The Cornea in Diabetes Mellitus

S. Akbar Hasan

12.1 Introduction

Although the cornea may appear disease free in the diabetic, marked biochemical and ultrastructural abnormalities are present altering form and function. Awareness of these manifestations of corneal disease in diabetes can lead to steps that prevent more overt complications.

Corneal manifestations of diabetes mellitus have been studied less extensively than diabetic retinopathy. Early clinical observations of the diabetic cornea included endothelial changes such as Descemet’s folds and pigment deposition on the endothelium.1 In addition, diabetics were noted to have impaired corneal sensitivity resulting in a neurotrophic keratitis with corneal ulceration.2,3 Over the last few decades, a more detailed knowledge of the pathophysiological changes to the cornea has been gained.

12.2 Pathophysiology

Early studies examined the polyol pathway and its effects in diabetic corneal disease.4–6 In the polyol pathway, aldose reductase is the rate-limiting enzyme in which glucose is converted into sorbitol. Elevated glucose levels spur an increase in aldose reductase activity resulting in sorbitol accumulation. These products have been identified in corneal epithelial and endothelial cells in animal models of

S.A. Hasan (*)

Department of Ophthalmology, Mayo Clinic, Jacksonville, FL 32082, USA

e-mail: hasan.saiyid@mayo.edu

diabetes.7–9 Furthermore, studies have revealed faster re-epithelialization rates after abrasion as well as improved epithelial morphological changes in animals treated with aldose reductase inhibitors, confirming the enzyme’s role in diabetic corneal disease.10,11 Evidence suggests that the inhibition of aldose reductase reduces dysmorphological changes in the corneal endothelium as well.12,13 Nonetheless, the mechanism linking the accumulation of by-products of the polyol pathway to ultrastructural corneal changes has not been elucidated.

Other studies have identified the role of matrix metalloproteinases (MMP) in corneal disease.14 These zinc enzymes are responsible for the degradation of the extracellular matrix components and play an essential role in corneal wound healing.15 Increased expression of MMPs has been demonstrated in hyperglycemia.16 Enhanced production and activity of MMPs likely damages basement membrane, including type IV collagen and limits epithelial cell migration resulting in poor epithelial healing.

Advanced glycation end products (AGEs) may also have a role in diabetic corneal disease, just as they have been linked to diabetic retinopathy and cataract.17–19 Chronic hyperglycemia results in the formation of AGEs on proteins, through a process of nonenzymatic glycation. N-(carboxymethyl) lysine (CML) has been identified as a dominant AGE antigen in tissue proteins.20 CML immunoreactivity is increased in the epithelial basement membrane of diabetic corneas, resulting from the nonenzymatic glycation of laminin, the major basement membrane component.21 The accumulation of AGEs on the epithelial basement membrane may therefore be involved in diabetic corneal epitheliopathy.

12.3Anatomy and Morphological Changes

Anatomically overlaying the cornea and safeguarding its health and stability, the tear film is comprised of three layers: aqueous, mucin, and lipid. The cornea consists of three cellular layers, separated by two basement membranes. The corneal epithelium is composed of a layer of stratified squamous cells and has an underlying basement membrane. The stroma consists of an extracellular matrix of collagen and glycoaminoglycans, keratocytes, and nerve cells. Its anterior portion is known as Bowman’s layer and consists of collagen fibers and proteoglycans. Descemet’s membrane is the basement membrane of the corneal endothelium and consists primarily of type IV collagen. Lastly, the corneal endothelium is comprised of a single layer of cells in a uniform mosaic pattern.22 Diabetes alters the tear film as well as producing ultrastructural changes throughout the cornea.

Diabetics may suffer from tear film abnormalities resulting in ocular discomfort, burning, and foreign body sensation. All components of the tear film in diabetes are altered resulting in abnormal tear film breakup time (BUT), fluorescein staining,

Schirmer I testing and Rose Bengal or Lissamine Green staining.22,25 The severity of the tear film

dysfunction correlates with the severity of the diabetic retinopathy, with proliferative diabetic changes associated with a more diminished tear film function. In addition, conjunctival impression cytology demonstrates a higher grade of conjunctival squamous metaplasia as well as a lower goblet cell density in the diabetic patient.23 These changes have been related to the status of metabolic control and stage of diabetic retinopathy. The tear lipid layer is also less uniform in the diabetic. Increasing derangement of the tear lipid layer has been correlated with the degree of diabetic keratoepitheliopathy.24 Abnormalities in aqueous, mucin, and lipid tear film layers contribute significantly to the poor ocular surface seen in diabetics.

