Ocular Pathology

MISSION FOR VISION

2010-04-28T18:04:00.000-07:00

The primary goal of Mission for Vision is to conduct research leading to effective treatments and cures for human eye diseases. The top priority is funding basic science or clinically relevant projects that search for understanding the causes of human-eye-disease. Mission for Vision also seeks to provide information related to eye disease for the public. Below are our most popular sites for information.

Tutorials and Study Guides (free)
Anatomy of the Eye
Basic Histology Primer
Ocular Pathology Tutorial
Study Guide for Anatomy of the Eye, Orbit and Relevant Neuroanatomy-www.medrounds.org
Ophthalmology Resident Manual (www.medrounds.org)
Ophthalmologic Pathology Board Review www.medrounds.org

Articles
Complications of LASIK
Dry Eye Disease

Glaukomflecken

2008-03-01T16:13:00.000-08:00

Definition: Glaukomflecken was described clinically as flecks of patchy anterior subcapsular opacities associated with severe elevation of intraocular pressure. Glaukomflecken is also referred to as cataracta disseminata subepithlias, and glaukomatosa acuta).
History: In 1931 Vogt first described cases of disseminated subepithelial lens opacities in patients after an acute attack of glaucoma [1].
Incidence/ Prevalence: The precise incidence is not known.
Etiology: Glaukomflecken results from infarction of anterior lens epithelial cells. Glaukomflecken has been reported frequently after acute angle closure glaucoma. Some suggest that obstruction of outflow with a resulting milieu of toxins results in the necrosis or that pressure exerted from corneal-iris/lens touch may cause the disorder [2].
Clinical Findings: After an episode of acute glaucoma accompanied by severe elevation of intraocular pressure, the lens may develop the irregular patches of anterior subcapsular opacification of glaukomflecken. Hypopyon has been associated, albeit rarely, with glaukomflecken and an acute intraocular pressure rise.[3]
Histopathology: Foci of anterior subcapsular epithelial cell necrosis may be seen with anterior cortical cataract. [4].These changes may be seen after trauma or with lens iris adhesion. In the case shown of severe intraocular pressure after traumatic hyphema arrow 1 points to the erythrocytes in the anterior chamber. Subcapsular epithelium sports either effete nuclei (arrow 2) or apoptotic/necrotic nuclei (arrow 3) in association with globular degeneration of anterior cortical lens fibers (arrow 4).
Treatment: New lens fiber growth continues after the glaukomflecken episode.[5] Of course management of intraocular pressure and appropriate therapeutic maneuvers directed at the underlying disorder as treatment of lens opacity as needed.
References
1. Vogt A: Lehrbuch und Atlas der Spaltlampenmikroskopie des lebenden Auges. Zweiter Teil: Linse und Zonula. Berlin: Julius Springer; 1931:565.
2. Winstanley J: Iris atrophy in primary glaucoma. Trans Opthalmol Soc UK 1961;81:23-38.
3. Eu Eong KG et al. Int Ophthalmol. 1993;17:127-9.
4. Anderson DR: Pathology of the glaucomas. Br J Opthalmol 1972;56:146-157.
5. Yip et al. Can J. Ophthalmology 2007;42:321-2.

Angle Recession, Traumatic

2008-02-19T16:58:00.001-08:00

Definition: Angle recession is considered a sequel of blunt eye trauma in which the ciliary muscle is torn between the longitudinal and circular layers. An obtuse anterior chamber angle results from tearing of the ciliary muscle as there is posterior displacement of the iris root. The longitudinal or meridional ciliary muscle remains attached. (Click here for a review of ciliary muscle anatomy). This distinguishes recession from cyclodialysis, where the entire ciliary body including the longitudinal muscle is detached.
Incidence/ Prevalence: A gonioscopic survey in a South African town, revealed recession in about 15% of people. (Ref. 1) The majority showed bilateral angle recession. Recession was more common in men. 5.5% of patients with angle recession had glaucoma. In patients with 360 degrees of angle recession, 8.0% had glaucoma. Excessive alcohol consumption was significantly related to the presence of angle recession in women. The prevalence of monocular blindness due to trauma was 2.5%.
Etiology: Angle recession is caused by significant blunt trauma. In our experience it is common in boxers. The initial injury is often accompanied by hyphema, so that patient who present with hyphema must be followed for later development of angle recession and glaucoma.
Clinical Findings: On gonioscopy, the ciliary body band is increased in size and irregularly widened. OCT has been recommended to give a 3D image of the recessed angle and more accurately determine the extent without putting pressure on the anterior segment.(Ref. 2).
Gross pathology: The diagnosis of angle recession can be subtle because of anatomic variations of the angle. Yanoff suggests a diagnostic method in sections of the eye that involves drawing a line through the optic axis (pink arrowed line in diagram) and then drawing a second line (yellow arrowed lines in picture) parallel to the first but which includes the scleral spur. If the angle recess is located posterior and lateral to the line (as the white arrow indicates) then there is angle recession. In the normal angle the yellow line would pass at the iris root.
Under gross dissection the normal wedge of the ciliary body is effaced as the ciliary body is stripped from the sclera and moves interiorly. While an unaffected angle has a wedge with the presenting base of the ciliary body anteriorly, the concussive angle deformity shows a fusiform shape of the ciliary body anteriorly. There is a greater area of the ciliary body that is exposed anteriorly. The iris root and pars plicata are displaced posteriorly. There may be fibrous tissue in ciliary body.
Histopathology: The same principles seen in the gross examination apply to histologic sections for diagnosis. The relationship of the sclera spur (arrow #1) reveals the posterior displacement of the iris-ciliary body complex. Residual meridional ciliary muscle strands are seen attached to the sclera (arrow #2). The effaced ciliary muscle shows pigment as it is reflected posteriorly (arrow #3). Angle injury to the outflow tract is indicated by pigment laden macrophages and fibrosis over the trabecular meshwork (arrow 4). The remaining attached longitudinal ciliary muscle is evident at arrow # 5. Circular muscle fibers are seen at arrow #6. Radial ciliary muscle fibers are evident at arrow #7. Secondary complications of angle recession include obstruction of the trabecular meshwork by synechiae or endothelialization over the trabecular meshwork. The synechiae are sequelae of inflammation and hemorrhage. Endothelialization may reflect injury to the cornea. The final result is glaucoma, which if untreated may result in glaucomatous atrophy (see image below).

Treatment: The glaucoma is treated as open angle glaucoma. Some have indicated that trabeculectomy with antimetabolite therapy is more effective than other surgical treatment in these patients. (Ref. 3)
Prognosis: About 6% of patients develop glaucoma after angle recession from the mechanisms of trabecular meshwork obstruction described above. Additional mechanisms include damage and scarring to the outflow apparatus, cataract and phacolytic glaucoma.

References:
1. Salmond JF et al. The detection of post-traumatic angle recession by gonioscopy in a population-base glaucoma survey. Ophthalmology 1994.
2. Keisuke Kawana, Yoshiaki Yasuno, Toyohiko Yatagai, Tetsuro Oshika (2007) High-speed, swept-source optical coherence tomography: a 3-dimensional view of anterior chamber angle recession Acta Ophthalmologica Scandinavica 85 (6) , 684–685
3. Mermoud et al. Ophthalmology 1993.

Phacolytic Glaucoma

2008-02-19T16:57:00.000-08:00

PHACOLYTIC REACTIONS
Definition: Phacolytic glaucoma was originally defined as open-angle glaucoma associated with hypermature cataract.

History: Phacolytic glaucoma was coined in 1955 by Flocks et al. [1].

Etiology: Phacolytic glaucoma is produced by blockage of aqueous outflow by both soluble lens protein and macrophages (as part of the inflammatory response) that obstruct the trabecular meshwork. [2][3]
Incidence/Prevalence: This disorder has markedly decreased in incidence in the U.S. because of earlier cataract extraction. In a large series in India 115 cases of phacolytic glaucoma were reported from 27,073 patients with cataract.[3].

Clinical Findings: Most patients present with pain, a red eye, elevated intraocular pressure, and of course chronic visual loss. The protein and cells will be visualized in the anterior chamber.

