Neuropathic/Nociplastic Ocular Pain

Disease Overview

Summary

Neuropathic/nociplastic ocular pain (NOP) refers to a group of persistent ocular pain symptoms (e.g., burning, increased sensitivity to light or wind, shooting pains originating in one or both eyes) that are caused by nerve abnormalities. When a lesion or disease is identified, the pain is considered to be neuropathic in origin and when nerve dysfunction occurs without a known lesion or disease, it is considered nociplastic in nature.¹ NOP may co-exist with ocular surface abnormalities (e.g., reduced tear production, tear instability, epithelial disruption) or it may occur in isolation.² In the past, individuals with NOP were often misdiagnosed as having dry eye (DE), an umbrella term representing various symptoms (e.g. sensations of dryness, discomfort, poor or fluctuating vision) that are associated with signs of tear or ocular surface dysfunction (e.g. tear instability, corneal and/or conjunctival epithelial disruption, ocular surface inflammation, high or unstable tear osmolarity).³ In recent years, there has been an understanding that in some individuals, chronic ocular pain (COP) complaints can be caused by nerve abnormalities to a greater degree than tear abnormalities, although both may contribute to symptoms in an individual patient. A limitation in the field is that the frequency in which NOP significantly contributes to ocular pain complaints is not well known.

The epidemiology of NOP has not been well studied, with some information buried within the DE literature. Overall, DE symptoms are common in the general population. In the US, a population-based study out of Beaver Dam, Wisconsin found that 14% of individuals between the ages of 48 and 91 years reported some symptoms, including dryness and foreign body sensation.⁴ A similar frequency was found in Salisbury, Maryland with 15% of the population reporting one or more symptoms (dryness, grittiness, burning, redness, crustiness, eyelids stuck shut) often or all the time.⁵ These numbers were even higher in Asia, where 34% of participants in a Taiwanese study⁶ and 28% of participants in an Indonesian study⁷ reported these same symptoms often or all of the time. As noted above, ocular surface abnormalities are one cause of symptoms. However, it is well recognized that ocular symptom severity is often not related to ocular surface findings^{8, 9}, suggesting that symptoms in many individuals are caused by other factors.

One such factor is corneal nerve dysfunction, which may manifest as hyposensitivity (“neurotrophic phenotype”) or hypersensitivity (“neuropathic/nociplastic phenotype”).¹⁰ Corneal nerve hyposensitivity often manifests with cornea epithelial cell disruption with minimal ocular symptoms¹¹ while corneal nerve hypersensitivity often manifests with pain out of proportion to ocular surface findings. In the latter case, ocular pain often persists despite treatment with traditional dry eye treatments.¹²

A neuropathic/nociplastic origin to ocular pain is suggested in individuals who have a particular set of symptoms (e.g., burning sensation, light or wind sensitivity)¹³, risk factors (e.g., pain that started after surgery, migraine, fibromyalgia, traumatic brain injury)^14-16 and treatment response history (e.g., poor response to therapies aimed at correcting ocular surface abnormalities).¹² NOP symptoms can be present in one or both eyes and start spontaneously or after trauma or surgery. NOP can be persistent, agonizing and severely affect quality of life and ability to work. When untreated, persistent symptoms can lead to extreme distress. The severity of symptoms is often not recognized, and patients may be seen as drug-seeking or overly anxious by healthcare providers. A challenge is that many patients have few physical signs of ocular damage, and the underlying cause of symptoms can be overlooked. Thus, there is a need to educate patients, eye care providers and pain specialists on this condition, recognize its effect on patients’ health and functioning and treat patients with empathy and urgency.

