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Ophthalmic Pathology
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Case 1 -
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Aphakic Bullous Keratopathy
Michele M. Bloomer - UCSF , San Francisco, CA
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Clinical History
Case #1 A 31 year old female with a history of congenital cataracts and microphthalmos underwent cataract surgery and was left aphakic. Over the next few years the patient’s vision deteriorated and she developed pain. The patient also has a history of glaucoma controlled by topical drops. Best corrected visual acuity at presentation was 20/200. Her cornea was opaque with a central corneal thickness of 904µm. She had several corneal epithelial defects. A penetrating keratoplasty was performed and the cornea button was sent to pathology.
Case #2 A 19 year old female patient with Down Syndrome had progressively decreasing vision. Her best corrected visual acuity is Count Fingers at 4 ft. A penetrating keratoplasty is performed and the corneal button is submitted to pathology.
Case #3 A 73 year old female patient with progressive, painless loss of vision bilaterally underwent cataract surgery in her left eye one year ago. Visual acuity did not improve postoperatively and has continued to decline. She also has developed pain in her left eye. A penetrating keratoplasty is performed on her left eye.
Case 1A - Figure 1
(H&E, 1.25x) Full thickness corneal button from a penetrating keratoplasty. Overall corneal thickness is increased secondary to stromal edema. |
Case 1A - Figure 2
(PAS, 10x) Bullous keratopathy: diffuse epithelial thinning with focal disruption consistent with a ruptured bulla, epithelial basement membrane thickening, supepithelial fibrosis, focal destruction of Bowman's membrane, anterior keratocyte depletion, anterior stromal scarring and posterior stromal edema. |
Case 1A - Figure 3
(PAS, 20x) Higher power view of anterior cornea highlighting diffuse epithelial thinning, epithelial basement membrane thickening, supepithelial fibrosis, focal destruction of Bowman\'s membrane, anterior keratocyte depletion and anterior stromal scarring |
Case 1A - Figure 4
(PAS, 20x) Endothelial failure: Descemet's membrane stains positively with PAS, severe endothelial cell loss. |
Introduction:
The cornea provides the anterior barrier separating the intraocular contents from the external
environment. The tear film baths the exterior surface and the internal surface is in contact with the
aqueous humor. Corneal clarity is necessary for optical functioning and any process that interferes with
this, such as corneal edema or scarring compromises vision. The cornea consists of five layers with
highly organized structure and function to allow for the transmission of light.
The corneal epithelium is typically four to six cells thick. The basal layer of cells has a columnar
appearance and is adherent to an underlying basement membrane. Chronic corneal edema causes bullous
separation of the epithelium from the underlying Bowman's membrane. The overlying epithelium often
becomes thinned and the bullae rupture exposing the nerve endings that penetrate through Bowman's
membrane leading to pain. The epithelial defects heal by expansion of the basal epithelial cells at the
edges of the defects. When this process occurs repeatedly defects in Bowman's membrane appear with
subsequent focal areas of subepithelial fibrosis. Bowman's membrane is an anterior condensation of
keratocytes and does not regenerate if damaged. The corneal stroma consists of keratocytes that secrete
collagen and extracellular matrix material. The collagen is normally arranged in a lamellar pattern to
allow for the least amount of light scatter. The stromal layer normally exists in a relatively
dehydrated state (78% water) due to the pumping mechanism of the corneal endothelial cells. The
posterior stroma is lined by a basement membrane known as descemet's membrane that is secreted by the
corneal endothelium. This endothelium is a monolayer of cells that has no in vivo mitotic activity and
undergoes attrition with aging, inflammation, trauma and other disease processes. Luckily, we are born
with a reserve of corneal endothelial cells so that the mechanism for keeping the stroma deturgesced
remains viable until a critical threshold of cells is reached (approximately 500cells/mm2). Chronic
corneal edema leads to permanent changes in the stroma including scarring that affects the ability of the
cornea to transmit light.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The specimen submitted is a full thickness corneal button from a penetrating keratoplasty fixed in 10%
neutral buffered formalin. The specimen was then bisected and half is submitted for processing. Cross
sectional cuts allow examination of all corneal layers from epithelium to endothelium. This specimen is
dissuely thickened secondary to stromal edema. A focal disruption in the epithelium with tapered edges
and separation from the underlying Bowman's membrane is indicative of bullous keratopathy. The
epithelial basement membrane is diffusely thickened with areas of subepithelial fibrosis. Focal
destruction of Bowman's membrane with anterior keratocyte depletion and anterior stromal scarring
suggests chronicity. The posterior stroma has a "cotton candy" appearance seen with increased corneal
stromal hydration (corneal edema). Descemet's membrane stains strongly with periodic acid schiff(PAS).