Histopathology: The proteinaceous material and macrophage accumulate in the angle structures and trabecular meshwork (arrow 1). Macrophages can be found on the anterior (arrow 2) and posterior (arrow 3) surface of the iris, around the lens capsule and lens zonule, (arrow 4), along the inner surface of the retina, and on the optic nerve head. The lens may appear shrunken with loss of nuclear and cortical material and the lens capsule may appear collapsed (arrows 5).

Treatment: Cataract removal and irrigation of the anterior chamber with removal of lens proteins has been very effective. If the disorder is not promptly recognized and treated, the visual prognosis is generally poor due to optic atrophy, uveitis, and corneal edema. [3] Spontaneous recovery with resorption of lens and resolution of the glaucoma has been reported. [4]
References:
1. Flocks M et al. A clinicopathologic study of 138 cases of glaucoma associated with hypermature cataract. Arch Ophthalmol 1955;54:37-45.
2. Epstein DL et al. Obstruction of aqueous outflow by lens particles and by heavy molecular weight soluble lens protein. Invest Ophthalmol Vis Sci 1978;17:272-277.
3. Pradhan et al. Indian Journal of Ophthalmology 2001;49:204.

4. Blaise et al. J Cataract Refract Surg. 2005;31:1829-30.

Axenfeld Anomaly and Syndrome

2008-02-19T16:56:00.001-08:00

Definition: Axenfeld anomaly, also called posterior embryotoxon, is a congenital anomaly in which Schwalbe’s line (arrow #1) is anteriorly displaced and associated with iris bands that extend to the cornea (arrow #2). If the development of the meshwork is defective and glaucoma is present, the condition is called Axenfeld syndrome. The Rieger anomaly is the term used to describe iris and pupillary abnormalities in combination with the findings of the Axenfeld anomaly. The Reiger anomaly is associated with the later onset of glaucoma. If the Rieger anomaly is associated with dental and skeletal abnormalities, the condition is called the Rieger syndrome.
History: Axenfeld described this abnomality in 1920.
Incidence/Prevalence: 50% of patients with the Axenfeld anomaly have been reported to progress to develop glaucoma.
Etiology: Mutations of the FOXC1 gene and in the PITX2 gene have been described in families with the Axenfeld-Rieger syndrome (1,2).
Clinical Findings: Axenfeld anomaly manifests as a crescentic shaped opacity in the peripheral cornea. Schwalbe’s line is not visible normally, so the presence of this ring is clinically diagnostic. Strands may extend from the iris periphery to the cornea. If the angle structures are normal and there is no glaucoma this is called the Axenfeld anomaly.
Histopathology: Sections show anterior displacement and usually thickening of Schwalbe's line. Schwalbe's line appears in section as a collagenous nubbin (arrow 3 in Figure). Frequently, iris processes extend from the peripheral iris to insert at Schwalbe's line on the cornea (arrow 4). Notice in the photograph that there is a thin Descemet's membrane and endothelium on either side of Schwalbe's line indicating it is abnormally displaced anteriorly and interposed between clear cornea.
Treatment: Trabeculostomy and trabeculectomy have been performed in patients with Axenfeld syndrome.
References:
1. Panicker SG et al. Invest Ophthalmol Vis Sci. 2002; 243:3613-6.
2. Borges AS et al. J Glaucoma. 2002;11:51-6

Pigment Dispersion Syndrome

2008-02-16T08:53:00.000-08:00

Definition: Pigment dispersion syndrome is characterized by the deposition of iris pigment on the cornea endothelial surface, trabecular meshwork, anterior iris, lens capsule and lens zonule sometimes in association with glaucoma (½ of cases the cases of pigment disperstion syndrome).
History: Sugar and Barbour described pigment dispersion syndrome in 1949.
Incidence/ Prevalence: Pigment dispersion syndrome is associated with myopia, male gender, begins between the ages of 20-45 years, with a reported prevalence of up about ~2.5% in "whites", a population at risk. Familial cases are rare but are inherited in an autosomal dominant pattern. Glaucoma is present in 50% of the cases.
Etiology: In 1979 the concept was proposed that the iris bowed posteriorly in the midperiphery to rub against zonular fibers releasing pigment from the iris (1). The iris may have an irregular pupillary surface (#1 arrow in figure). The evidence for the zonular friction theory is that the anterior chamber in these patients is unusually deep in the midperiphery and that zonular fibers are found in proximity of the iris radial transillumination slits (# 2 red arrows in the gross photograph of the back of the iris). A reverse pupillary block mechanism has been invoked in which aqueous cannot flow into the posterior chamber because of the lens iris contact. The bowing may be worsened during forward movement of the lens as occurs during accommodation although increases in intraocular pressure and pigment dispersion with acccomodation are more controversial.
Pigment dispersion may be associated with a variety of other conditions in which pigment epithelium or uveal melanocytes are injured, such as uveitis (uveitic glaucoma) or uveal melanoma. These conditions are characterized by pigment within the trabecular meshwork and in macrophages littering the angle. The dispersed pigment is presumed to be iris pigment epithelium mechanically rubbed off by contact with lens zonular fibers.
Clinical Findings: There is a mid peripheral iris transillumination defect, iridonesis pigmentation anterior iris surface. Pigmentation on the posterior corneal surface is called Krukenberg’s spindle. There can be pigmentation of the lens (arrow #3), trabecular meshwork, pars plana.The pigmentation may precede the glaucoma by as much as 20 years.

Gross and Histopathology: Pigment is present on the lens zonule (arrow #4 above). Extracellular pigment becomes trapped in the trabecular meshwork (arrow #5). Scattered pigment may be seen lying on the anterior surface of the iris (arrow #6).Intracellular pigment may be found in macrophages lining the uveal cords and/or in endothelium lining the meshwork. Deposition of pigment tends to be mainly inferior on the cornea (arrow #5). Krukenberg’s spindle manifests histologically as pigment laden endothelial cells (arrow 7).
Treatment: Some believe that laser iridotomy may relieve the reverse pupillary block mechanism and reverse the posterior bowing of the iris. A decrease in pigment granules dispersed after laser has been published (2).
References:
1. Campbell DG. Pigmentary dispersion and glaucoma. A new theory. Arch Ophthalmol. 1979;97:1667-72.
2. Küchle M, Nguyen NX, Mardin CY, Naumann GO. Effect of neodymium:YAG laser iridotomy on number of aqueous melanin granules in primary pigment dispersion syndrome.
Graefes Arch Clin Exp Ophthalmol. 2001; 239:411-5.
3. Ritch R et al. Prevalence of pigment dispersion syndrome in a population undergoing glaucoma screening. AJO 1993:115:707.

Exfoliation Syndrome

2008-01-27T11:47:00.000-08:00

Exfoliation Syndrome (pseudoexfoliation) text contributions by Vicki Chan, M.D.
Definition: Exfoliation syndrome is characterized by the pathologic deposition of grey white flakey and fibrillary extracellular material on anterior segment structures often associated with chronic open-angle glaucoma.
Prevalence/Incidence: Exfoliation syndrome is the most common identifiable cause of open-angle glaucoma worldwide and accounting for 6-42% of open angle glaucoma between the ages of 50 and 70. Increased intraocular pressure occurs in ~ 20% of patients with exfoliation syndrome. Exfoliation syndrome is quite common in Iceland ~10% of the population at large (Arnarrson et al 2007). The prevalence increases markedly with age. In Sweden the incidence was 2.1% at age 66 and 25% at age 87 (Astrom et al. 2007).
History: Exfoliation syndrome was first described by John G. Lindberg in 1917.
Etiology: A number of nongenetic factors, including dietary factors, autoimmunity, infectious agents, and trauma, have also been hypothesized to be involved in pathogenesis. Upregulated genes in this syndrome include fibrillin-1, latent transforming growth factor B-binding protein (LTBP)-1 and LTBP-2, the cross-linking enzyme transglutaminase (TGase)-2, TIMP-2, A-kinase anchor protein (AKAP)-2, apolipoprotein D, and the adenosine receptor (AdoR)-A3. Preliminary linkage analyses identified three putative gene loci: 2p16, 2q35-36, and 3q13-q21.
Clinical Presentation: Exfoliation syndrome may present with white-grey, fibrillar-granular deposits in the anterior chamber, including focal retrocorneal flakes and classic "target-like" lens deposits. Patients often have elevated intraocular pressures, secondary to blockage of aqueous outflow, either by accumulation of fibrils in the trabecular meshwork or pupillary blockage from lens destabilization. Gonioscopy may reveal an inferior, scalloped pigmented deposition just anterior to Schwalbe's line, referred to as Sampaolesi's line (unnumbered black arrows). Patients also have rigid irises with reduced dilating properties, which may be secondary to fibril deposition in the stroma and muscle. Degenerative changes may create the "moth-eaten" pattern of peripupillary atrophy (red arrows in figure); degeneration of iris blood vessels can also manifest in spontaneous hematomas; and the destruction of the blood-aqueous barrier can present with flare and pseudouveitis. Exfoliation syndrome is associated with complications from zonular rupture and posterior displacement of the lens during cataract surgery. The syndrome may also be associated with cardiovascular and cerebrovascular morbidities.

