April 2019


Presentation Spotlight
Ocular surface and diabetes
Diagnostics and evolving treatments

by Stefanie Petrou Binder, MD EyeWorld Contributing Writer

Meibomian gland dysfunction leads to an evaporative type of dry eye syndrome. Patients complain of pain,
discomfort, and burning.
Source: Esen Akpek, MD


Ocular surface complications associated with diabetes may be easy to overlook, thanks to the clinician’s focus on well-known and serious diabetic side effects and comorbidities, such as diabetic retinopathy, cataract, and glaucoma. The effects of diabetes on the ocular surface are poorly understood, however, virtually all components of the ocular surface can be influenced by diabetic complications, according to a presentation given at the 36th Congress of the European Society of Cataract and Refractive Surgeons.
“Seventy percent of diabetic patients, during the long history of the disease, may suffer from diabetic keratopathy or ocular surface involvement of some kind,” said Mario Nubile, MD. “The involvement and the severity of this clinical condition is strictly related to the age of the patient, duration of the diabetic disease, and poor glycemic control. It can go from very mild dry eye disease to a very severe form of neurotrophic corneal ulcerations.”
The impact of diabetes on the ocular surface can result from several mechanisms that include defective wound healing in the corneal epithelium, abnormalities of sub-basal nerves, and loss of the corneal endothelial pump function.1 “Patients with diabetes are at a higher risk of suffering from dry eye disease, and the reason is because peripheral neuropathy secondary to hyperglycemia and microvascular damage to the corneal nerves can block the feedback mechanism that controls tear secretion,” Dr. Nubile explained. “Insulin insufficiency that disrupts the metabolic balance of the corneal and lacrimal tissues results in ocular dryness, and hyperglycemia triggers inflammation that may help in maintaining this vicious circle.”

Symptoms and mechanisms

Patients can have a wide range of symptoms, including an itchy sensation, stinging/burning, a gritty/sandy sensation, light sensitivity, excessive tearing, or blurry vision/poor night vision, with at least 50% of diabetic patients experiencing them. The lids and the conjunctiva can be affected, as well, with these patients prone to infections like blepharitis or conjunctivitis.
Dr. Nubile observed that collagen may also be affected, altering the mechanical properties of the cornea in diabetic patients. “There is an increased corneal stiffness resulting from hyperglycemia. We have to expect an overestimation of IOP measurements in these patient and other effects when dealing with ectatic disease, which is a consideration in refractive surgery candidates,” he said.


Diabetic keratopathy relies on two main mechanisms: One is damage to the corneal unmyelinated nerves due to axonal degeneration from hyperglycemia, and the other is the reduced wound healing capability of the corneal epithelium, related to the alteration of the equilibrium between the epithelial cells and the basal membrane.
Clinical manifestations of keratopathy include: punctate keratopathy, poor wound healing, recurrent corneal epithelial defects, ulcers, or a propensity to corneal infections. Additionally, stress to the ocular surface in the form of refractive or corneal surgery or contact lens wear can play a role in destabilizing the already compromised ocular surface.

Corneal neuropathy

“Corneal neuropathy involves a mechanism of damage to the corneal nerves that is related to hyperglycemia in diabetic patients, through different mechanisms. One is the oxidative stress/age products, and the other involves metabolic pathways like the protein kinase C pathway and others. All of them lead to damage of the corneal nerves,” he said.
Diabetic neuropathy has a 50% prevalence in diabetic patients and constitutes 27% of the U.S. annual cost of diabetes ($66 billion), raising the importance of diagnostics and disease prevention, according to Dr. Nubile. Traditional methods of evaluating the peripheral nerve fibers of the cornea include biothesiometry (vibration perception), skin punch, and sural/peroneal nerve biopsy.2 Also, confocal microscopy is a good diagnostic modality to follow disease progression in diabetic-related peripheral neuropathy.
“It has been proven that with confocal microscopy, which is a non-invasive tool with relatively low expenses, we can assess different degrees of alteration in the morphology and density of the corneal nerves, in vivo, even in patients with minimal signs of peripheral neuropathy.3 Other studies have shown that both quantitative and qualitative analyses are possible using confocal microscopy of the cornea, which can be repeated over time to evaluate disease progression4,” he said.

Neurotrophic keratitis

Corneal damage through diabetes ultimately results in what is called neurotrophic keratitis, which is a corneal degeneration characterized by the reduction or absence of corneal sensitivity, due to an impairment of corneal innervation of the trigeminal nerve. The sensory and trophic functional impairments lead to the consequent breakdown of the corneal epithelium, affecting the health and integrity of the tear film, epithelium, and stroma. Seventy percent of diabetic patients have altered corneal nerves. These individuals are at a high risk of developing neurotrophic keratitis, according to Dr. Nubile, particularly if they have suffered corneal injuries, have other corneal comorbidities, or have had surgery.5
Neurotrophic keratitis is classified into different stages: mild, moderate, or severe. Mild is when the epithelial is altered, moderate is when there is persistent epithelial defects without stromal defects that include hypo-anesthesia/anesthesia, and severe is when the stroma is involved from ulcers to lysis.6
As diabetic patients may request LASIK, clinicians should be aware that refractive laser surgery should be avoided in individuals with diabetes that fail to demonstrate tight glycemic control and have any evidence of ocular or peripheral complications. There is also a greater risk of ocular surface complications following pars plana vitrectomy, cataract surgery, and keratoplasty.
Treatments of diabetes-related ocular surface abnormalities include: systemic therapy for diabetes (blood glucose level control), artificial tears, antibiotics, bandage contact lens, tarsorrhaphy, and AMT, most of which are implemented to repair the ocular surface, not address the etiology of the disorder.
The treatment of neurotrophic keratitis has shown progress. New approaches in the treatment of diabetes-related ocular surface abnormalities are both systemic and topical. Their aim is to regenerate the corneal nerves.

About the doctor
Mario Nubile, MD

Excellence Eye Research Center University Gabriele d’ Annunzio of Chieti
Pescara, Italy


1. Shih KC, et al. A systematic review on the impact of diabetes mellitus on the ocular surface. Nutr Diabetes. 2017;7:e251.
2. Petropoulos IN, et al. Diagnosing diabetic neuropathy: something old, something new. Diabetes Metab J. 2018;42:255–269.
3. Patel DV, McGhee CNJ. Mapping of the normal human corneal sub-basal nerve plexus by in vivo laser scanning confocal microscopy. Invest Ophthalmol Vis Sci. 2005;46:4485–8.
4. Wang EF, et al. In vivo confocal microscopy of the human cornea in the assessment of peripheral neuropathy and systemic disease. Biomed Res Int. 2015;2015:951081.
5. Mastropasqua L, et al. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017;232:717–724.
6. Dua HS, et al. Neurotrophic keratopathy. Prog Retin Eye Res. 2018;66:107–131.

Financial interests
: None

Contact information
: m.nubile@unich.it

Ocular surface and diabetes Diagnostics and evolving treatments Ocular surface and diabetes Diagnostics and evolving treatments
Ophthalmology News - EyeWorld Magazine
283 110
220 167
True, 4