Authors: Thomas W. McNally, Francisco C. Figueiredo
Categories: Case Report, Neuropathic cornea pain, Neuropathic eye pain, Neuropathic pain, Refractive surgery
Source: Ophthalmology and Therapy
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 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 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 the 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.
Keywords: Neuropathic pain, Refractive surgery, Neuropathic cornea pain, Neuropathic eye pain
Corneal neuropathic pain (CNP) is a rare and debilitating condition characterized by corneal pain in the absence of a noxious stimulus [1–3]. CNP causes a variety of ocular surface symptoms in addition to pain, which include foreign-body sensation, photophobia, burning, irritation, and epiphora [4–7]. As a result, CNP has a significant impact on patients’ quality of life and adversely affects function and independence [8–10].
Research to date has focused on the pathophysiology of CNP, which has aided the development of various drug targets and treatment modalities [2, 11]. However, there is limited research to date on the impact on patients’ lives and the patient perspective of CNP [7, 12, 13]. The primary objective of this article is to improve our understanding of how CNP affects patients and to highlight areas of unmet need in our understanding and management of CNP by providing insights into the challenges faced by patients and physicians in the diagnosis, assessment, and management of corneal neuropathic pain.
In this article, we present the patient and physician perspective on CNP with information from interviews with patients and clinicians with experience in managing CNP. We do not include primary research carried out by the authors.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Participants provided informed written consent to be involved in this article.
Corneal neuropathic pain (CNP) is often considered a diagnosis of exclusion [1, 7]. CNP is also referred to as ocular neuropathic pain, corneal neuralgia, keratoneuralgia, corneal allodynia, chronic ocular surface pain (COSP), and “phantom cornea”. Although patients often report severe symptoms, there are typically no visible or objective examination findings in the standard ophthalmological clinic setting. As a result, diagnosis is often delayed and many patients are misdiagnosed with dry eyes syndrome due to the overlap in symptoms [1, 5]. Other differential diagnoses include trigeminal neuralgia, oculofacial pain, referred pain, dry eye, corneal insults (chemical injury, abrasion, erosion, or ulcer), post-herpetic neuralgia, and uveitis [14]. Unfortunately, due to the disparity in severity of symptomology and the observable signs on examination, patients’ symptoms are commonly thought to be “psychological” or “functional”, and patients report feeling ignored and neglected [2].
However, research has demonstrated a pathophysiological mechanism for the development of CNP, with clinical signs detectable using adjunct corneal imaging techniques, such as in vivo confocal microscopy [15, 16]. 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. Causes of CNP include dry eye disease, corneal trauma or infection, ocular surgery (i.e., excimer laser refractive surgery, cataract) and UV exposure. Importantly, CNP is commonly associated with other systemic disorders and has a strong association with depression, anxiety, and fibromyalgia [2, 8, 15].
The cornea has one of the highest densities of nerve fibers of any tissue in the body [6]. Corneal nerve fibers can detect chemical, thermal, and mechanical stimuli, which may be manifested as pain, or dysesthesia, by patients with CNP. While pain is an important protective mechanism, CNP is due to pain sensation in the absence of a painful stimulus (allodynia) and excessive pain in response to painful stimuli (hyperalgesia) [1, 5].
It is important to distinguish central and peripheral sensitization in the assessment of patients with CNP as it impacts the management. Peripheral sensitization is caused by persistent corneal damage (e.g., from surgery or trauma) and inflammation (e.g., from ocular surface disease), which drives a transition from acute nociceptive pain to chronic neuropathic pain. Inflammatory mediators encourage aberrant nerve regeneration, which results in hypersensitivity of the corneal nerves. Central sensitization occurs at the level of the pre-synaptic trigeminal nerve endings. Chronic inflammation causes upregulation of excitatory neurotransmitters (e.g., NMDA), which causes amplification of the neuronal response to stimuli. This leads to perceived pain in the absence of a painful stimulus and is responsible for the so-called “pain without stain” phenomenon [7, 17].
Soon after having LASIK surgery in 2012, I knew something was not quite right with my eyes. I began by going back to the practice where the surgery was performed and expressed my concerns regarding the problems I was experiencing, which were mainly dryness, discomfort, and light sensitivity.
I was assured it was all part of the normal healing process and it was probably down to some dryness I was suffering post-surgery. I was told the dryness would improve, and as would the symptoms I was experiencing alongside it. I began with many different dry-eye treatments. Firstly, it was artificial tears and warm compresses and then more advanced treatments like punctal plugs, steroids, and Restasis.
Over the following months, I would continue to have follow-up appointments at the practice and I was also referred by my GP to the local eye hospital for assessment too.
