Ocular Neuropathic Pain
Ocular neuropathic pain, also referred to as corneal neuropathic pain, is a condition where corneal pain is seen in response to normally non-painful stimuli. This results from repeated direct damage to corneal nerves. Aberrant regeneration with upregulation of nociceptors responsible for processing of painful stimuli leads to hyper-responsivity and increased perception of pain in response to even normally unpainful stimuli. The distorted neuronal excitability which persists even after the tissue has healed is the basis of symptoms of self-sustained chronic corneal pain persisting even in the absence of stimuli and clinical signs – the so called corneal “pain without stain” or “phantom cornea’. This condition is the ocular analogue of systemic neuropathic pain, complex regional pain syndrome or reflex sympathetic dystrophy (RSD). Ocular or corneal neuropathic pain, corneal neuropathy, corneal neuralgia, kertaoneuralgia, and corneal allodynia are all terms that are used to describe the same disease entity.
Corneal neuropathic pain negatively impacts the quality of life of patients. The unpleasant and often severe sensation of pain, light sensitivity, irritation results in impaired functioning and inability to perform activities of daily living; including reading, driving and working. The impact on physical and social functioning can be debilitating. This condition is being increasingly recognized in patients with chronic dry eye syndrome who don’t seem to respond to conventional dry eye treatment and whose severity of symptoms seem disproportionate to clinical examination. It is a particularly challenging condition in post-refractive surgery patients who suffer from chronic intractable pain. Corneal pain is also considered as a part of the complex pain syndrome and can be associated with systemic pain syndromes. Associated symptoms of anxiety and depression also dramatically affect quality of life and in extreme cases can even lead to induction of suicidal thoughts. Due to relatively recent recognition of the problem, poorly understood underlying mechanisms and no signs on slit lamp examination, these symptoms of pain are often unfortunately ignored by ophthalmologists.
Causes of Corneal Neuropathic Pain
Triggers that lead to corneal nerve damage result in corneal neuropathy. Damage to nerves during refractive surgeries, ocular surface diseases such as chronic dry eye disease, recurrent corneal erosions, corneal neuropathic infections such as herpetic simplex and zoster, systemic neuropathic conditions such as diabetes, exposure to topical and systemic drugs, radiation keratopathy and chemotherapy.Figure 1.
Anatomy of Corneal Nerves
The human cornea is one of the most densely innervated tissues. The density of central corneal nerve endings is estimated to be around 7000 nerve terminals per square millimeter. The corneal density of nociceptors in nerve endings is about 300-600 times that of skin and 20-40 times that of tooth pulp. The corneal peripheral sensory nerves are derived from the ophthalmic division of the trigeminal nerves. These nerve endings are initially myelinated. They penetrate the corneal epithelium and Bowman’s layer in a radial fashion 1mm from the corneo – scleral limbus and lose myelination at the site of penetration. After penetration, majority of the nerves turn 90 degrees and run parallel to the epithelial surface in the subbasal layer forming the corneal subbasal corneal nerve plexus. These subbasal nerves run towards the corneal center in a clockwise centripetal pattern. Some of the nerves terminate as free nerve endings.
Physiology of Corneal Nerves
The subbasal nerve plexus contains both - unmyelinated (80%; C fibers) and myelinated nerve fibers (20%; A-d fibers). The bulbous nerve endings contain the nociceptors. The nociceptors are functionally heterogenous and are classified based on the type of the stimuli they respond to. Polymodal nociceptors (70%, majorly C unmyelinated fibers) respond to a large variety of stimuli including heat, mechanical, endogenous and exogenous inflammatory stimuli. The other nociceptors are mechanoreceptors and cold receptors. This nociceptive system responds to various stimuli at the ocular surface and project to the central nervous system, and helps to sustain ocular surface health.
Corneal Pain Pathway
Acute nociceptive pain pathway
Initially, in the presence of a noxious stimulus, the nociceptors get activated. Transduction mechanism at the nociceptors coverts the external, often mechanical stimulus into electrical impulses along the trigeminal nerve endings. These impulses are then transmitted along the corneal pain pathway - i.e. the trigeminal brainstem complex, trigeminal subnucleus interpolaris/caudalis transition region, upper cervical cord junction and posterior thalamus. These inputs are then processed in the corneal pain region of the cerebral cortex. This perception of acute pain is a protective mechanism. However with repeated injury this pain pathway becomes maladaptive and loses the protective mechanism and develops into non –protective neuropathic pain. The processes involved are peripheral and central sensitization.