Histological Findings: The hallmark of exfoliation syndrome is the pathologic production and accumulation of an abnormal fibrillar extracellular material in anterior segment tissues. The material is multifocally produced in the lens epithelium, nonpigmented ciliary epithelium, trabecular endothelium, corneal endothelium, vascular endothelial cells, and virtually all cell types of the iris. These bundles of fibrils may cover the lens zonule (black arrows white number 1) and anchorage sites in the nonpigmented ciliary epithelium, destabilizing the zonule and increasing the risk of lens dislocation. Under the dissecting microscope one can see the fibrillar material deposited on the posterior iris and ciliary processes (white arrows 1). The posterior iris epithelium has accentuated ridges or circumferential folds (white arrows 2) that often have a sawtooth appearance on microscopy black arrow 2 . Light microscopy of anterior chamber structures (posterior cornea, ciliary body, lens capsule, etc.) will reveal collections of "filings" standing on end (black arrow 3). In the figure, deposition of fibrils (number 3) are seen on the surface of the lens capsule (number 4) with the subjacent anterior capsular epithelium (number 5) and lens fibers (lower number 5). There may be accumulated material within Descemet's membrane and the lens capsule.
Electron microscopy can verify these as abnormal fibrils by a periodicity (fibril banding) of approximately 50 nanometers. In the image shown (22,000 magnification) numerous fibrils are seen with a distinctive banding pattern (arrow 6). One of the hypotheses about pathogenesis of pseudoexfoliation syndrome posits that there is overproduction or expression of microfibrils by a variety of cells. As a result of various factors, it is suggested that the microfibrils cross link with one another to form aggregates. Supporting this hypothesis, there are areas in which the fibrils aggregate to form darker complex masses (arrow 7). Staining for HNK-1 carbohydrate epitope and LTBP-1 may also help in confirming the diagnosis.
Treatment: Exfoliation syndrome is strongly associated with nuclear sclerosis. Complications are often related to the weakened zonules. Secondary glaucoma often will require combination therapy and close follow up. Of note, exfoliation patients may have small, "pseudonormal" optic discs that must be monitored carefully. Argon laser trabeculoplasty often has an immediate pressure lowering effect, with reported initial success rates up to 80%.
References:
1. Hammer T, Schlotzer-Schrehardt U, Naumann GO. Unilateral or Asymmetric Pseudoexfoliation: An Ultrastructural Study. Arch Ophthamol. 2001;119:1023-1031.
2. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921-937.
3. Schlötzer-Schrehardt U, Zenkel M, Küchle M, et al. Role of transforming growth factor-β1 and its latent form binding protein in pseudoexfoliation syndrome. Exp Eye Res. 2001;73:765–780.
4. Zenkel M, Pöschl E, Mark K et al. Differential gene expression in pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2005;46:3742–3752.
5. Arnarsson A, Damji KF, Sverrisson T, Sasaki H, Jonasson F. Pseudoexfoliation in the Reykjavik Eye Study: prevalence and related ophthalmological variables. Acta Ophthalmol Scand. 2007;85:822
6. Astrom et al. Acta Ophthalmol Scand. 2007 Dec;85(8):832-7. Epub 2007 Nov 6.

Lens-Induced Granulomatous Endophthalmitis

2007-07-22T10:32:00.000-07:00

Definition: Lens-induced granulomatous endophthalmitis is also known as phacoanaphylactic endophthalmitis, phacoantigentic and phacoallergic endophthalmitis. A granulomatous reaction to lens fibers that may appear zonal occurs in the setting of trauma and lens capsule rupture.

Incidence/ Prevalence: Very little good data exist on the exact incidence of this disease (see clinical findings).
Etiology: About 80% of cases are related to trauma, including surgical operations. Retained cortical fragments in the capsular bag after cataract operations have been reported to produce this disorder. (Ref 1). Occasionally presumed spontaneous rupture may be the culprit. Experimental studies, immunofluorescence and immunoperoxidase techniques, suggest that the inflammation is mediated by IgG.
Clinical Findings: Less than 5% of cases are diagnosed correctly clinically. The time of injury varied from 2 days to 59 years in one series (Ref 2). However, most sources state that it may occur as soon as 24 hours after surgery. Numerous anterior chamber cells, flare, keratic precipitates, posterior synechiae are often clinical findings. In the clincial photograph the lens is acutely ruptured and lens material (red arrow) rests adjacent to the cornea with pigment and a cellular anterior chamber infiltrate. The choroid is more often involved than clinically realized (Ref 2).

Histopathology: Histologically, lens-induced granulomatous endophthalmitis classically is described as a central nidus of degenerating lens material surrounded by concentric layers of inflammatory cells (zonal granuloma). Multinucleated giant cells (arrow 1) and neutrophils(arrow 2) may be present within the inner layer adjacent to the degenerating lens material. In the photo below multinucleated giant cells (arrow 4) are associated with the central lens fibers. There is usually evidence of lens rupture (arrows 3); the lens capsule is disrupted here. Lymphocytes and histiocytes may make up the intermediate mantle of cells. In chronic cases, there may be fibrosis surrounding the histiocytes (top of photograph).

Cytologic preparations show numerous histiocytes (black arrows) in proximity of degenerate lens material.
Treatment: Cycloplegics, corticosteroids and prompt removal of the lens are the usual therapeutic modalities.
Prognosis: With prompt lens removal the prognosis is largely dependent on other traumatic injuries. However, there may be associated sympathetic ophthalmitis.

References:

1. J Cataract Refract Surg. 2007;33:921-2.

2. Int Ophthalmol. 1991;15:271-9.

Mittendorf's dot

2007-07-14T12:20:00.000-07:00

Definition: Mittendorf’s dot, also called the hyaloid body, is the embryologic remnant of the hyaloid artery as it joins the tunica vasculosa lentis.
Incidence/Prevalence: Mittendorf’s dot is present in normal eyes. It may be associated with posterior lenticonus.
Etiology: Mittendorf's dot represents the remains of the anterior end of the hyaloid artery.
Clinical Findings: On ophthalmoscopy Mittendorf’s dot may be visible as a black/gray axial or slightly nasal paraxial dot at the posterior apex of the lens. By slit lamp microscopy, Mittendorf’s dot is white. Attached one may find a thread-like structure, the remains of the anterior end of the hyaloid artery. The fibrous tissue of the fetal vasculature may extend through a gap in the lens and produce a posterior polar cataract. Progression may occur in the latter instance but is otherwise unusual.
Pathology: The hyaloid vascular system regresses usually by about 7 months. In the figure of this very premature infant, the tunical vasculosa lentis surrounds the lens (arrows 1) and is contiguous with the hyaloid vascular system (arrow 2). Notice the glial sheath of the hyaloid artery (arrow 3). Mittendorf's dot is evident as a white opacity on the posterior surface of the lens in an axial location of this adult autopsy eye (arrow 4).
Treatment: No treatment is generally necessary.

