The cornea possesses the highest density of nerves in the human body. Corneal hypoesthesia/hypesthesia is defined as a reduction in sensitivity of the cornea. Impairment can range from mild to complete anesthesia, and greater degree of esthesia is associated with worse complications.
The nerves of the cornea have several important roles:
- Sensory function: perception of stimuli
- Trophic function: regulation of nutrition
The nasociliary nerve from the ophthalmic branch (V1) of the trigeminal nerve (CN V) provides most of the afferent innervation for the cornea. The cornea also has innervation from the maxillary nerve as well as from sympathetic and parasympathetic nerve fibers such as the short ciliary nerves. Corneal hypoesthesia can be due to reduction of corneal subbasal plexus nerves, but subbasal plexus innervation can also be normal in the setting of hypoesthesia.
Afferent corneal nerves release various factors, such as substance P and calcitonin gene-related peptide (CGRP), which maintain the stroma and epithelium as well as regulate their proliferation. However, their specific roles related to esthesia have yet to be clearly elucidated. The factors are produced in the trigeminal ganglion and released by neurons in the cornea, conjunctiva, and lacrimal glands.
Substance P is a neuropeptide that binds to neurokinin receptors, preferentially neurokinin-1 which exists on corneal epithelial cells. Neurokinin-1 is also found on dendritic cells, macrophages, mast cells, lymphocytes, peripheral neurons, vascular and lymphatic endothelial cells. When substance P binds neurokinin-1, it activates phospholipase C-dependent activities, adenylate cyclase and Akt/protein kinase B, resulting in DNA synthesis, cell proliferation, survival, and motility, vasodilation, as well as endocrine, paracrine, and pain signaling. Decreasing substance P levels have been seen with increasing corneal nerve density.
CGRP is a neuropeptide that binds to the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1); it can also bind to adrenomedullin and amylin. CLR is coupled to Gs alpha subunit proteins which promotes the cAMP-protein kinase A pathway, resulting in stimulation of phospholipase C and protein kinase C, increased intracellular calcium levels, and vasodilation. CGRP is involved in lymphocyte differentiation and production of cytokines.
It has been found that substance P is reduced in the tears of patients with corneal hypoesthesia, diabetic patients, and patients that use topical NSAIDs. On the other hand, substance P has been found to be increased in patients with allergic and vernal keratoconjunctivitis, as well as initially postoperatively after LASIK. Similarly, CGRP has been seen to be either heightened or unchanged following various corneal surgeries.
Factors released by neurons work in combination with factors produced by stromal and epithelial cells. In return, stromal and epithelial cells release nerve growth factors and cytokines that promote corneal nerve health, such as insulin-like growth factor-1 and epidermal growth factor. As such, damage to neurons or stromal/epithelial cells can result in a positive feedback loop. For example, injury to the nerves will impact epithelial cells, resulting in decreased production of nerve growth factors, further insulting the nerve cells.
It is important to note that decreased trophic function does not always follow decreased sensation or vice versa. This is demonstrated in partial ganglionic or preganglionic damage, such as with intracranial masses or demyelination, presumably due to neurons being preserved in the trigeminal ganglion. Balloon compression of the trigeminal nerve can result in preganglionic and ganglionic damage at V1 and as such is associated with corneal hypoesthesia. Comparably, microvascular decompression of the trigeminal nerve has preservation of corneal esthesia, as it is preganglionic and occuring at the level of the brainstem.
Following neuronal damage, such as with surgery, decreased epithelium mitosis and hindered healing has been reported. Corneal sensitivity following transplantation is usually fully anesthetic centrally while the peripheral cornea retains sensation. Recovery of sensation is associated with ABO-histocompatibility as well as recipient corneal sensitivity. Hypoethesia may be more pronounced if the transplant is due to herpes or chemical injury. Additionally, the eyes of patients with dry eye have decreased epithelial and nerve density as well as altered cellular morphology. Just like the skin, corneas exhibit sensory adaptation, as seen with contact lens tolerance with time and reduction of corneal sensitivity in contact lens wearers. After sleeping or other activities with prolonged eyelid closure, corneas exhibit heightened sensitivity. As such, patients with decreased ability to close their eyelids often have reduction in corneal sensitivity.
As diabetic retinopathy is a neuropathy, it can result in damage to corneal nerves and thus hypoesthesia. An additional cause for corneal hypoesthesia in patients with diabetes is laser damage to afferent nerves following panretinal photocoagulation. This has also been associated with efferent nerve damage resulting in internal ophthalmoplegia. It is interesting to note that Risarestat, an aldose reductase inhibitor, has been reported to reverse hypoesthesia and normalize epithelial cell morphology in diabetic patients that were studied in Japan.
