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Newborn primary congenital glaucoma: Histopathologic features of the anterior chamber filtration angle
Short Reports Newborn primary congenital glaucoma: Histopathologic features of the anterior chamber filtration angle Lynn P. Perry, MD, PhD,a,b Frederick A. Jakobiec, MD, DSc,a,b Fouad R. Zakka, MD,a,b and David S. Walton, MDb
We present histopathologic findings that have not been previously reported as associated with abnormalities of the anterior chamber angle underlying newborn primary congenital glaucoma as a distinct entity. The major histopathologic findings were partial absence and retrodisplacement of Schlemm’s canal, hypoplasia of the trabecular meshwork, broad attachment of ciliary muscle to the meshwork, and anterior insertion of hypoplastic iris with the formation of a pseudomembrane. These profound anatomic derangements explain why goniosurgery is frequently unsuccessful in cases of newborn glaucoma.
Case Report
F
or assessing the pathologic findings, the histology of two normal infant anterior segments are illustrated in Figure 1A, B. A black girl and her monozygotic twin born at 35 weeks’ gestation of nonconsanguineous parents presented at the Massachusetts Eye and Ear Infirmary at 6 days of age with apparent bilateral corneal opacifications. There was no family history of glaucoma. Ophthalmologic examination revealed an intraocular pressure of 45 mm Hg bilaterally in both children by Perkins tonometry while the children were sleeping. The patient’s right cornea was thickened, with central corneal hydrops, peripheral clouding (Figure 1C), and a shallow anterior chamber. The left cornea was homogeneously cloudy, with a deep anterior chamber. The irides of both eyes were dark brown and smooth, with no stromal collarettes. Gonioscopy was performed in the left eye during an examination under anesthesia through a window created by the removal of a small area of corneal epithelium. The iris inserted anteriorly, with minimal exposed trabecular meshwork and no visible scleral spur or ciliary body band. The angle of the right eye could not be visuAuthor affiliations: aDavid G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; bDepartment of Ophthalmology, Harvard Medical School, Boston, Massachusetts Supported in part by the Heed Foundation (LPP). Submitted March 28, 2012. Revision accepted June 13, 2012. Published online November 16, 2012. Correspondence: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 (email: [email protected]). J AAPOS 2012;16:565-568. Copyright Ó 2012 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.06.012
Journal of AAPOS
alized. Initial medical treatment was followed by the placement of a glaucoma drainage device in the left eye at 7 weeks of age. A subsequent successful mitomycin-C trabeculectomy was performed at 2 years of age. At 7 years of age, her best-corrected visual acuity was 20/60 in the left eye; the optic disk appeared normal, without cupping. With extensive corneal disease and severe glaucoma, the visual prognosis for the right eye was extremely poor, and consequently surgery was not performed. The right eye was enucleated when the girl was 8 years of age for cosmesis due to progressive buphthalmos associated with an intraocular pressure of 40 mm Hg. On gross examination, the enucleated eye measured 26 mm horizontally and vertically and 34 mm anteroposteriorly. The cornea measured 16 mm 15 mm and was densely opacified centrally. The iris was profoundly thinned and lacked surface crypts, with pigment tracking into the angle. The optic nerve head was markedly cupped. Histopathologic examination disclosed a central posterior internal stromal defect devoid of Descemet’s membrane (Figure 1D), accompanied by stromal thinning at the limbus (Figure 1E). A normal thickness Descemet’s membrane was present peripherally and formed rolled structures at the edges of the central defect (Figure 1D, inset). Peripherally, Descemet’s membrane ended without an obvious Schwalbe’s line. Bowman’s membrane was completely absent and a few small vessels were found in the anterior stroma (Figure 1F). The iris inserted anteriorly with adhesion to the trabecular meshwork (Figure 2A, B). A delicate interrupted layer of pigmented cells with fine vessels originating from