Posterior Lenticonus

2007-07-13T08:36:00.000-07:00

Definition: Posterior lenticonus is a developmental anomaly of the lens in which the posterior portion of the lens bulges outward in a cone-shape.
Incidence/Prevalence: Posterior lenticonus is much more common than anterior lenticonus. Sporadic and inherited cases have been described, particularly X-linked and autosomal dominant inheritance patterns. Inherited cases are more common than sporadic cases.
Etiology: Associations include microcornea, anterior lentiplanus, glycinuria and Duane’s syndrome. [Ref 1] Although Alport’s syndrome is mostly associated with anterior lenticonus, simultaneous anterior and posterior lenticonus have been described in Alport’s syndrome.[Ref 2] It has been written that the abrupt thinning in the posterior capsule at the point of the lenticonus is the cause of the bulge on the basis of mechanical issues. This dogma of course does not adequately explain the inheritance patterns or associations! The association with Mittendorf's dot is particularly provocative.
Clinical Findings: Posterior lenticonus may be present at birth or develop in the following months. Amblyopia may be present. Posterior lenticonus may occur as an isolated ocular finding. There is a slight female predominance. Posterior lenticonus most commonly is unilateral but may be bilateral. There may be a high degree of astigmatism. Retinoscopy will show a distorted myopic reflex. Oblique lighting with the slit lamp is helpful to see the cone shape. With progression the cone and surrounding lamellae may opacify.
Gross and Histopathology: Histologic reports feature a thin posterior lens capsule. There is one report of an associated posterior subcapsular cataract. In the photograph (arrow 1) a rounded bulging of the posterior capsule is seen. This might be better termed lentiglobus because it is not truly cone shaped.
Treatment: If visually significant (opacified) or if amblyopia is present, lens removal is indicated. An anterior capsulorhexis with clear lens removal by aspiration and IOL placement within the capsular bag is the usual treatment. Often removal of the lens will restore vision. [Ref 3]
References
1. Surv Ophthalmol. 2003 Mar-Apr;48(2):125-44.
2. Indian J Ophthalmol. 2005 Sep;53(3):212-3.
3. J Cataract Refract Surg. 2006 Feb;32(2):261-3.

Marfan's Syndrome- Lens Displacement

2007-07-04T14:35:00.000-07:00

Definition: Marfan's syndrome is a disorder of connective tissue with ocular, musculoskeletal, and cardiovascular manifestations.
Incidence/Prevalence: the most common cause of lens dislocation from a genetic mutation. The incidence is about 0.7/100,000 live births. The prevalence is 7-17/100,000 population.
Etiology: Marfan's syndrome is an autosomal dominant disorder caused by mutations in the fibrillin gene on chromosome 15. Fibrillin is a glycoprotein that is a major component in elastic tissue and is important in lens zonules. 50-80 percent of patients with Marfan’s syndrome have ectopia lentis.
Clinical Findings: Lens dislocation upward or superortemporally is the most common manifestation of ectopia lentis due to inferior zonule compromise. However, a 360 degree compromised lens zonule is possible in which case the lens floats in the posterior chamber.
Histopathology: The lens is usually displaced upward or in a superotemporal direction, and axial myopia is often present. In the accompanying images the lens is displaced upward because of inferior zonular compromise. The inferior border of the lens is concave in areas of zonular dehiscence (arrows #1 in gross photo). The displacement superiorly is evident by the increased distance between the lens and iris inferiorly (arrow #3 below) and their near apposition superiorly. The lens may bulge posteriorly (arrow #4 in microscopic photo). Sections generally show some morphologically normal appearing zonular fibrils that are decreased in number, and others that are short and in disarray. Associated findings include iris hypoplasia with transillumination defects and numerous iridociliary processes (arrows 2).
Treatment: When visual symptoms cannot be corrected medically, lens removal with trans-scleral or iris fixation may produce acceptable results. Sulcus placement may be difficult especially if there are numeorus enlarged cilio-iridal processes that bridge the ciliary sulcus and block the placement of a haptic.

Cortical Cataract

2007-07-02T08:36:00.000-07:00

Definition: An opacity in the cortex of the lens, for which the key histologic criterion is the presence of globular degeneration.
Incidence/Prevalence: It is a common form of cataract and usually cortical changes are found accompanying nuclear sclerosis
Etiology: The eosinophilic globules are aggregates of lens crystallins.
Clinical Findings: Symptoms include glare while driving and, if the cataract is axial, a decrease in vision particularly with reading. Degenerative changes in the lens cortex may take on various appearances; spokes, fissures, lamellar separations, dot and wedge shaped opacities, rosettes and even a sunflower appearance have been described. With progression, the cortex may become mature and the nucleus floats within the bag. If the cortical material escapes from the lens capsule and produces wrinkles in the capsule, the lens is said to be hypermature.
Histopathology: The hallmark of the cortical cataract is globular degeneration. The process starts with alterations in cellular morphology with swelling and aggregation of protein. The lens cell membranes eventually break down releasing globules. Morgagnian globules consist of eosinophilic collections of protein (aggregates of lens crystallins) of various sizes that have lost cell membranes. Slits that appear as a result of cortical cataract usually contain eosinophilic material. This distinguishes cataract from artifactual separation of fibers during sectioning. As slits coalesce to form larger clefts, the cataract manifests spoke-like or wedge-shaped opacities.

Treatment: Surgical removal of the cataract generally restores vision.

Nuclear Sclerosis Cataract

2007-07-01T16:14:00.001-07:00

Definition: An opacity in the nucleus of the lens, for which the key histologic criterion is melding or homogenization of lens fiber cells.
Incidence/Prevalence: It is the most common form of cataract and is especially common in older individuals. Subject prevalence for nuclear lens changes is about 3 fold higher than for posterior subcapsular opacities (Reference 1).
Etiology: There are many associations with nuclear cataract. The biochemical changes involve aggregation of lens crystallins as a predominant feature.
Clinical Findings: Symptoms include decreased vision and glare. The patients may experience progressive myopia as the refractive power of the lens accompanies the increased size of the cataractous lens. As the yellow color of the lens increases the patients may notice a subjective difference in their evaluation of colors (this is often referred to as the blue period for artists). Presumably photo-oxidation and the chromophore content accounts for the yellow to brown pigmentation.
Gross: The opacity may appear yellow to brown and loses transparency. In the photograph of a yellow to brunescent nuclear cataract one can appreciate the well defined nature of the nucleus (delimited by the arrows 1). The color varies but the brown pigment near the upper arrow is quite evident. The lens becomes more rigid and difficult to remove surgically as was the case for this lens.
Histopathology: Sections usually show a subtle melding of nuclear fiber cells that gives a homogenous eosinophilic appearance. The lens cells lose their concentric laminations. In the photomicrograph the lens fibers appear to be one mass of pink (arrow 2). The cleft (arrow 3) is an artifact of histologic sectioning. The cells generally do not undergo lysis and the lens cell membranes are generally preserved. The changes are often missed by the uniformed microscopist.
Treatment: Surgical removal of the cataract generally restores vision.
References:
Ophthalmic Epidemiol. 1997;4;195-206.

Anterior Subcapsular Cataract

2007-07-01T14:38:00.001-07:00

Definition: An opacity in the lens positioned just posterior to the anterior lens capsule and is characterized by the proliferation of anterior lens epithelial cells.
Incidence/Prevalence: Anterior subcapsular cataract is less common than nuclear, cortical, or posterior subcapsular cataract. The subject prevalence for anterior subcapsular opacities is about 1/5 that of posterior subcapsular opacities (Reference 1).
Etiology: There are many associations with anterior subcapsular cataracts including inflammation, trauma, mitotics, amiodarone and atopic dermatitis. In animal models anterior subcapsular cataract has been produced with alkali burns. Some investigators suggest an epithelial to mesenchymal transition in these cells.
Clinical Findings: A focal star-shaped or irregular opacity beneath the anterior capsule as seen with a slit beam.
Histopathology: Sections usually show a multilayer of spindled epithelial cells beneath the lens capsule. In the photomicrograph the posterior pigmented layer of the iris is visible (black arrow 1). Previous posterior synechiae to the lens capsule is evidenced by the brown pigment deposition from the iris (black arrow 2). The multilayered lens epithelium is visible (white arrow 3 in figure) and to the left one can see that it is contiguous with a single layer of the normally present anterior lens epithelium. The photomicrograph at higher magnification shows the anterior subcapsular cateract at higher magnifcation, white arrow (the image below has been inverted). Sometimes the anterior lens capsule may be retracted and form slight protrusions.
Treatment: Surgical removal of the cataract generally restores vision.

