Congenital Corneal Anesthesia

SURVEY OF OPHTHALMOLOGY

VOLUME 52  NUMBER 1  JANUARY–FEBRUARY 2007

MAJOR REVIEW

Congenital Corneal Anesthesia K. Ramaesh, FRCOphth,1 J. Stokes, FRCOphth,2 E. Henry, FRCS,2 G.N. Dutton, MD, FRCOphth,1 and B. Dhillon, FRCOphth2 1

Tennent Institute of Ophthalmology, Gartnaval General Hospital, Glasgow; and 2Princess Alexandra Eye Pavilion, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

Abstract. Congenital corneal anesthesia is a rare clinical entity that poses a diagnostic dilemma, particularly in the pediatric age group. The sensory deficit may be confined to the cornea, or extend to other divisions of the trigeminal nerve. The sensory deficit may occur as an isolated abnormality, as part of a complex neurological syndrome, or it may occur in association with multiple somatic abnormalities and congenital insensitivity to pain. This condition usually presents between the ages of 8 to 12 months. Poor vision, photophobia, conjunctival injection, and corneal ulceration in the absence of pain and distress in a child should alert the clinician to the possibility of anesthetic cornea. In the early stages of presentation, punctuate keratopathy is the main feature, which may progress to non-healing persistent corneal epithelial defects. This stage may progress to acute corneal lysis and perforation. In most patients, conservative approaches such as copious lubrication, prevention of selfharm and cautious use of bandage contact lenses are effective in preventing progressive corneal damage. Tarsorrhapy is effective in promoting epithelial healing and permanent lateral tarsorraphy may prevent further development of epithelial defects. Amniotic membrane graft may be considered in order to improve epithelial healing. Corneal grafts carry a poor prognosis. Accurate initial diagnosis, evaluation, and proper management are paramount to prevent visual loss due to long-term complications of corneal anesthesia. This review of the literature outlines the problems and approaches in diagnosis, evaluation, and management of this rare condition (Surv Ophthalmol 52:50--60, 2007. Ó 2007 Elsevier Inc. All rights reserved.) Key words.

congenital corneal anesthesia



corneal ulceration

I. Introduction



neurotrophic keratitis

delayed healing of established corneal epithelial injuries. Punctate keratitis and epithelial loss may also occur spontaneously in the presence of reduced corneal sensation and may progress to corneal perforation. They may also lead to the development of infectious keratitis. The lack of the afferent limb of corneal sensation causes the mucous component of the tear film to increase, causing it to become more viscous.118 More than 24% of eyes with corneal anesthesia following trigeminal root alcohol injection developed serious keratopathy, although the potential for neurotrophic keratitis can vary.26

Intact corneal sensation plays a vital role in maintaining the integrity of the corneal epithelium. Not only is it an important mechanism in preventing injury through the blink reflex and reflex tearing,8,76,80,112 it also aids healing of epithelial defects by promoting epithelial cell proliferation. Enhanced epithelial cell proliferation is thought to be mediated by neurotransmitters and nerve growth factors released from corneal nerve ending.19 Reduced or absent corneal sensation therefore renders the corneal surface vulnerable to occult injury and 50 Ó 2007 by Elsevier Inc. All rights reserved.

0039-6257/07/$--see front matter doi:10.1016/j.survophthal.2006.10.004

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Absent or reduced corneal sensation may be acquired or congenital in origin. Congenital lack of corneal sensation may be complete congenital corneal anesthesia (CCA) or partial to varying degrees (congenital corneal hypoesthesia).18,22,97,102 An epithelial defect in the setting of corneal anesthesia therefore requires prompt and aggressive therapy to prevent possible perforation. Management of congenital corneal anesthesia should place emphasis on the prevention of epithelial defects. The care of patients with CCA is life-long.

