This article was originally published in a sponsored newsletter.

No one likes to have pain of any kind. If I were to ask, “Have you had any pain lately?” most “healthy” individuals might recall a pulled muscle or back strain, sports injuries or general aches and pains. It would be uncommon for someone think about eye pain first, unless the eye pain was bad enough to override memories of other pain.

In cases of pulled muscles or sports injuries, the pain is acute and of limited duration (hopefully). There are conditions that could cause acute eye pain, such as ulcerative keratitis. Acute pain is typically defined as rapid onset, usually with a defined timeline, but as we all know, acute pain can become chronic if left unchecked. Ocular surface conditions generally are described as chronic, with symptoms waxing and waning until they become constant over time. It is unclear to me if eye pain is different from other types of pain in terms of severity and impact on quality of life. There are studies comparing dry eye pain with other types of pain in terms of impact on daily activities, and dry eye pain rates higher than some common systemic conditions such as angina. Dry eye pain also isn’t generally described as “stabbing” or like other, more “acute” or “severe” symptoms.

This brings us to ocular neuropathic pain, also referred to as corneal neuropathic pain, a condition where corneal pain is described as severe in the absence of corneal signs. The pain might be reported in response to normally non-painful stimuli, like light or wind. Neuropathic pain is thought to be related to damage to and perhaps over-response of the corneal nerves. It is difficult to understand a patient’s level of symptoms and the impact on quality of life, especially if the staff or the doctor don’t ask the right questions.

What should we do on both sides of the equation, whether there are symptoms and no signs or we observe overt signs with limited symptoms? These scenarios could be dry eye in early and late stages, respectively. The first case could also be ocular neuropathic pain, which requires a careful assessment of systemic health. The second scenario could be neurotrophic keratitis, either with or without concurrent dry eye, and requires corneal sensitivity testing. Straightforward dry eye, by comparison, might be easier to diagnose and manage than cases like these that reflect the outliers of the pain and symptom spectrum.

An easy approach to dry eye includes symptom and systemic health assessment, slit lamp examination with fluorescein staining, lid and meibomian gland assessment and TBUT. If something seems off, consider corneal sensitivity testing or further systemic pain evaluation to cover the spectrum of ocular surface disease.

Kelly K. Nichols, OD, MPH, PhD
Editor

Pearls for Differential Diagnosis of and Referral for Neuropathic Pain

Corneal neuropathic pain (CNP) occurs when corneal nerves are injured, either from peripheral (i.e., dry eye disease, contact lens wear, ocular surgery) or systemic (i.e., lupus, diabetes, fibromyalgia) etiologies.¹ It is a complex condition characterized by an abnormal pain response to normally non-painful stimuli such as wind or light.

CNP can be challenging to diagnose because patients’ symptoms mirror those of dry eye disease. These symptoms can include itching, dryness, watering, irritation, burning and sensitivity. While there is currently no standardized diagnostic criteria for CNP, these signs and symptoms that can increase your suspicion of this disease:

• CNP is more common in patients with a history of cataract, refractive or other ocular surgery, herpes infection or chronic pain disorders such as migraines and fibromyalgia.^1,2
• Allodynia and hyperalgesia can differentiate CNP from dry eye disease. Allodynia is pain in response to normally non-painful stimuli (i.e., light or wind) and can manifest as a burning sensation. Hyperalgesia is increased sensitivity to stimuli leading to exaggerated pain responses.
• Symptoms of CNP may manifest solely in the eyes, but many patients report discomfort or throbbing sensations in adjacent areas (such as heaviness of the eyelids, pressure around the eyes or aching in the forehead or temples), or describe pain that extends from the eye to the rear of the head.²
• Clinically, CNP is described as “pain without stain,” where the patient's symptoms of pain do not correlate to the clinical appearance. If a thorough slit lamp exam reveals absent or minimal signs of ocular surface disease despite significant symptoms, CNP should be on your differential. Additionally, patients with CNP most often report corneal hypersensitivity with corneal sensitivity testing.²
• The proparacaine test (using a topical anesthetic to reduce peripheral pain) can help distinguish between peripheral and central sources of pain. If proparacaine does not alleviate patients’ symptoms, suspect a centralized or non-ocular pain source. Confocal microscopy can visualize corneal nerve abnormalities but may not be widely available in most offices.

Given these nuances, caring for patients with CNP involves a multidisciplinary care team approach, especially referral to a corneal specialist who has in vivo confocal microscopy. Whether depression and anxiety are a cause or consequence of CNP, a mental health provider with experience in treating patients with chronic pain can be beneficial. Additionally, neuropathic pain can exist elsewhere in the body which can manifest as chronic pain disorders. Care teams that involve primary care, neurology and rheumatology may also be warranted.