Corneal hypoesthesia can be due to many causes, such as medication, surgery, infection/trauma, and various diseases;
- Topical beta-blockers i.e. timolol, betaxolol, carteolol, levobunolol, metipranolol
- Topical atropine
- Topical anesthetics i.e. proparacaine, tetracaine, benoxinate (oxybuprocaine), cocaine, lidocaine
- Topical NSAIDs i.e. diclofenec, ketorolac, bromfenac, flurbiprofen, nepafenac
- Topical carbonic anhydrase inhibitors i.e. dorzolamide, brinzolamide
- Topical sulfacetamide
- Systemic neuroleptics, antihistamines, & antipsychotics
- Refractive: dependent upon depth of ablation
- Ptosis repair
- Corneal collagen crosslinking: epi-off is more reduced and for longer than epi-on
- Limbal stem cell deficiency
- Keratoconus: worsens as keratoconus progresses
- Dry eye syndrome
- Corneal dystrophy
- Exposure keratopathy secondary to lagophthalmos e.g. exophthalmos, facial nerve palsy, eyelid coloboma, ectropion
- Spheroidal degeneration
- Pseudoexfoliation syndrome
- Herpes simplex epithelial keratitis
- Herpes zoster ophthalmicus
- Ocular Leprosy
- Multiple sclerosis
- Adie’s tonic pupil
- Facial nerve palsy
- Progressive Supranuclear Palsy
- Parkinson's Disease
- Myasthenia gravis
- Intracranial masses compacting CN V e.g. acoustic neuroma, neurofibroma, angioma, aneurysm, embolism
- Familial dysautonomia (Riley-Day syndrome): dermatome in remaining area of CN V is not involved
- Congenital trigeminal anesthesia: dermatome of CN V is involved, can be isolated or associated with other congenital defects
- Type 1: primary hypoplasia of the trigeminal nuclei
- Type 2: abnormal mesodermal/ectodermal development e.g. Möbius Syndrome, Goldenhar syndrome, anhidrotic ectodermal dysplasia
- Type 3: focal brainstem (e.g. CN VIII or CN IX) dysfunction
- Congenital analgesia
- Parry-Romberg syndrome
- Bassen-Kornzweig syndrome
- CHARGE syndrome
- VACTERL and MURCS associations
- Contact lenses: regardless of type, reduction improves after disuse but recovery depends upon length of time of wear
- Irradiation near or on the eye
- Vitamin A deficiency
Thorough history should be taken to determine if the patient has any potentially causative surgeries, infections, medications, or family history of the associated diseases.
Signs & Symptoms
Patients will not have symptoms to report aside from intermittent ocular redness and blurry vision until complications of corneal hypoesthesia results in severe vision loss. Hypoesthesia is associated with decreased blinking, increased tear mucus, and alacrima. Patients may have nocturnal lagophthalmos. Babies and young children will only blink to menacing gestures and may have self-inflicted corneal injuries.
Depending upon length and severity of the hypoesthesia, patients may develop exposure keratopathy, identifiable by punctate keratitis in the inferior cornea. This can become a larger epithelial defect associated with corneal infiltrates and ulcers.
Patients may develop neurotrophic keratitis, which presents with punctate keratitis, decreased TBUT, stromal haze, persistent epithelial defects, stromal opacification, stromal melting, corneal ulceration, and corneal perforation in later stages. Neurotrophic keratitis is also associated with edema and Descemet's folds.
Patients may not develop any ocular signs if appropriate blinking is maintained and injury is avoided.
Corneal esthesiometry is used to measure the tactile sensation of the cornea. Eye drops should not be instilled prior to esthesiometry as they can alter the measurement. Cotton tipped applicator is useful for qualitative, rough estimate of sensation, while a handheld esthesiometer (i.e. Cochet-Bonnet with contact, CRCERT-Belmonte without contact) is used for quantitative assessment. Patients with intractable recurrent corneal ulcers should have frequent corneal esthesiometry, especially if the patient does not complain of symptoms.
Fluorescein staining under slit lamp examination will reveal if keratopathy has ensued.
Patients diagnosed with corneal hypoesthesia should be instructed to pay close attention to new onset ocular redness or blurry vision in order to minimize complications from potential corneal ulcers, foreign bodies, and infections that they may not notice. These patients should also be closely monitored postoperatively following ocular surgery since they may not have enough pain signals to alert them to infections or other complications. If it has been determined that blink reflex is compromised, patients should be instructed to instill preservative-free lubricating eye drops regularly or have punctal occlusion (as long as there is no active ocular inflammation). Children with hypoesthesia must have lubricating eye drops instilled frequently until they learn to blink voluntarily. Temporary tarsorrhaphy or botulinum-induced ptosis may be indicated in children if eye drops are insufficient to maintain ocular lubrication. If nocturnal lagophthalmos is occurring, patients should tape their eyelids closed prior to sleeping.