Introduction

The cornea has the densest sensory innervation in the body and can be a powerful producer of pain.¹⁷ Ocular surface pain is a frequent cause of visits to eye care providers and pain clinics, with a substantial negative impact on an individuals’ quality of life and mental health.¹⁸ Ocular surface pain can arise from a number of factors including tear film and anatomical abnormalities, environmental exposures and nerve dysfunction of the peripheral nerves and also central nerves that connect the cornea and conjunctivae to the brain.¹⁹ Causes of ocular surface pain are typically divided into nociceptive and neuropathic/nociplastic. Nociceptive causes include an unhealthy tear film (e.g., low tear production, rapid tear break up), anatomic abnormalities of the eyelids, conjunctiva and cornea, and environmental insults (e.g., low humidity, air pollution). However, corneal nerves and their central connections may become dysfunctional, leading to ocular surface pain. NOP falls under the umbrella terms of “ocular surface pain”, “ocular pain”, “eye pain” and “oculofacial pain”. NOP is a condition where individuals have ocular surface pain that is generated by nerve dysfunction. While there are no consensus criteria for the diagnosis, new advances in the understanding of clinical presentations and the neurobiology involved in ocular sensation have led to the classification of NOP as a distinct and important disease entity.

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Synonyms

neuropathic dry eyes
neuropathic corneal pain
corneal neuropathy
corneal neuralgia
keratoneuralgia
NOP

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Signs & Symptoms

Symptoms of NOP include a host of ocular pain symptoms that have been described as dryness (with minimal or no relief with over-the-counter lubricating drops), burning, shooting, pressure-like pain, foreign body sensation, grittiness, aching, stabbing or cutting sensation and/or throbbing. Pain may occur spontaneously or be evoked by light (e.g., fluorescent room lights, sunlight), wind (e.g., indoor fans, in-clinic “air puff test” for eye pressure) and/or temperature changes (e.g., air conditioning, hair dryers, seasonal variation). One or both eyes may be involved. The onset may be sudden, as is usually the case when there is an identifiable trigger (such as trauma or surgery to the eye) or insidious. While the pain is typically chronic, its severity can range from mild to excruciating.²⁰

Symptoms of NOP may be isolated to the eyes, but many individuals experience pain or aching in areas around the eye (e.g., heavy eyelids, pressure around the eyes, aching in the cheek bones, forehead, or temple) or describe pain radiating from the eye to the back of the head.

Visible ocular defects are notably absent or out of proportion to ocular surface findings in many people with NOP. Given the shared and interrelated symptomatic pictures of NOP and DE, a thorough ocular surface examination is indicated when either condition is suspected. In general, absent or minimal signs of ocular surface disease (e.g., corneal epithelial disruption, low tear production, rapid tear break -up, anatomical abnormalities, meibomian gland dysfunction) points to NOP as a potential contributor to pain.

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Causes

The exact cause of NOP is not fully understood, and onset may occur in the presence or absence of a particular trigger. It is suggested that any initial insult to the eye may result in chronic nerve abnormalities in susceptible individuals, manifesting as chronic ocular pain. The initial trigger may be any of the following:

Trauma (e.g., corneal abrasion, radiation therapy, traumatic brain injury)
Chemical exposures (e.g., preservatives in topical medications, chemical burns, systemic chemotherapy)
Infection (e.g., herpes simplex virus, herpes zoster virus)
Eye surgery (e.g., refractive, cataract, glaucoma, and retinal surgery)
Systemic disease (e.g., autoimmune or inflammatory conditions, diabetes, fibromyalgia)
Other neurological disease (e.g., trigeminal neuralgia, migraine).

Symptoms of NOP often begin soon after an initial trigger but can have a delayed onset. Refractive surgeries (e.g., laser assisted in situ keratomileusis (LASIK) and photorefractive keratectomy [PRK]) have been most closely aligned with NOP although chronic ocular pain can occur after any ocular surgery.¹⁶ NOP can co-exist with ocular surface abnormalities and these abnormalities may further impact peripheral nerve function. Nevertheless, NOP often occurs in the absence of any identifiable cause and does not require any initial damage to the eye for diagnosis.