II. Molecular Basis of Neurotrophic Keratitis The search for the underlying mechanism began in 1954 when Sigelman reported that sectioning of trigeminal nerves in animal studies resulted in characteristic neurotrophic keratitis despite tarsorrhaphy.103 The mechanism underlying neurotrophic keratopathy is thought to be related to reduced levels of neuro-transmitters.11,19 Cavanagh and Colley reported that epithelial mitosis in the cornea is reduced by rising levels of intracellular cyclic adenosine monophosphate (cAMP) and is associated with rising intranuclear levels of cyclic guanosine monophosphate (cGMP).19 Adrenergic neurotransmitters and prostaglandin raise intracellular cAMP levels, thereby reducing epithelial mitosis; whereas acetylcholine (derived from the sensory nerve endings) increases intracellular cGMP and therefore promotes epithelial cell growth.19 Cavanagh and Colley therefore postulated that there is dual regulation of corneal epithelial proliferation linked to the sensory and sympathetic nerves and their neurotransmitters.19 In animal studies, epithelial defects in anaesthetic corneas are exacerbated by cervical sympathetic denervation.101 This observation supports Cavanagh and Colley’s theory of dual and antagonistic control of corneal epithelial regeneration. Furthermore, the absence of acetylcholine in dysautonomic eyes, which is associated with neurotropic keratopathy (Riley--Day syndrome), suggests that similar biochemical events may occur in congenital corneal anesthesia.79 Substance P is a neuropeptide present in corneal nerves, and has been found to stimulate DNA synthesis and corneal epithelial cell growth.42 Sensory denervation in animal models depletes substance P.42 These findings suggest that substance P may also play a role in corneal epithelial wound healing. Observations such as these may lead to the development of new medical therapies for neurotrophic keratopathy associated with CCA.

III. Clinical Classification of CCA Congenital corneal anesthesia is a rare clinical entity, which may be confined to the cornea only, or it may be associated with anesthesia in the distribution of the first and second divisions of the trigeminal nerve. Corneal sensory deficit is typically bilateral but unilateral cases have been reported.2,22,105,112 Concurrent involvement of the cornea and the conjunctiva is a universal finding.2,3,18,97 It may also be associated with other ocular, systemic, and neurological conditions.2,4,13,14,16,18,70,97 CCA typically occurs without any systemic anomalies. The sensory deficit is usually confined to the cornea and ophthalmic division of the trigeminal nerve.97 When the condition is associated with other systemic abnormalities there is a spectrum of trigeminal nerve deficits.2,40,49,74 Corneal sensory deficit is typically bilateral but unilateral cases have also been reported.2,22,105,112 Although more than 50 cases of congenital corneal anesthesia have been reported in the ophthalmic literature, there is no one generally accepted classification. Shorey et al classified CCA into two groups, CCA either occurring as an isolated anomaly or in association with systemic anomalies.102 Rosenberg introduced a neurological classification for congenital trigeminal anesthesia, which is also applicable to cases with ophthalmic involvement.97 A. ROSENBERG CLASSIFICATION

Rosenberg classified congenital trigeminal anesthesia (CTA) into three groups based on the presence and type of any associated abnormalities.97 1. Group 1 CTA occurs in isolation with no associated systemic or other neurological anomalies. Bilaterality is common in this group and unilateral cases seldom occur.3,94 The ophthalmic division of the trigeminal nerve is the most common division to be involved. Involvement of the second and third divisions of the trigeminal nerve has been occasionally reported. The absence of other neurological or mesoectodermal abnormalities is the hallmark of this group.97 2. Group 2 In this group corneal anesthesia is associated with ectodermal and/or mesenchymal disorders such as Goldenhar syndrome (OAVD-oculo-auriculo-vertebral dysplasia),8,14,16,80 Mo¨bius syndrome,49,74,92 VACTERL association (vertebral, anal, cardiovascular, tracheoesophageal, renal, and limb defects),24 MUCUS association (Mu¨llerian duct and renal

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aplasia, cervical somite dysplasia),32 Riley--Day syndrome (familial dysautonomia), and congenital insensitivity to pain.119 The sensory abnormality may be either unilateral8,14,112 or bilateral.80 This heterogeneous group has multiple aetiologies having in common injury early in embryogenesis. In the Goldenhar syndrome group unilaterality is common.8,14,16,80 In the non-Goldenhar syndrome group bilaterality is common.24,32,49,74,101 3. Group 3 The third group of corneal anesthesia occurs without somatic malformations, but with associated focal brain stem abnormalities.96 Rosenberg reported a 22-month-old child in this group presenting with ‘‘one-and-a-half syndrome’’ with unilateral absent corneal sensation. Ipsilaterally there was reduced response to pinprick in the distribution of first and second division of the trigeminal nerve. Bernhart (quoted by Rosenberg) described a case of numbness of the face with ipsilateral sixth and seventh nerve paralysis.96 The etiology in this case is thought to be due to focal neural dysgenesis secondary to a prenatal injury, possibly vascular in nature.114