References:

1. Ophthalmic Epidemiol. 1997;4;195-206.

Posterior Subcapsular Cataract

2007-07-01T12:36:00.000-07:00

Definition: An opacity in the lens positioned just anterior to the posterior lens capsule and characterized by the posterior migration of lens epithelial cells from the lens bow.
Incidence/Prevalence: Posterior subcapsular cataract may be the most common abnormality involving the lens epithelium.
Etiology: The lens is composed largely of crystallins which aggregate in cataract formation. There are many associations with posterior subcapsular cataracts including chronic vitreal inflammation, ionizing radiation, trauma and prolonged use of corticosteroids.
Clinical Findings: Younger individuals may be affected and the symptoms include complaints of glare at night with bright headlights or poor vision with accommodation. Near vision may often be more affected than distance vision. Usually the earliest sign is a focal dot-like area on the posterior capsule or a reflective sheen. With progression, translucent opacities appear (the swollen Wedl cells) on the posterior capsule that have been likened to a “cloth of gold” or “fish eggs”. Posterior capsular cataract is associated with cortical degeneration and nuclear sclerosis.
Gross: An opacity that is central and irregular is the most frequent finding (arrow 1). Tangential lighting with transillumination will reveal that the opacity lies adjacent to the posterior lens capsule. Because cataracts are usually associated with other lens changes, careful examination will often reveal spokes or other cortical changes (arrow 2).
Histopathology: Normally, the posterior capsule is devoid of epithelium. The presence of nucleated lens epithelial cells (arrow 3) anterior to the posterior capsule (arrow 4) is the key histologic criterion for posterior subcapsular cataract. Posterior subcapsular cataract begins with presumed proliferation and posterior migration of epithelial cells from the lens bow. These cells, also known as bladder or Wedl cells may enlarge five or six fold. However, they do not always appear swollen in sections.
Treatment: Surgical removal of the cataract generally restores vision. In children medicated with steroids, posterior subcapsular cataract may be abated when the steroids are stopped.

Congenital Rubella Cataract

2007-06-30T14:46:00.000-07:00

Rubella Cataract
Definition: The rubella induced cataract is a congenital cataract that follows German measles infection (rubella) in the mother. Exposure usually occurs in the first or second trimester of pregnancy. Cataract is one of many manifestations of the congenital rubella syndrome.
Incidence/Prevalence: About 100,000 cases of congenital rubella syndrome occur in the world each year. Rubella accounts for about 5-25% of pediatric cataracts in India. The incidence of rubella cataracts plummeted after introduction of the vaccine circa 1970. The frequency of cataracts in congenital rubella syndrome is about 10-15 % or slightly less than rubella retinopathy. During the U.S. epidemic of 1963-4, about 12.5 million people were infected and about 10,500 cases of congenital rubella occurred.
Etiology: Norman McAlistair Gregg linked congenital cataracts with maternal rubella infection in 1941. Rubella virus is an enveloped RNA virus. Congenital infection persists through pregnancy and may be recovered from patients as old as 2 years and 11 months of age (Menser et al. 1967, Lancet ,19: 387).
Clinical Findings: The cataracts are often bilateral, usually central, and may be lamellar, nuclear or membranous. Occasionally resorption of the cataractous center results in a clear pupillary axis. Infection early in pregnancy is associated with a worse cataract than infection of later onset. Other ocular features include nystagmus, strabismus, microphthalmos, corneal opacities, retinopathy, glaucoma and a small pupil that is difficult to dilate. The classical triad of congenital rubella syndrome is comprised of sensorineural hearing loss, ocular abnormalities and congenital heart disease.
Gross Morphology: Frequently a dense cataract is seen centrally or anteriorly. In the photography there appears to be a more clear zone posterior to the angled white opacity.

Histopathology: Histologically, the lens is usually microspherophakic. Frequently, there is accompanying liquefaction and necrosis of lens. The iris is often bowed forward by the lens. In the accompanying gross and microscopic figures, the lens appears small and cataractous. The triangular opacity is prominent anteriorly and seen both in the gross and microscopic examination. Retained lens fiber nuclei are present. The nuclei may appear pyknotic or karyorrhexic. At white arrow #1 faded nuclei are apparent. Rubella virus may be cultured from surgically removed lenses up to ~3 years of age. PCR techniques may be more sensitive. (Indian J Med Res. 2007 Jan;125(1):73-8)

A non-granulomatous uveitis affecting particularly the iris has been described by Font and Zimmerman.
Treatment: Prevention through immunization of children and women before they become pregnant is the best approach. Cataract removal can be performed.

Congenital Syphilitic Stromal Keratitis

2007-03-10T11:13:00.000-08:00

Definition: Syphilitic stromal keratitis is a form of chronic stromal keratitis with vascularization. The term interstitial keratitis was coined in the 1800’s by Hutchinson for congenital syphilis and unfortunately (from the pathologists perspective) is still used.
Incidence/Prevalence: Syphilitic stromal keratitis is the most common manifestation of untreated late congenital syphilis; it occurs in about 20-50% of patients. The prevalence of syphilis is about 10-50 early cases per 100,000 in the U.S. population. At least 12 million cases of syphilis have been reported in adults annually in the world with estimates between 500,000- 1 million affected pregnancies. It has been estimated that about 40% of cases of untreated congenital syphilis will get syphilitic stromal keratitis.
Etiology: Transplacental infection of the fetus is produced by the spirochete, Treponema palladium. The late onset of congenital syphilitic keratitis is thought to be explained by an immune response to microbes or their antigens. Organisms have been identified in the aqueous of patients with congenital syphilis. [Ref 1&2]
Clinical Findings: The initial presentation of congenital syphilis (late untreated) has its onset between ages 5 and 20 as an acute stromal keratitis and iridocyclitis. 80% of cases are bilateral although the initial presentation involves first one eye followed in weeks to months by the fellow eye. Clinically, there are deep stromal chronic infiltrates and edema that may produce several patterns. Multifocal, sectoral, peripheral, punctate, linear, ring and deep infiltrates are all described. Vessels grow in toward the central deep cornea from the periphery. Scrolls of Descemet’s membrane produce the “glasleitern” which has a distinctive web-like clinical pattern.
Histopathology: The corneal stroma shows scarring at variable depths (numbers 1), deep stromal vascularization (arrow 2) and during the active phase intense lymphocytic inflammation. The histopathologic findings are frequently termed interstitial keratitis; the findings are similar to a scar after infection and are not specific for syphilis. However, about 88% of specimens may show a multi-lamellar intact Descemet’s membrane [Ref 3]. In the figure Descemet's membrane is folded and multilaminar (arrow 3). Scrolling of Descemet's membrane may also be seen. Secondary guttata are quite common (blue arrows ) but not specific .
Treatment: Penicillin and topical steroids may shorten the course of disease according to some authors while others suggest that the infants must be treated by 3 months of age in congenital syphilis to prevent the onset of keratitis.
Prognosis: Resolution occurs spontaneously after weeks to months. About 75% of patients will recover vision but if left untreated, stromal keratitis recurs in about 10% of patients albeit in a milder form. Ghost vessels may persist for years.