Peripheral sensitization is the adaptation of the peripheral pain system to repeated injurious stimuli. Persistent damage and inflammation results in transition from acute nociceptive pain to chronic neuropathic pain. Severe (often surgical – such as keratorefractive surgery) or repeated injury induces tissue inflammatory response. Pro-inflammaory mediators such as prostaglandins, cytokines and neuropeptides are released. These neuropeptides induce nerve regeneration. Unregulated and ineffective nerve sprouting at the ends of the injured nerve stumps leads to formation of traumatic neuromas. Formation of neuromas further causes sustained inflammation leading to a vicious cycle. Upregulation of ion channels, modification of intrinsic membrane potentials and lowering of the firing threshold makes the nociceptors abnormally hypersensitive to mechanical and chemical stimuli. This hypersensitivity results in aberrant firing thus generating ectopic nerve stimuli. The unregulated generation of ectopic stimuli even in the presence of sub-threshold stimuli is known as peripheral sensitization.
In addition to the modulation at the level of nociceptors in the presynaptic trigeminal nerve endings, persistent inflammation and nerve damage also act post synaptically in the spinal cord causing direct depolarization along the central pain pathway. These changes occurring in the CNS in response to repeated nerve stimulation is known as central sensitization. Upregulation of excitatory neurotransmitters, mainly NMDA and inhibition of inhibitory neurotransmitters is also seen. This causes more rapid response to similar stimulus in the future – known as neuronal plasticity. This amplification of the neuronal hypersensitivity becomes permanent and persists despite removal of the initial stimulus and apparent healing of the injured tissue resulting in neuropathic pain. This perpetuates pain and dysesthesia even in response to stimuli which are normally non-painful. This is responsible for the “pain without stain” or phantom cornea.
Patients generally present with corneal pain of varying severity. Other symptoms are the dry eye like symptoms – foreign body sensation, burning and reflex tearing. Also severe photosensitivity – photoallodynia, allodynia and dysesthesias can be seen. Focal facial dystonia and blepharospasms may also be noted. Corneal neuropathy has been shown to be associated with other chronic pain syndromes as well and patients often complain of non-ocular pain. Headaches often migraine type are reported. Additionally, these patients frequently have symptoms of anxiety, depression and apathy.
No clinical findings are generally seen on slit lamp examination. The ocular surface appears healthy. However neuropathic pain may be a component of dry eye syndrome. In such cases surface staining, abnormalities on osmolarity testing and other signs of dry eye and surface disease may be present.
Identification of cause
Identification of the inciting insult is important. History of refractive surgery, ocular surface diseases, infections, systemic disorders, radiation exposure and topical and systemic drugs must be elicited.
Quantification of pain
Ocular Pain Assessment Survey (OPAS) is used to quantify pain and impact on quality of life. Other dry eye questionnaires like OSDI may be used, but are not specific for pain.Figure 2.
Assessment of ocular surface health and function
Ocular surface health is assessed by Slit lamp examination, use of vital stains, Schirmer’s test, tear break up time, tear osmolarity and tear proteomics. Function of corneal nerves can be assessed using corneal esthesiometry. Both contact (Cochet-Bonnet) and non-contact (Belmonte) esthesiometry is used.
Differentiating between peripheral and central neuropathic pain
Proparacaine administration helps to differentiate whether neuropathy is peripheral only with sensitization at the level of corneal nociceptors or has progressed to central sensitization. Complete relief of pain in response to proparacaine represents purely peripheral pain however partial relief or no relief at all indicated progression to central sensitization. Incomplete response to surface lubrication also indicates central component of pain.
In vivo confocal microscopy
In vivo confocal microscopy is a sophisticated techniques which enables in vivo, ultra-high resolution quasi-histological evaluation of the corneal ultrastructure. It is a very useful for diagnosis of corneal neuropathy as it provides direct evidence of nerve injury and allows both qualitative and quantitative measurement. IVCM shows decreased density of corneal subbasal plexus. Increased hyper-reflectivity, tortuosity, formation of beading and neuromas is also seen. Figure 3. Corneal epithelial changes including decreased superficial and epithelial cell densities with increased superficial cell size are seen. In addition, increased of corneal dendritic cells in the subbasal cells provide evidence of inflammation and immune activation.
Principles and considerations in management of neuropathic pain
- Most important consideration is individualized management of neuropathic pain. Every patient needs to be graded according to etiology of corneal neuropathy and severity of symptoms. Focus on restoring the ocular surface health – by preventing further insults to the corneal nerves and decreasing ocular surface inflammation is an important starting point.
- Identification of the stage of the disease process, i.e. whether neuronal maladaptation and central sensitization has started. Neuro-regenerative strategies help in reversing damage to corneal nerve plexus. Local ocular surface treatment is generally insufficient for patients with central sensitization. More invasive central pain pathway modulation is needed if central sensitization has occurred.
- Generally a multimodal therapy is appropriate with a focus of both ocular surface and nociceptor modulation. Step wise therapy with escalation depending on treatment response is used. Multi-specialty approach is needed as ocular neuropathic pain has been shown to be a part of complex pain syndromes and frequently requires inputs from pain specialists, neurologists and psychiatrists.
