Corneal Sensitivity Testing Procedure for Ophthalmologic and Optometric Patients

The main functions of the cornea are to protect the contents of the eye and to focus light on the retina¹. The cornea is the most densely innervated structure in the human body, with 7000 nerve receptors per mm², and, consequently, is one of its most sensitive tissues^2,3. The corneal nerves originate from the ophthalmic branch of the trigeminal nerves and play a key role in maintaining corneal homeostasis and integrity by mediating protective reflexes such as blinking and tear production, providing trophic support to the ocular surface, and stimulating wound healing by releasing neuromediators^1,4,5,6.

Damage with subsequent dysfunction of corneal nerves (hypersensitivity or hyposensitivity) can contribute to ocular surface diseases^3,7,8. In fact, neurosensory abnormalities have been recognized as potential contributors to dry eye disease symptoms and signs and were incorporated into the 2017 Tear Film and Ocular Surface definition of dry eye disease: "a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles^6,9,10." Additionally, injury or dysfunction anywhere along the trigeminal nerve pathway can lead to neurotrophic keratitis (NK)¹¹, a degenerative condition of the cornea; its stages include epithelial keratopathy, ulceration, and perforation, which may result in subsequent vision loss³.

Ocular surface pain can be categorized as nociceptive or neuropathic in origin⁸. In neuropathic ocular surface pain, nerves become hypersensitive because of the effects of a lesion or disease of the somatosensory pathway, which is often caused by maladaptive healing after trauma or surgery⁸. Abnormalities in corneal nerves have also been reported in other eye diseases, including glaucoma, thyroid eye disease, keratoconus, diabetic keratopathy, and Fuch's endothelial dystrophy^12,13,14,15, and these findings are reproducible in animal models^6,16,17. Notably, nerve abnormalities are not always identified as a component of eye disease, and a neurotrophic or neuropathic component to pain is often missed, underscoring the need for more diagnostic procedures to assess for the presence of nerve abnormalities¹⁸. Since ocular surface diseases may involve or induce corneal nerve dysfunction, a concise technique to assess corneal nerve function provides considerable diagnostic value.

Corneal sensitivity testing assesses a patient's reaction to brief corneal stimulation, providing functional insight into the status of the corneal nerves (absent, reduced, normal, or increased sensitivity)^13,19. For example, in patients with neurotrophic keratitis, studies have found positive relationships between corneal sensitivity and parameters of corneal nerve innervation as assessed using in vivo confocal microscopy^20,21, including corneal nerve fiber length (R² = 0.2951, P = 0.0016)²¹. A positive correlation between corneal sensitivity and corneal nerve density has also been observed in herpes simplex keratitis (r = 0.55, P < 0.001) and dry eye disease (r = 0.644; P = 0.045)^22,23. However, abnormal corneal innervation does not always correlate with aberrant corneal sensitivity¹³.

Alterations in corneal sensitivity have been reported in dry eye disease (including both Sjögren's dry eye disease and diabetes mellitus-related dry eye disease); ocular neuropathic pain; neurotrophic keratitis; Fuch's endothelial dystrophy; and ocular treatments for glaucoma including topical drops, laser trabeculoplasty, slow coagulation transscleral cyclophotocoagulation, and micropulse ciliary body ablation^{3,8,12,24,25,26,27,28,29}. Additionally, short-term hypoesthesia can be secondary to refractive surgery³⁰. Reduced or absent corneal sensitivity is a hallmark of neurotrophic keratitis and is key to its diagnosis^3,11,31. Reduced corneal sensitivity often presents with low tear production and epithelial disruption, and increased sensitivity can signal ocular neuropathic pain, although neuropathic mechanisms can contribute to pain even in individuals with reduced or normal corneal sensitivity^9,32.

Corneal sensitivity can be assessed using either qualitative or quantitative methods, although quantitative methods are primarily limited to research settings^{2,8,11,31,33,34,35}. Quantitative assessments are made using either the Cochet-Bonnet esthesiometer or Belmonte's gas esthesiometer; a new non-contact esthesiometer, the Corneal Esthesiometer Brill, was recently registered by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for corneal sensitivity testing^36,37,38,39. The limitations associated with the Cochet-Bonnet and Belmonte's gas esthesiometers, including the cost and the challenge of maintaining sterility, render their use infrequent in clinical practice³. Qualitative methods can be easily performed by eye care providers or physician extenders, as they are low cost, readily available, and require little training and time^8,33,37. Furthermore, there is insufficient published guidance on how to conduct corneal sensitivity testing and how corneal sensitivity scores as part of a clinical workup may inform diagnosis. Here, we detail a protocol for corneal sensitivity testing that is cost-effective, easy to comprehend, accessible, and can be readily adopted by eye care providers across clinical settings.