If there is concern for progression to neurotrophic keratitis, medications (e.g. topical NSAIDs and beta-blockers) should be replaced with those that do not affect esthesia, or earlier surgical intervention for glaucoma should be considered. Topical antimicrobials, such as moxifloxacin, should be started prophylactically in instances of epithelial defects as well as vitamin C supplementation. Larger epithelial defects can be treated with autologous serum tears, bandage contact lens, and/or amniotic membrane placement. If there is active inflammation and neovascularization, a topical steroid such as prednisolone may be started, but this may prolong the healing process of any epithelial abnormalities. If hypoesthesia is not due to complete lack of corneal innervation (i.e. congenital) and keratopathy progresses to neurotrophic keratitis, cenegermin (i.e. Oxervate), a human recombinant nerve growth factor, can be started to improve corneal sensation. Cenegermin has been shown to resolve epithelial defects and corneal ulcers. Price must be considered when prescribing cenegermin. A newer technique called corneal neurotization, involving placement of a nerve graft, was recently developed to return sensation and trophic function to the cornea. It is a very complex surgery involving cornea, plastics, and neurosurgery that is done when there are zero nerves present in the cornea or when cenegermin is ineffective. It is important to note that treatment involving regeneration of corneal nerve fibers, such as with cenegermin or corneal neurotization, will initially result in pain due to recovery of sensation.
If persistent epithelial defects or ulceration has led to scarring in the visual axis, a superficial keratectomy could be performed to remove the scar tissue. Severe corneal thinning can be treated with tissue adhesives or glue, while corneal perforation requires amniotic membrane/corneal transplant.
Outlooks for patients with corneal hypoesthesia are good as long as decreased corneal sensitivity is recognized and monitored early. Without maintenance of blinking or intervention, such as with topical lubricants or surgery, corneal hypoesthesia can lead to keratopathy, permanent vision loss from corneal scarring, and need for transplantation, as well as amblyopia in children.
- Yang AY, Chow J, & Liu J. Corneal innervation and sensation: The eye and beyond. Yale J Biol Med. 2018;91(1):13-21.
- Dhillon VK, Elalfy MS, Al-Aqaba M, Gupta A, Basu S, Dua HS. Corneal hypoesthesia with normal sub-basal nerve density following surgery for trigeminal neuralgia. Acta Ophthalmol. 2015;94(1):e6-e10. doi:10.1111/aos.12697.
- Mastropasqua L, Lanzini M, Dua HS, et al. In vivo evaluation of corneal nerves and epithelial healing after treatment with recombinant nerve growth factor for neurotrophic keratopathy. Am J Ophthalmol. 2020;217:278-286. doi:10.1016/j.ajo.2020.04.036.
- Hwang DD-J, Lee S-J, Kim J-H, Lee S-M. The role of neuropeptides in pathogenesis of dry eye. J Clin Med. 2021;10(18):4248. doi:10.3390/jcm10184248.
- Hwang DD-J, Lee S-J, Kim J-H, Lee S-M. The role of neuropeptides in pathogenesis of dry eye. J Clin Med. 2021;10(18):4248. doi:10.3390/jcm10184248.
- Gao S, Li S, Liu L, et al. Early changes in ocular surface and tear inflammatory mediators after small-incision lenticule extraction and femtosecond laser-assisted laser in situ keratomileusis. PLoS ONE. 2014;9(9). doi:10.1371/journal.pone.0107370.
- Yamada M, Ogata M, Kawai M, & Mashima Y. Decreased substance P concentrations in tears from patients with corneal hypesthesia. Am J Ophthalmol. 2000;129(5):671-672. doi:10.1016/s0002-9394(00)00415-3.
- Yamada M, Ogata M, Kawai M, Mashima Y, & Nishida T. Substance P in human tears. Cornea. 2003;22(S1):S48-S54. doi:10.1097/00003226-200310001-00007.
- Fujishima H, Takeyama M, Takeuchi T, Saito I, & Tsubota K. Elevated levels of substance P in tears of patients with allergic conjunctivitis and vernal keratoconjunctivitis. Clin Exp Allergy. 1997;27(4):372-378. doi:10.1111/j.1365-2222.1997.tb00721.x.
- Campos M, Hertzog L, Garbus JJ, & McDonnell PJ. Corneal sensitivity after photorefractive keratectomy. Am J Ophthalmol. 1992;114(1):51-54. doi:10.1016/s0002-9394(14)77412-4.
- Rao GN, Ganti S, & Aquavella JV. Specular microscopy of corneal epithelium after epikeratophakia. Am J Ophthalmol. 1987;103(3):392-396. doi:10.1016/s0002-9394(14)77762-1.
- Martin XY & Safran AB. Corneal hypoesthesia. Surv Ophthalmol. 1988;33(1):28-40. doi:10.1016/0039-6257(88)90070-7.
