A PATIENT PRESENTS with a pristine cornea, without signs of inflammation or staining. There appears to be nothing physically wrong, but the patient is complaining of extreme ocular discomfort, photophobia, and pain. How can this be? They may have corneal neuropathic pain (NP), also referred to as “pain without stain” (Moshirfar et al, 2023). This phrase references the unexpected paradox in which a patient experiences significant ocular discomfort despite having an unremarkable clinical evaluation.

Traditional artificial tears and medications are not effective. Corneal NP is often chronic due to maladaptive changes in peripheral and central somatosensory nerves and disconnected in time from ocular surface abnormalities. These maladaptive changes may originate from a precipitating injury and might persist even once it has resolved (Woolf and Mannion, 1999; Galor et al, 2018).

A case-control study utilizing confocal microscopy to examine eyes with corneal allodynia and healthy controls demonstrated that those with corneal allodynia had decreased corneal epithelial cell densities and fewer and shorter corneal nerves (Hamrah et al, 2017). Individuals who have NP have been found to have a lower pain threshold and to experience pain at greater intensity than those who do not have NP (Maier et al, 2010).

Proposed mechanisms of the observed lower pain threshold include peripheral and central sensitization. The nerve endings of corneal nociceptors interact with the tear film, which is susceptible to repeated injury from inflammation or the environment. It is hypothesized that this repeated nerve injury causes maladaptive neuronal plasticity, which leads to the development of corneal NP (Galor et al, 2018).

The maladaptive changes in peripheral sensitization are thought to include nerve firing due to unprompted generation of action potentials and increased stimulatory neurotransmitter release at presynaptic terminals (Galor et al, 2018). Central neuronal changes that result in increased transmission of pain are altered gene expression, posttranslational modifications of signaling cascades, changes in ion channel opening, and production of inflammatory mediators (Woolf and Salter, 2000; Woolf, 2011).

An important aspect of treating corneal NP is differentiating peripheral sensitization from central sensitization. Persistent pain following instillation of topical anesthetic on the ocular surface could indicate a central etiology of NP because topical anesthetics reduce firing of peripheral nociceptors; this should reduce allodynia in patients who have peripheral sensitization (Galor et al, 2018).

Treatment for corneal NP also depends on whether there is peripheral or central nerve involvement. Autologous serum tears are therapeutics that target peripheral sensitization of corneal NP (Galor et al, 2018). These serum tears contain trophic factors, including epidermal, platelet derived, and transforming growth factors (Phasukkijwatana et al, 2011). Nerve growth factors may even help promote health and regeneration of the corneal stroma, epithelium, and sensory nerves (Galor et al, 2018). In a retrospective study of 16 patients who had photophobia and no ocular surface disease on exam, autologous serum tear use after one and a half to six months led to statistically significant improvements in symptoms and corneal nerve parameters (Aggarwal et al, 2015).

Treatments for central and/or peripheral sensitization of corneal NP include calcium channel alpha 2 delta ligands (gabapentin and pregabalin), antidepressants, anticonvulsants, nerve blocks, omega-3 fatty acids, and non-pharmacological approaches including exercise, massage, and acupuncture (Galor et al, 2018; Finnerup et al, 2015). Scleral lenses may also play a role in the management of corneal neuralgia following LASIK (Parminder and Jacobs, 2015).

Believe your patients. Even if there are minimal ocular signs, their symptoms are real. Don’t discount their struggles to find healing therapies. If ocular symptoms are out of proportion to clinical signs and your patient does not respond to traditional dry eye therapies, consider corneal NP. CLS

References

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