Every doctor I saw told me my eyes look ‘pretty good’, and there appeared to be ‘minimal staining’ and the dryness seemed to be improving. However, I did not seem to be noticing much relief in terms of my symptoms. What they described as ‘dryness’ was more of a burning or aching feeling in my eyes. They also felt very sensitive to any air movement or bright lighting. This was affecting me both indoors and outdoors too. I used to enjoy swimming and playing golf, but my eyes became too sensitive in those kinds of environments so I had to avoid them. I purchased a special pair of goggles that block the air getting to my eyes to help provide some comfort when outside. I soon became quite frustrated with things and wished I had never gone for this surgery, which was only to correct a small vision prescription that I started needing glasses for.
Over the next few years, I continued to have follow-up appointments at the hospital. The practice where I had the surgery would no longer see me, as they were unable to help me any further with my problems. The doctors at the hospital also could not see any reasons why I was still so symptomatic. I was regularly told the ocular surface looks healthy and the doctors did not seem to understand my problem. I was given different types of artificial tears to try and just told to use them more often if my eyes felt worse, this, however, still did not offer me any lasting comfort.
This all continued for some time. I would have some better days where I may forget about my eyes briefly and then worse days depending on what I was doing when nothing seemed to help them apart from closing them and wishing the day was over. I still had to avoid certain activities that aggravated how my eyes felt. My job involves working on computers for long periods of time which would also affect how my eyes felt. At first, I tried to work through it but then I had to change my shifts and have regular breaks during the day to give my eyes a rest or I would feel the level of pain and discomfort increase.
More recently, I had an appointment with the consultant who diagnosed me with chronic neuropathic corneal pain. He explained how eye surgeries can damage the corneal nerves and sometimes they do not heal correctly. They can become hyper-sensitive and sense pain and dryness that is not there or certainly not at a level like it is being felt. I began researching this condition and could see other patients with very similar symptoms to myself who seemed to struggle to get a diagnosis and treatments to help them too.
The consultant enrolled me in a study for a new trial medication for this condition. During this time, I was to record my symptoms that I experienced as well as having check-ups every few weeks. This was the first time I seemed able to express what I felt and answer questions that where all relevant to how it was affecting my life.
Now the study has finished I have been able to start addressing this condition. I was started on autologous serum drops where I saw a noticeable difference after just a few weeks in regards to the burning pain I was experiencing. I am also awaiting an appointment with a pain specialist to look into medication to address the pain directly. It has been a long journey and something that will require long-term management. It can be frustrating having to be meticulous with the treatment regime which includes many different eye drops, but I am happy things are going in the right direction now and I have started to feel a bit more positive with life.
I am a 53-year-old man from Whitley Bay in the North East of England who, up until December 2016, was an Associate Director at Built Environment Consultants and a Chartered Electrical Engineer by profession. My work involved the day-to-day running of a team of engineers involved in the design of major projects such as hospitals, power stations, universities, airports etc. This typically involved working 50–60 h per week, extensive travel both nationally and internationally, a high percentage of time in front of a computer screens and in meetings with almost all this time spent within air-conditioned, dry-air environments.
I have been short-sighted since my early teens and used daily disposable contact lenses in my teens and early 20s to correct my vision. As these sometimes felt uncomfortable after a short period of wear, in my mid-20s I decided to investigate laser eye surgery as a possible long-term solution. A local clinic advised that I was a suitable candidate for photorefractive keratectomy (PRK) eye surgery and after listening to success stories from friends, along with the reassurance received from the clinic, I underwent this procedure. Unfortunately, this was unsuccessful, and I ended up with a diagnosis of mild blepharitis and a slight deterioration of vision in both eyes. However, this condition did not greatly affect my life and was dealt with by wearing glasses full time and using warm compresses, eyelid washes, and over-the-counter artificial tear eye drops.
In December 2015, I developed Bell’s palsy, causing weakness and paralysis to the right side of my face, making it difficult to eat, drink, and blink my right eye fully. Luckily, my condition was diagnosed by the NHS within 24 h of the onset of symptoms and treated with a course of prednisone. Once diagnosed, I rested at home and, after 10 days or so, returned to work feeling that my symptoms had diminished. I increased the hours in front of my computer screens to catch up on workload but was unaware that my right eye was not fully blinking. Over the next few months, my right eye became increasingly uncomfortable, so I decided to seek expert medical advice.
In February 2016, I made an appointment to see Professor Figueiredo and his initial diagnosis was bilateral dry eyes, bilateral blepharitis, noting a history of laser refractive surgery and Bell’s palsy to the right eye. The professor and his team at The Newcastle Eye Centre became my main providers of treatment and eye-care advice.