RAMAESH ET AL TABLE 1

New Classification of Congenital Corneal Anesthesia 1. Isolated corneal involvement Familial a. Normal corneal nerves b. Reduced corneal nerves Isolated 2. Associated with other ocular conditions a. Hereditary fleck corneal dystrophy b. Contralateral anophthalmos and microsomia 3. Decreased sensation in the distribution of the trigeminal nerve with no other neurological and systemic features Familial Sporadic 4. Associated with neurological disorders a. Mo¨bius syndrome b. Riley--Day syndrome c. Generalized insensitivity to pain and muscle weakness d. Vertebral and other congenital defects e. Cerebellar ataxia, cogwheel ocular pursuits, anal atresia, and abnormal optokinetic nystagmus 5. Associated with somatic disorders a. MURCS (Mu¨llerian duct and renal aplasia, cervical somite dysplasia) b. Goldenhars syndrome (OAVD—oculo-auriculovertebral dysplasia) c. Hypo-hydrotic ectodermal dysplasia d. VACTERL association (vertebral, anal, cardiovascular, tracheoesophageal, renal, and limb defects) 6. Congenital insensitivity to pain

4. Shortcomings of Rosenberg Classification Birndorf reported a family of fleck corneal dystrophy associated with decreased corneal sensation. The authors argued these cases represent reduced corneal sensation as a part of fleck corneal dystrophy.13 Rosenberg’s classification does not allow for this association to be recognized. Furthermore, in Rosenberg’s classification of CTA, there is no category congenital insensitivity to pain, which is a well recognized cause of CCA. B. NEW WORKING CLASSIFICATIONS

We have developed a step-wise examination system that classifies the nature and extent of the disorder and seeks evidence of the total range of associated conditions. This approach is summarized in Table 1. In this approach after having identified corneal anesthesia of congenital origin, the next step of examination focuses upon the evaluation of the trigerminal nerve distribution and general sensation, neurological evaluation of cranial nerves and limbs. This will progress to assessment of developmental milestones and higher functions. This approach will allow identification of any systemic association that will enable a better approach to the problem.

1. Congenital Insensitivity to Pain Congenital insensitivity to pain is a well-defined entity.52,77,116,119 Insensitivity to any noxious stimulus causing pain and discomfort is a prominent feature of this hereditary sensory neuropathy that may cause cornea insensitivity.12,59,77,116,119 Infants and children with this disorder often bite their tongue, fingers, and lips.119 Wound healing is slow, and the injuries can be destructive in nature. Dyck et al have classified this conditions into five types: sensory radicular neuropathy, congenital sensory neuropathy, familial dysautonomia (Riley--Day syndrome), congenital insensitivity to pain with anhidrosis (CIPA), and congenital indifference to pain.31 The latter two types may present with self-inflicted corneal injury, keratitis, corneal ulcers, and scarring.102,108,116,119 In CIPA a mutation in the gene encoding for the Trk/NGF receptor has been described.57,58

III. Inheritance Although the inheritance of CCA is not well defined, a familial pattern has been documented. Most cases are non-familial and sporadic. Clarke

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et al described CCA in a family consistent with an autosomal dominant pattern of inheritance (no cutaneous involvement).22 An autosomal dominant pattern has also been described by Purcell.94 Birndorf13 has described a mother and son with hereditary fleck corneal dystrophy and corneal anesthesia. In a case report, Appenzeller reported two siblings with a syndrome of corneal opacity secondary to corneal anesthesia, generalized insensitivity to pain, and muscle weakness.4 No recognized teratogen or chromosomal abnormality has been attributed to the development of isolated CCA.

