Corneal dystrophies are a group of inherited corneal diseases that are typically bilateral, symmetric, slowly progressive, and without relationship to environmental or systemic factors.1 The classic classification is on the basis of the corneal layer involved. In this report, a case of Meesmann epithelial dystrophy with late onset of symptoms and first diagnosis in a mature adult is described. The diagnosis and management of Meesmann dystrophy are discussed.
A 43-year-old white women presented for the first time to our clinic with complaints of slight redness, foreign body sensation, light sensitivity, and slightly reduced vision in the right eye for the past year. The symptoms were worse on awakening and had gradually increased in intensity over the past 12 months. By the time she was seen in our clinic, she was acutely light sensitive, having to wear sunglasses indoors. She had consulted several practitioners during that time and was prescribed at various times topical dexamethasone 0.1%, prednisolone 0.5%, and acyclovir 3%, none of which successfully relieved her symptoms. She was currently using topical lubricants as required (Refresh Tears, Allergan, Irvine, CA), which provided limited relief. She had recently been diagnosed with depression and prescribed citalopram 20 mg qd. She had never worn spectacles. Her previous ocular history was unremarkable, however, she had never had her eyes examined until the onset of symptoms in the last year. Her mother in the United Kingdom had suffered from an unusual eye condition requiring regular visits to an ocular specialist but as she was now deceased, no further information was available.
Visual acuity was measured at 6/6 “slow” right eye and 6/6−2 left eye. Pupils were equal, round, reactive to light, and accommodation in both eyes. Slit lamp examination of the right eye revealed moderate nasal and temporal limbal redness grade 2. Numerous (>100) small intraepithelial cysts were noted to be scattered throughout the entire cornea but denser centrally. No stromal involvement and no infiltrates were observed (see Video, Supplemental Digital Content 1, which provides a composite view of the cysts and underlying normal stroma, http://links.lww.com/OPX/A10). The epithelial surface appeared roughened and negative staining was observed overlying some of the epithelial cysts. The anterior chamber was quiet. Fig. 1 illustrates the ocular signs of the right eye on slit lamp examination. The left conjunctiva was normal and white. A smaller number of intraepithelial cysts were detected in the midperiphery and periphery of the inferior left cornea. The epithelium was clear centrally and no corneal staining was visible. As in the right eye, no stromal involvement or infiltrates were noted, and the anterior chamber was quiet.
Confocal microscopy (Confoscan 2, Fortune Technologies, Virgona, Italy) was performed on both corneas and revealed dense brightly reflective structures of about 15 μm in size in the basal epithelium (Fig. 2). The subject’s 7-year-old daughter was examined and no corneal abnormalities could be detected. On the basis of corneal appearance and symptoms, Meesmann dystrophy was diagnosed.
The differential diagnosis for Meesmann dystrophy includes epithelial basement membrane dystrophy (EBMD), recurrent corneal erosion (RCE), Thygeson’s keratitis, adenoviral keratoconjunctivitis, herpes simplex (HSV) keratitis, bullous kerapathy in Fuchs disease, and microcystic edema. EBMD (Cogan microcystic or map-dot-fingerprint dystrophy) may be confused with Meesmann dystrophy as epithelial microcysts are one of the possible corneal signs of EBMD and typical age of onset is early adulthood. EBMD, however, will often show more than one type of corneal lesions including dot-like opacities, subepithelial map-like patterns, or whorled fingerprint-like lines in one or both eyes.2 None of these patterns were present in this case. The epithelial microcysts tend to be localized in EBMD. A history of RCEs and/or previous episodes of acute pain are also more highly suggestive of EBMD. RCE occurs not only as a result of EBMD but also when an abnormally weak attachment between the basal cells and the basement membrane of the epithelium is present.2 RCE forms part of the differential diagnosis in this case as mild RCE may present without a frank epithelial defect and with epithelial microcysts only. Although the severe photophobia and the increased symptoms on awakening reported in this case can be suggestive of RCE, a prior history of trauma, which may have given rise to the recurrent erosions, was not present.
Thygeson’s keratitis, an idiopathic chronic superficial punctate keratitis, commonly affects young adults and is characterized by recurrent attacks of irritation, photophobia, and tearing. The epithelial lesions in Thygeson’s, however, are coarse, distinct, and granular and do not have the vesicular cystic appearance associated with Meesmann.2 A history of exacerbations followed by complete remission of symptoms is also more characteristic of Thygeson’s.3
The early stage keratitis associated with adenoviral keratoconjunctivitis could also be mistaken for Meesmann dystrophy as it initially presents with bilateral tearing, redness, foreign body sensation, photophobia, lid swelling, and reduced vision associated with punctate epithelial keratitis.2,3 Adenoviral keratoconjunctivitis subsequently causes multiple subepithelial infiltrates that are not characteristic of Meesmann disease. A history of recent upper respiratory tract infection, which usually precedes adenoviral disease, was not present here. HSV keratitis is often classified into several subtypes based on clinical presentation. The first of these subtypes, infectious epithelial keratitis typically presents with symptoms of mild discomfort, watering, and blurred vision and in its early stages, small raised corneal vesicles may be similar in appearance to Meesmann dystrophy.4,5 Such vesicles will, however, coalesce and form the typical dendritic and geographic ulcers within hours or days of first examination, which did not occur in this case. The bulk of the intraepithelial cysts in Meesmann dystrophy are not raised and will typically cover a larger area of cornea than HSV vesicles.