At a deeper level, NOP is thought to occur due to nerve abnormalities (i.e. sensitization) at the peripheral level (i.e., corneal surface or periocular skin) and/or in central pathways (i.e., trigeminal sensory pathway, thalamus, cerebral cortex).²¹ These changes result in over-activation of sensory neurons, experienced as pain with subnormal inputs (hyperalgesia) or abnormal inputs (allodynia).²² In the eye, hyperalgesia is often experienced as sensitivity to wind and allodynia as sensitivity to light. Importantly, nerve changes are dynamic, and there is no timetable for development of abnormalities or improvement in function. Thus, treatments may improve nerve function and pain even years after the onset of symptoms.

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Affected populations

NOP may affect individuals of any age, sex, ethnicity, or background. NOP often occurs with pain in other areas of the body (e.g., fibromyalgia, chronic joint pain, peripheral neuropathy) and with headaches (e.g., migraine).²³ Many individuals with NOP also have mood disorders (e.g., depression, anxiety), although it is not understood if this is a cause or consequence of disease or if both entities share common underlying factors.²⁴ Global abnormalities in sensory processing (e.g., glial activation, pre- and post-synaptic upregulation, neuro-inflammation), systemic inflammation and genetic predisposition have all been implicated in the development of chronic pain and are areas of research focus for NOP.

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Disorders with Similar Symptoms

Many conditions and events (e.g., infection, trauma or surgery, chemical/toxin exposure, allergy, dry eye, other ocular conditions) can irritate the ocular surface and lead to symptoms of ocular pain which can manifest as sensations of dryness, grittiness, itchiness, burning, wind or light sensitivity and more. Thus, all such ocular conditions must be in the differential of NOP and should be evaluated for in the eye clinic.

As above, dry eye (DE), in particular, is closely associated with NOP as many individuals with NOP have been diagnosed with DE. DE is an umbrella term that includes ocular symptoms that are associated with ocular signs (e.g., low tear production, rapid tear break-up, corneal epithelial disruption, crusting of the eyelashes, plugging or dropout of Meibomian glands). DE is further divided into sub-types. Aqueous tear deficiency (ATD) is defined by reduced tear production and is often accompanied by ocular surface inflammation. ATD is closely related to systemic immune conditions such as Sjögren’s disease and graft-versus-host disease. Evaporative tear deficiency (ETD) is defined by normal tear production and rapid tear instability. ETD is related to periocular skin diseases such as rosacea. Some view NOP as a subclassification of DE, while others view it as a separate diagnosis. Regardless, given significant overlap in symptoms, a thorough eye examination is warranted, and all other potential contributors to pain should be addressed and treated in any person suspected of NOP to prevent further ocular damage and an exacerbation of symptoms.

Referred pain may also present similarly to NOP, as abnormalities in other areas of the face (e.g., temporomandibular joint, dental tissues) can present with referred pain to the eye. In fact, in anecdotal cases, treatment of such abnormalities (e.g. improving denture fit) has improved eye pain. As such, a broad differential needs to be considered for eye pain, including disorders outside the eye.

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Diagnosis

A thorough history and clinical exam are essential to a diagnosis of NOP. As there are no universal criteria for diagnosis, NOP remains a clinical diagnosis. A combination of history, symptoms, physical examination and imaging findings are used to arrive at a diagnosis of NOP, after excluding other causes of ocular pain. The examination of an individual with suspected NOP begins with a comprehensive history, capturing initial triggers for pain, its time course, alleviating and exacerbating factors and treatment history.

It is helpful to assess current symptoms using standardized questionnaires to determine the severity and nature of symptoms, associated factors and functional disability. The modified Neuropathic Pain Symptom Inventory (NPSI-Eye)²⁵ and the Ocular Pain Assessment Survey (OPAS)²⁶ are two validated questionnaires that assess, quantify and characterize pain symptoms. In addition, the OPAS evaluates the impact of pain on quality of life. These questionnaires can be used to determine baseline symptoms, guide treatment and monitor for changes over time.

