Journal of Refractive Surgery

Review 

Pathophysiology and Treatment of Diffuse Lamellar Keratitis

Steven E. Wilson, MD; Rodrigo Carlos de Oliveira, MD

Abstract

PURPOSE:

To review cytokine- and chemokine-mediated mechanisms of diffuse lamellar keratitis (DLK) after lamellar corneal surgical procedures.

METHODS:

Review of the basic science and clinical literature.

RESULTS:

DLK can occur early or late (months to decades) after all lamellar corneal surgeries, including laser in situ keratomileusis, small incision lenticule extraction, anterior lamellar keratoplasty, and Descemet's stripping automated endothelial keratoplasty. It is most commonly triggered by epithelial injury during or after lamellar surgery, which leads to the release of interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α from the epithelium and into the stroma. These chemokines directly attract inflammatory cells into the cornea from the limbal blood vessels and also bind to receptors on keratocytes and corneal fibroblasts where myriad chemokines are upregulated that also chemotactically attract monocytes, macrophages, granulocytes, lymphocytes, and other bone marrow–derived cells into the corneal stroma. Other factors that can trigger DLK include retained blood in the interface, endotoxins and other toxins, and excessive keratocyte necrosis caused by femtosecond lasers. Infiltrating cells show a preference to enter any lamellar interface in the cornea, regardless of the time since surgery, because of the ease of movement toward the chemotactic attractants relative to the surrounding stroma with intact collagen lamellae and stromal cells that serve as relative barriers impeding motility. The mainstay of treatment is topical corticosteroids, but severe cases may also be treated with flap lift irrigation and systemic corticosteroids.

CONCLUSIONS:

DLK can occur early or late after any lamellar corneal surgical procedure and is most commonly triggered by epithelial-stromal-bone marrow–derived cellular interactions mediated by corneal cytokines and chemokines.

[J Refract Surg. 2020;36(2):124–130.]

Abstract

PURPOSE:

To review cytokine- and chemokine-mediated mechanisms of diffuse lamellar keratitis (DLK) after lamellar corneal surgical procedures.

METHODS:

Review of the basic science and clinical literature.

RESULTS:

DLK can occur early or late (months to decades) after all lamellar corneal surgeries, including laser in situ keratomileusis, small incision lenticule extraction, anterior lamellar keratoplasty, and Descemet's stripping automated endothelial keratoplasty. It is most commonly triggered by epithelial injury during or after lamellar surgery, which leads to the release of interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α from the epithelium and into the stroma. These chemokines directly attract inflammatory cells into the cornea from the limbal blood vessels and also bind to receptors on keratocytes and corneal fibroblasts where myriad chemokines are upregulated that also chemotactically attract monocytes, macrophages, granulocytes, lymphocytes, and other bone marrow–derived cells into the corneal stroma. Other factors that can trigger DLK include retained blood in the interface, endotoxins and other toxins, and excessive keratocyte necrosis caused by femtosecond lasers. Infiltrating cells show a preference to enter any lamellar interface in the cornea, regardless of the time since surgery, because of the ease of movement toward the chemotactic attractants relative to the surrounding stroma with intact collagen lamellae and stromal cells that serve as relative barriers impeding motility. The mainstay of treatment is topical corticosteroids, but severe cases may also be treated with flap lift irrigation and systemic corticosteroids.

CONCLUSIONS:

DLK can occur early or late after any lamellar corneal surgical procedure and is most commonly triggered by epithelial-stromal-bone marrow–derived cellular interactions mediated by corneal cytokines and chemokines.

[J Refract Surg. 2020;36(2):124–130.]

Smith and Maloney1 first described diffuse lamellar keratitis (DLK) in 1998 as a diffuse, multifocal, non-infectious inflammation localized to the lamellar interface after myopic keratomileusis or laser-assisted in situ keratomileusis (LASIK) (Figure 1). It has subsequently been reported with many lamellar corneal surgeries, including small incision lenticule extraction2,3 and Descemet stripping automated endothelial keratoplasty,4 and likely can occur after any corneal surgical procedure that includes a lamellar interface. The time of onset can be as soon as 1 day after surgery1 or as long as decades after LASIK and other lamellar surgeries.5,6

Slit-lamp photographs of stage III diffuse lamellar keratitis that occurred many years after laser in situ keratomileusis in response to epithelial trauma (original magnification [A] ×20, and [B] ×40).