Bullous keratopathy in late stage Fuchs endothelial dystrophy may present similar symptoms to Meesmann dystrophy of pain and discomfort worse on awakening and the presence of persistent microcysts in the epithelium. Although our patient reported worsening of symptoms on waking, there were no signs of stromal swelling or endothelial gutatta. Other causes of microcystic edema such as contact lens-induced hypoxia6 or toxic edema must also be excluded. There was no history of previous contact lens wear or toxic exposure in this case.
A therapeutic contact lens was prescribed for the relief of symptoms (Fig. 3). On the basis of the rationale that the highest possible oxygen transmissibility should be provided, a silicone hydrogel contact lens was fitted in the right eye: Purevision (Bausch & Lomb, Rochester, NY) +0.50 DS, 8.70 mm. An extended wear schedule was prescribed to provide ongoing symptomatic relief. This provided immediate and sustained relief of symptoms. A smoother epithelial surface was noted at the 1-week follow-up visit as evidenced by a reduction in the levels of negative staining observed.
At the 2-month follow-up visit, subepithelial infiltrates were noted in both corneas and lid roughness was substantially increased in the right palpebral conjunctiva. A viral corneal infection was suspected. The patient reported also having recently suffered from a miscarriage. Contact lens wear was temporarily discontinued for 1 month until resolution of the infiltrates was noted. Lubrication therapy was commenced. Preservative free unit dose carmellose sodium containing lubricating eyedrops were prescribed for use as required (Cellufresh, Allergan, Irvine, CA), and sorbitol preserved carbomer 980 lubricating gel was prescribed at bedtime (Viscotears liquid gel, CIBAVision, Atlanta, GA).
After 1 month, a softer modulus contact lens was fitted: CibaSoft (CIBAVision, Atlanta, GA) +0.50 DS, 8.6 mm with an aqua #2 tint (tinted pupil) in the right eye. With a nominal Dk/t of 10, this product has much lower oxygen transmissibility than the PureVision (Dk/t of 110). A tinted contact lens was prescribed to provide further relief from the ongoing photophobia. A daily wear schedule was prescribed with Viscotears liquid gel (CIBA Vision) nocte as required. A peroxide-based care system (AOSept, CIBAVision) was recommended for the disinfection of the contact lenses on nightly removal. Over the next 6 month, management included a combination of lubrication therapy: Cellufresh as required during the day and Viscotears nocte as required and intermittent contact lens wear during periods of exacerbation of the symptoms. The corneal appearance remained identical during that time with no progression of the epithelial dystrophy.
The patient was instructed to continue self-managing the condition on the basis of her symptoms, and a regular 6-month follow-up was scheduled. As high-oxygen permeability silicone hydrogel contact lenses with lower modulus become available, these may present a useful option for this patient.
Meesmann dystrophy was first described by Meesmann in 1938.7 Symptoms commonly include ocular irritation or foreign body sensation,8–10 tearing,8,10 glare and/or photophobia,8–10 reduced vision,8–10 conjunctival injection,8 and blepharospasm.11 The intensity of symptoms reported in the same families varies from asymptomatic to extreme photophobia and symptoms may be disproportionate to the corneal signs.8,9 Rupture of the cysts may cause the onset of symptoms,11 however, severe pain is infrequently reported.9,10,12 This case provides a good example of such disconnect between the corneal appearance and the reported symptoms. We speculate that rupture of cysts and exposure of corneal nerve endings was the underlying mechanism for the severe pain and photophobia reported by our patient. However, the levels of negative or positive staining observed during the visits remained very low. It is possible that these cysts ruptured on waking and had recovered by the time the patient was seen in our office.
Corneal changes include microcystic epithelial opacities, typically (up to 85% of cases) involving the entire epithelium as far as the limbus.8 Less often, specific regions of the epithelium are affected such as the upper third,8 the peripheral cornea,8,9 or a central diseased zone surrounded by a ring of clear epithelium and peripheral microcystic epithelium.8 Irregularly shaped areas of clear epithelium have also been described.10 The demarcation between diseased and normal epithelium is sharp.8 The intraepithelial cysts are typically rounded but can be more irregular8 and are roughly uniform in size.2 The epithelial microcysts are best observed on retroillumination. The disease seems to be bilateral, although a single case of unilateral Meesmann dystrophy has been reported.13 The corneal stroma is typically clear, although slight subepithelial opacities, corneal scarring, and vortex-like opacities have occasionally been observed.8,14
Age of onset of the intraepithelial cysts seems to be early childhood with cases described in infants as young as a few months old.2,8,10 It may therefore seem surprising that an earlier diagnosis was not suggested in this case, however, as the patient was emmetropic and had been asymptomatic up until a year ago, she had not had regular ocular examinations. Delayed or late onset cases have also been described,15 and this may be the case here. Meesmann dystrophy is generally described as non-progressive8 but significant worsening of symptoms with age as in this have been reported.10,11 It is possible that more cysts rupture with time leading to increased symptoms or alternatively, the corneal sensitivity to the rupturing of the cysts may change over time.