Corneal epithelial changes in the diabetic

include degeneration of basal epithelial cells resulting in a decrease in cell density.26,27 In addition,

abnormal glucose metabolism in the corneal

epithelium and its basement membrane results in thickening of the epithelial basement membrane as well as deterioration of basal cell adhesions.11 This loss of cellular adhesion likely limits cellular migration and can be partially explained by a reduction in the area of the basal cell membrane occupied by hemidesmosomes.28,29 In addition, in the diabetic cornea, nonenzymatic glycation of components in the epithelial basement membrane involved in adhesion complexes, such as nidogen- 1/entactin, laminin-1, laminin-10, and of an epithelial integrin [alpha]3[beta]1, has been demonstrated. This accumulation of AGEs in the corneal epithelial basement membrane may represent a molecular mechanism leading to abnormalities in epithelial cell adhesion.30–32

In the diabetic corneal stroma, keratocytes display degeneration of intracellular organelles and cytoplasmic vacuoles of various sizes with deposition of an amorphous material. Furthermore, collagen fibers demonstrate variable thickness.33 These ultrastructural changes are also likely a result of increased corneal AGEs, which leads to protein cross-linking and causes the destruction of cellular structures.34 Iclal et al. recently demonstrated the use of aminoguanidine (AG), an AGE inhibitor, prevented corneal stromal changes, confirming the importance of AGEs in inducing stromal changes. Within the stroma, abnormalities in the corneal nerves are also evident. Studies have demonstrated basal lamina thickening of Schwann cells and axonal degeneration. Morphological damage of the corneal subbasal nerve plexus in diabetic patients has been confirmed with confocal microscopy.35,36 These ultrastructural changes may be involved in corneal neuropathy.

Assessment of the posterior cornea in diabetes may reveal faint vertical lines at the level of Descemet’s membrane, a change initially described by Waite and Beetham.1,36 The etiology of Waite–Bee- tham lines, whether metabolic or mechanical, has yet to be elucidated. Corneal endothelial studies in the diabetic demonstrate a decrease in endothelial cell density and a greater coefficient of variation of

cell area with greater polymegathism and pleo- morphism.12,13,37–40 In animal studies, the diabetic

endothelium has demonstrated significant reduction in Na+/K+ ATPase activity, the key transport enzyme of the endothelial cell pump.41 In addition,

studies of central corneal thickness in the diabetic, although somewhat inconsistent, seem to suggest a

small increase in thickness as measured by pachy- metry.39,40,42–48 However, no association between

corneal thickness and retinopathy or diabetic control has been reported. These findings indicate that the corneal endothelium is probably more vulnerable to stress and trauma in the diabetic.

12.4 Clinical Manifestations

The effects of diabetes on the tear film and cornea produce many clinical manifestations. Numerous stu-

dies have demonstrated aqueous tear deficiency in diabetes (Fig. 12.1).49–60 The primary cause of the

aqueous tear deficiency may be due to the diminished sensitivity caused by neuropathy. This leads to a slow-

ing of the corneal reflex with a consecutive decrease in blinking frequency and tear secretion.61–63 In addi-

tion, a worsening of keratoconjunctivitis sicca correlates with the severity of diabetic retinopathy.64 Alterations in the tear lipid and mucin layer as measured by tear break up time and impression cytology contribute to a poor quality tear film and abnormal ocular surface manifested as fluctuation in vision and ocular discomfort. Slit-lamp examination of the cornea, with the assistance of vital staining, provides an accurate assessment of the status of the tear film and degree of superficial punctate keratopathy.

Fig. 12.1 Marked staining with Lissamine Green confirming severe aqueous tear deficiency in a poorly controlled diabetic patients

Fig. 12.2 Loose epithelium resulting in a recurrent corneal erosion in a long-standing diabetic patient

Diabetics are also prone to have epithelial healing problems exhibiting a loose and fragile epithelium (Fig. 12.2). Schultz et al. noted that about half of all diabetic patients will experience problems and present with diabetic epitheliopathy.64 Hyperglycemiainduced epithelial basement membrane abnormalities result in poor epithelial adhesion. This can lead to corneal abrasions, recurrent erosions, and persistent epithelial defects.65 The extent of epithelial fragility correlates with the degree of retinopathy. Patients with proliferative diabetic retinopathy demonstrated 84% greater fragility than diabetics without retinopathy and patients with nonproliferative retinopathy exhibited 41% greater corneal epithelial fragility.66

Diabetic corneal neuropathy, a manifestation of diabetic polyneuropathy, also plays a significant role in limiting epithelial wound healing. Diabetesinduced alterations in corneal nerves decreases

corneal sensitivity, resulting in corneal hypothe- sia.3,61–63,67,68 Corneal hypothesia disrupts epithelium

architecture and function, further delaying epithelialization in the stressed cornea.61,69,70 In severe cases,

diabetics may suffer from atraumatic, sterile neurotrophic corneal ulcers.