the anterior surface of the iris root extended over the rudimentary chamber angle (Figure 2A-D). The smooth muscle of the ciliary body also directly attached to the meshwork without the interposition of a scleral spur (Figure 2B). The trabeculae were typically fewer in number and often compacted when compared with the normal angle structure (Figure 2C), particularly temporally. Occasionally a small bundle of displaced ciliary smooth muscle cells was situated within the pigmented membrane and attached directly to the outer trabeculae (Figure 2D). A posteriorly displaced Schlemm’s canal was juxtaposed to the trabecular meshwork only nasally (Figure 2B); it was not visible in the temporal half of the outflow pathways. There was no scleral spur. The iris stroma was hypoplastic and extremely thin with a hyperplastic sphincter muscle that extended
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FIG 1. A, Normal anterior chamber angle from the enucleated globe of a 4-week-old black girl with retinoblastoma. There is a cellular and welldeveloped trabecular meshwork (TM) with a juxtaposed Schlemm’s canal (SC). Iris stroma originates approximately at the level of the scleral spur and exhibits surface folds and an anterior condensation layer of melanocytes (case courtesy of Dr. Ralph Eagle; hematoxylin and eosin, original magnification, 100). The inset reveals the scleral spur next to the iris root onto which inserts the meridional smooth muscle (SM) bundles of the ciliary body. The trabecular meshwork is separated from the muscle by the scleral spur (H&E, 200). B, Normal anterior chamber angle of an 8-week-old white infant girl from a globe enucleated for retinoblastoma. Schlemm’s canal is interrupted and somewhat collapsed in this section (case courtesy of Dr. Ralph Eagle; H&E, 100); inset, the scleral spur is situated between the ciliary smooth muscle and the trabecular meshwork (H&E, 200). C, A 12-month-old black child with bilaterally enlarged corneas and a central opacification in the right eye. D, The right enucleated globe displayed a thickened central cornea with large central corneal opacification (CCO). The stroma is looser immediately adjacent to the posterior ulcer. The small nubbins of Descemet’s membrane (arrows) abruptly terminate at the edges of the ulcer; the right nubbin is shown in the inset with mild pigmentation of the endothelium (H&E, 25; inset, 200). E, Section through paracentral cornea lacks a continuation of posterior ulcer. Note the peripheral corneal stromal thinning (arrow) characteristic of buphthalmic eyes. The iris stroma is atrophic and there is no pupil in this section (H&E, 10). F, Slightly acanthotic corneal epithelium is devoid of an underlying Bowman’s membrane. Small blood vessels (arrows) are found in the superficial stroma (H&E, 200). ACA, anterior chamber angle; CP, ciliary processes; IS, iris stroma; SM, smooth muscle of ciliary body; SM, smooth muscle; SP, scleral spur; TM, trabecular meshwork.
toward the chamber angle (Figure 2E). The retina showed diffuse loss of ganglion cells associated with advanced optic nerve head cupping (Figure 1F).
Discussion Childhood glaucomas are a diverse group of conditions that can be associated with significant permanent vision
loss. Approximately half of all childhood glaucomas are primary congenital glaucomas (PCG) that result from hereditary nonsyndromic developmental anomalies of the anterior chamber angle structures (trabeculodysgenesis).1-4 It is useful to divide PCG into three subsets: newborn PCG, evident at birth or within the first months of life and associated with severe corneal edema; infantile
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567