The endothelium is severely atrophic.
Differential Diagnoses:
- Pseudophakic bullous keratopathy
- Aphakic bullous keratopathy
- Fuchs' endothelial dystrophy
- Keratoconus
- Chronic corneal edema
Final Diagnosis:
Aphakic bullous keratopathy
Case Discussion:
Pseudophakic or aphakic bullous keratopathy is a clinical diagnosis made in patients with unresolving
bullous corneal edema after cataract surgery. Pseudophakic refers to patients who had an intraocular
lens implant placed and aphakic refers to patients who where left without a lens implant. Patients
present with decreased vision due to corneal edema and pain from ruptured epithelial bullae. Aphakic and
pseudophakic bullous keratopathy were the leading causes of corneal degeneration for many years due to
the endothelial trauma induced as a result of cataract surgery. Advances in surgical techniques and lens
implant designs have reduced the incidence of pseudophakic/aphakic bullous keratopathy dramatically over
time. The mechanism involves damage to the corneal endothelial cells as a direct result of trauma from
the surgical procedure or ongoing damage from the lens implant after surgery. Normal corneal endothelium
is composed of a monolayer of honeycomb shaped cells that are tightly adherent to one another. The
corneal endothelial cells have membrane bound sodium-potassium ATPase pump and intracellular carbonic
anhydrase activity that is responsible for maintaining the stroma is a relatively hypotonic state
compared to the anterior chamber aqueous fluid. This gradient allows for passive bulk fluid movement
that keeps the stroma deturgesed. Corneal endothelial cells are not capable of mitosis in vivo. Viable
endothelial cells undergo morphological changes to try and compensate for the lost cells. The remaining
cells enlarge (polymegathism) and display a greater variation in cell shape (pleomorphism). These
changes can be seen in vivo using confocal microscopy and have been correlated with reduced endothelial
function. Endothelial cell counts below 500 cells/mm2 are at risk for developing bullous keratopathy.
The pathology shows a diffusely thickened and cloudy corneal button grossly. Figure 1 demonstrates a
low power view of a penetrating keratoplasty specimen from this patient with aphakic bullous keratopathy.
Note the relatively uniform thickness across the specimen. A ruptured corneal bulla is shown in figure
2. Note the thinned epithelium with tapered edges at the breakpoint. The anterior corneal stroma has a
thickened and irregular arrangement of collagen indicative of stromal scarring that results from chronic
stromal edema. The posterior stroma has a "cotton candy" appearance due to increased stromal hydration.
A higher power view in figure 3 shows diffusely thinned and irregular caliber of epithelium with
thickened basement membrane, subepithelial fibrosis, focal Bowman's membrane destruction, decreased
anterior stromal keratocytes with thickened, irregularly arranged collagen. Note the lack of
inflammatory cells in this case of chronic bullous corneal edema. Period acid-Schiff stain in figure 4
highlights diffuse descemet's membrane thickening. Note the paucity of endothelial cells on the
posterior corneal surface (endothelial failure).
Keratoconus is in the differential diagnosis of decreased vision secondary to corneal edema. However,
keratoconus is a progressive ectatic disease that leads to corneal edema secondary to episodes of acute
hydrops when the cornea becomes thinned leading to acute ruptures in descemet's membrane. Figure 5 shows
a low power view of a PKP specimen from a patient with keratoconus demonstrating inferior paracentral
thinning characteristic of this disorder. Keratoconus is a non-inflammatory, bilateral disorder of
unknown etiology. Some cases of keratoconus appear to be inherited, but the genetics remain an enigma.
