NORD gratefully acknowledges Divy Mehra, BS and Anat Galor MD, MSPH, Surgical Services, Miami Veterans Affairs Medical Center and Bascom Palmer Eye Institute, University of Miami and Noah Hanna, Corneal Neuralgia Patients Group, for the preparation of this report.
Neuropathic ocular pain (NOP) refers to a constellation of persistent ocular pain symptoms (i.e., burning, increased sensitivity to light or wind, shooting pains originating in one or both eyes) that may present with or without ocular surface abnormalities.1 In the past, NOP was considered a sub-type dry eye (DE), which is an umbrella term that represents various symptoms (e.g. sensations of dryness, pain, poor or fluctuating vision) and/or signs (e.g. decreased tear production, rapid tear break up, corneal epithelial disruption, ocular surface inflammation, high or unstable tear composition). In recent years, however, there is an understanding that NOP is better represented as an entity on its own.
Understanding the epidemiology of NOP is challenging as data regarding symptoms has been 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 symptoms, which included dryness and foreign body sensation.2 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.3 These numbers were even higher in Asia, where 34% of participants in a Taiwanese study4 and 28% of participants in an Indonesian study5 reported these same symptoms often or all of the time. Ocular surface abnormalities (e.g. tear film and anatomy) are one cause of ocular symptoms. However, it is well recognized that ocular symptom severity does not correlate well with ocular surface findings6, suggesting that symptoms in many individuals are driven by other factors.
One such factor is corneal nerve dysfunction, which may manifest as hyposensitivity (“neurotrophic phenotype”) or hypersensitivity (“neuropathic phenotype”).7 Corneal nerve hyposensitivity often manifests with cornea epithelial cell disruption with minimal ocular symptoms 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.8
A neuropathic origin to ocular pain is suggested in individuals who have a particular set of symptoms (e.g., burning sensation, light or wind sensitivity), risk factors (e.g., pain that started after surgery, migraine, fibromyalgia) and treatment response history (e.g., poor response to therapies aimed at correcting ocular surface abnormalities).9 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 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.
The cornea has the densest sensory innervation in the body and can be a powerful producer of pain. 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. Ocular surface pain can arise from a number of factors including tear film and anatomical abnormalities, environmental exposures and nerve dysfunction of the peripheral and central nerves that connect the cornea and conjunctivae to the brain. Causes of ocular surface pain are typically divided into nociceptive and neuropathic. 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.
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.10
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 cases of NOP. Given the shared and interrelated symptomatic pictures of NOP and dry eye, 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.
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:
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. NOP can co-exist with ocular surface abnormalities (e.g., tear film, epithelial irregularity, degenerative processes) 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) and/or in central pathways (i.e., trigeminal sensory pathway, thalamus, cerebral cortex). These changes result in over-activation of sensory neurons, experienced as pain with subnormal inputs (hyperalgesia) or abnormal inputs (allodynia).11 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.
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 migraine headaches (both with and without ocular aura).12 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. 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.
A thorough history and clinical exam is 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)13 and the Ocular Pain Assessment Survey (OPAS)14 are two validated questionnaires that assess, quantify and characterize pain symptoms. In addition, the OPAS evaluates 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 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.
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. 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 Cochet-Bonnet or Belmonte aesthesiometers. 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 Belmonte aesthesiometer is not commercially available. It applies a non-contact air jet to the cornea to generate mechanical (air flow), thermal (hot and cold air pulses), or chemical (varying CO2 concentrations) stimuli. It has a wider testing range and can determine sensation and pain thresholds in each eye. While both decreased and increased corneal sensation can be seen in NOP, individuals with NOP most often report corneal hypersensitivity.
Testing the effect of a topical anesthetic on pain can be used to differentiate peripheral versus central sources 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.15 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.16 Microneuromas, or abrupt endings of nerve fibers on imaging, have been identified as potential markers of peripheral neuropathic pain17, although this finding has not been replicated by other groups.18
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. The majority of 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 (initiated at 300 mg daily and titrated to a therapeutic goal of 600-900mg TID, must be adjusted for renal insufficiency) and pregabalin (initiated at 75 mg daily and titrated to 150mg BID).19 Other oral neuromodulators may be used alone or in conjunction with α2δ ligands. These include tricyclic antidepressants (TCAs, e.g., nortriptyline initiated at 10-25 mg and titrated to 50-100mg once daily), and serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., duloxetine initiated at 20 mg and titrated up to 60mg once daily).
In individuals with a suspected peripheral component to pain, local therapies can be tried, including blood products.20 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.21 Availability of blood products, however, may be limited to academic centers and blood-processing eye banks.
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, neuropathic eye pain often coexists with neuropathic pain elsewhere in the body, manifesting as joint/back pain, fibromyalgia 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 requires the destigmatized management of underlying psychiatric and neurologic conditions with individualized and multitargeted systemic approaches.
Several investigational therapies are being evaluated for use in NOP. For example, 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 frequented 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. 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 protocol22 or a modified protocol23 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.19
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.
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