Blood Staining of the Cornea

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

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

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

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

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)

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

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.

LASIK Complications

The pathologic complications of LASIK are legion. The most common seen in the ocular pathology laboratory include: keratectasia requiring corneal transplant, corneal perforation requiring cornea transplant, stromal scarring, epithelial implantation and ingrowth, and infectious keratitis. For a more complete list click on this link.

Scar formation after Lasik
Any incision in the corneal stroma results in the disruption of the stromal lamellae. LASIK entails an initial tangential incision to a hopefully predetermined depth. Then the flap is extended with a broad horizontal cut. If all goes well the disruption may be minimal. A thin faint line is visible at the interface between the lamellar flap and the residual stroma that is accentuated in PAS stains (arrows 3). Focal scarring may be present (arrow 4).
However, occasionally, there may an exuberant scar formation. If revisions or "enhancements" are attempted, the risk of scarring becomes greater. In the figure, the LASIK wound (arrows 1) is seen as a linear configuration that merges with its associated scarring (number 2). The scar is evident as a focal absence of keratocytes and an obliteration of corneal lamellae. In this case, the scar is particularly exuberant. The stroma is actually bulging centrally because of the scar. Several enhancements were performed in this case.

Keratectasia after LASIK

Definition: thinning of the corneal stroma with bulging of the cornea

Etiology: There is a debate whether keratectasia is a forme fruste of keratoconus. In some cases this is clearly not the case as the flap was either made too deeply or the remaining stromal bed was too thin after the usual obliteration with laser. In the image provided the lighted arrow points to the LASIK wound which is very deep in the stroma. In this case the cornea was removed for scar formation. One can see that Bowman's layer is quite irregularly thinned as well. In about 1/2 of the cases of keratectasia the residual stromal bed, that can be calculated from published data, is greater than 250 microns. This suggests that the arbitrary target of 250 microns for calculated residual stromal bed at the time of surgery may be too low or perhaps irrelevant in some cases. At the minimum this complication should be carefully explained to the patient as it is one of the most common sources of litigation.

Incidence/Prevalence: The reported incidence of keratectasia after LASIK is about 0.7%. Clinical Findings: Keratectasia usually occurs within about 30 months (mean 11.8 months) after LASIK. The patients often notice a change in their refraction and frequently some LASIK "enhancement" is made, which makes matters worse. The patients may be fit with contact lenses to at least partially restore vision. But if the keratectasia is progressive, the patient may no longer be able to be fit and then will require a penetrating keratoplasty.
Gross: The keratectatic cornea is thinned and usually shows scar formation. The bulge associated with the clinical appearance may not be obvious because of fixation of a thin cornea often produces folding and distortion.
Microscopic: The central cornea is markedly thinned (number 5). The interface between stromal bed and flap is evident as a thin line even at low magnification (arrows 3). Often there is an area of iron staining in the epithelium just as one sees in keratoconus. The absence of any abnormalities of Bowman's layer other than the LASIK incision would be evidence against a previous diagnosis of keratoconus.