FIG 2. A, A partially obstructive interrupted pigmented nasal chamber angle membrane emerges from the stroma of the iris root to cover the nasal trabecular meshwork. The iris stroma anomalously manifests a prominent bundle of smooth muscle (Masson trichrome, original magnification, 100). Inset: A clump of pigmented tissue (arrow) adheres to the trabecular meshwork in the iris region of the nasal chamber angle (periodic acid Schiff, 50). B, Ciliary smooth muscle with scattered melanocytes indicative of the patient’s race attaches directly (arrows) and broadly to the nasal trabecular meshwork. The remainder of the trabecular meshwork is covered by a vascularized (crossed arrows) pigmented chamber angle membrane extending from the stroma of the iris root. SC, retrodisplaced Schlemm’s canal (H&E, 200). C, The temporal chamber angle structures were less well developed than those nasally. The thickened iris root (arrows) inserts anteriorly and supplies a pigmented thin chamber angle membrane. There is a subjacent hypoplastic trabecular meshwork. The smooth muscle of the ciliary body shows interspersed melanocytes (H&E, 100). D, Temporal chamber angle with a pigmented membrane covering trabecular meshwork and containing an ectopic small bundle of misdirected ciliary smooth muscle cells (arrow) (H&E, 200). E, atrophic underdeveloped iris showing a thin delicate component of stroma with vessels (arrows) and a thicker bundle of aberrant smooth muscle anterior to the pigmented neuroectodermal layers (top panel). Trichrome stain showing haphazardly arranged reddish bundles of smooth muscle cells (bottom panel); the iris stroma is delicate, hypoplastic, and rarefied and harbors projecting vessels (arrow). The iris sphincter muscle was hyperplastic. (Top, periodic acid Schiff, 200; bottom, Masson trichrome, 200). F, There is deep cupping of the optic nerve head from prolonged and end-stage glaucoma. The inset demonstrates the absence of ganglion cells and a thin nerve fiber layer (arrows) (H&E, 25; inset, 100). C, cupping; CAM, chamber angle membrane; HTM, hypoplastic trabecular meshwork; IM, hyperplastic aberrant iris sphincter muscle; IS, iris stroma; LC, lens capsule and subcapsular epithelium; SM, ciliary body smooth muscle; TM, trabecular meshwork.
primary congenital glaucoma, which occurs usually within the first year of life; and late-recognized primary congenital glaucoma, diagnosed after 1 year of age. Newborn PCG2 is the most severe form on the spectrum, portending a poor
Journal of AAPOS
long-term vision prognosis compared to later onset infantile PCG. The following chamber angle anomalies were identified on pathologic examination in the current case: partial
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(temporal) absence of an otherwise retrodisplaced Schlemm’s canal and nondevelopment of the scleral spur; hypoplasia of temporal trabecular meshwork; broad attachment of ciliary muscle to the meshwork; anterior displacement of the iris insertion; and extension of vascularized, pigmented iridial tissue onto the meshwork as a partially obstructive interrupted membrane. The iris stroma was markedly hypoplastic with aberrant bundles of smooth (sphincter) muscle. The angle findings are not consistent with a Barkan’s membrane covering a normal functional aqueous outflow system.5 Unlike infantile PCG, which responds well to goniosurgery, newborn PCG does not respond well to standard-angle surgical approaches, including trabeculotomy and goniotomy.2-4 The corneal opacification in this case could be considered to be a Peters anomaly, which typically presents with rudimentary Descemet’s membrane that ends abruptly in the central cornea and typically has associated iris strands. The normal thickness of Descemet’s membrane, rolled structures at the edges of the defect, and
Volume 16 Number 6 / December 2012 lack of iris strands in this case, however, are more consistent with a large Haab’s stria.6 References 1. Ho CL, Walton DS. Primary congenital glaucoma: 2004 update. J Pediatr Ophthalmol Strabismus 2004;41:271-88. 2. Walton DS, Katsavounidou G. Newborn primary congenital glaucoma: 2005 update. J Pediatr Ophthalmol Strabismus 2005;42:333-41. 3. Hollander DA, Sarfarazi M, Stoilov I, et al. Genotype and phenotype correlations in congenital glaucoma. Trans Am Ophthalmol Soc 2006;104:183-95. 4. Wright JD Jr, Robb RM, Dueker DK, Boger WP 3rd. Congenital glaucoma unresponsive to conventional therapy: A clinicopathological case presentation. J Pediatr Ophthalmol Strabismus 1983;20:172-9. 5. Barkan O. Pathogenesis of congenital glaucoma: gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955;40:1-11. 6. Hammersmith KM, Rezende RA, Cohen EJ, Eagle RC Jr, Rapuano CJ. Congenital corneal opacities: Diagnosis and management. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea: Fundamentals, diagnosis and management. 3rd ed. St. Louis: Mosby Elsevier; 2011: 252-4.