One clinical indicator of NOP is disproportionately intense symptoms in the presence of few or minimal signs of ocular surface disease. Thus, an unremarkable ocular surface exam, or persistent/unchanged symptoms after treatment of the ocular surface should raise the possibility that neuropathic or nociplastic mechanisms underlie pain. In particular, topical lubricating drops often provide no or minimal alleviation of ocular symptoms and can even exacerbate symptoms in individuals with NOP and hyperalgesia.

Corneal sensitivity can be examined in clinic with the use of a cotton tip or dental floss. Corneal sensation is measured in all ‘quadrants’ (central, superior, inferior, nasal, temporal) or simply in the center of the cornea.²⁷ In the clinical arena, sensitivity is often assessed qualitatively using a 0-3 numerical scale (0= no sensation, 1=reduced, 2=normal, and 3=increased). In the research arena, sensitivity can be evaluated using more sophisticated tools, namely the Brill, Cochet-Bonnet or Belmonte aesthesiometers.²⁸ The Cochet-Bonnet utilizes a 6cm nylon microfilament that is slowly brought in contact with the cornea and retracted until sensation is felt. Corneal sensation is quantified on a 0-6 cm scale, with 0 cm representing no sensation and 6 cm full sensation. A limitation of Cochet-Bonnet is that most healthy individuals can detect the sensation at 6 cm, thus limiting the ability to test for hypersensitivity. The Brill aesthesiometer is a new commercially available device that applies a non-contact air jet to the cornea to generate mechanical (air flow), stimuli. It has a 6-point testing range (1 representing the lowest air flow and 6 indicating that the air flow was not felt at the highest level). The device potentially detects both decreased (level 5 or 6) and increased (level 1) sensitivity, although this concept needs to be further examined. Individuals with NOP can have decreased, normal, or increased corneal sensation, but individuals often report corneal hypersensitivity.

In patients with a suspected NOP component, examining the effect of a topical anesthetic on pain can further localize the source of pain. Application of a topical anesthetic (such as proparacaine 0.5%) quiets corneal nerve inputs and thus largely eliminates nociceptive and peripheral neuropathic sources of pain. Individuals who experience persistent pain after anesthesia (30 seconds to 2 minutes after placement of anesthesia) are likely to have centrally mediated or non-ocular surface sources of pain.

Imaging of the cornea using in vivo confocal microscopy (IVCM) provides an anatomic picture of corneal nerves and inflammatory cells, most often in the central cornea.²⁹ The subbasal nerve plexus, just under the corneal basal epithelium, is commonly imaged although nerves can also be detected in the stroma. Nerve abnormalities have been described in the setting of various DED sub-types, most often decreased nerve density and an increased number of inflammatory cells in individuals with ATD (i.e., decreased tear production) and systemic immune disorders.³⁰ Microneuromas, or abrupt endings of nerve fibers on imaging, have been identified as potential markers of peripheral neuropathic pain³¹, although this finding requires further study.

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Standard Therapies

Treatment
The goal of treatment in individuals with NOP is to improve nerve function and further to treat and avoid noxious stimuli that can worsen the neuropathic cascade. As such, following a thorough evaluation, the first step in management is to treat all nociceptive sources of pain, as ongoing nociceptive traffic can lead to peripheral nerve abnormalities. These include therapies such as artificial tears, topical anti-inflammatories (e.g., short term corticosteroids, cyclosporine, lifitegrast), nutritional supplements (e.g., omega-3 supplementation) and antibiotics (e.g. azithromycin). However, if pain persists despite these therapies or in individuals with the appropriate history and clinical findings (i.e. pain out of proportion to ocular surface signs, corneal hypersensitivity, persistent pain after anesthesia), therapies targeting underlying neural pathways should be considered.

When starting therapy in an individual with NOP, a realistic understanding of the treatment approach is important. Important features include an understanding that:

1. A multi-modal approach to therapy is often needed.
2. Most agents used to treat nerve pain have a slow onset of action and clinical effects are often not seen for weeks to months.
3. Chronic therapy is often required for years.
4. Current therapies often reduce pain but do not completely eliminate it.
5. Depression and anxiety must be addressed simultaneously with pain.