Meesmann dystrophy is geographically widespread with reports of cases in Germany,7,8,10 the United States,10,16 the Netherlands, Austria, Switzerland, France, Denmark, the UK (Northern Ireland),11,17 Saudi Arabia,15 Taiwan,12 and Japan.18 Recent advances in genetic techniques have allowed the molecular basis of Meesmann corneal dystrophy to be elucidated. Meesmann dystrophy has been ascribed to mutations in the cytokeratin 12 (K12) and/or the cytokeratin 3 (K3) genes on chromosomes 17q and 12q, respectively (OMIM 12210019).17 Several different mutations10–12,16–18 have been shown to occur in the two responsible genes suggesting that Meesmann is possibly more widespread than originally described. Once mutation has occurred, transmission is autosomal dominant with either incomplete penetrance and/or delayed onset of phenotypic expression.15,19 One study suggested that mutations in the K12 gene may be associated with a more severe phenotype of Meesmann dystrophy than K3 mutations.18 In this case, the familial history was difficult to ascertain. The only family member available for examination was her 7-year-old daughter, who was unaffected.
The K12 and K3 cornea specific keratins form the intermediate filament cytoskeleton of corneal epithelial cells. Transgenic mice studies have confirmed the role of K12 in corneal epithelial fragility.20 Ultrastructurally, mutations in these genes translate in a highly disorganized epithelium with thickening of the epithelium and its basement membrane2,11,21,22 and the presence of surface intraepithelial cysts.2,8,11,22 Marked vacuolization and dense periodic acid Schiff positive intracytoplasmic inclusions21 were observed in the deeper epithelial layers.11 High magnification in vivo descriptions of Meesmann dystrophy such as can be obtained with the confocal microscope are rare.14 The confocal microscopy appearance of Meesmann dystrophy described in the single case series published to date differs significantly from that shown in Fig. 2 in this report with surprisingly large hyporeflective lesions described as ranging in size from 5 to 145 μm.14 Interestingly, the diagnosis of Meesmann dystrophy in this case series was subsequently questioned.23 A previous report seems more consistent with our confocal microscopy investigation, describing hyperreflective cystic lesions of 10 to 50 μm.24 These findings are consistent with the appearance described in ultrastructural studies.
Intrafamilial variation between individuals is common both in clinical appearance and symptoms reported, suggesting some environmental influences or interference from other disease-modifying genes.11,16 Individual anatomical variations in the sub-basal nerve plexus and/or limbal stem cells may underpin some of these differences and ongoing examination of such cases with in vivo confocal microscopy may provide further clues.
This case presented with unusually intense symptoms, which complicated the diagnosis and management of the condition. The difficulty in correctly diagnosing this dystrophy is evidenced by the range of treatments (i.e., topical dexamethasone, prednisolone, and acyclovir) prescribed in the 12 month before presentation.
Management of Meesmann dystrophy typically requires minimal intervention with treatment other than lubrication not being normally required.2 Although rare, there are reports of cases being severally handicapped by Meesmann dystrophy. A 40-year-old Danish women reported photophobia so severe that the windows of her family home were permanently masked with black plastic sheets.8 This case was managed with therapeutic contact lenses that allowed her to return to work. Her 2-year-old daughter also suffered from extreme photophobia and constant tearing and was reportedly unable to leave home without wearing a hat and sunglasses.8 It is interesting to note that there are reports in the literature of Meesmann dystrophy cases being intolerant to contact lens wear because of epithelial fragility.17,19 Although these abnormal corneas may be more vulnerable to traumatic injuries and infections, therapeutic contact lenses can be an excellent treatment option in more symptomatic cases as demonstrated here.
The use of a topical cycloplegic such as 1% cyclopentolate or 2% homatropine for the relief of symptoms in severely photophobic cases remains a treatment option. Hypertonic agents (e.g., hypertonic saline) could also be considered in cases such as this one where exacerbation of symptoms on waking is reported. Hypertonic agents may help stabilize the diseased epithelium potentially affected by the physiological overnight corneal edema.
Surgical interventions typically used for recalcitrant RCE such as manual epithelial debridement, excimer laser phototherapeutic keratectomy, and lamellar and penetrating keratoplasty should be considered in severely debilitating cases in the hope of stabilizing the corneal epithelial and associated symptoms. The risk of recurrence with all surgical procedures is high as the corneal stem cells retain the mutated genes and the chances of remaining disease free for longer than 1 month are low.11,13,22 Autologous stem cell transplantation appeared successful in the short term for the single unilateral Meesmann dystrophy case.13 Anterior stromal puncture is not recommended in Meesmann dystrophy cases because the extent of the area of the epithelium affected by the disease is large and the process could result in widespread scarring.
We thank Dr. Con Petsoglou for referring the case.
School of Optometry and Vision Science
The University of New South Wales
Sydney, NSW 2052
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