IV. Clinical Features and Evaluation CCA may be an isolated abnormality or part of a complex neurological syndrome with multiple somatic abnormalities. It may be asymptomatic and diagnosed only by clinical suspicion and careful examination. It may alternatively present as unilateral or bilateral keratitis or frank corneal ulceration refractory to treatment.8 This mode of presentation typically occurs before the age of 3 years, usually between 8 months and 12 months. Poor vision or photophobia with conjunctival injection in the absence of ocular irritation or pain should raise the suspicion of CCA.18 Keratitis, when it occurs, tends to be severe and affects the interpalpebral zone of the cornea.18 Ulceration of the fellow eye within 1 year was common; however, Anseth reported a case in which the cornea did not become ulcerated after 7 years of follow-up, although this may be attributed to prophylactic lubricant treatment.3 The first signs of CCA become manifest in infancy and early childhood, and in the very early stages, the diagnosis may be difficult to make.119 Recurrent episodes of redness and discharge in a child may mimic conjunctivitis;80 however, the diagnosis should be suspected in any child presenting with corneal erosions and keratitis without any apparent distress or pain, accompanied by reduced blinking and lacrimation.119 An impassive or absent reaction to eye drops can alert the clinician to the diagnosis. Accurately assessing the depth of corneal anesthesia with an esthesinometer is important as lower levels of sensation tend towards more severe corneal disease. Punctate keratitis may be asymptomatic. Pediatric and neurological examination is essential to rule out any associated systemic conditions. Corneal opacities, recurrent corneal erosions, and keratitis in childhood, combined with facial injury due to self-mutilation, may be the first sign of CCA.3 Trope et al reported a case in which it was unclear whether the eye scratching behavior was the primary

cause of corneal damage or whether it arose secondary to another corneal disturbance.108 Healed bilateral corneal scarring and collapse of the nasal septum from self-inflicted injury has also been reported.102 Despite the predisposition to serious complications, the clinical course can often be benign in a significant number of cases. Hewson found that only one-third of the patients developed keratitis in his series.55 Out of the six bilateral and seven unilateral cases only three had diffuse punctate erosions and responded promptly to patching.94 In one reported case of Goldenhar syndrome with CCA, the patient did not develop corneal ulceration during follow-up.112 A. EVALUATION OF THE CORNEAL SENSATION

Clarke et al observed a decrease in the density of corneal nerves in four cases of CCA. In a unilateral case of CCA reported by Clarke et al, a definitive asymmetry of corneal nerve density was observed between the affected and unaffected eye.22 Interestingly in some of the unaffected family members there was also a decrease in the density of corneal nerves.22 The distribution of the corneal nerves can be normal23,63,97 or absent on slit-lamp biomicroscopy,3 indicating that the presence of corneal nerves reveals nothing about their functional status. A cotton wisp can be used to assess corneal sensation. Alternatively, various esthesiometers are available for this purpose.9,23,29,68,82 A Cochet-Bonnet esthesiometer measures the corneal sensation objectively.23 In a cooperative patient, examination is carried out in the seated position fixing the gaze at an object, while the nylon thread of the aesthesiometer is applied perpendicularly to the cornea. An objective withdrawal or subjective response from the patient is the end point. The readings are expressed as the length of the nylon filament necessary to elicit a response. A range of 40 to 60 mm is considered normal.18,100 B. STAGES OF DISEASE PROGRESSION

Mackie divided the progression of the neurotrophic corneal changes into three stages.76 Interestingly, corneal changes in congenital corneal anesthesia also follow a similar course. 1. Stage I Stage I is characterized by geographic dry spot formation on the cornea without obvious keratopathy, punctate keratopathy, and blotting paper cornea where there is delayed uptake of fluorescein. The punctate keratopathy is probably an expression of epithelial cell death, perhaps in the absence of an

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RAMAESH ET AL

adequate replacement mechanism. This stage can become chronic, leading to epithelial hyperplasia, underlying stromal nebulae and corneal vascularization (Figs. 1 and 2). 2. Stage II Stage II is marked by acute epithelial detachment, often occurring in an area covered by the upper lid. The mechanism of epithelial loss is similar to that of recurrent corneal erosion, and it is aggravated by poor tear wetting of the corneal surface.19 If this stage persists, a punched-out oval or circular epithelial defect may develop, which is characteristic of neurotrophic keratitis (Fig. 3). This stage may progress to stage III. 3. Stage III

Fig. 2. Cornea of the same patient stained with fluorescein showing multiple epithelial defects.