Journal of AAPOS
We present histopathologic findings that have not been previously reported as associated with abnormalities of the anterior chamber angle underlying newborn primary congenital glaucoma as a distinct entity. The major histopathologic findings were partial absence and retrodisplacement of Schlemm’s canal, hypoplasia of the trabecular meshwork, broad attachment of ciliary muscle to the meshwork, and anterior insertion of hypoplastic iris with the formation of a pseudomembrane. These profound anatomic derangements explain why goniosurgery is frequently unsuccessful in cases of newborn glaucoma.
Case Report
F
or assessing the pathologic findings, the histology of two normal infant anterior segments are illustrated in Figure 1A, B. A black girl and her monozygotic twin born at 35 weeks’ gestation of nonconsanguineous parents presented at the Massachusetts Eye and Ear Infirmary at 6 days of age with apparent bilateral corneal opacifications. There was no family history of glaucoma. Ophthalmologic examination revealed an intraocular pressure of 45 mm Hg bilaterally in both children by Perkins tonometry while the children were sleeping. The patient’s right cornea was thickened, with central corneal hydrops, peripheral clouding (Figure 1C), and a shallow anterior chamber. The left cornea was homogeneously cloudy, with a deep anterior chamber. The irides of both eyes were dark brown and smooth, with no stromal collarettes. Gonioscopy was performed in the left eye during an examination under anesthesia through a window created by the removal of a small area of corneal epithelium. The iris inserted anteriorly, with minimal exposed trabecular meshwork and no visible scleral spur or ciliary body band. The angle of the right eye could not be visuAuthor affiliations: aDavid G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; bDepartment of Ophthalmology, Harvard Medical School, Boston, Massachusetts Supported in part by the Heed Foundation (LPP). Submitted March 28, 2012. Revision accepted June 13, 2012. Published online November 16, 2012. Correspondence: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 (email: [email protected]). J AAPOS 2012;16:565-568. Copyright Ó 2012 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.06.012
Journal of AAPOS
alized. Initial medical treatment was followed by the placement of a glaucoma drainage device in the left eye at 7 weeks of age. A subsequent successful mitomycin-C trabeculectomy was performed at 2 years of age. At 7 years of age, her best-corrected visual acuity was 20/60 in the left eye; the optic disk appeared normal, without cupping. With extensive corneal disease and severe glaucoma, the visual prognosis for the right eye was extremely poor, and consequently surgery was not performed. The right eye was enucleated when the girl was 8 years of age for cosmesis due to progressive buphthalmos associated with an intraocular pressure of 40 mm Hg. On gross examination, the enucleated eye measured 26 mm horizontally and vertically and 34 mm anteroposteriorly. The cornea measured 16 mm 15 mm and was densely opacified centrally. The iris was profoundly thinned and lacked surface crypts, with pigment tracking into the angle. The optic nerve head was markedly cupped. Histopathologic examination disclosed a central posterior internal stromal defect devoid of Descemet’s membrane (Figure 1D), accompanied by stromal thinning at the limbus (Figure 1E). A normal thickness Descemet’s membrane was present peripherally and formed rolled structures at the edges of the central defect (Figure 1D, inset). Peripherally, Descemet’s membrane ended without an obvious Schwalbe’s line. Bowman’s membrane was completely absent and a few small vessels were found in the anterior stroma (Figure 1F). The iris inserted anteriorly with adhesion to the trabecular meshwork (Figure 2A, B). A delicate interrupted layer of pigmented cells with fine vessels originating from the anterior surface of the iris root extended over the rudimentary chamber angle (Figure 2A-D). The smooth muscle of the ciliary body also directly attached to the meshwork without the interposition of a scleral spur (Figure 2B). The trabeculae were typically fewer in number and often compacted when compared with the normal angle structure (Figure 2C), particularly temporally. Occasionally a small bundle of displaced ciliary smooth muscle cells was situated within the pigmented membrane and attached directly to the outer trabeculae (Figure 2D). A posteriorly displaced Schlemm’s canal was juxtaposed to the trabecular meshwork only nasally (Figure 2B); it was not visible in the temporal half of the outflow pathways. There was no scleral spur. The iris stroma was hypoplastic and extremely thin with a hyperplastic sphincter muscle that extended