Ocular surface treatment
- Eye lubrication and treatment of dry eye – like symptoms: Artificial tears are used to prevent surface dryness and provide symptomatic relief. By decreasing the hyper-osmolarity of tears, over-stimulation of the nociceptors is stopped. Tears, ointments and gels are all used depending on patient tolerance. If used more than 4 times, preservative free tears are recommended. Punctal plugs to increase the tear lake are also useful.
- Topical and systemic antibiotics to treat blepharitis are often used. Systemic fish oil or flax seed oil to treat evaporative component of dry eye disease has also been used.
- Scleral lenses Scleral lenses, specifically prosthetic replacement of the ocular surface ecosystem (PROSE) has been shown to be effective in treatment of post LASIK corneal neuralgia. The PROSE devices are made of rigid gas permeable lenses, are custom designed and provide fluid ventilation to the cornea.
- Steroids: Short courses of topical steroids have been shown to be useful to decrease surface inflammation. This works both to stop the vicious cycle of inflammation and nerve damage and also provides symptomatic relief. Generally these agents are tapered and discontinued once the inflammation is controlled to prevent formation of cataracts and increased intraocular pressure. Steroids with decreased ocular side effects like fluorometholone and loteprednol are preferred.
- Non-steroidal anti-inflammatory therapies: Topical cyclosporine 0.5% has been shown to decrease the surface inflammation. Also a new drug –lifitegrast has been shown to decrease surface inflammation. These agents modulate T cell mediated inflammation.
Autologous serum tears – These therapies target the underlying pathophysiology of aberrant nerve regeneration subsequent to repeated injury in neuropathic pain. Various neurotrophic growth factors and epithelial growth factors such as the nerve growth factor (NGF), insulin-like growth factor-1, transforming growth factor β, fibronectin, substance P and epidermal growth factor, which help in proliferation, differentiation and maintenance ocular surface health, are present in high concentrations in serum tears. NGF is present in high concentrations in serum compared to tears and plays an important role in nerve regeneration and restoration of function of nerves. Serum tears are also effective in dry eye and neurotrophic conditions of the cornea.Figure 4.
Systemic analgesics, anti-depressives and anti-psychotics
Studies have shown that patients with neuropathic pain also have non ocular symptoms of discomfort. This disease entity is a part of the systemic complex pain syndrome. The systemic pain intensity correlates with depression and PTSD correlate with the dry eye like symptoms. These patients are treated with tri-cyclic antidepressants (e.g., amytriptyline, nortriptyline), anti-convulsants (e.g. carbamazepine), NSAIDS, dronabinol, tramadol, gabapentin/pregabalin are also used with variable success. 
Central pain modulation
These treatments have shown to be effective in chronic intractable pain with central sensitization.
- Electrical neurostimulation - These treatments use the principle of pain gating. Direct neuro-stimulation of the large diameter afferent fibers along the corneal pain pathway using percutaneously placed monopolar electrodes. . Specifically, the area of trigeminocervical complex where the nociceptive corneal afferents in the spinal trigeminal tract synapses with the second order neurons in the area of the C1 C2 levels of the cervical cord is targeted. Direct stimulation inhibits the small diameter nociceptor terminals. However, this is technically challenging and can have complications as migration of the lead. Trans Magnetic Stimulation (TMS) has also been recommended for neuropathic pain.
- Intrathecal infusion of analgesics – Intrathecal infusion of fentanyl and bupivacaine at the cervical cord level has recently shown to have good long term pain relief. Complications include catheter tip granuloma formation.
Vitamin B supplementation has been shown to be effective in herpes, diabetic neuropathy and neuropathic pain. This is because of the analgesic effects and anti-nociceptive effects. Vitamin B 12 topical therapy leads to re-innervation and re-epithelization of the corneal surface. Vitamin 12 acts through the blockade of the cyclooxygenase pathway. It has anti-nociceptive effects by increasing the serotonin levels in different regions of the brain, inhibiting the nociceptive neurons in spinal cord. Decreasing response of thalamic neurons, or by activating opioid receptors. Vitamin D supplementation has also been shown to be effective in specific cases. Cardiovascular exercise, dietary modification, meditation, and acupuncture have also been shown to be effective.
Botulinum toxin A has also been shown to be a potential treatment. Patients who underwent BoNT-A treatments for chronic migraine also reported improvements in dry eye and photophobia symptoms, which may be explained by 1) convergence in nociceptive signaling, sensitization, and signal amplification in migraine, photophobia, and dry eye symptoms in the trigeminal cervical complex and posterior thalamus and 2) the role of inflammatory mediators such as calcitonin gene related peptide in both migraines and photophobia. 
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