Figure 1.

Slit-lamp photographs of stage III diffuse lamellar keratitis that occurred many years after laser in situ keratomileusis in response to epithelial trauma (original magnification [A] ×20, and [B] ×40).

DLK can be sporadic or epidemic.7 Sporadic cases are commonly associated with surgical issues such as epithelial defects, epithelial slough with a microkeratome during flap cutting, or retained blood in the interface.7,8 Epidemic clusters of DLK are typically associated with toxins associated with sterilizers, cleaning and other solutions, marking pen ink, or surgical suite airflow issues.9–14 However, some users of early models of femtosecond lasers also reported clusters of cases of DLK.15,16

The severity of DLK can vary from a minor self-limiting inflammation, especially at the flap edge where the epithelium is transected by microkeratomes or femtosecond lasers, to severe inflammation associated with flap melting, scarring, and irregular astigmatism. Linebarger et al.17 developed the most widely used classification system for DLK:

  • Stage I: White granular cells in the periphery with sparing of the visual axis. Usually on day 1.
  • Stage II: White granular cells in the visual axis. Typically between days 1 and 3.
  • Stage III: Clumping of granular cells with haze and reduced vision.
  • Stage IV: Stromal necrosis and melt, often leading to secondary hyperopia and irregular astigmatism).

Stage III and IV DLK cases are rarely seen but should be considered ophthalmic emergencies and treated aggressively.

Triggers of DLK

The most common trigger for DLK is corneal epithelial injury. This may occur intraoperatively, such as when a microkeratome produces an abrasion or even complete sloughing of the epithelium. Some refractive surgery patients have occult anterior basement membrane dystrophy without a history or slit-lamp signs and the surgeon discovers that merely touching the epithelium with a surgical sponge or spatula produces an epithelial defect. In these patients, this epithelial injury can trigger DLK. However, any epithelial trauma, even decades after LASIK or other lamellar corneal surgeries, can produce DLK because the potential space at the interface remains indefinitely within the cornea and the epithelial injury triggers a wound healing response that preferentially involves and is potentiated within the stromal interface.

Another common intraoperative cause of DLK is retained blood in the interface because of the cytokines and chemokines that are normally present in blood. This usually occurs when the microkeratome or femtosecond laser cut is close to the limbus and blood extravasates from the limbal blood vessels. Usually, this can be removed by sponging and profuse irrigation just prior to repositioning the flap that tamponades these perilimbal blood vessels. However, a trace of blood often remains in the interface.

Another common trigger for DLK is flap cutting using a femtosecond laser, especially with earlier model femtosecond lasers (30 kHz or lower with the IntraLase femtosecond laser; Advanced Medical Optics, Irvine, CA) that delivered more energy to the cornea.15,18,19 Femtosecond lasers trigger keratocyte necrosis versus keratocyte apoptosis primarily produced by microkeratomes, where the blade draws epithelial debris, including pro-apoptotic cytokines such as interleukin-1 (IL-1), into the interface.18,19 Chaotic necrosis is more inflammatory than controlled apoptosis, with release of all intracellular contents that attract bone marrow–derived cells such as monocytes, macrophages, and neutrophils into the stroma. Also, early models of femtosecond lasers were intentionally designed to produce a gap in the epithelium at the flap edge that helped the surgeon locate the flap edge, but also broke apart many more epithelial cells and released higher levels of IL-1α, IL-1β, and tumor necrosis factor (TNF)-α into the underlying stroma. These two factors led to a much greater incidence of DLK when LASIK was performed with these early model femtosecond lasers, especially at the flap edge (peripheral DLK). The IntraLase 60-kHz laser and later models and the femtosecond lasers of other manufacturers, such as Alcon and Zeiss, reduced the energy delivered by the laser during LASIK flap cutting and therefore decreased keratocyte necrosis. This reduced the inflammatory response after LASIK to levels similar to those obtained with LASIK performed with microkeratomes.17,18