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FIG 1. A, Normal anterior chamber angle from the enucleated globe of a 4-week-old black girl with retinoblastoma. There is a cellular and welldeveloped trabecular meshwork (TM) with a juxtaposed Schlemm’s canal (SC). Iris stroma originates approximately at the level of the scleral spur and exhibits surface folds and an anterior condensation layer of melanocytes (case courtesy of Dr. Ralph Eagle; hematoxylin and eosin, original magnification, 100). The inset reveals the scleral spur next to the iris root onto which inserts the meridional smooth muscle (SM) bundles of the ciliary body. The trabecular meshwork is separated from the muscle by the scleral spur (H&E, 200). B, Normal anterior chamber angle of an 8-week-old white infant girl from a globe enucleated for retinoblastoma. Schlemm’s canal is interrupted and somewhat collapsed in this section (case courtesy of Dr. Ralph Eagle; H&E, 100); inset, the scleral spur is situated between the ciliary smooth muscle and the trabecular meshwork (H&E, 200). C, A 12-month-old black child with bilaterally enlarged corneas and a central opacification in the right eye. D, The right enucleated globe displayed a thickened central cornea with large central corneal opacification (CCO). The stroma is looser immediately adjacent to the posterior ulcer. The small nubbins of Descemet’s membrane (arrows) abruptly terminate at the edges of the ulcer; the right nubbin is shown in the inset with mild pigmentation of the endothelium (H&E, 25; inset, 200). E, Section through paracentral cornea lacks a continuation of posterior ulcer. Note the peripheral corneal stromal thinning (arrow) characteristic of buphthalmic eyes. The iris stroma is atrophic and there is no pupil in this section (H&E, 10). F, Slightly acanthotic corneal epithelium is devoid of an underlying Bowman’s membrane. Small blood vessels (arrows) are found in the superficial stroma (H&E, 200). ACA, anterior chamber angle; CP, ciliary processes; IS, iris stroma; SM, smooth muscle of ciliary body; SM, smooth muscle; SP, scleral spur; TM, trabecular meshwork.
toward the chamber angle (Figure 2E). The retina showed diffuse loss of ganglion cells associated with advanced optic nerve head cupping (Figure 1F).
Discussion Childhood glaucomas are a diverse group of conditions that can be associated with significant permanent vision
loss. Approximately half of all childhood glaucomas are primary congenital glaucomas (PCG) that result from hereditary nonsyndromic developmental anomalies of the anterior chamber angle structures (trabeculodysgenesis).1-4 It is useful to divide PCG into three subsets: newborn PCG, evident at birth or within the first months of life and associated with severe corneal edema; infantile
Journal of AAPOS
Volume 16 Number 6 / December 2012
Perry et al
567
FIG 2. A, A partially obstructive interrupted pigmented nasal chamber angle membrane emerges from the stroma of the iris root to cover the nasal trabecular meshwork. The iris stroma anomalously manifests a prominent bundle of smooth muscle (Masson trichrome, original magnification, 100). Inset: A clump of pigmented tissue (arrow) adheres to the trabecular meshwork in the iris region of the nasal chamber angle (periodic acid Schiff, 50). B, Ciliary smooth muscle with scattered melanocytes indicative of the patient’s race attaches directly (arrows) and broadly to the nasal trabecular meshwork. The remainder of the trabecular meshwork is covered by a vascularized (crossed arrows) pigmented chamber angle membrane extending from the stroma of the iris