References:

1. Watson SL, Le DTM. Corneal neuropathic pain: a review to inform clinical practice. Eye. 2024 Apr 16. https://doi.org/10.1038/s41433-024-03060-x
2. National Organization for Rare Diseases (NORD). Neuropathic ocular pain. Published 2021. Updated April 5, 2021. Accessed April 25, 2024. https://rarediseases.org/rare-diseases/neuropathic-ocular-pain/

The cornea has one of the highest densities of nerves than any other body tissue and can detect chemical, thermal and mechanical stimuli. Corneal neuropathic pain (CNP) is a rare but debilitating condition where patients experience corneal pain, foreign-body sensation, photophobia, epiphora, burning and irritation in the absence of a painful stimulus. It can dramatically negatively impact a patient’s quality of life.

Patients report severe symptoms but, on examination, CNP presents as “pain without stain,” meaning there are few to no objective findings (i.e., corneal staining). CNP can develop in two ways: corneal injury or disease of peripheral corneal nerves leads to peripheral sensitization due to aberrant regeneration of corneal nociceptors and nerve fibers, or central sensitization develops due to upregulation of excitatory neurotransmitters because of chronic inflammation, which leads to amplification of neuronal response to stimuli.

CNP is often considered a diagnosis of exclusion, making it difficult to diagnose and treat. It can be secondary to dry eye disease, corneal trauma or infection, ocular surgery (e.g., laser refractive surgery, cataract) and UV exposure. In fact, many patients with CNP are often misdiagnosed with dry eye syndrome because of similar and overlapping symptoms. CNP is also commonly associated with other systemic disorders and has a strong association with depression, anxiety and fibromyalgia. Unfortunately, there is no cure for CNP. Management entails attempting to curtail symptoms and must be individualized for each patient.

This month’s article focuses on what is known about CNP and, importantly, how patients’ perspectives of their condition can pose a significant challenge for physicians. The authors analyzed two patients who developed CNP after refractive surgery. Both patients experienced eye discomfort after the procedure but were assured by their eye care professionals that this side effect was normal as their corneal nerves regenerated and healed. Their eyes looked healthy and their discomfort was attributed to dry eyes after surgery. They were prescribed heavy lubrication.

Patient one’s eye discomfort continued for years with her seeking help from numerous eye care and general physicians. Eventually, her original surgeon told her that they would not see her anymore because they could find nothing wrong with her eyes and there was nothing more they could do. It wasn’t until years later after seeing another consultant that she was diagnosed with CNP and she was started on autologous serum drops that significantly improved her symptoms. She has also sought help from a pain specialist.

Patient two also experienced significant burning and pain after refractive surgery that was attributed to blepharitis and dry eye. He too sought care from numerous physicians who prescribed a variety of treatments including punctal plugs, botulinum toxin injections, autologous serum, amniotic membranes and even a three-day course of IV methylprednisolone. He also experienced financial burden from seeking care for his constant pain and his job was severely impacted.

The authors validate these patients’ perspectives that diagnosing and managing CNP is challenging. There are no clearly defined or established diagnostic criteria for CNP; reported symptoms and symptom severity differ between patients, and there are minimal to no observable or measurable signs. The authors stress that a careful and thorough patient history that asks about previous ocular surgeries, ocular disease (i.e., dry eye, herpes keratitis), systemic conditions (i.e., fibromyalgia, trigeminal neuralgia) and other co-morbidities (i.e., depression, post-traumatic stress disorder) is crucial. It is also important that clinicians recognize the patient’s journey in that they have likely seen other physicians who unable to help, which delayed the CNP diagnosis and added to patient (and doctor) frustration. It is essential to understand that management will be a slow process that requires patience from both clinicians and patients.

Corneal Neuropathic Pain: A Patient and Physician Perspective
Thomas W. McNally and Francisco C. Figueiredo
Ophthalmol Ther. 2024 Feb;13:1041-1050. doi:10.1007/s40123-024-00897-z

Corneal neuropathic pain (CNP) is a debilitating condition characterized by pain in the absence of a noxious stimulus. Symptoms such as ocular stinging, burning, photophobia, irritation, and a deep aching pain can be severe despite a seemingly normal ocular surface on examination. CNP may develop due to either peripheral or central sensitization. Peripheral sensitization develops due to aberrant regeneration of corneal nociceptors and nerve fibers as a result of corneal injury or disease of peripheral corneal nerves. Whereas, central sensitization develops due to upregulation of excitatory neurotransmitters as a result of chronic inflammation, which leads to amplification of neuronal response to stimuli. Unfortunately, due to the disparity in severity of symptomology and the observable signs on examination, patients’ symptoms are commonly thought thought to be "psychological" or "functional", and patients report feeling ignored and neglected. Additionally, diagnosis is often delayed which adversely affects patient outcomes. Research to date has focused on the scientific aspects of corneal neuropathic pain: its pathophysiology, epidemiology, investigations, and management. Research into the patient personal experience and the challenges faced by individual patients and their clinicians is lacking. We present patient and physician perspective on the journey of both patients in order to provide insights into the challenges faced by patients and physicians in the diagnosis, assessment, and management of corneal neuropathic pain.