Either epithelium-off or epithelium-on riboflavin–ultraviolet cross-linking can trigger DLK in an eye that had prior lamellar corneal surgery19 (eg, in the treatment of ectasia after LASIK). It is to be expected that epithelium-off cross-linking could produce DLK because of the large epithelial injury associated with the procedure.20 However, even epithelial-on DLK produces epithelial injury due to the epithelial permeabilization step with agents such as benzalkonium chloride and ethylenediaminetetraacetic acid (EDTA) that allow riboflavin to enter the stroma in sufficient concentrations for ultraviolet-driven cross-linking.20,21

Any condition that increases inflammation in the eyelids or anterior segment of the eye can increase the risk of developing DLK after lamellar corneal surgery. A common condition that should be treated prior to LASIK because of this concern is ocular rosacea or meibomian gland dysfunction syndrome with a significant inflammatory component.22,23 Other examples of conditions that could predispose to DLK include prior viral keratitis (especially if there was associated keratitis) or late viral keratitis after LASIK.25 Patients with ocular atopic diseases are also predisposed to develop DLK and should be pretreated with corticosteroids prior to LASIK or other lamellar corneal surgeries, and may need postoperative corticosteroids for longer than the typical 1-week course following LASIK.26–28

Most epidemics of DLK are attributable to toxins such as bacterial endotoxins in sterilizer reservoirs, instruments, supplies, or solutions.9,11,12 Other outbreaks have been attributed to changes in surgical implements such as marking pens,13,14 cleaning solutions,10 sponges,29 gloves,30 blades, or water sources that are contaminated with a toxin such as endotoxin. The onset of a series of DLK cases should prompt a review of recent changes in any aspect of the operating room or instrumentation used for lamellar corneal surgery. Faulty operating room air purification systems have also been reported.31 In some cases, the etiology of an epidemic of DLK was never pinpointed.11 Care should be taken in incorporating new solutions, markers, sterilizers, and other surgical implements into a practice that is not currently experiencing issues with DLK.

Pathophysiology of DLK

DLK is merely a normal corneal wound healing response to a trigger that is enhanced by unimpeded, rapid transit of bone marrow–derived inflammatory cells across the cornea within the lamellar interface and potentiation by the accumulated inflammatory cells. The most common cause is intraoperative or late injury to the epithelium. Injury to the epithelium results in the immediate release of IL-1α, IL-1β, and TNF-α from the epithelium and into the underlying stroma (Figure 2).32–34 These cytokines are not only themselves chemotactic to bone marrow–derived cells, but also bind to IL-1 and TNF-α receptors on keratocytes and corneal fibroblasts, and upregulate the expression of chemokines such as granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic and activating factor (MCAF or MCP-1), neutrophil-activating peptide (ENA-78), granulocyte-macrophage colony-stimulating factor receptor (GM-CSFRa), and monocyte-derived neutrophil chemotactic factor (MDNCF or IL-8)35 that attract monocytes, macrophages, neutrophils, eosinophils, lymphocytes, fibrocytes, and other bone marrow–derived cells from the limbal blood vessels into the cornea (Figures 34).35 Monocytes, macrophages, fibrocytes, and other bone marrow–derived cells also produce cytokines and chemokines that attract other bone marrow–derived cells and thereby potentiate the inflammatory response.36–38 Once they are in the stroma, many of these cells transit across the cornea via the lamellar interface because movement is unimpeded by collagen lamellae and stromal cells and therefore large concentrations of these cells, which produce their own chemokines to attract more bone marrow–derived cells, accumulate in the interface. Thus, the DLK response is self-perpetuating in the absence of treatment because the responding bone marrow–derived cells and surrounding corneal fibroblasts pour out large quantities of chemotactic cytokines and chemokines. The inflammatory cells and corneal fibroblasts/keratocytes also release collagenases, metalloproteinases, and other enzymes that can alter the stroma surrounding the lamellar interface, and even facilitate melting of the stroma in stage IV DLK.39

Constitutive (continuous) production of interleukin (IL)-1α in an unwounded human corneal epithelium (e). Injury to the epithelium such as a traumatic abrasion or microkeratome blade results in the release of the IL-1α into the surrounding stroma (s) where it binds to receptors on keratocytes and corneal fibroblasts and upregulates production of many wound healing–associated effectors including chemokines, metalloproteinases, and collagenases. From Wilson SE, Schultz GS, Chegini N, Weng J, He YG. Epidermal growth factor, transforming growth factor alpha, transforming growth factor beta, acidic fibroblast growth factor, basic fibroblast growth factor, and interleukin-1 proteins in the cornea. Exp Eye Res. 1994;59(1):63–71. ©1994 Elsevier Ltd. Reprinted with permission.