The disease typically presents at puberty and progresses through the third and fourth decade, often
arresting in adulthood. Association of keratoconus with atopic disease and Down's syndrome, as well as
non-inflammatory connective disorders is well established. Histopathologic changes have been described
in all corneal layers in keratoconus. The epithelium may be thinned or thickened with deposition of
ferritin particles within and between the epithelial cells located at the base of the cone (Fleischer
ring). Bowman's membrane develops characteristic interruptions as shown in figures 6 & 7 that can
lead to subepithelial fibrosis, figure 8. The stromal collagen fibrils are normal sized in keratoconic
corneas, however the number of collagen lamellae is low, especially in the area of the cone. Breaks in
descemet's membrane as seen in figure 9 & 10 lead to rapid fluid influx into the stroma causing
sudden painless loss of vision (acute hydrops). It takes weeks to months for these episodes to resolve
with multiple episodes leading to dense scarring as in figures 8 & 9.
Fuchs' endothelial corneal dystrophy is also in the differential diagnosis, but is an asymmetric,
bilateral, slowly progressive disease. Ernest Fuchs first described the disease in 1910. It affects 4%
of the population over 40 years of age with symptoms usually presenting in the 5th or 6th decade,
although earlier onset forms had been documented. Women are predominately affected. Like aphakic and
pseudophakic keratopathy there is a loss of endothelial cells over time, however in Fuchs' dystrophy
there is also diffuse thickening of descemet's membrane with nodular excrescences along the posterior
surface. These nodules can be seen clinically at the slitlamp and are referred to as corneal guttae.
Patients have a higher risk of corneal edema after cataract surgery but the diagnosis is usually known
preoperatively. The surgical treatment of choice for Fuchs' endothelial dystrophy is now focused on
replacement of descemet's membrane and endothelium. Descemet's membrane specimens are diaphanous
membranes that are best evaluated by periodic acid-Schiff stain, Figure 11.
Review of the Literature/Treatment Options:
Surgical treatment options for aphakic/pseudophakic bullous keratopathy include full thickness
penetrating keratoplasty (PKP), as in this case where the longstanding edema leads to anterior corneal
scarring in addition to endothelial failure. PKP was the standard option until more recently. Now
pathologists are receiving partial thickness corneal specimens for this entity, as well as other corneal
diseases. The variety of corneal specimens received for pathological evaluation today reflects a growing
arsenal of surgical procedures developing with the aim to address specific level of dysfunction while
decreasing the risk of surgical complications. PKP is now reserved for disease processes involving the
majority of corneal layers. Alternative surgical procedures that replace the anterior cornea, i.e. deep
anterior lamellar keratoplasty (DALK), can be used to treat pathology limited to the anterior cornea as
in some cases of keratoconus (see figures 12 &13). Procedures such as descemet's membrane
endothelial keratoplasty (DMEK) or descemet's stripping automated endothelial keratoplasy (DSAEK) are
used for pathology limited to descemet's membrane, i.e. early aphakic/pseudophakic bullous keratopathy
and Fuchs' endothelial dystrophy (figure 11).
Conclusion(s):
Aphakic/pseudophakic bullous keratopathy is a less common diagnosis given advances in cataract
surgery. It may be treated with either a full thickness penetrating keratoplasty or a partial thickness
procedure based on the extent of pathology. Cross sectional evaluation with hematoxylin and eosin as
well as periodic-acid Schiff stains help identify the characteristics histopathological findings
discussed above.
References:
- DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg 2011; 37:588-598.
- Alomar TS, Al-Aqaba M, Gray T, Lowe J, Dua HS. Histological and confocal microscopy changes in chronic corneal edema: implications for endotelial transplantation. IOVS 2011; 52:8193-8207.
- Kohnen T. Compromised corneal endothelium and cataract: how should we decide? J Cataract refract Surg 2011; 37:1377-1378.
- Heindl LM, Hofmann-Rummeit C, Schiotzer-Schrehardt U, Kruse FE, Cursiefen, C. Histologic analysis of descemet stripping in posterior lamellar keratoplasty. Arch Ophthalmol. 2008;126(4):461-464.
- Sherwin T, Brookes NH. Morphological changes in keratoconus: pathology or pathogenesis. Clin Experiment Ophthalmol 2004; 32:211-217.
- Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol 2011; 95:1044-1050.
- Gutti V, Bardenstein DS, Iyengar S, Lass JH. Fuchs' endotelial corneal dystrophy. 2010; Ocular disease; Ch 5:34-41.
- Louttit MD, Kopplin LJ, Igo, Jr, RP, et al. A multicenter study to map genes for Fuchs endothelial corneal dystrophy: baseline characteristics and heritability. Cornea 2012; 31(1):26-35.
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