It is not uncommon to encounter a patient with complaints of ocular irritation, especially with the ubiquity of dry eye and ocular surface disease due to our modern screen-centric lifestyle. However, you may come across a patient who has complaints of chronic pain, often described as “burning,” “aching,” “tenderness,” “foreign body-like sensation,” “itching,” or “stinging,” even though their ocular surface appears relatively healthy. This presentation is often referred to as “pain without stain.”¹ This is burning eye syndrome (BES), also known as neuropathic ocular pain (NOP) or neuropathic corneal pain (NCP), which is often considered a subset of dry eye disease (DED).

Understanding the pathophysiology and clinical signs and symptoms of BES is crucial in order to diagnose the condition and provide appropriate intervention.

Pathophysiology
The cornea contains nerve endings referred to as nociceptors. Nociceptors are typically activated by a stimulus that is strong enough to cause tissue damage.² When this occurs, a signal is generated that travels from the corneal nerves along the trigeminal sensory pathway to the brain where a painful sensation is perceived to encourage retreat from and avoidance of the noxious stimulus.³

Sensory signals originating at the cornea do not simply go from point A to B, however. Instead, they are processed and modulated at several different levels as they travel from the nerves at the corneal surface to the trigeminal nucleus caudalis (TNC), ventral trigeminothalamic tract, ventral posteromedial nucleus of the thalamus, and ultimately to the primary somatosensory cortex and reticular formation.^4-8
             
In cases of BES, the function of this pathway is altered. Neuropathic pain is thought to stem from damage to the nerves, such as in cases of chronic DED, herpetic infection, trauma, or refractive surgery, resulting in inflammation.^{1, 9-11} If this inflammation becomes chronic, changes in gene expression and a decrease in the activation threshold of corneal nociceptors occurs, resulting in hypersensitization of the nerves.¹ Other comorbidities, such as depression and anxiety, have been associated with this neuropathic subset of DED as well, although a complete understanding of these potential BES risk factors is still being elucidated.¹

Additionally, in an attempt to heal themselves, the nerves can regenerate abnormally, resulting in anatomical changes to their structure, including the development of microneuromas that can spontaneously fire causing pain even when no stimulus is present.^{9, 11}

If hypersensitization, exposure to noxious stimuli, or inflammation of the corneal nerves persist, neuroplastic changes to the higher-order corneal somatosensory pathway can also develop.^1,9 The changes to this pathway are thought to involve increased action of excitatory glutamate and decreased effectiveness of inhibitory gamma-aminobutyric acid (GABA) at the TNC. The result is more efficient processing of pain, sensitization to previously sub-threshold stimuli (e.g., cold, dry air, light), and sensations of pain even when no noxious stimulus is present at the ocular surface.^1,9,12 This hypersensitization and dysregulation of the corneal nerves and the higher-order sensory pathway are referred to as peripheral and central sensitization, respectively.^1,9-11

Other potential factors have been implicated in the development of BES, including nerve growth factor (NGF), although the role it plays in BES is complex. It has been suggested that chronically elevated NGF levels may be responsible for hypersensitization of the corneal nerves, however NGF has also successfully been used for the treatment of BES and corneal hypersensitivity, as NGF is naturally involved in nerve maintenance and repair.¹ Additionally, NGF is upregulated in the presence of nerve damage,¹³ so the extent to which it is a causative versus correlated factor in BES is in question. When viewed as a causative factor, the topical use of NGF would be expected to exacerbate the hypersensitivity present in BES, however the opposite has been shown to occur, including in my own clinical experience. This seemingly paradoxical response suggests the effects of NGF on BES may be case dependent or its effects may differ depending on the progression of the disease (i.e., NGF may increase hypersensitivity during initial nerve damage/development of BES but decrease hypersensitivity after nerve damage/BES becomes chronic).

Clinical signs and symptoms
Changes in pain processing most commonly manifest as dysesthesias including allodynia, photoallodynia, and hyperalgesia as well as sensations of spontaneous pain.^{1, 9-11, 14-16} Allodynia occurs when a nonirritating stimulus causes pain.¹⁶ A common example is a gentle breeze that would normally go unnoticed causing discomfort. Photoallodynia is a subcategory of allodynia that refers to significant pain caused by light.¹⁴ Patients experiencing photoallodynia may report significant discomfort when encountering bright lights, such as the fluorescent lighting present in many retail stores or office settings, but may even experience discomfort under normal lighting conditions as well. These are typically patients who will come into your office wearing sunglasses and continue to wear them in the exam room even if the lights are dimmed. Hyperalgesia refers to painful stimuli causing greater pain than would be expected.¹⁵ For example, the mild discomfort caused by a minor poke to the eye, that would typically resolve quickly, would instead elicit substantial pain that is slow to dissipate in a patient with hyperalgesia. Spontaneous pain is the phenomenon of perceiving pain even if there is no stimulus present, which can be due to ectopic signaling from damaged peripheral nerves in peripheral BES or abnormal impulse generation from the higher-order sensory pathway in centralized BES.^1,9-12  

