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The cornea is the most richly innervated structure in the human body, with 7,000 senso-ry nociceptors per square mil-limeter, providing the means

to monitor for touch, heat, cold, and noxious stimuli.1 This innervation provides a wealth of information to the brain, which then responds and makes adjustments to maintain homeostasis of the ocular surface. Homeostasis includes protection and lubrication of the ocular surface via basal and reflex tear secretion as well as the blink reflex.2

When patients describe how their eyes are feeling to us, we assume that

those descriptions of sensations of discomfort such as “burning” and “grit-tiness” are accurate and are caused by actual stimuli proportionate to the level of discomfort. What we are actually assuming is that our patients’ neurosensory systems are functioning normally and that the descriptors they use arise from actual physical stimuli.

However, what if we were to assume that the symptoms our patients were describing were modi-fied in some way, or that they were not caused by physical stimuli? How might that change our approach to managing these patients? Perhaps more important, how would we

recognize that this dysfunction exists in any given patient?

WHEN THINGS DON’T ADD UPIt has been a recognized and

accepted frustration among clinicians that, in the management of dry eye disease (DED), there is often a dis-crepancy between symptoms and clinical signs.3 We all likely have seen patients who present with significant symptoms of severe irritation or pain, but upon examination they show minimal if any signs of ocular surface disease. Conversely, it’s also likely that we have been puzzled by patients who present with diffuse corneal epitheli-opathy, a sign of severe ocular surface disease, who paradoxically express no complaint of discomfort.

The key to understanding both of these clinical pictures is to account for alterations in function in the neurosen-sory system. But how does this happen?

DEFINITIONS AND ANATOMYNeuropathic pain is defined by

the International Association for the Study of Pain as “pain initiated or caused by a primary lesion or dysfunc-tion of the nervous system.”4 This may arise from injury to the peripheral cor-neal nerves and nociceptors or from systemic injury or illness.

The most peripheral portion of the neurosensory pathway begins at the nociceptors, which exist in several

NEUROPATHICDISEASE IN THE CORNEA

Tips for identifying and managing neuropathic pain in patients with dry eye.

BY SCOTT G. HAUSWIRTH, OD, FAAO

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subtypes to detect different stimuli that may cause harm to the tissues of the ocular surface, such as heat, cold, mechanical stimuli, and several types of chemical stimuli. When these nocicep-tors are triggered, a signal is generated that is then conducted upward through the first-order and second-order neurons and then to the thalamus for the perception of sensation or pain.

If there is injury or inflammation to the ocular surface, however, pro-inflammatory mediators released in the cornea may cause damage to the peripheral axons located therein, leading to a process called peripheral sensitization, which lowers the acti-vation threshold and intensifies the signal.5,6 This sensitization causes the patient to have an increased percep-tion of discomfort, even when the stimulus is mild. In addition, because the upward-travelling signal is intensi-fied and our neurologic systems are plastic and can change over time, this increased signal may cause lowering of the thresholds at the synapses between the first and second order neurons, which may eventually lead to pain that occurs independent of what is occurring at the cornea.7,8

Peripheral contributors to periph-eral sensitization include DED, ocular surgery, and ocular infection.9 Systemic conditions that may also contribute include disorders such as fibromyalgia or small-fiber polyneuropathy.10

Autoimmune diseases such as fibromy-algia create higher amounts of inflam-mation in the body; the presence of cytokines such as interleukin 1, tumor necrosis factor–alpha, and others increases the chances of the neurologic signal becoming altered at the synapse, leading to amplification of the signal and intensification of symptoms. In addition, comorbid conditions associ-ated with neuropathic pain include anxiety and depression.10

EPIDEMIOLOGYThere is little real understanding

about how frequently neurosensory dysfunction occurs in clinical prac-tice. A first-of-its-kind multicenter study is now under way in an attempt to establish the prevalence of neuropathic pain in patients with dry eye. Begun earlier this year, the Neurosensory Abnormalities in Symptomatic Ocular Surface Patients (NCT04838223) is a single-visit observational study being conducted at 22 locations across the United States, involving both optometry and ophthalmology practices. This study is set up as a single visit and involves assessment of symptoms as well as stressing the neurosensory system for response. Several centers will also contribute by imaging the subbasal nerve plexus and screening for anatomic changes to the corneal nerves.

DIAGNOSIS Diagnosis of neuropathic pain is

challenging. A careful history should be taken to determine if there was an initial triggering event such as surgery or an infection, as well as analysis of symptomology. In many instances, however, identifying neu-ropathic disease is a process of exclu-sion. Symptoms may be quantified using validated questionnaires such as the Ocular Surface Disease Index, Standardized Patient Evaluation of Eye Dryness, or Ocular Pain Assessment Survey.

Thorough diagnostic testing should be performed to rule out other sources of discomfort. Examination of the cornea and ocular surface via biomi-croscopy and vital dye testing using both sodium fluorescein and lissamine green is recommended. Tear film tests such as tear breakup time, osmolarity, and interferometry are also useful. For example, a very rapid tear breakup time may also trigger signals mimicking chronic burning or pain in an other-wise normal neurosensory system.

If the patient is experiencing intense discomfort and all of these tests are normal, then the proparacaine chal-lenge test may be used.10 In this test, one drop of 0.5% proparacaine HCl is instilled, and the patient reports to what degree his or her pain is muted. This assists in determining the degree of centralization; any peripheral nociception is nullified. If the patient reports a change in pain level after instillation of proparacaine, from 8 on a scale of 10 to 4 out of 10, then we infer that approximately 50% of the pain may stem from centralized dysfunction.