References:
1. Goldman J.N. and Girard KF. Intraocular treponemes in treated congenital syphilis, Arch Ophthalmol 78 (1967), pp. 47–50.
2. Smith J.L. and Israel C.W., The presence of spirochetes in late seronegative syphilis, JAMA 199 (1967), pp. 980–985
3. Waring et al. AJO 1976

Fungal Keratitis

2007-03-02T14:35:00.000-08:00

Definition: Infection of the cornea caused by fungus.
Incidence/Prevalence: The incidence is less than 5% of corneal infections in the U.S. The most common organisms include Aspergillus, Candida, and Fusarium. There is a predilection for fungal keratitis for warmer humid climates. Aspergillus and Fusarium are more common in the southern U.S. Candida makes up a greater percentage of fungal keratitis in the northern U.S.
Etiology: Plant matter bearing fungus that penetrates the cornea (e.g. gardening) is a common source of fungal keratitis. Contact lens wear, use of topical steroids, cornea surgery, or keratitis from non-fungal causes are all risk factors. Candida is the most common cause of fungal keratitis. Paecilomyces lilacinus is known to contaminate intraocular lenses. Aspergillus is also a common source of fungal keratitis.
Clinical Findings: Patients may present with a dry fluffy infiltrate in the cornea with feathered margins that are usually white to gray in color. The lesions are usually slowly expansive and indolent and as it progresses to involve the deeper stroma. In the image one can compare the region of necrotizing keratitis (yellow arrow 1) to the relatively less involved cornea (yellow arrow 2) to see the dense white infiltrate that opacifies the cornea. The fungus has infiltrated and destroyed much of the deep stroma to involve the anterior chamber (#3 black arrow). A histologic section in the same area is shown below (black arrows). The initial signs of inflammation may be minimal but as the disease worsens so does the ocular injection.
Histopathology: The hallmark of fungal keratitis is the necrotizing keratitis (black arrow 1) that in general is associated with both an acute and granulomatous inflammatory infiltrate. Neutrophils (#3 black) as well as histiocytes and even multinucleated giant cells comprise the infiltrate. In the cornea there is often ulceration and a severe necrotizing stromal keratitis. In this setting special stains such as Grocott-Gomori methenamine-silver nitrate (GMS stained image #5), and periodic acid Schiff will often highlight the fungal elements. Fungus has penetrated to the anterior chamber (black arrow 5).
The high magnification image shows a fungus with hyphal structures that branch into 2 parts (dichotomous) at 45 degree angles (arrow 1). The hyphae are 'sepatated'. This is a section of Aspergillus.

In the image shown above, there is a large fungal mass that has infiltrated and replaced the necrotic cornea. Descemet's membrane may be seen at the bottom of this PAS stained slide. At higher magnification once sees a mass of pseudohyphae that are so dense that the branching pattern is difficult to discern but the fungal elements are clearly very strongly PAS positive.

An image of a GMS stained section at the edge of the fungal mass shows budding yeast (red arrow 4). These 3 images depict Candida sp.
Fusarium (red arrow 1) is usually distinguished by its thin hyphae with very rare septae and a right angle branching pattern. Other fungal organisms, including Candida and organisms causing mucormycosis, are visible with routine H&E preparations, although better seen with special stains.
Treatment: Antifungal agents include polyenes, e.g. amphotericin and natamycin, that bind to ergosterol, a component of fungal cell walls, and disrupt the fungal cell wall. Imidazoles, such as ketoconazole, fluconazole interrupt ergosterol synthesis. Fluorinated pyrimidines, such as fluocytosine, work by selective transport mechanism involving a permease into the fungal cell and then blockage of thymidine synthesis.
Candida is often treated with topical amphotericin B (up to 0.3%). Flucytosine may be added and in severe cases oral fluconazole.
Aspergillus filamentary keratitis has been treated with topical amphotericin B, natamycin, as well as oral itraconazole, and ketoconazaole.
Fusarium has been treated with natamycin and ketoconazole.
Mechanical debridement has been used to try to improve penetration of the drug and often is done for diagnostic purposes initially.

Blood Staining of the Cornea

2007-02-26T15:20:00.000-08:00

Definition: Corneal blood staining is defined as deposition of hemoglobin and its breakdown products in the cornea.
Incidence/Prevalence: Corneal blood staining occurs in the setting of traumatic hyphema, which has an incidence of 17/100,000. The majority of cases, about 80%, occur in males. The incidence of blood stained corneas in traumatic hyphema varies between 2-11%, but rises if there is a total hyphema to 33-100% in various studies.
Etiology: A combination of hyphema and resultant elevated intraocular pressure are believed to be important in the pathogenesis of blood stained corneas. A patient with hyphema and intraocular pressure greater than 25 mm Hg for 6 days is associated with greatest risk of corneal blood staining. Other predisposing factors are injury to Descemet’s membrane or endothelial damage. Some authors have stated that cytotoxic oxygen species are induced from the reaction of light with porphyrins. The notion that exposure to light may contribute to endothelial and keratocyte degeneration has been advanced.
Clinical: The clinical signs in the progression of corneal blood staining include fine yellow granules in the posterior stroma, yellow discoloration of the stroma, red to brown stromal color followed by shades of green, black, and grey. Note in the illustration a traumatic hyphema (number 1). The cornea peripheral to arrow 2 is white and that located more centrally is yellow to brown (blood staining). The lens is cataractous (number 3). Corneal blood staining may extend to Bowman's layer and even the epithelium in severe cases. Clearance of the blood staining begins peripherally and progresses centrally, and can take up to 3 years. Notice

in the cross section of the cornea above that the blood staining is relatively absent at the periphery (arrow number 2) and most dense centrally. Similarly there is a clear demarcation between the anterior and posterior stroma (white arrow 3) indicative of more rapidly clearing posteriorly.
Pathology: Histopathology features erythrocytic debris and hemoglobin particles between corneal lamellae (arrows 4). In the illustration the hemoglobin particles have managed to make their way up above Bowman's layer (arrow 5). There may be degeneratiive endothelial cells and keratocytes (often seen in the late phases). Trichrome stain provides a dramatic contrast of the blood products in the cornea against the blue-green collagenous background (number 6). Frozen sections demonstrate fluorescence presumably corresponding to the hematoporphyrin derivative that is associated with toxicity. Some keratocytes in blood-stained corneas show hemosiderin and engulfed hemoglobin products. Areas of cleared cornea contain less hemosiderin. Clearing occurs peripherally first from the posterior stroma.
Treatment: Prevention is contingent on removal of the hyphema. Clot removal via an anterior chamber wash-out procedure is usually performed before 6 days of raised intraocular pressure (25 mm Hg or greater) and certainly with the first sign of blood staining. Options for management of the blood staining include observation, spontaneous clearance, or penetrating keratoplasty.
Prognosis: Cases of corneal blood staining secondary to hyphema have cleared spontaneously. One case cleared after 2 years without known intraocular pressure elevation. Many cases will have opacified corneas that require penetrating keratoplasty.

Gottsch JD et al. Arch Ophthalmol 1989;107:1497-500
Fraser C. Et. Al. Spontaneous resolution of corneal blood staining. Clin Experiment Ophthalmol 2006; 34: 279-80.