Figure 2.

Constitutive (continuous) production of interleukin (IL)-1α in an unwounded human corneal epithelium (e). Injury to the epithelium such as a traumatic abrasion or microkeratome blade results in the release of the IL-1α into the surrounding stroma (s) where it binds to receptors on keratocytes and corneal fibroblasts and upregulates production of many wound healing–associated effectors including chemokines, metalloproteinases, and collagenases. From Wilson SE, Schultz GS, Chegini N, Weng J, He YG. Epidermal growth factor, transforming growth factor alpha, transforming growth factor beta, acidic fibroblast growth factor, basic fibroblast growth factor, and interleukin-1 proteins in the cornea. Exp Eye Res. 1994;59(1):63–71. ©1994 Elsevier Ltd. Reprinted with permission.

Upregulation of monocyte chemotactic and activating factor (MCAF) in stromal keratocytes after epithelial scrape injury in a cryofixed rabbit cornea. (A) Little MCAF was detected in keratocytes in unwounded rabbit corneas with immunocytochemistry, although some was detected at the apical surface of the epithelium (arrow). (B) At 4 hours after epithelial scrape injury, upregulation of MCAF protein was noted in keratocytes/corneal fibroblasts in the mid to posterior stroma (arrows). Less MCAF is detected in anterior keratocytes because these cells are undergoing apoptosis in response to the epithelial injury (original magnification ×200). Hong JW, Liu JJ, Lee JS, et al. Proinflammatory chemokine induction in keratocytes and inflammatory cell infiltration into the cornea. Invest Ophthalmol Vis Sci. 2001;42(12):2795–2803. Reprinted with permission.

Figure 3.

Upregulation of monocyte chemotactic and activating factor (MCAF) in stromal keratocytes after epithelial scrape injury in a cryofixed rabbit cornea. (A) Little MCAF was detected in keratocytes in unwounded rabbit corneas with immunocytochemistry, although some was detected at the apical surface of the epithelium (arrow). (B) At 4 hours after epithelial scrape injury, upregulation of MCAF protein was noted in keratocytes/corneal fibroblasts in the mid to posterior stroma (arrows). Less MCAF is detected in anterior keratocytes because these cells are undergoing apoptosis in response to the epithelial injury (original magnification ×200). Hong JW, Liu JJ, Lee JS, et al. Proinflammatory chemokine induction in keratocytes and inflammatory cell infiltration into the cornea. Invest Ophthalmol Vis Sci. 2001;42(12):2795–2803. Reprinted with permission.

Entry of CD45+ bone marrow–derived cells into the corneal stroma after epithelial scrape injury in the mouse cornea. (A) In the unwounded cornea with intact epithelium (e), only a few CD45+ cells (arrows), likely surveilling macrophages and neutrophils, are detected in the stroma (original magnification ×100). (B) At 24 hours after epithelial scrape injury, the healing epithelium (e) is a monolayer and numerous CD45+ bone marrow–derived cells (arrows, monocytes, macrophages, neutrophils, lymphocytes, fibrocytes, etc.) have entered the corneal stroma (original magnification ×100). Blue is DAPI stain. (C) If only CD45+ cells are shown (same section as B), the large number of CD45+ cells entering the stroma is better appreciated (original magnification ×100). (D) At higher magnification, numerous CD45+ cells are noted transitioning through the stroma that were attracted by epithelial and keratocyte/corneal fibroblast cytokines and chemokines. If there were a lamellar interface present in the cornea (not shown), many of the CD45+ cells would concentrate in that interface due to the easier transit unimpeded by collagen lamellae and stromal cells.

Figure 4.

