Corneal Clarity

Inflammation: Blessing or Blemish?

By Thomas John, MD

Humans live in a noxious environment and survival requires proper functioning defense mechanisms. Inflammation is our body's reaction to any physical trauma, injury or infection. We need inflammation to survive. Without it we would all perish soon after we are born due to the invasion of our bodies by numerous micro-organisms. While inflammation can be a blessing as a way of protection, the blemish in my title refers to the often collateral tissue damage it can cause that can result in scarring — when that occurs in the central cornea, it can compromise the individual's vision.

Beyond the eye, inflammation has been associated with aging, cancer, heart disease and even the demise of the individual! In other words, crossing the artificial, iatrogenic boundaries of specialization such as ophthalmology, we realize that inflammation is not disease-specific, and it can affect the entire body. Human survival is a balancing act between inflammation and anti-inflammation. Increased, uncontrolled inflammation can cause disease and even death, while very little or no inflammation causes decreased immune function — which can also lead to disease and even death. The eye is not immune to this delicate balance.

Understanding Inflammation

Let us take a journey into the world of inflammation. The process appears to be affected by various factors, including what we eat, the amount of sleep we get, how much we exercise, daily stress levels, environmental pollutants, chemicals that we are exposed to and much more. We are beginning to unravel the mysteries of inflammation as it pertains to our well-being and survival. Ocular inflammation is far reaching in its purview, including extraocular sites — such as the orbit (orbital and periorbital cellulitis), eyelids (blepharitis, meibomian gland dysfunction) and ocular sites — tears (dry eyes), conjunctiva (conjunctivitis), sclera (episcleritis, scleritis), cornea (sterile keratitis, sterile melt), uvea (uveitis, pars planitis), vitreous (vitritis), choroid (choroiditis), retina (retinitis, cystoid macular edema) and optic nerve (optic neuritis).

Slit-lamp photo of the cornea showing SPK secondary to dry eye.

Ocular inflammation can occur in vascularized structures such as the orbital tissues, eyelids, conjunctiva, retina and uvea, or in non-vascular tissue such as the cornea. Classic clinical characteristics of acute inflammation include redness, pain, heat and swelling; such a response can be seen in periorbital or orbital cellulitis or following injury. An inflammatory response consists of a complex network of both regulators and effectors in the form of immune cells and soluble mediators.

Inflammation can be acute or chronic, and chronic inflammation can result from environmental antigens such as pollen, as in seasonal allergic conjunctivitis, viral or microbial infection, autoimmune reaction, or from continued activation of inflammatory molecules in tissues. In perspective, inflammation may be considered as the second line of defense. The first line, or innate resistance, includes mechanical means; namely, skin and surface epithelial layers of the eye and elsewhere (gastrointestinal and respiratory tracts), as well as eyelid blinking, coughing, sneezing, etc.; it also includes biochemical barriers such as tears and other bodily secretions (saliva, mucus, etc.). The third line of bodily defense includes the adaptive or acquired immunity; namely, antibody production.

The components of inflammation include cells, mediators and elements of the immune system, both innate and acquired. The fixed cells include the vascular cells, while the migratory cells are polymorphonuclear leukocytes (PMNs), macrophages/monocytes, lymphocytes, eosinophils, basophils, platelets and dendritic cells. The cell surface receptors of note are pattern recognition receptors (PRRs), pathogen-associated molecular patterns (PAMPs), toll-like receptors, scavenger receptors and complement receptors. The cytokines, interleukins and interferons all play a role as well. Interleukins (IL) are produced by macrophages and lymphocytes in response to a pathogen or stimulation by inflammatory products; e.g., IL-1 is a proinflammatory cytokine, while IL-10 is an anti-inflammatory cytokine. Macrophages can also produce tumor necrosis factor-alpha. Interferon (produced and released by virally infected host cells) can take the form of INF-alpha, INF-beta and INF-gamma. Some of the common biomarkers of inflammation are white-cell count, erythrocyte sedimentation rate (ESR), albumin, acute-phase reactant proteins such as C-reative protein, serum amyloid A protein, von Willebrand factor antigen, fibrinogen, cytokines such as interleukin, IL-1beta, IL-6, IL-18, TNF-alpha, and adhesion molecules like E-selectin, P-selectin, intercellular adhesion molecule (IACM) ICAM-1 and VCAM-1.