With these points in mind, within a multimodal approach, pain does improve to some extent in most people with NOP, followed by improvements in the ability work and function.

In individuals with a suspected central component to pain, systemic neuromodulators are often used. α2δ-calcium channel blockers are first-line oral options for treating neuropathic pain and are used for eye pain, including gabapentin and pregabalin.³² Other oral neuromodulators may be used alone or in conjunction with α2δ ligands. These include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, topiramate and low dose naltrexone.

In individuals with a suspected peripheral component to pain, local therapies can be tried, including blood products.³³ After a peripheral blood draw, serum is extracted and diluted for use as autologous serum tears (AST). ASTs contain several growth factors that are beneficial for nerve and epithelial health (e.g. nerve growth factor (NGF), epithelial growth factor (EGF), transforming growth factor-β (TGF-β) and other vitamins. Platelet rich plasma (PRP) is another blood-derived product that provides an even higher concentration of growth factors and cell adhesion molecules than AST and has been used to treat post-LASIK eye pain among other ocular surface conditions. Availability of blood products, however, may be limited to academic centers and blood-processing eye banks. Other agents investigated in the treatment of NOP (especially with concomitant corneal nerve hyposensitivity) include topical insulin and NGF, although these have not been robustly tested in controlled studies.

Glasses are often used in conjunction with neuromodulatory strategies to help individuals with wind and light sensitivity. Onion/wrap around googles can help with wind and odor sensitivity whereas FL-41 tinted lenses (which preferentially block wavelengths ~480 nm) can help with indoor light sensitivity.

There is a strong association between NOP and other neurologic and psychiatric mood disorders, and interdisciplinary treatment is imperative to the delivery of effective holistic care. Individuals with NOP frequently suffer from depression, anxiety, insomnia and post-traumatic stress disorder. Further, NOP can coexist with neuropathic pain elsewhere in the body, manifesting as joint/back pain, fibromyalgia, headache and other chronic pain disorders. These conditions are common and can be functionally debilitating. Individualized and regular support from providers, both medical and mental health, can be instrumental in helping patients cope with these distressing and chronic conditions. Eye care providers should form partnerships with appropriate individuals to facilitate the holistic care of patients. The multidisciplinary team may include a neurologist, pain or headache specialist, acupuncturist, psychologist, psychiatrist and primary care physician, as appropriate. As in other pain conditions, psychotherapy techniques (e.g., cognitive behavioral, desensitization, relaxation and acceptance-based therapies) can be helpful. Restoring patient comfort and function are fundamental goals of treatment which require the destigmatized management of underlying psychiatric and neurologic conditions with individualized and multitargeted systemic approaches.

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Clinical Trials and Studies

Several investigational therapies are being evaluated for use in NOP. For example, new topical therapies are being investigated for the treatment of chronic pain in clinical trials (e.g., transient receptor potential vanilloid-1 (TRPV1) antagonists, a lipid conjugated chemerin peptide agonist of the ChemR23 G-protein coupled receptor). In the clinical arena, other oral neuromodulatory medications beyond calcium channel blockers, TCAs and SNRIs may be used, including antiepileptics (e.g., topiramate, lamotrigine, carbamazepine), analgesics (e.g., mexiletine) and low dose naltrexone. Overall, opioid therapies are avoided in the treatment of NOP as opioids can reduce pain in the short-term but have negative consequences on nerve function (they can worsen hyperalgesia) in the long-term, with a few specific exceptions (e.g., intrathecal pain pump in refractory conditions).

NOP is frequently associated with migraine headaches, and recent explorations have identified trigeminal system abnormalities as a contributor to both diseases. Thus, treatments for migraine have been explored in NOP, including transcutaneous electrical nerve stimulation (TENS) and botulinum toxin type A (BoNT-A) injections. Specifically, the Cefaly (Cefaly Technology, Herstal, Belgium), which is frequently used in the treatment of migraine has been found to reduce ocular pain in the short and long term in some individuals.³⁴ However, it is not known which device, parameters or frequency of use, are optimal for NOP. Botulinum toxin A injections are given in the distributions of the trigeminal and occipital nerves as a treatment for chronic migraine. Botulinum toxin using the full migraine protocol³⁵ or a modified protocol³⁶ has also improved ocular pain symptoms in some individuals.