Salzmann’s Nodular Degeneration of the Cornea

2007-02-17T11:15:00.001-08:00

Definition: This clinical entity was described in 1925 by Maximilian Salzmann in the German literature as usually following trachoma or phlyctenular keratitis. It is characterized by multiple superficial blue white nodules in the midperiphery of the cornea. Recently the pathologic hallmark has been claimed to be the deposition of oxytalan elastic microfibils (Reference 2).
Incidence/Prevalence: Considered rare. The published age range is wide, 4-70, and there is not a clear gender predilection although some series found the disease was predominant in middle aged women (Reference 1).
Etiology: Salzmann's nodular degeneration has been associated with trachoma, interstitial keratitis, vernal keratoconjunctivitis, phlyctenular keratoconjunctivitis, ocular trauma, measles, scarlet fever, and previous surgery. The condition may be considered a special form of corneal scarring whose pathogenesis is unknown. It may very well be one final common pathway of corneal scarring. Oxytalan fibers are presumably one of the three types of elastic fibers: oxytalan, elaunin, and elastin. Oxytalan fibers presumably occur early in elastogenesis and can be segregated from mature elastic fibers by the oxidized aldehyde fuchsin stain (see below). Oxytalan fibers have been identified in cornea scarring from many causes including trauma, keratoconus, and anterior staphyloma (also non-specific).
Clinical Findings: Most often Salzmann's nodular degeneration is unilateral, but it may be bilateral with single or multiple lesions that usually measure between 1-3 mm in size. There may be an accompanying iron line. Usually asymptomatic but patients may develop recurrent corneal erosions or decreased vision from scarring. The nodules are sometimes arranged in a spokelike pattern (numbers 1 in the image).
Histopathology: Sections of the cornea show thinning of the epithelium or denudation as shown above (arrow 1), destruction of Bowman’s layer (number 2 above and arrow 1 below), duplication of the epithelial basement membrane and disorganization of collagen lamellae in the superficial anterior stroma (number 2). These histologic findings are entirely non-specific and can be seen in scarring from any cause. Some authors have touted the oxidized aldehyde fuchsin stain to identify blue violet coloring in the stromal oxytalan fibers (arrows 2 below). Tendon serves as a good control tissue in the same block. Oxytalan fibers are aggregates of fibrillar material. Ultrastructurally, there are aggregates of electron dense collections of small microfibrils (white arrows 3). They are quite small 10 nm in diameter. The tubular appearance in cross sections requires magnification on the order 72-100 thousand times on the electron microscope for identification. Comparison to larger collagen fibrils is helpful (number 4). Consideration should be given to placing the specimen in a solution of glutaraldehyde/paraformaldehyde prior to the biopsy.
Treatment: Medical therapy consists of lubrication, warm compresses, lid hygiene, topical steroids, and/or oral doxycycline and has been successful in over half of the patients in some series. In cases in which vision is compromised or there is discomfort unremedied by medical therapy, the nodules may be removed by superficial, lamellar or penetrating keratectomy depending on their extent. Excimer laser has been used to smooth the surface after removal.
References:
1. Farjo et al Cornea 2006.
2. Obata H et al. Cornea 2006

Herpes Simplex Virus Stromal Keratitis

2007-02-14T08:24:00.000-08:00

Definition: Herpes simplex virus keratitis is a viral infection of the cornea caused by Herpes simplex. It is characterized in early stages by a linear arborizing pattern of opacification and swelling of epithelial cells called a dendrite (green arrow represent the histologic appearance of the dendrite captured in this rare image). This involvement may be self limited or may in recurrent episodes progress to a severe keratouveitis with vision threatening consequences.
Incidence/Prevalence: In the US: Approximately 20,000 new cases of ocular HSV occur in the United States annually, and more than 28,000 reactivations occur in the United States annually. Of the US population, a history of external ocular HSV infection is present in 0.15%. HSV keratitis is one of the most frequent causes of corneal blindness in the United States with 500,000 people experiencing HSV-related ocular disease.
Etiology: Herpes simplex vius has been isolated from corneas in some cases of chronic stromal keratitis by culture, electron microscopy, PCR and immunohistochemistry.
Clinical Findings: The clinical manifestations vary according to the stage of infection. The first attacks are painful, with photophobia, tearing, ciliary injection. A dendrite composed of a plaque of opaque cells may be evident. This is followed by a dendritic ulcer, then a subepithelial infiltrate. There may be slight cell and flare. Vesicles and ulcers may occur concomitantly on the mucosa or lids.
In later attacks there may be a foreign body sensation and cornea becomes more hypoethestic. The attacks may feature stromal keratouveitis with deeper ocular structures being involved. The cornea may show granular opacities or a florid necrotizing keratitis with ulceration. In the photograph, there is a discoid infiltrate (arrows 1) in a red eye with a severe inflammatory reaction (number 2). A Wessely ring (presumably immune in origin) may be present. Vascularization and scarring follow. There is usually epithelial edema, endothelial inflammation (see arrow 1 below) and uveitis. There may be posterior synechiae, rubeosis irides, secondary glaucoma.

Histopathology: The overview of most pathology cases shows marked thinning of the central stroma (notice the thinned central stroma between the red arrows). Previous ulceration leaves a stroma divot in which hyperplastic epithelium may partially fill the gap (red arrows). Sections generally show evidence of epithelial hydropic changes with disruption and an irregularly thinned, disrupted and frequently absent Bowman’s layer (arrow3) that may be replaced by inflammatory pannus. There is accompanying chronic inflammation usually in the anterior stroma (arrow 2) but often in the posterior stroma in severe cases. There may be disruptions in Descemet’s membrane and a retrocorneal fibrous and inflammatory membrane. Note the pigmented laden macrophages arrow 1. The inflammation is often granulomatous. The finding of giant cells and histiocytes on Descemet’s membrane (arrows 4 and 5, respectively) or between Descemet’s membrane and the stroma should invoke a careful search for inclusions of Herpes keratitis. Immunohistochemistry may show reactivity of antibodies directed against Herpes antigens. In this case stromal keratocytes react strongly to anti-HSV 1&2 antigens (lighted arrow).
Corneal scrapings obtained from a dendrite and prepared using the Giemsa stain will reveal the presence of intranuclear viral inclusions (Cowdry A) that have a ground glass appearance. Infected epithelial cells may coalesce to from multinucleated giant cells.

Treatment: Herpetic stromal keratitis can be treated with topical prednisolone drops every 2 hours accompanied by a prophylactic antiviral drug such as trifluridine or acyclovir. The steroid drops are tapered slowly and antiviral agent prevents reinfection with shed virus.
Prognosis: One of the hallmarks of herpes simplex virus (HSV) infection is the establishment of a lifelong latent infection accompanied by periods of recurrent disease. The course depends on the severity of recurrences and the ensuing complications including indolent and stromal ulceration, uveitis, synechiae, rubeosis irides, secondary infection and secondary glaucoma.

Cavernous Atrophy of the Optic Nerve

2007-02-07T13:30:00.000-08:00

Cavernous Optic Atrophy of Schnabel
Definition: degeneration of the optic nerve characterized by cystic spaces in the anterior portion.
Incidence/ Prevalence: The prevalence is 2.1% in an autopsy series. These changes occur commonly in patients with glaucoma after acute IOP elevation, but are perhaps more common in nonglaucomatous elderly patients with generalized arteriosclerotic disease (Ref 1.)
Etiology: In most cases it is thought that vascular disease plays the primary role. The cystic spaces are created by the loss of neuronal tissue that is more sensitive to ischemic injury than the surround supportive connective tissue. In some cases it is associated with glaucoma, perhaps by a vascular mechanism.
Clinical Findings: Most of the patients are elderly (mean age 88), most in women (81%), the condition is usually unilateral (82%). Glaucoma was present in only 23.7% of patients in this series (Reference 1).

Histopathology: Cavernous optic atrophy of Schnabel is characterized microscopically by large cystic spaces (surrounded by arrows 1 in gross and microscopic figures) containing mucopolysaccharide material, which stains with alcian blue dye, posterior to the lamina scleralis. The intracystic material is thought to be vitreous that penetrates into the parenchyma through the internal limiting membrane of the optic nerve head.
In the illustration below, we interpret this to be a focal infarction of the optic nerve that is the beginning of cavernous atrophy. The arrows surround the lighter area that forms a myxoid or cystic appearance. The arachnoid space (number 2) is widened and the dura is thickened (number 3). Most patients are believed to have arteriosclerosis as was evident in narrowing and hyalinization of central retinal artery wall. In this patient the vessels appear patent (arrow 5). Ganglion cells and nerve fiber layer loss are present in the retina in this case (arrow 4). Cupping and retrodisplacement of the lamina scleralis are also evidence of co-existent glaucoma especially if in combination with patent and normal appearing central retinal arteries. At higher magnification the cystic spaces are lined by thin septa forming a web of neurofibrillary material. This case had only a hint of alcian blue material suggesting it is really a very early lesion.
Treatment: By definition, the diagnosis of cavernous atrophy is made once an eye has been removed and the optic nerve has been sectioned. The fellow eye should be examined in cases to determine if glaucoma is present.

Reference: Giarelli L, Schnabel cavernous degeneration Arch Pathol Lab 2003:10:1314-9.