Treatment Considerations

When there is tissue injury, cells release signals at the molecular level that result in vascular dilation with increased blood flow and vascular permeability. These in turn lead to fluid exudation containing immunoglobulins and leukocytes that somewhat differ during the acute and chronic inflammation stages. In avascular tissues like the cornea, cellular infiltration and its secondary deleterious effects mainly manifest inflammation. This is in contrast to the highly vascular tissues of the eye such as the uvea, where uveitis can manifest with florid intraocular inflammation that can be granulomatous or non-granulomatous.

In both instances, whether involving the cornea or the uvea, significant inflammation requires anti-inflammatory treatment with corticosteroid medications to prevent or limit potential tissue damage. However, such steroid treatment is only a temporary fix due to the potential corticosteroid side effects such as cataract and glaucoma. Thus we have to consider alternative treatment modalities, especially in chronic ocular inflammation.

On the other hand, conjunctival inflammation usually does not require corticosteroid treatment. In fact, it does not even require antibiotic treatment if it is viral conjunctivitis. A few exceptions include adenoviral conjunctivitis with keratitis, where the subepithelial, central corneal infiltrates compromise vision, or an eyelid pseudomembrane that causes significant discomfort to the patient. When we look at cystoid macular edema, prevention is better than cure, and we are now embracing the concept of pre-cataract surgery treatment with anti-inflammatory eye drops. Post-cataract macular edema, even in the best scenario, does not revert to the fully normal preoperative status. Inflammation leaves its permanent mark on the quality of vision, and quality of vision is the new paradigm for the ophthalmologists meeting patient expectations in today's world.

Its Role in Dry Eye

We now know that the same inflammation that we are concerned with in the whole body can be a crucial factor in the all-too-common dry eyes or dysfunctional tear syndrome. These problems are consuming an increased amount of chair time in our clinics. Inflammation may have a biphasic effect in dry eyes — that is, in the early stages, inflammatory mediators may have a direct effect on the nerve endings and cause more patient symptoms than signs, while in the later stages of dry eye syndrome, the same inflammation causes decreased corneal sensation, which in turn causes a dampening effect on the afferent feedback loop, subsequently decreasing tear production and resulting in clinical signs that the clinicians now see as superficial punctate keratitis (SPK) and other signs of dry eye.

The result of such inflammation is excess production of metalloprotienases that damage the epithelial cells on the ocular surface, contributing to the SPK. In the more severe forms of dry eye, inflammation can transform normal ocular surface epithelium to skin-like squamous metaplasia that damages and/or eliminates normal goblet cells and decreases or terminates mucous production, culminating in a compromised, unstable tear film that can lead to permanent blindness. Yet another instance of uncontrolled inflammation leading to the demise of vision!

This clearly underscores the importance of controlling such inflammation with appropriate anti-steroids are associated inflammatory medications, and considering their safety for long-term use. While ketone steroids are associated with increased intraocular pressure and cataract, the only ester steroid, loteprednol etabonate, has less chance of such side effects and may be a preferred drug in such treatments. On the horizon but not yet FDA approved is the selective glucocorticoid receptor agonist (SEGRA), also known as dissociated glucocorticoid receptor agonist (DIGRA). It is designed to have many of the desired anti-inflammatory and immunosuppressive properties of glucocorticoid drugs but with fewer side effects.

Treatment of inflammation is all about timing and proper clinical judgment. Anti-inflammatory treatment can be somewhat complex! While such treatment controls inflammation and decreases or limits collateral tissue damage, it can also cause significant adverse effects if there is active infection at the target tissues of concern. Therefore, it is important to ascertain that there is no active infection present at the time of administering potent anti-inflammatory treatment.

Inflammation is usually a blessing, but we need to titrate, regulate and tame it to prevent it from becoming a blemish! The very inflammation that destroys the micro-organisms can also destroy our blood vessels, heart, lungs, brain and the eye. Remember, human survival depends on the body's balancing act between inflammation and anti-inflammation, a yin-yang theory at work, and the eye is no exception! OM

Thomas John, MD, a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, III. E-mail him at tjcornea@gmail.com.