In some individuals, especially those with pain after surgical intervention, sensitization of local sensory nerves around the eye contributes to chronic ocular pain. Such individuals often present with cutaneous allodynia (pain upon palpation of the orbital bones). The local nerves in the area around the eyes can be targeted with periocular nerve block injections. Periocular nerve blocks consistent of an anesthetic-steroid combination (e.g., bupivacaine or lidocaine + methylprednisolone, triamcinolone, or dexamethasone) and injections can be administrated by palpating the orbital landmarks, without the need for additional devices such as fluoroscopy.³⁷

In more severe cases of refractory pain, nerve blocks to areas of autonomic control or downstream pain processing are offered in some pain clinics. Common areas of blockade include the sphenopalatine ganglion (an area of parasympathetic efferent control) and the superior cervical ganglion (an area of sympathetic efferent control). These blocks do require administration of medication under fluoroscopy and are thus not amendable to being performed in the eye clinic. Cervical intrathecal pain pumps have been used in rare cases to alleviate eye pain.

Overall, the complexity of this condition, and the new diagnostic tools and therapies that accompany it, often require coordinated care with one or more specialists or experts in the condition for effective management.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

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1. 1. Galor A, Moein HR, Lee C, et al. Neuropathic pain and dry eye. Ocul Surf 2018;16(1):31-44.

1. 1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15(3):276-83.

1. 1. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol 2000;118(9):1264-8.

1. 1. Bandeen-Roche K, Munoz B, Tielsch JM, et al. Self-reported assessment of dry eye in a population-based setting. Invest Ophthalmol Vis Sci 1997;38(12):2469-75.

1. 1. Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2003;110(6):1096-101.

1. 1. Lee AJ, Lee J, Saw SM, et al. Prevalence and risk factors associated with dry eye symptoms: a population based study in Indonesia. Br J Ophthalmol 2002;86(12):1347-51.

1. 1. Ong ES, Felix ER, Levitt RC, et al. Epidemiology of discordance between symptoms and signs of dry eye. Br J Ophthalmol 2018;102(5):674-9.

1. 1. Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of discordance between symptoms and signs in dry eye disease. Ophthalmology 2017;124(3):280-6.

1. 1. Galor A, Felix ER, Feuer W, et al. Corneal nerve pathway function in individuals with dry eye symptoms. Ophthalmology 2021;128(4):619-21.

1. 1. Vera-Duarte GR, Jimenez-Collado D, Kahuam-Lopez N, et al. Neurotrophic keratopathy: general features and new therapies. Surv Ophthalmol 2024;69(5):789-804.

1. 1. Galor A, Batawi H, Felix ER, et al. Incomplete response to artificial tears is associated with features of neuropathic ocular pain. Br J Ophthalmol 2016;100(6):745-9.

1. 1. Kalangara JP, Galor A, Levitt RC, et al. Characteristics of ocular pain complaints in patients with idiopathic dry eye symptoms. Eye Contact Lens 2017;43(3):192-8.

1. 1. Farhangi M, Diel RJ, Buse DC, et al. Individuals with migraine have a different dry eye symptom profile than individuals without migraine. Br J Ophthalmol 2020;104(2):260-4.

1. 1. Diel RJ, Mehra D, Kardon R, et al. Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway. Br J Ophthalmol 2021;105(6):751-60.

1. 1. Levitt AE, Galor A, Weiss JS, et al. Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders. Mol Pain 2015;11:21.

1. 1. Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15(3):404-37.

1. 1. Pouyeh B, Viteri E, Feuer W, et al. Impact of ocular surface symptoms on quality of life in a United States veterans affairs population. Am J Ophthalmol 2012;153(6):1061-66 e3.