Despite treatment, discomfort in my right eye continued to increase, and in July 2016 Professor Figueiredo noted worsening health of my ocular surface. Up to this time, I had continued to work long hours and Professor Figueiredo advised that, due to the severity of this condition, I should take a short period of time off work to allow my eyes to recover. He prescribed a number of dry eyes eye ciclosporin A eye drops/ointment, VitA-POS ointment and Clinitas; as well as some pressure-lowering drops as I was found to be a steroid timoptol and saflutan. I was advised to use a microwavable heat bag each morning and evening before washing my eyes with OCuSOFT lid scrubs and to take omega 3 oil tablets with vitamin D daily. As I was found to be a steroid responder, steroid eye drops could not be used.
Over the next few months, I continued to be very symptomatic, and the professor and his team tried several treatments and medication changes
By October 2016, the pain while working full time became too severe so, following consultations with The Newcastle Eye Centre, I took the decision to go on long-term sick leave.
In 2017, The Newcastle Eye Centre confirmed that I had developed ocular Neuralgia which, along with severe dry eyes, I am still suffering with this today. This diagnosis has offered me some comfort in explaining what has always felt like an inordinate level of discomfort. It does, however, give me some concerns with regards to my future quality of life and eye care since research into this condition still seems to be developing.
My full-time absence from work spanned from October 2016 to April 2017 and my employer was fully supportive of this decision on the understanding that I planned to eventually return to work. During this period, I took a proactive approach in the health of my eye, installing a humidifier in my home, not looking at a computer screen, TV, or even books, and instead spending most of my time outdoors and listening to the radio. My eye became less inflamed and painful while rested so, following consultations with my GP and The Newcastle Eye Centre, I made the decision to phase myself back into my job initially by working Monday, Wednesday, and Friday mornings. I installed a humidifier on my desk and tried to limit my time in front of a PC, which was easier said than done. Unfortunately, my return to work, even on a part time basis, greatly exacerbated my symptoms, and in December 2017 following further consultation with my GP and The Newcastle Eye Centre, I made the decision to again go on long-term absence from work, but this time until my symptoms decreased dramatically.
Dealing with my personal insurance provider was straightforward but my employer’s insurance company initially rejected my claim. Both policies required access to my medical records and a report by my eye specialist prior to them triggering any monthly payments, but my employer’s insurer also required me to submit a claim for income support, which was rejected, and I required substantial intervention from my employer’s HR department and a further report by my eye specialist in support of my claim. I am currently still covered by my private insurance plan.
I have been examined by numerous eye specialists since the onset of my symptoms, whether at The Newcastle Eye Centre or at opticians and my experiences with professionals in this area have been exceptional. The care and treatment I received for my symptoms has been incredibly proactive and I find it entirely rational that my diagnosis of ocular neuralgia was so difficult to diagnose given that the visual symptoms viewed by the specialists did not necessarily match the pain I felt from this condition. There is only one instance where I found that lack of knowledge in this area could have had a detrimental impact on my welfare. This is when a specialist suggested that stress could be an underlying cause of my symptoms and perhaps a treatment for depression and anxiety would be a more suitable course of action. I feel the notes from this specialist’s clinic increased the potential to steer my future medical care in the wrong direction. It also created a seed of doubt with my employer’s insurance provider regarding the authenticity of my previous diagnosis and my claim for payments. An additional report from my primary eye specialist was required to reassure this insurance provider of my diagnosis.
My current medication has not changed a great deal with the exception that Viscotears at night has been replaced with an ointment, Hylo-Night.
The lifestyle changes I have made due to my condition may seem extreme, especially leaving what I found to be a rewarding and enjoyable career, but I feel I had no choice, as my symptoms while working were completely debilitating and my eye health was on a downward spiral, even with reduced hours. I am still symptomatic with severe dry eyes and ocular neuralgia but since leaving work I am more in control of my lifestyle choices and as such, the condition of the surface of my right eye seems stable and less inflamed. I find that high levels of artificial light from electrical devices such as TV’s, some luminaires, and the PC, are uncomfortable to look at. This does not, however, seem to be the case for natural lighting. Adjusting a TV to a low and warm lighting setting seems to help, as does limiting my time looking at any of these devices. I make a conscious effort to reduce my time in dry air environments, spending much of my time outdoors. I have also found reading books too uncomfortable and now prefer to listen to audiobooks and radio.
I currently spend much of my time looking after the older and younger generations of my family and travel extensively with my wife. I have tried traveling internationally by airplane and storing my frozen medication in high-quality coolers with frozen gel packs. Unfortunately, the medication does not always remain frozen, especially when airport security insist on removing the gel packs for X-raying. We now find the safest way to travel with my frozen and refrigerated medication is by motorhome complete with a fridge freezer.