Stage III is characterized by stromal lysis, which may lead to perforation of the cornea.

V. Differential Diagnosis of CCA Reduced corneal sensation particularly in children may result from neurotropic infections, such as herpes simplex keratritis67 or leprosy.61,67 Reduction in corneal sensitivity is a hallmark of herpetic keratitis. It is not limited to the vicinity of dendritic lesions, but usually spread over large corneal areas.72,73 Improvement of corneal sensitivity occasionally occurs following superficial lesions, but it depends on the severity of the lesions.72,73 Following herpetic stromal keratitis, practically no recovery occurs. Although uncommon, cerebellopontine angle tumors should be considered in the differential diagnosis.

Fig. 1. Slit-lamp bio microscopic photograph of a 29-yearold patient with congenital corneal anesthesia. Repeated epithelial break down has resulted in stromal scarring and corneal vascularisation.

VI. Management The key to successful management of an anesthetic cornea is fastidious care of the epithelial surface to prevent progression to more advanced stages of neurotrophic keratitis. The first line of management at early stages includes topical antibiotics, lubricants and artificial tears, and taping the lids. A. MEDICAL

1. Lubricants and Artificial Tears Epithelial disturbances, which are the hallmark of stage I, require simple topical lubrication or ointment, preferably preservative-free to prevent preservative-induced toxicity.22,63 Frequent application of preservative-free lubricants is effective in promoting the epithelial healing during the punctate

Fig. 3. Active corneal ulcer in another patient with bilateral congenital corneal anesthesia.

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keratitis stage.80 Lacrimal punctal occlusion may be considered as a long-term measure of tear preservation. 2. Bandage Contact Lenses and Protective Glasses Short-term use of bandage soft contact lenses in early stage 1 disease can be effective, particularly when the epithelium is desiccated but not exfoliated. They can promote epithelial migration, basement membrane regeneration, and epithelialstromal adhesion by protecting the ocular surface from the sweeping action of the upper lid.28 Collagen corneal bandage lenses have been reported to accelerate re-epithelialization and prevent relapse of recurrent erosions.93,117 However, longterm, continuous use of contact lenses in neurotrophic keratitis may predispose to bacterial keratitis, vascularization, and scarring.62,76 Protective glasses may prevent inadvertent trauma to the cornea and may offer protection from polluted environment the development of keratitis.3 3. Anti-inflammatory Agents The presence of inflammation in conjunction with a neurotrophic ulcer renders treatment more difficult. Corneal epithelial healing is inhibited by the inflammatory response in the absence of sensory innervation.19 a. Corticosteroids The use of topical corticosteroids, which are effective in reducing ocular surface inflammation, should be monitored carefully because of the risk of precipitating stromal lysis and perforation.78,115 b. Progestational Steroids In the setting of stromal thinning, progestational steroids may be indicated; although the antiinflammatory potency is less than corticosteroids, they have minimal effect on stromal repair and collagen synthesis.89 In addition, topical or systemic medroxyprogesterone (Provera) has shown potent anti-collagenolytic activity in experimental animal models.51,83 c. Non-steroidal Anti-inflammatory Agents Topical non-steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce inflammation at least as effectively as corticosteroids following routine cataract surgery.20,33--36 The effect of NSAIDS on stromal wound repair, collagen synthesis, collagenolytic activity, and inhibition of neovascularisation has not, however, been adequately