Band Keratopathy

2007-02-06T06:52:00.000-08:00

Calcific Band Keratopathy
Definition: Dystrophic calcification of Bowman’s layer or superficial anterior cornea that forms a distinctive calcified band across the central cornea.
Incidence/Prevalence: Exact incidence of calcific band keratopathy is unknown.
Etiology: Band keratopathy derives its name from the distinctive appearance of calcium deposition in a band across the central cornea. Band keratopathy can occur from a variety of causes, both systemic and local. Bank keratopathy is associated with chronic corneal edema (perhaps the most common treatable cause accounting for over 1/4 of cases in one series), phthisis bulbi, chronic iridocyclitis, severe glaucoma, hyperparathyroidism, vitamin D excess, sarcoidosis or renal disease. The latter 4 are related to abnormal calcium metabolism. Severe dry eye may also precede band keratopathy. Herpes keratitis may predispose to band keratopathy. The use of phosphate salts in steroid preparations may precipitate calcium in patients with epithelial defects.
Clinical Findings: Seen clinically as calcific plaques in the interpalpebral zone, band keratopathy is characterized by the deposition of calcium in the epithelial basement membrane, Bowman’s layer, and anterior stroma. There is usually an intervening region of cornea between the limbus and the calcification that is unaffected. In the macroimage of the cornea one can see the unaffected cornea (number and arrow 1), the band of calcification spanning arrows labeled 2 and incidental arcus senilis (yellow number 3).
Histopathology: In early cases there is a stippled basophilia of Bowman’s layer (number 1 in the figures) in H&E sections. As the disorder progresses, the calcium deposits merge to form a linear array along Bowman’s layer. In the figure arrow 2 shows the linear array forming. The deposits may spill over into the anterior stroma (arrow 3). Special stains can be used to document that the substance is calcium. The von Kossa stain reacts to give a black color.

Treatment: Generally, the cornea epithelium is abraded physically or chemically. 19% ethanol can be used to gently remove the epithelium and rolled to the side. The calcium is rubbed off, often with a sponge soaked in a solution of ethylenediamine-tetraacetic acid (EDTA). The epithelium is replaced and a bandage contact lens is worn temporarily. Excimer laser has been used effectively but may cause a myopic shift.

References
Najjar DM et al.

Persistent Hyperplastic Primary Vitreous (PHPV)

2007-02-05T09:10:00.000-08:00

Definition: PHPV is a congenital condition with persistent hyaloid vasculature and mesenchymal tissue from the embryonic primary vitreous in a microphthalmic eye. It is often seen in combination with other syndromes. The syndrome has been renamed recently as persistent fetal vasculature.
Incidence/Prevalence: Rare. About 50 cases were seen in a busy pediatric referral surgery practice over 10 years (Ref 2).
Etiology: Described by Reese in 1949, PHPV is thought to be congenital. As the ectoderm of the lens plate and neuroectoderm of the optic vesicle separate, vasoformative mesenchymal tissue normally grows in to the space. In PHPV the tissue is thought to persist, hence the name. Recently it was discovered that mice lacking a tumor suppressor gene (Arf) have an anomaly similar to human PHPV. (Ref 1) PHPV has been described in association with neurofibromatosis 2 and Axenfeld-Rieger syndrome with its concomitant chromosomal abnormality.
Clinical Findings: The disease may be either unilateral (90%) or less commonly bilateral (10%). The patient usually has leukocoria, markedly reduced vision and a small eye.
Gross: The earliest or most mild findings are elongation of the ciliary processes and the eye may be normal in size. In more severe cases the eye is small (as shown in the figure). There may be an accompanying retinal detachment that is considered by most to be tractional. In the figure there is clearly blue subretinal exudate that fills the vitreous cavity around the retinal detachment (arrow 1). In most cases, fibrovascular or primitive vasoformative tissue (number 2) and mesenchymal tissue, including cartilage, mature adipose tissue and smooth muscle, arise from the primitive tissue behind the lens. Often times a hyaloid vessels is seen attaching to the mesenchymal tissue which is directly behind the lens. The mesenchymal tissue is attached laterally to elongated and centrally dislocated ciliary processes (arrow 3), a characteristic pathologic feature. Retinal dysplasia may be seen in the retina behind the lens (arrow 5). Microophthalmia, cataract (here a generalized cortical cataract) and a variety of anomalies of the anterior chamber angle are seen with PHPV. In this figure the iris completely occludes the angle and trabecular meshwork with extensive peripheral and central (arrow 4) anterior synechiae.
Treatment: Lensectomy with or without anterior or total vitrectomy, and trabeculectomy are generally the procedures that are performed depending on the clinical presentation. The retinal detachment can be repaired. Attempts at early surgical rehabilitation prior to 77 days may have a better visual outcome. (Ref 2)

References:
Thorton J.D. IOVS 2007

Hunt A. BJO 2005.

Coccidioidomycosis

2007-02-04T14:42:00.000-08:00

Coccidioidomycosis Uveitis and Retinitis
Definition: Fungal systemic infection caused by inhalation of airborne spores from Coccidioides immitis.
Etiology: Coccidioidomycosis is a fungus found in the soil. It is related to dust storms. The ocular disease was described in 1948.
Incidence/Prevalence: Cocci is prevalent in regions considered Sonoran desert zones including the southwestern United States, parts of Mexico as well as Central and South America. In the U.S. it is most notable in the San Joaquin valley of California and Arizona. In Arizona in 2001 the incidence was reported as 43/100,000 population, a marked rise from 1995.
Systemic Clinical Findings: The disease has 4 different presentations, asymptomatic, primary pulmonary illness, persistent pulmonary disease, and disseminated disease. Clinical manifestations occur in only about 40% of infected persons. The most common presentation is a influenza-like illness. However it can progress to severe pneumonia and, rarely, extrapulmonary disseminated disease. Only a few arthroconidia, the mycelial form, can infect people. Persons at highest risk for disseminated disease include blacks, Filipinos, pregnant women in their third trimester, and immunocompromised persons.
Ocular Clinical Findings: Ocular Coccidioidomycosis generally segregates into 4 groups.

1. External eye disease including the eyelids and conjunctiva as the most common sites.

2. Anterior uveitis- presenting with hypopyon, iridocyclitis and a red eye. Pulmonary findings may be difficult to find in this subgroup and therefore must be suspected in cases of anterior uveitis of unknown origin in the proper clinical setting.

3. Posterior retinitis and uveitis- usually as part of the presentation of severe disseminated disease and often discovered late in the disease course. Many presumed cases have been described. Most cases documented pathologically originated from enucleation or autopsy. The posterior disease shows focal small white lesions that may be superficial and deep to retinal blood vessels.

4. Anterior and posterior disease- all cases that have been documented had initial involvement of the anterior segment and underwent vitrectomy. All eyes were lost.

Gross: The retina features single superficial discrete white lesions, which are granulomata surrounding the organisms (arrow 1). The choroid shows slightly less discrete white lesions with blurred margins (arrow 2).

Microscopic: In every tissue the key findings are granulomata that contain both spherules and endospores. In the figure, one sees a discrete granuloma in the inner nuclear layer. There is a spherule which contains endospores that are even visible on hematoxylin and eosin stains. Note that the endospores (inside the spherule at arrow 3) do not have nuclei (different from tachyzoites and bradyzoites of toxoplasmosis that are so often confused by ophthalmology residents). The spherule (arrow 3) is surrounded by a multinucleated giant cell (arrow 4). PAS and GMS highlight the organism.

Here the choroidal granuloma, really a single multinucleated giant cell in the figure (arrow 5) surrounds the PAS positive spherule. Multiple endospores are seen within the spherule, which also stain with PAS. This spherule is intact.
The GMS stain captures a ruptured spherule (arrow 6) that is releasing endospores (arrow 7).
Treatment: Amphotericin B is the drug of choice for pulmonary Coccidioidomycosis that is persistent or in which there is evidence of dissemination. The drug penetrates poorly into tissue and so it is administered intracamerally (intraocularly). Immunotherapy has been given for the disease with some success. Liposomes are sometimes used as a vehicle for slow release.
Prognosis: In the patients most at risk the disease may be fatal. Patients with anterior uveitis have a uniformly poor prognosis for useful vision. The lesions of the posterior segment have a better prognosis provided the patient survives the systemic illness.