Pipeline
Patrick Vollmer, OD, FAAO, and Assem Patel, MS
Vita Eye Clinic, Shelby, NC

B12 as a Treatment for Peripheral Neuropathic Pain

Neuropathic pain arises from a specific injury (e.g., lesion) or a disease in the somatosensory system and impacts 7% to 10% of the overall population. Various etiologies of neuropathic pain have been identified, including diabetes mellitus as the most common. From the molecular level, this condition can cause imbalances in excitatory and inhibitory somatosensory signaling, changes in ion channels and variations in the modulation of pain signals that lead to the symptoms of neuropathic pain. The occurrence of this disorder is expected to rise due to aging of the global population and increased prevalence of diabetes. Patients suffering from neuropathic pain report symptoms ranging from uncomfortable to debilitating. Treatment options are constantly evolving to preserve quality of life in these patients.¹

One of the better-studied treatments is water-soluble vitamin B12 to diminish neuropathic pain. It is believed that B12 accomplishes relief by promoting myelination, increasing nerve regeneration and decreasing ectopic nerve firing.² For example, it is well known that patients suffering from diabetes (a peripheral vascular disease) are at a substantially higher risk for vitamin B12 deficiency and neuropathy.³ Daily supplementation for vitamin B12 has been clinically proven to increase blood serum levels, causing the symptoms of neuropathy to improve.²

Didangelos and colleagues recently conducted a study examining the effect of vitamin B12 supplementation of 1,000 μg/day for one year in patients with diabetic neuropathy.³ Ninety individuals, all with B12 levels less than 400 pmol/L, were enrolled into this prospective, double-blind, placebo-controlled clinical trial. Out of the 90, 44 were randomized to an active treatment group that received B12 and 46 were randomized into a control group that received a placebo. Each subject was assessed for the following measurements: sural nerve conduction velocity, sural nerve action potential, vibration perception threshold, cardiovascular autonomic reflex tests, sudomotor function (i.e., measuring electrochemical skin conductance in hands and feet), Michigan Neuropathy Screening Instrument Questionnaire and Examination and questionnaires to evaluate quality of life and level of pain. The researchers concluded that oral vitamin B12 supplementation of 1,000 μg/day for one year in patients with diabetic neuropathy significantly increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score and quality of life. However, the cardiovascular autonomic reflex test and Michigan Neuropathy Screening Instrument Examination did not show improvement with this regimen.³

Further, homocysteine (a sulfur amino acid and a product of methionine metabolism) is upregulated in patients with peripheral neuropathy and the resultant hyperhomocysteinemia occurs when homocysteine is not metabolized by the body.⁵ This elevation of homocysteine in the blood can lead to further vascular damage, neurodegenerative disease and other clinical conditions.^4,5 With adequate B12 supplementation however, blood homocysteine levels are lowered.⁵

Therefore, vitamin B12 is a crucial to and has many functions and benefits in the human body. One of its more important roles is in the synthesis of myelin and production of neurotransmitters for the nervous system. It is not unexpected that there is a connection between vitamin B12 insufficiency and diabetes. However, more clinical studies are needed to prove the efficacy of vitamin B12 supplementation in neuropathic pain in diabetes mellitus as well as other etiologies.

References:

1. Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017 Feb;16(3):17002. doi:10.1038/nrdp.2017.2
2. Julian T, Syeed R, Glascow N, Angelopoulou E, Zis P. B12 as a treatment for peripheral neuropathic pain: a systematic review. Nutrients. 2020 Jul;12(8):2221. doi:10.3390/nu12082221
3. Didangelos T, Karlafti E, Kotzakioulafi E, et al. Vitamin B12 supplementation in diabetic neuropathy: a 1-year, randomized, double-blind, placebo-controlled trial. Nutrients. 2021 Feb;13(2):395. doi:10.3390/nu13020395
4. Pratama S, Lauren BC, Wisnu W. The efficacy of vitamin B12 supplementation for treating vitamin B12 deficiency and peripheral neuropathy in metformin-treated type 2 diabetes mellitus patients: a systematic review. Diabetes Metab Syndr. 2022 Oct;16(10):102634. doi:10.1016/j.dsx.2022.102634
5. Science Direct. Homocysteine. Accessed April 30, 2024. https://www.sciencedirect.com/topics/medicine-and-dentistry/homocysteine