addressed.54 Although they may provide a potentially useful adjunctive treatment to corticosteroids in other clinical situations, the use of topical NSAIDS for neurotrophic ulceration with inflammation should be avoided due to their tendency to aggravate corneal hyposthesia.106 4. Anti-collagenolytic Agents a. Tetracyclines Topical and systemic tetracycline derivatives have also been recently shown to be efficacious in reducing collagenase activity.15,17,44--47,51 The effect is probably due to chelation of zinc at the active site of the enzyme15 and is independent of its antimicrobial properties.17,44 Tetracycline derivatives also inhibit polymorphonuclear leukocyte (PMN) activity.43 They can indirectly reduce ulceration by scavenging PMN-generated reactive oxygen compounds such as superoxide dismutase, thereby preventing it from converting inactive procollagenase to actively destructive collagenase.49 5. Biological Agents There has been recent interest in the application of biological agents to promote epithelial wound healing. These agents include epidermal growth factor (EGF),95,99,104 fibronectin, nerve growth factor,66 and autologous serum. EGF, nerve growth factor, and fibronectin are investigational medications, and as yet are unavailable for clinical use. a. Epidermal Growth Factor Epidermal growth factor (EGF) is a polypeptide originally isolated from mouse submaxillary glands that has been shown to experimentally enhance healing of corneal epithelial wounds.25,56,88,98 It stimulates the uptake of DNA, RNA, and protein precursors by corneal epithelium and promotes epithelial hyperplasia and migration of cells to cover the denuded surface.25,39,56,60,104,107 Epidermal growth factor has been reported to favorably influence epithelial migration in human studies of alkali injury.95,99,104 b. Nerve Growth Factor Recent report by Lambiase et al on the dramatic re-epithelialization of corneal neurotropic ulcers following topical application of nerve growth factor may prove to be an important advance in the application of growth factors for therapeutic purposes.66 Fourteen eyes of 12 patients treated with nerve growth factor began healing 2 to 14 days after the initiation of treatment and all the patients had complete healing of their corneal ulcers within 6

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weeks. Although this study is uncontrolled, the novel use of nerve growth factor in the management of neurotropic corneal ulcer is innovative and similar, more rigorous, studies will validate this study.66 In this study it was observed the epithelial attachment to the basement membrane is not enhanced, and a combination with an attachment factor such as fibronectin to facilitate migrationadhesion might be theoretically promising.87,104 c. Fibronectin Fibronectin is a multimeric glycoprotein present in the extracellular matrix that promotes cell--cell and cell--matrix adhesion, but has no effect on cell mitosis or migration.10,85,86 Fibronectin produced by epithelial cells and keratocytes is detectable within hours of corneal epithelial injury. It is distributed on the bare basement membrane ahead of and under the advancing epithelium where it persists until re-epithelialization is complete.7,41 Although few clinical trials report improvement in corneal epithelial healing, this agent has not been used to treat anesthetic cornea.50,84 d. Autologous Serum Fox et al used artificial tears containing autologous serum to achieve symptomatic and objective improvement in patients with severe kerato-conjunctivitis sicca who did not improve on commercially available artificial tears.38 More recently, autologous serum and plasma has been used effectively for the treatment of persistent epithelial defects in ocular surface diseases.111 Autologous serum is a valuable adjunct in the treatment of neurotropic corneal disorders. B. SURGICAL

1. Tarsorrhaphy Tarsorrhaphy has been found to be effective in promoting epithelial healing when conservative measures fail, and prophylactic lateral tarsorrhaphy can often prevent the development of epithelial defects.55,75 With regard to self-mutilation, the use of elbow splints allows rapid healing when combined with appropriate topical treatment. The addition of goggles may provide further protection for the eyes.108 2. Human Amniotic Membrane Transplantation The technique of amniotic membrane transplantation was first used in the early part of this century as a biological dressing to promote healing of skin wounds.27 Ocular use dates back to the 1940s when it was used for the plastic repair of the ocular surface