root. SC, retrodisplaced Schlemm’s canal (H&E, 200). C, The temporal chamber angle structures were less well developed than those nasally. The thickened iris root (arrows) inserts anteriorly and supplies a pigmented thin chamber angle membrane. There is a subjacent hypoplastic trabecular meshwork. The smooth muscle of the ciliary body shows interspersed melanocytes (H&E, 100). D, Temporal chamber angle with a pigmented membrane covering trabecular meshwork and containing an ectopic small bundle of misdirected ciliary smooth muscle cells (arrow) (H&E, 200). E, atrophic underdeveloped iris showing a thin delicate component of stroma with vessels (arrows) and a thicker bundle of aberrant smooth muscle anterior to the pigmented neuroectodermal layers (top panel). Trichrome stain showing haphazardly arranged reddish bundles of smooth muscle cells (bottom panel); the iris stroma is delicate, hypoplastic, and rarefied and harbors projecting vessels (arrow). The iris sphincter muscle was hyperplastic. (Top, periodic acid Schiff, 200; bottom, Masson trichrome, 200). F, There is deep cupping of the optic nerve head from prolonged and end-stage glaucoma. The inset demonstrates the absence of ganglion cells and a thin nerve fiber layer (arrows) (H&E, 25; inset, 100). C, cupping; CAM, chamber angle membrane; HTM, hypoplastic trabecular meshwork; IM, hyperplastic aberrant iris sphincter muscle; IS, iris stroma; LC, lens capsule and subcapsular epithelium; SM, ciliary body smooth muscle; TM, trabecular meshwork.
primary congenital glaucoma, which occurs usually within the first year of life; and late-recognized primary congenital glaucoma, diagnosed after 1 year of age. Newborn PCG2 is the most severe form on the spectrum, portending a poor
Journal of AAPOS
long-term vision prognosis compared to later onset infantile PCG. The following chamber angle anomalies were identified on pathologic examination in the current case: partial
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Perry et al
(temporal) absence of an otherwise retrodisplaced Schlemm’s canal and nondevelopment of the scleral spur; hypoplasia of temporal trabecular meshwork; broad attachment of ciliary muscle to the meshwork; anterior displacement of the iris insertion; and extension of vascularized, pigmented iridial tissue onto the meshwork as a partially obstructive interrupted membrane. The iris stroma was markedly hypoplastic with aberrant bundles of smooth (sphincter) muscle. The angle findings are not consistent with a Barkan’s membrane covering a normal functional aqueous outflow system.5 Unlike infantile PCG, which responds well to goniosurgery, newborn PCG does not respond well to standard-angle surgical approaches, including trabeculotomy and goniotomy.2-4 The corneal opacification in this case could be considered to be a Peters anomaly, which typically presents with rudimentary Descemet’s membrane that ends abruptly in the central cornea and typically has associated iris strands. The normal thickness of Descemet’s membrane, rolled structures at the edges of the defect, and
Volume 16 Number 6 / December 2012 lack of iris strands in this case, however, are more consistent with a large Haab’s stria.6 References 1. Ho CL, Walton DS. Primary congenital glaucoma: 2004 update. J Pediatr Ophthalmol Strabismus 2004;41:271-88. 2. Walton DS, Katsavounidou G. Newborn primary congenital glaucoma: 2005 update. J Pediatr Ophthalmol Strabismus 2005;42:333-41. 3. Hollander DA, Sarfarazi M, Stoilov I, et al. Genotype and phenotype correlations in congenital glaucoma. Trans Am Ophthalmol Soc 2006;104:183-95. 4. Wright JD Jr, Robb RM, Dueker DK, Boger WP 3rd. Congenital glaucoma unresponsive to conventional therapy: A clinicopathological case presentation. J Pediatr Ophthalmol Strabismus 1983;20:172-9. 5. Barkan O. Pathogenesis of congenital glaucoma: gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955;40:1-11. 6. Hammersmith KM, Rezende RA, Cohen EJ, Eagle RC Jr, Rapuano CJ. Congenital corneal opacities: Diagnosis and management. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea: Fundamentals, diagnosis and management. 3rd ed. St. Louis: Mosby Elsevier; 2011: 252-4.
Journal of AAPOS