oeil d'un chat prive de papille. Bull Soc Ophthalmol Fr 39:265-272, 1926. 42. Saunders LZ, Rubin LF: Ophthalmic Pathology of Animals. New York, S Harger, 1975, pp 155-158. 43. Whinery RD, Blodi FC: Hypoplasia of the optic nerve: A clinical and histopathologic correlation. Trans Am Acad Ophthalmol Otolaryngol 67:733-738, 1963. 44. Hill K, Cogan DG, Dodge PR: Ocular signs associated with hydraencephaly. Am J Ophthal-
Downloaded From: http://archopht.jamanetwork.com/ by a Michigan State University User on 06/14/2015
mol 51:267-275, 1961. 45. Mottet K: The effect of the removal of somatopleur on the development of motor and sensory neurons in the spinal cord and ganglia. J Comp Neurol 96:519-553, 1952. 46. Black DD: Study of an atypical cerebral cortex. J Comp Neurol 23:351-369, 1913. 47. Kuwabara T, Weidman TA: Development of the prenatal rat retina. Invest Ophthalmol 13:725-739, 1974. 48. Kuwabara T: Development of the optic nerve of the rat. Invest Ophthalmol 14:732-745, 1975. 49. Hicks SP: Mechanism of radiation anencephaly, anophthalmia, and pituitary anomalies: Repair in the mammalian embryo. Arch Pathol 57:363-378, 1954. 50. Hicks SP, D'Amato CJ: Effects of radiation on the developing embryo and fetus, in Progress in Gynecology. New York, Grune and Stratton, 1963, vol 4, pp 65, 70. 51. Silverstein AM, Parshall CJ, Osburn BI, et al: An experimental virus-induced retinal dysplasia in the fetal lamb. Am J Ophthalmol 72:22-34, 1971. 52. Andersen SR, Bro-Rasmussen F, Tygstrup I: Anencephaly related to ocular development and malformation. Am J Ophthalmol 64:559-566, 1967. 53. Halsey JH, Allen N, Chamberlin HR: The morphogenesis of hydranencephaly. J Neurol Sci 12:187-217, 1971. 54. Friede RL: Developmental Neuropathology. New York, Springer-Verlag, 1975, pp 102-122. 55. Yakovlev PI, Wadsworth RC: Schizencephalies: A study of the congenital clefts in the cerebral mantle: Part II. J Neuropathol Exp Neurol 5:169-206, 1946. 56. Escourolle R, Poirier J: Manual of Basic Neuropathology. Philadelphia, WB Saunders Co, 1973, pp 173-174. 57. Tedeschi CG (ed): Neuropathology: Methods and Diagnosis. Boston, Little Brown & Co, 1970, p 603. 58. Lindenberg R, Swanson PD: Infantile hydranencephaly: A report of five cases of infarction of both cerebral hemispheres in infancy. Brain 90:839-850, 1967. 59. Myers RE: Cystic brain alteration after incomplete placental abruption in monkey. Arch Neurol 21:133-141, 1969. 60. Hartley WJ, Alexander G, Edward MJ: Brain cavitation and micrencephaly in lambs
exposed
to
prenatal hyperthermia. Teratology
9:299-304, 1974.
61. Norman RM: Malformations of the nervous system, birth injury and diseases of early life, in Greenfield's Neuropathology. London, Edward Arnold, 1963, pp 324-440. 62. Mann I: The Development of the Human Eye. London, British Medical Association, 1964, pp 68-149.