Another tool available in clinical practice is in vivo confocal microscopy, which allows visualization of the corneal subbasal nerve plexus and may dem-onstrate nerve morphology changes. The appearance of certain alterations of normal anatomy such as microneu-romas has been associated with corneal neuropathic disease (Figure).11

s

In patients who exhibit mismatch between signs and symptoms of DED, alterations in function in the neurosensory system may be at work.

s

A multicenter study is under way to establish the prevalence of neuropathic pain in patients with dry eye.

s

Because inflammation is a critical factor for inciting physiologic change in both the peripheral and central portions of the somatosensory nervous system, it must be addressed.

AT A GLANCE

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MANAGEMENTAs with diagnosis, management of

neuropathic pain is challenging. There has generally been a lack of under-standing of this disorder with respect to corneal disease, although this has been changing recently.

Because inflammation seems to be such a critical factor for inciting physio-logic change in both the peripheral and central portions of the somatosensory nervous system, it must be addressed. Antiinflammatory therapy is an essen-tial part of the treatment regimen.12 Minimizing the ability to generate nociceptive signals may also be helpful, so any therapy that protects the cornea and/or boosts the tear film will likely be a part of the therapeutic plan as well. The latter may include items such as meibomian gland–targeted procedures, scleral lenses, etc.

Neuroregenerative therapies such as autologous serum tears can be quite useful.13 This is a treatment I employ regularly in this patient group. Patients with contributing systemic disease and other forms of peripheral neuropathy may show improvement with treatments such as alpha lipoic acid or omega-3 fatty

acid supplementation.For patients who have centralized

neuropathy and do not respond well to topical proparacaine, systemic medica-tions and alternative therapies may be useful for maintaining improved func-tionality. These can include gamma-aminobutyric acid inhibitors, tricyclic antidepressants, and antiepileptic med-ications.9 Alternative therapies such as acupuncture have been shown to be helpful in patients with chronic pain in meta-analyses.14

And finally, in a significant percent-age of patients with severe centralized pain, I enlist the help of pain manage-ment specialists. These practitioners may opt to perform periocular nerve blocks using lidocaine and dexameth-asone, radiofrequency ablation, or advanced systemic therapies.

An important management aspect to consider is that these patients are suf-fering, and this is a source for emotional stress and exhaustion. Make sure your patients have the resources and support to access options to maintain their mental well-being. This is not a com-monly encountered area in eye care, but it is a crucial one from a longitudinal standpoint. Relief of neuropathic pain

increases the prognosis for improving functionality and can be vital for improving the patient’s quality of life.

A CHALLENGING ENTITY Corneal neuropathic pain is a chal-

lenging entity that is often confusing and frustrating for both the patient and the clinician. Knowledge of the etiology and pathologic process of neuropathic pain is growing, as is clini-cal awareness of this potentially debili-tating disorder. We can expect to have increased data regarding its prevalence in the near future. With these changes and increasing awareness, it seems like-ly that the way we approach patients with “pain without stain” will be much different—and hopefully changed for the better—in coming years. n

1. Rosenthal P, Baran I, Jacobs DS. Corneal pain without stain: is it real? Ocul Surf. 2009;7(1):28-40.2. Belmonte C, Nichols JJ, Cox SM, Brock JA, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017;15(3):404-437.3. Nichols KK, Nichols JJ, Mitchel GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004;23:762-770.4. Classification Committee of the Neuropathic Pain Special Interest Group (Ne-uPSIG) and Task Force for the Classification of Chronic Pain of the International Association for the Study of Pain (IASP). IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160(1):53-59.5. Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor alpha-1, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects of heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci. 2000;20(16):6289-6293.6. Lin CR, Amaya F, Barrett L, et al. Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther. 2006;319(3):1096-1103.7. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal somatosensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24(20):4832-4839.8. Reichling DB, Levine JD, Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 2009;32(12):611-618.9. Goyal S, Hamrah P. Understanding neuropathic corneal pain – gaps and current therapeutic approaches. Semin Ophthalmol. 2016:31(1-2):59-70.10. Dieckmann G, Goyal S, Hamrah P. Neuropathic corneal pain: approaches for management. Ophthalmology. 2017;124(11 Suppl):S34-S47.11. Labbe A, Alawani H, Van Went C, et al. The relationship between subbasal nerve morphology and corneal sensation in ocular surface disease. Invest Ophthalmol Vis Sci. 2012;53(8):4926-4931.12. Shaheen BS, Bakir M, Jain S. Corneal nerves in health and disease. Surv Ophthalmol. 2014;59(3):263-285.13. Aggarwal S, Colon C, Kheirkhah A, Hamrah P. Efficacy of autologous serum tears for treatment of neuropathic corneal pain. Ocul Surf. 2019;17(3):532-539.14. Ju ZY, Wang K, Cui HS, Yao Y, et al. Acupuncture for neuropathic pain in adults. Cochrane Database Syst Review. 2017;12(12):CD012057.

SCOTT G. HAUSWIRTH, OD, FAAOn Assistant Professor of Ophthalmology,

University of Colorado School of Medicine, Sue Anschutz-Rodgers Eye Center, Aurora, Colorado

n Member, Modern Optometry Editorial Advisory Boardn scott.hauswirth@cuanschutz.edu n Financial disclosure: Advisor (BioTissue, Dompe,

Oyster Point); Investigator (Sylentis)

Figure. Microneuromas such as the one shown here (bright spot in image) via in vivo confocal microscopy have been associated with corneal neuropathic disease.