Endothelial changes in the diabetic can alter function. Abnormal corneal endothelial morphology, polymegathism, and pleomorphism, coupled with an increase in corneal thickness in the diabetic, are indications of corneal endothelial dysfunction. Alterations in endothelial pump function may place the cornea at greater risk for decompensation following stress-related injury and surgical trauma.

12.5 Ocular Surgery

Ocular surgery places the diabetic cornea at risk. Recognition of the clinical manifestations of diabetes on the cornea is essential in developing a strategy to minimize intraoperative and postoperative complications. Anterior segment surgery, primarily cataract surgery with phacoemulsification

and lens implantation, is associated with endothelial cell loss.71–73 This mechanically induced cell loss is greater in the diabetic cornea.74,75 As such,

greater effort and care should be utilized to minimize surgical trauma, by avoiding phaco power near the cornea and using viscoelastics generously to cushion the endothelium. Attention to wound construction and manipulation is also important in an attempt to minimize epithelial injury as well.

Posterior segment surgery, pars plana vitrectomy, in the diabetic places much greater stress on an already compromised corneal epithelium. The need for vitrectomy often suggests the presence of significant diabetic retinopathy, which is associated with a marked increase in epithelial fragility as well as an increase in corneal hypothesia.61,66 Vitrectomy also requires increased operative time, which further traumatizes the epithelium. These factors increase the rate and severity of intraoperative epithelial defect formation. In complex cases, pars plana vitrectomy in diabetics may require intraoperative corneal epithelial debridement to aid in visualization of the posterior pole, often resulting in a poorly healing abrasion and persistent epithelial defect.76,77 Whether inadvertent or intentional, an epithelial defect in this setting may result in delayed visual recovery, predispose patients to infection, and result in a persistent epithelial defect with associated stromal scarring and thinning. In early studies, diabetes accounted for 80–100% of all postvitrectomy keratopathy and diabetic postvitrectomy keratopathy was identified in up to 65% of patients.76–80 More recent studies, however, reported 6–15% of diabetic eyes had postoperative corneal complications suggesting that improved preoperative surgical preparation and intraopera-

tive technique to minimize corneal trauma likely accounts for the decrease.46,81–83

Improvements in viewing lens systems, surgical technique, and recognition of avoiding corneal

epithelial trauma have reduced the rate of postvitrectomy keratopathy. Handheld infusion lenses have been demonstrated to induce greater corneal epithelial injury than sew-on lenses. Noncontact lens systems do not physically touch the cornea and have the lowest rate of epithelial injury.84 In difficult cases, intraepithelial corneal edema may obscure visualization of the retina and require intraoperative debridement. Greater awareness in protecting and preserving an intact corneal epithelium will decrease the need for debridement and can lead to better postvitrectomy outcomes. GarciaValenzuela et al.85 report suggestions to minimize epithelial debridement rates. The use of GenTeal gel instead of Goniosol as a lubricant decreased the rate of epithelial debridement from 54 to 14%. This decrease is likely related to the preservatives found in Goniosol, especially benzalkonium chloride, which are toxic to the corneal epithelium.

The corneal endothelium can also be compromised during pars plana vitrectomy in the diabetic. Endothelial cell loss may lead to corneal decompensation limiting visual acuity and possibly requiring the need for endothelial transplantation. The causes of postoperative endothelial cell dysfunction are multifactorial and include intraocular irrigating solu-

tions, lens status, capsular integrity, and the use of adjunctive intraocular gas.46,82,86–90 These factors,

coupled with the effects of diabetes on endothelium cell function, place the diabetic at greater risk of long-term corneal compromise with decompensation and the development of bullous keratopathy.

Severe diabetic retinopathy can result in complex tractional detachments requiring the use of silicone oil. The effects of silicone oil on the cornea can result in band keratopathy, epithelial irregularities,

corneal neovascularization, and persistent stromal edema with endothelial cell damage.91,92 The risk of

endothelial dysfunction may be reduced by avoiding silicone oil overfill and subsequent damage with the corneal endothelium. In addition, to prevent contact of oil with the cornea, supine positioning of the patient with aphakia should be avoided. Furthermore, an inferior iridectomy is important to permit the flow of aqueous, avoiding pupillary block. In the Silicone Study Report 7, preoperative and postoperative risk factors for the development of corneal complications associated with silicone oil use included aphakia or pseudophakia, iris