1. 1. Sanchez V, Cohen NK, Felix E, Galor A. Factors affecting the prevalence, severity, and characteristics of ocular surface pain. Expert Rev Ophthalmol 2023;18(1):19-32.

1. 1. Galor A, Levitt RC, Felix ER, et al. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye (Lond) 2015;29(3):301-12.

1. 1. Choudhury A, Reyes N, Galor A, et al. Clinical neuroimaging of photophobia in individuals with chronic ocular surface pain. Am J Ophthalmol 2023;246:20-30.

1. 1. Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf 2012;10(1):2-14.

1. 1. Galor A, Covington D, Levitt AE, et al. Neuropathic ocular pain due to dry eye is associated with multiple comorbid chronic pain syndromes. J Pain 2016;17(3):310-8.

1. 1. Galor A, Britten-Jones AC, Feng Y, et al. TFOS lifestyle: impact of lifestyle challenges on the ocular surface. Ocul Surf 2023;28:262-303.

1. 1. Farhangi M, Feuer W, Galor A, et al. Modification of the neuropathic pain symptom inventory for use in eye pain (NPSI-Eye). Pain 2019;160(7):1541-50.

1. 1. Qazi Y, Hurwitz S, Khan S, et al. Validity and reliability of a novel Ocular Pain Assessment Survey (OPAS) in quantifying and monitoring corneal and ocular surface pain. Ophthalmology 2016;123(7):1458-68.

1. 1. Galor A, Lighthizer N. Corneal sensitivity testing procedure for ophthalmologic and optometric patients. J Vis Exp 2024(210).

1. 1. Merayo-Lloves J, Gomez Martin C, Lozano-Sanroma J, Renedo Laguna C. Assessment and safety of the new esthesiometer BRILL: comparison with the Cochet-Bonnet Esthesiometer. Eur J Ophthalmol 2024;34(4):1036-45.

1. 1. Alhatem A, Cavalcanti B, Hamrah P. In vivo confocal microscopy in dry eye disease and related conditions. Semin Ophthalmol 2012;27(5-6):138-48.

1. 1. Patel S, Hwang J, Mehra D, Galor A. Corneal nerve abnormalities in ocular and systemic diseases. Exp Eye Res 2021;202:108284.

1. 1. Moein HR, Akhlaq A, Dieckmann G, et al. Visualization of microneuromas by using in vivo confocal microscopy: An objective biomarker for the diagnosis of neuropathic corneal pain? Ocul Surf 2020;18(4):651-6.

1. 1. Patel S, Mittal R, Sarantopoulos KD, Galor A. Neuropathic ocular surface pain: emerging drug targets and therapeutic implications. Expert Opin Ther Targets 2022;26(8):681-95.

1. 1. Aggarwal S, Kheirkhah A, Cavalcanti BM, et al. Autologous serum tears for treatent of photoallodynia in patients with corneal neuropathy: efficacy and evaluation with in vivo confocal microscopy. Ocul Surf 2015;13(3):250-62.

1. 1. Mehra D, Mangwani-Mordani S, Acuna K, et al. Long-term trigeminal nerve stimulation as a treatment for ocular pain. Neuromodulation 2021;24(6):1107-14.

1. 1. Diel RJ, Kroeger ZA, Levitt RC, et al. Botulinum toxin A for the treatment of photophobia and dry eye. Ophthalmology 2018;125(1):139-40.

1. 1. Venkateswaran N, Hwang J, Rong AJ, et al. Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients. Am J Ophthalmol Case Rep 2020;19:100809.

1. 1. Small LR, Galor A, Felix ER, et al. Oral gabapentinoids and nerve blocks for the treatment of chronic ocular pain. Eye Contact Lens 2020;46(3):174-81.

INTERNET

Corneal Neuralgia Patients Group/Facebook https://www.facebook.com/groups/1713169018917451/ Accessed Jan 22, 2025.

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