As demonstrated by the above perspectives, the assessment, diagnosis, and management of patients with CNP presents various difficulties for both patients and physicians. Currently, no clearly defined diagnostic criteria for CNP has been established and it is instead considered a diagnosis of exclusion [1, 2]. Symptoms, and their severity, vary significantly among patients and often include the sensation of burning, irritation, foreign-body and light sensitivity [9, 11, 16]. However, the disparity between observable/measurable signs and symptom severity makes assessment challenging, as CNP is often referred to as “pain without stain”. A thorough medical history is paramount and potential causes of CNP must be sought, e.g., (1) previous refractive surgery and cataract surgery; (2) eye diseases, such as dry eye, herpes keratitis, radiation keratopathy and ocular trauma; (3) systemic disease (fibromyalgia, trigeminal neuralgia, among others), and (4) comorbidities (anxiety, depression, posttraumatic stress disorders). Additionally, ocular pain and quality-of-life questionnaires, such as the Ocular Pain Assessment Survey (OPAS), play an important role in the evaluation of CNP, as commonly there are limited examination findings to guide management [5, 17]. Importantly, peripheral sensitization can be distinguished from central sensitization by the proparacaine challenge test [7]. Topical proparacaine hydrochloride 0.5% is applied and if the patient experiences complete or partial relief, then it is likely they have solely peripheral or mixed sensitization, respectively. If there is no relief, or the pain worsens, they can be considered to have central sensitization, which is more challenging to treat [7]. Novel investigation techniques have been used in the evaluation of CNP, but their availability is limited. For example, in vivo confocal microscopy demonstrates tortuosity, microneuromas, and beading of corneal nerve fibers [5, 7, 17].
The clinician must be aware of the patient journey and the fact that the road to diagnosis is often long, complex, and psychologically demanding for the patient. The severity of symptoms can be debilitating, leading to long-term sick leave and the potential for financial difficulties associated with the illness. Often patients see multiple healthcare professionals, even multiple ophthalmologists, before they see a corneal specialist who makes the CNP diagnosis [5]. Due to a lack of awareness of CNP among healthcare professionals, diagnosis is often delayed and patients can be made to feel stigmatized, frustrated, and that they are not being listened to. As a result, symptoms are commonly severe at the time of diagnosis and patients have often understandably lost faith in clinicians [6, 7]. However, invariably the diagnosis comes as a significant relief.
Unfortunately, currently there is no cure for CNP and management instead consists of symptom control. The successful management of CNP is challenging and must be customized, taking into consideration individual patient factors [2, 18]. It requires patience on behalf of both the patient and clinician as the efficacy of various treatment modalities varies from patient to patient. Likewise, a good rapport and doctor–patient relationship is extremely important as trust is required both ways when trialing new treatments. A step-wise approach to management should be adopted, with the importance of good compliance stressed. Even with successful treatments, symptoms of CNP may not improve for 4–6 weeks after treatment initiation so being honest, clear, and empathetic about this with patients at the outset is important and helps improve compliance and trust [1]. Invariably, patients will try multiple topical and systemic therapies before the right regimen for them is identified, which requires patience, consistency, and commitment from both the clinician and patient.
Generally, management comprises a multimodal and multi-disciplinary approach which includes stabilization of the ocular surface, anti-inflammatory medication, management of comorbidities, and neuroregeneration [1, 6, 7, 17]. Additionally, patients benefit from validation that their condition is real, as there is a strong psychological component to chronic pain [7, 17]. As illustrated above, simply feeling that their concerns are being taken seriously can help patients psychologically. Optimal management of CNP involves a multi-disciplinary, patient-centered approach.
While the management of CNP can be challenging, it is also immensely rewarding. Patients are often relieved to have a diagnosis and to feel that they are being taken seriously. CNP adversely affects quality of life and so the improvement in quality of life through effective management and lifestyle changes (e.g., exercise, nutritional intervention strategies) is both rewarding for the clinician and encouraging for the patient.
CNP is an under-researched condition that has a significant impact on the quality of life of patients. No cure exists, but effective symptom management requires patience, trust, consistency, and commitment on behalf of both the clinician and the patient. Diagnosis of CNP is challenging and often delayed, which leads to severe symptoms at diagnosis and consequently poor patient outcomes. Therefore, we propose that further research, raising awareness and improving clinician, allied health professional, and patient education should be a priority.
Thomas McNally drafted the manuscript and incorporated the patient perspectives. Franicsco C Figueiredo reviewed all versions of the manuscript and was involved in the edit process and the response to reviewers’ comments. Franicsco C Figueiredo is the responsible clinician for both patients and obtained the patient-perspective sections.
No funding or sponsorship was received for this study or publication of this article.
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Thomas McNally and Francisco Figueiredo have nothing to disclose.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Participants provided informed written consent to be involved in this article.
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.