Entry of CD45+ bone marrow–derived cells into the corneal stroma after epithelial scrape injury in the mouse cornea. (A) In the unwounded cornea with intact epithelium (e), only a few CD45+ cells (arrows), likely surveilling macrophages and neutrophils, are detected in the stroma (original magnification ×100). (B) At 24 hours after epithelial scrape injury, the healing epithelium (e) is a monolayer and numerous CD45+ bone marrow–derived cells (arrows, monocytes, macrophages, neutrophils, lymphocytes, fibrocytes, etc.) have entered the corneal stroma (original magnification ×100). Blue is DAPI stain. (C) If only CD45+ cells are shown (same section as B), the large number of CD45+ cells entering the stroma is better appreciated (original magnification ×100). (D) At higher magnification, numerous CD45+ cells are noted transitioning through the stroma that were attracted by epithelial and keratocyte/corneal fibroblast cytokines and chemokines. If there were a lamellar interface present in the cornea (not shown), many of the CD45+ cells would concentrate in that interface due to the easier transit unimpeded by collagen lamellae and stromal cells.

Blood left in the lamellar interface contains cytokines such as IL-1α and TNF-α, as well as bone marrow–derived cells that produce cytokines and chemokines. Thus, retained blood can itself initiate a DLK response.

Endotoxins are toxic lipopolysaccharide and lipoprotein complexes associated with bacterial (usually Gram negative) cell walls that trigger inflammation via multiple mechanisms that include induction of proinflammatory cytokines.40–42 They are heat resistant and often accumulate in sterilizers and other equipment, including those used in the production of surgical supplies such as sponges, marking pens, drapes, and gloves.43 Regardless of the source, deposition of endotoxins in the interface in lamellar corneal surgery can trigger an inflammatory cellular response that develops into DLK.40–42 Many DLK epidemics have been attributed to endotoxins in surgical equipment, supplies, and solutions.27,29,30

Treatment of DLK

Prophylaxis is the mainstay of DLK prevention. Patients with predisposing factors associated with DLK, such as severe ocular rosacea or atopy, can be pretreated with corticosteroids for several days prior to surgery (typically four times per day) and then continue with corticosteroids at a higher than normal dose for several days to a few weeks after surgery (typically starting at six times per day, with a taper over time). Patients with a history or signs of recurrent corneal erosion are best treated with photorefractive keratectomy. Use of surgical supplies and solutions that are endotoxin free is clearly of great importance. Guidelines for servicing sterilizers and other operating room equipment should be rigorously followed.

If a series of DLK cases is encountered, then endotoxin exposure should be suspected and a search for the offending item should be initiated. Publications about several prior epidemics can be helpful in identifying the culprit.27,29–31 Careful attention should be paid to recent operating room purchases or changes in procedures.

Corticosteroids are the mainstay of treatment for actual cases of DLK. Stage I and II cases usually respond quickly to potent topical corticosteroids such as prednisolone acetate 1% given every hour for 24 to 48 hours and then gradually tapered as inflammation decreases. Stage III DLK is best treated with flap lifting and profuse irrigation followed by intensive potent corticosteroid treatment. This irrigation can remove large numbers of bone marrow–derived monocytes, macrophages, neutrophils, and other inflammatory cells that potentiate the DLK through the production of cytokines and chemokines. Some stage IV cases really require more of a debridement or removal of flap remnants followed by intensive topical corticosteroid treatment, but caution is warranted because this may worsen irregular astigmatism. In some of these severe cases, adjunctive oral corticosteroids, such as prednisone 60 mg per day followed by a taper, have been useful.

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Authors

From Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Supported in part by U.S. Public Health Service grants RO1EY10056 (SEW), DOD VR180066 (SEW), and P30-EY025585 from the National Eye Institute, National Institutes of Health, Bethesda, Maryland, and Research to Prevent Blindness, New York, New York.

The authors have no proprietary or financial interests in the materials discussed herein.

AUTHOR CONTRIBUTIONS

Study concept and design (SEW, RCD); writing the manuscript (SEW); critical revision of the manuscript (SEW, RCD)

Correspondence: Steven E. Wilson, MD, Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: wilsons4@ccf.org

Received: December 28, 2019
Accepted: January 14, 2020

10.3928/1081597X-20200114-01

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