A major clinical sign that a patient has an element of neuropathic pain is a subjective nonresponse to traditional DED therapies. Patients with BES will often report little to no improvement with the use of routine, palliative treatments including artificial tears and warm compresses, or even with the use of prescription medications including topical anti-inflammatory agents (when used in isolation). In such cases, there will often be improvement in objective signs and testing measures (e.g., tear breakup time, tear meniscus height, lipid layer thickness, etc.), but a lack of improvement in patient-reported symptoms. This lack of subjective improvement (including the previously mentioned “pain without stain” (Figure 1), symptoms of allodynia and hyperalgesia, and the presence of any condition that could potentially cause nerve damage, such as refractive surgery (e.g., LASIK, PRK),¹⁷ herpetic infection,¹⁸ uncontrolled dry eye disease,^11,19 as well as systemic neuropathies (e.g., trigeminal neuralgia, small-fiber polyneuropathy, diabetes)^11,14,19 and pain disorders (fibromyalgia),^6,20 should warrant suspicion of BES.

Another way to assess the presence of BES is the “Proparacaine Challenge,” where a drop of topical anesthetic is instilled, and the patient’s response evaluated. If the patient reports no improvement in symptoms within 30-60 seconds after installation, this is indicative of BES. The reason: The anesthetic will block the signaling of any noxious stimuli at the ocular surface, meaning the persistent pain is coming from the nerves themselves, rather than the external environment.^10,20 A caveat: This assessment primarily tests for the presence of centralized BES. Although a complete lack of improvement is consistent with centralized neuropathic pain, patients with mixed BES can experience partial improvement, and those with purely peripheral BES may report complete relief of their symptoms, which would also be the case in traditional dry eye.¹⁰ Therefore, in cases of partial or complete symptom improvement, the aforementioned nonresponse to standard DED therapy can be helpful in diagnosing peripheral BES.

Anatomical changes to nerve structure can also occur in BES, such as the presence of microneuromas or changes in nerve plexus density, which can be observed with in vivo confocal microscopy (Figure 2). However, there are conflicting findings regarding the exact manner in which nerve structure is altered in BES.¹⁰

Appropriate intervention
The following interventions have demonstrated efficacy in the treatment of BES: (See “In the Pipeline,” below.)
         • Biologic treatments. Autologous serum tears, platelet-rich plasma (PRP), amniotic membranes, and topical nerve growth factor (NGF) have all been shown to be beneficial in treating NOP/BES, as they possess anti-inflammatory properties and growth factors that encourage nerve repair.^1,9,10,21-26
           • Topical anti-inflammatory agents. The use of anti-inflammatory agents, such as topical corticosteroids and immunomodulators, can be helpful in mitigating any active inflammation contributing to nerve damage.^1,10
         • Contact lenses. Some patients have reported that soft bandage contact lenses and scleral lenses are soothing. However, others have experienced an exacerbation of symptoms with contact lens use, so their efficacy will often be case dependent.¹⁰
         • Systemic treatments. Antidepressants, nerve pain medications, anticonvulsants, low-dose opioid antagonists, opiates, serotonin-noradrenaline reuptake inhibitors (SNRIs), and antiarrhythmics have been shown to be especially effective against centralized BES.⁵ Specific medications that have been used in the treatment of BES include first-line systemic agents nortriptyline, desipramine, and carbamazepine, second-line agents low-dose naltrexone and tramadol, and third-line agents gabapentin, pregabalin, duloxetine, and mexiletine.¹⁰ There is also a strong association between psychological conditions, such as depression and anxiety, and DED and neuropathic pain, so it is recommended that patients who are also affected by these conditions be comanaged with a mental-health professional.^10,11
         • Lifestyle changes. Dietary changes including omega-3 fatty acid supplementation, which itself has been shown to potentially aid in nerve repair,¹³ can be helpful in the management of BES. Regular exercise, meditation, and acupuncture may also be beneficial as they have been shown to reduce chronic pain.^10,17
          • Managing concomitant ocular surface disease. Any concomitant ocular surface diseases, such as traditional dry eye, meibomian gland dysfunction, blepharitis, ocular rosacea, etc. should also be addressed as they may not only exacerbate the symptoms of BES, but in some cases can be contributing factors to its initial development.

Takeaways
NOP/BES can be challenging to manage for both the patient and their optometrist. The condition often goes undiagnosed or misdiagnosed and finding effective treatments can sometimes be difficult. However, with a growing number of treatment options and an ever-improving understanding of the condition, optometrists are in an excellent position to care for patients experiencing NOP/BES and to help provide relief for a disruptive and debilitating disease. OM

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Cory J. Lappin, OD, MS, FAAO, practices at Phoenix Eye Care and the Dry Eye Center of Arizona. As the head of the practice’s ocular surface and dry eye disease clinic, he is dedicated to implementing the most up-to-date treatments and cutting-edge research.