- Achtsidis V, Tentolouris N, Theodoropoulou S, et al. Dry Eye in graves’ ophthalmopathy: Correlation with corneal hypoesthesia. Eur J Ophthalmol. 2013;23(4):473-479. doi:10.5301/ejo.5000259.
- Bourcier T, Acosta MC, Borderie V, et al. Decreased corneal sensitivity in patients with dry eye. Invest Ophthalmol Vis Sci. 2005;46(7):2341. doi:10.1167/iovs.04-1426.
- Rogell GD. Corneal hypesthesia and retinopathy in diabetes mellitus. J Ophthalmol. 1980;87(3):229-233. doi:10.1016/s0161-6420(80)35257-3.
- Hosotani H, Ohashi Y, Yamada M, & Tsubota K. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112. Am J Ophthalmol. 1995;119(3):288-294. doi:10.1016/s0002-9394(14)71169-9.
- Risarestat. Inxight Drugs, National Center for Advancing Translational Sciences, National Institutes of Health. https://drugs.ncats.io/drug/6I9DQB98QI.
- Nassaralla BA, McLeod SD, & Nassaralla JJ. Effect of myopic LASIK on human corneal sensitivity. J Ophthalmol. 2003;110(3):497-502. doi:10.1016/s0161-6420(02)01897-3.
- Pérez-Santonja JJ, Sakla HF, Cardona C, Chipont E, & Alió JL. Corneal sensitivity after photorefractive keratectomy and laser in situ keratomileusis for low myopia. Am J Ophthalmol. 1999;127(5):497-504. doi:10.1016/s0002-9394(98)00444-9.
- Li M, Zhou Z, Shen Y, Knorz MC, Gong L, & Zhou X. Comparison of corneal sensation between small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK for myopia. J Refract Surg. 2014;30(2):94-100. doi:10.3928/1081597x-20140120-04.
- Kumar RL, Koenig SB, & Covert DJ. Corneal sensation after Descemet stripping and automated endothelial keratoplasty. Cornea. 2010;29(1):13-18. doi:10.1097/ico.0b013e3181ac052b.
- Spadea L, Salvatore S, Paroli MP, Vingolo EM. Recovery of corneal sensitivity after collagen crosslinking with and without epithelial debridement in eyes with keratoconus. J Cataract Refract Surg. 2015;41(3):527-532. doi:10.1016/j.jcrs.2014.06.030.
- Dogru M, Karakaya H, Özçetin H, et al. Tear function and ocular surface changes in keratoconus. J Ophthalmol. 2003;110(6):1110-1118. doi:10.1016/s0161-6420(03)00261-6.
- Stuart A. New and emerging treatments for neurotrophic keratitis. EyeNet Mag. 2021 Dec:25-27. https://www.aao.org/eyenet/article/new-emerging-treatments-neurotrophic-keratitis
- Urrets-Zavalía JA, Maccio JP, Knoll EG, Cafaro T, Urrets-Zavalia EA, & Serra HM. Surface alterations, corneal hypoesthesia, and iris atrophy in patients with climatic droplet keratopathy. Cornea. 2007;26(7):800-804. doi:10.1097/ico.0b013e31806bef31.
- Reddy VC, Patel SV, Hodge DO, & Leavitt JA. Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease. Cornea. 2013;32(5):631-635. doi:10.1097/ico.0b013e3182574ade.
- Goldberg MF. Ophthalmologic studies of familial dysautonomia. Arch Ophthalmol. 1968;80(6):732. doi:10.1001/archopht.1968.00980050734011.
- Purcell JJ & Krachmer JH. Familial corneal hypesthesia. Arch Ophthalmol. 1979;97(5):872-874. doi:10.1001/archopht.1979.01020010430005.
- Keys CL. Familial trigeminal anesthesia. Arch Ophthalmol. 1990;108(12):1720. doi:10.1001/archopht.1990.01070140074032.
- Wong VA, Cline RA, Dubord PJ, & Rees M. Congenital trigeminal anesthesia in two siblings and their long-term follow-up. Am J Ophthalmol. 2000;129(1):96-98. doi:10.1016/s0002-9394(99)00290-1.
- Villanueva O, Atkinson DS, & Lambert SR. Trigeminal nerve hypoplasia and aplasia in children with goldenhar syndrome and corneal hypoesthesia. J Am Pediatr Ophthalmol Strab. 2005;9(2):202-204. doi:10.1016/j.jaapos.2004.12.016.
- Cheung A & Scott I. Ocular changes during pregnancy. EyeNet Mag. 2012;16(5):41-43. https://www.aao.org/eyenet/article/ocular-changes-during-pregnancy
- Liebman SD. Riley-day syndrome (familial dysautonomia). Arch Ophthalmol. 1957;58(2):188. doi:10.1001/archopht.1957.00940010200005.