RAMAESH ET AL

in the treatment of chemical injuries to the eye.69 Kim and Tseng successfully reintroduced the technique to reconstruct ocular surface irregularities and currently the indication of AMT is ever increasing.64,65,71,90,91,110 Amniotic membrane serves as ‘‘transplanted basement membrane’’ facilitating migration of epithelial cells and reinforces epithelial cell adhesion.109 Amniotic membrane provides a potential substrate and various growth factors that promote epithelialization and enhance wound healing.30 Amniotic membrane dissolves over a period of time and the corneal stroma opacity is variable. A remarkable reduction in ocular inflammation was achieved with corneal epithelialization. Amniotic membrane transplantation can be considered as an alternative substrate to cover non-healing neurotrophic corneal ulcers.5,21,65,71 Single-layered21 and multi-layered65 amniotic membrane has been successfully grafted to encourage neurotrophic corneal ulcers. 3. Tissue Glue Small corneal perforations may initially be managed with tissue glue combined with a bandage contact lens.37,48,113 The function of cyanoacrylate glue is to provide tectonic support in addition to creating a barrier effect.6,37,48,81,113 Ultra structural studies of actively melting human corneas have shown stimulated polymorphonuclear leukocytes, phagocytosis, and degranulation, whereas in a quiet descemetocele the presence of polymorphs is negligible.37 Collagenases produced by polymorphs and degenerating corneal epithelium are positively implicated in corneal melting. These observations initiated the clinical usage of cyanoacrylate glue in the treatment of noninfectious corneal ulcers.37 The barrier effect of the glue inhibits access of the PMNs to the melting site and prevents further ulceration. The tectonic support to the stroma enhances neovascularization and repair. As the ulcer heals the glue loosens spontaneously, but may remain in place for many months.6,37,48,113 4. Penetrating Keratoplasty The issue of performing penetrating keratoplasty on anesthetic corneas for visual rehabilitation has not been addressed by any large series in the literature. Stromal neovascularization, which is often associated with neurotrophic corneas, combined with poor epithelial sensation add significant risks against graft survival.95 The success rates of penetrating keratoplasty in anesthetic corneas is low.95 Scarring of the graft appears to be a rule rather than an exception. Anseth reported a case of lamellar keratoplasty failing due recurrent scarring.3

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One of the two patients reported by Clarke had two penetrating keratoplasties and another had lamellar keratoplasty.22 There is an increased risk of rejection and failure secondary to inflammation, stromal neovascularisation, poor wound healing, and persistent epithelial sloughing.3,22 Careful maintenance of the ocular surface and partial tarsorrhaphy are vital to success in these cases. Long-term contact lens wear combined with chronic use of antibiotics and steroids increase the risk of graft infection. 5. Other Techniques Cervical sympathectomy may help to protect the anesthetic cornea.53 In the past, this procedure was performed to manage acquired neurotrophic keratitis but has been abandoned due to high mortality and morbidity.1 Application of this technique to manage congenital corneal anesthesia has been not reported.

IX. Conclusion Improvement in vision and stable corneal epithelial integrity can be established for long periods of time once healing has been achieved.3,18,55,105 The remission, for reasons that are not clear, will persist even after the discontinuation of the therapeutic contact lenses, topical medications, and tarsorrhaphy. This could be due to the development of better adhesion of the epithelium to the underlying basement membrane. In summary, CCA may be an isolated abnormality, or part of a complex of neurological or somatic abnormalities. Although the sensory loss is present from birth, the typical age of onset of symptoms and signs is between 8 and 12 months. Rarely, cases may remain asymptomatic. When associated with a more generalized neurological or somatic disorder, there is usually no diagnostic difficulty; however, in the case of suspected isolated CCA, careful pediatric and neurological assessment, combined with detailed neuroimaging (MRI), is mandatory to exclude co-existing pathology. Treatment is lifelong and can be fraught with pitfalls, particularly if there is a need to resort to surgery on the cornea. With meticulous care and attention to the ocular surface and with a wellmotivated patient, the long-term visual prognosis can remain good.

X. Method of Literature Search MEDLINE was searched (1966--2005) with key words congenital, cornea, corneal, anesthesia, anesthesia and neurotophic. Relevant papers quoted in published literature were also reviewed.

References 1. Adams GG, Cullen JF: Neuroparalytic keratitis and the effect of cervical sympathectomy following operative procedures for trigeminal neuralgia. Scott Med J 32:86--8, 1987 2. Aleksic S, Budzilovich G, Reuben R, et al: Congenital trigeminal neuropathy in oculoauriculovertebral dysplasiahemifacial microsomia (Goldenhar-Gorlin syndrome). J Neurol Neurosurg Psychiatry 38:1033--5, 1975 3. Anseth A: Congenital bilateral corneal anesthesia. Acta Ophthalmol (Copenh) 46:909--11, 1968 4. Appenzeller O, Kornfeld M, Snyder R: Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children. Arch Neurol 33:733--8, 1976 5. Azuara-Blanco A, Pillai CT, Dua HS: Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol 83:399--402, 1999 6. Bansal DC, Sandhu PS, Khosla AD: Clinical evaluation of cyanoacrylate glue in corneal perforations. Indian J Ophthalmol 35:197--9, 1987 7. Barlati S, Marchina E, Quaranta CA, et al: Analysis of fibronectin, plasminogen activators and plasminogen in tear fluid as markers of corneal damage and repair. Exp Eye Res 51:1--9, 1990 8. Baum JL, Feingold M: Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 75:250--7, 1973 9. Belmonte C, Acosta MC, Schmelz M, et al: Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer. Invest Ophthalmol Vis Sci 40: 513--9, 1999 10. Berman M, Manseau E, Law M, et al: Ulceration is correlated with degradation of fibrin and fibronectin at the corneal surface. Invest Ophthalmol Vis Sci 24:1358--66, 1983 11. Berman MB, Cavanagh HD, Gage J: Regulation of collagenase activity in the ulcerating cornea by cyclicAMP. Exp Eye Res 22:209--18, 1976 12. Biedner B, Dagan M, Gedalia A, et al: Congenital insensitivity to pain with neuroparalytic keratitis. Ann Ophthalmol 22:312--3, 1990 13. Birndorf LA, Ginsberg SP: Hereditary fleck dystrophy associated with decreased corneal sensitivity. Am J Ophthalmol 73:670--2, 1972 14. Bowen DI, Collum LM, Rees DO: Clinical aspects of oculoauriculo-vertebral dysplasia. Br J Ophthalmol 55:145--54, 1971 15. Brion M, Lambs L, Berthon G: Metal ion-tetracycline interactions in biological fluids. Part 5. Formation of zinc complexes with tetracycline and some of its derivatives and assessment of their biological significance. Agents Actions 17:229--42, 1985 16. Budden SS, Robinson GC: Oculoauricular vertebral dysplasia. Its association with sensorineural deafness and other abnormalities. Am J Dis Child 125:431--3, 1973 17. Burns FR, Stack MS, Gray RD, et al: Inhibition of purified collagenase from alkali-burned rabbit corneas. Invest Ophthalmol Vis Sci 30:1569--75, 1989 18. Carpel EF: Congenital corneal anesthesia. Am J Ophthalmol 85:357--9, 1978 19. Cavanagh HD, Colley AM: The molecular basis of neurotrophic keratitis. Acta Ophthalmol 192(Suppl):115--34, 1989 20. Chang MS, Chiou GC: Prevention of lens protein-induced ocular inflammation with cyclooxygenase and lipoxygenase inhibitors. J Ocul Pharmacol 5:353--60, 1989 21. Chen HJ, Pires RT, Tseng SC: Amniotic membrane transplantation for severe neurotrophic corneal ulcers. Br J Ophthalmol 84:826--33, 2000 22. Clarke MP, Sullivan TJ, Kobayashi J, et al: Familial congenital corneal anaesthesia. Aust NZ J Ophthalmol 20:207--10, 1992 23. Cochet P, Bonnet R: Lesthesiometrie corneenne: Realisation et interet pratique. Bull Soc Ophtalmol Fr 6:541, 1961

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V. Differential diagnosis of CCA VI. Management A. Medical

The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Dr K. Ramaesh, Tennent Institute of Ophthalmology, Gartnaval General Hospital, 1053 Great Western Road, Glasgow, G12 0YN, UK.

Outline I. Introduction II. Molecular basis of neurotrophic keratitis III. Clinical classification of CCA A. Rosenberg classification 1. 2. 3. 4.

Group 1 Group 2 Group 3 Shortcomings of Rosenberg classification

1. Lubricants and artificial tears 2. Bandage contact lenses and protective glasses 3. Anti-inflammatory agents a. Corticosteroids b. Progestational steroids c. Non-steroidal anti-inflammatory agents 4. Anti-collagenolytic agents a. Tetracyclines 5. Biological agents a. b. c. d.

Epidermal growth factor Nerve growth factor Fibronectin Autologous serum

B. New working classifications 1. Congenital insensitivity to pain III. Inheritance IV. Clinical features and evaluation A. Evaluation of the corneal sensation B. Stages of disease progression 1. Stage I 2. Stage II 3. Stage III

B. Surgical 1. Tarsorrhaphy 2. Human amniotic membrane transplantation 3. Tissue glue 4. Penetrating keratoplasty 5. Other techniques IX. Conclusion X. Method of literature search