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Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 22

Corneal perforation associated with ocular rosacea and neurotrophic keratopathy

Tecnologico De Monterrey, School of Medicine and Health Sciences, Institute of Ophthalmology and Visual Sciences, Monterrey, México

Date of Submission29-May-2020
Date of Decision11-Jun-2020
Date of Acceptance04-Jul-2020
Date of Web Publication19-Aug-2020

Correspondence Address:
Dr. Julio C Hernandez-Camarena
Institute of Ophthalmology and Visual Sciences, Hospital Zambrano Hellion TecSalud, Batallón De San Patricio 112, 66278, San Pedro Garza García, NL
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/PAJO.PAJO_24_20

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Rosacea is a dermatologic condition that affects the midfacial region. This chronic inflammatory disease can present with ocular manifestations distinguished by meibomian gland dysfunction, dry eye, and in severe cases, corneal ulceration and perforation. Neurotrophic keratopathy is an ocular condition with a reduced or absent corneal sensation associated with a corneal epitheliopathy. We present a 68-year-old man with both ocular rosacea and neurotrophic keratopathy who developed a corneal perforation. It was managed successfully with a tectonic keratoplasty in addition to topical steroids, lubrication, and oral tetracyclines. The perforation is explained by the superposition of both pathologies which lead to dry eye syndrome, along with chronic inflammation of the ocular surface. The effective follow-up and treatment of any epithelial defect in these patients is a major factor for corneal melting and perforation prevention.

Keywords: Corneal hypoesthesia, neurotrophic keratopathy, ocular rosacea, ocular surface disease, persistent epithelial defect, tectonic keratoplasty

How to cite this article:
Lopez-Martinez M, Gomez-Elizondo DE, Morales-Mancillas NR, Valdez-Garcia JE, Hernandez-Camarena JC. Corneal perforation associated with ocular rosacea and neurotrophic keratopathy. Pan Am J Ophthalmol 2020;2:22

How to cite this URL:
Lopez-Martinez M, Gomez-Elizondo DE, Morales-Mancillas NR, Valdez-Garcia JE, Hernandez-Camarena JC. Corneal perforation associated with ocular rosacea and neurotrophic keratopathy. Pan Am J Ophthalmol [serial online] 2020 [cited 2022 Oct 4];2:22. Available from: https://www.thepajo.org/text.asp?2020/2/1/22/292652

  Introduction Top

Rosacea is a chronic inflammatory disease that primarily affects the skin and eyes. Skin findings are characterized by flushing, erythema, telangiectasias, papules, and pustules.[1] Ocular manifestations range from mild palpebral affection ( Meibomian gland More Details dysfunction, telangiectasia, and erythema of the lid margin) to severe ocular surface chronic inflammation that may trigger structural changes in the cornea which can lead to thinning and corneal perforation.[2]

Neurotrophic keratopathy is a degenerative disease caused by partial or total loss of the sensitive corneal nerve fibers characterized by epithelial defects and wound healing alterations that, without treatment, can lead to corneal ulceration and perforation.[3] The most common cause is herpes simplex virus infection, followed by chemical, physical, and iatrogenic lesions (ocular and cerebral surgery). Other described etiologies are systemic diseases such as multiple sclerosis and diabetes mellitus.[4] The diagnosis requires a complete clinical history, emphasizing the risk factors for trigeminal nerve damage. The ophthalmologic evaluation must focus on assessing corneal sensitivity.

  Case Report Top

A 68-year-old male with long-term type II diabetes mellitus medically treated with metformin presented with complaints of foreign body sensation and right red eye. Uncorrected visual acuity (UCVA) was counting fingers at 1 m in the right eye (OD) and 20/150 in the left eye (OS). Slit-lamp examination revealed severe conjunctival hyperemia, corneal opacity with a 2-mm circular paracentral epithelial defect, and lipoid arcus in OD [Figure 1]. The OS had a central corneal opacity that extended to the stroma. Both eyes showed meibomian gland dysfunction, thickened palpebral margins, and telangiectasias [Figure 2]. Cochet-Bonnet esthesiometer was found to be reduced (OD [mm]: central 35, temporal 45, nasal 40, superior 40, inferior 40; OS [mm]: central 35, temporal 45, nasal 45, superior 40, inferior 40). Noninvasive tear breakup time (niTBUT) (Keratograph 5M, OCULUS Optikgeräte GmbH) was 5.2 s and 4.9 s in OD and OS, respectively. Ocular surface disease index (OSDI) score (62.5, 12 answered questions) and SICCA ocular staining score using lissamine green/fluorescein stains (score = 8, both eyes) were performed. Ultrasonic pachymetry showed corneal thinning in both eyes (central corneal thickness 450 μm and 446 μm in OD and OS, respectively). Posterior blepharitis, ocular rosacea, and bilateral corneal opacity were diagnosed. The patient started treatment with preservative-free 0.15% hyaluronic acid eye drops hourly in OD and four times a day in OS, oral doxycycline 100 mg/day, and eyelid hygiene measures. The paracentral epithelial defect in OD had a complete resolution after the 2nd day of treatment.
Figure 1: Slit-lamp photograph showing the right eye with corneal opacity and a circular paracentral epithelial defect

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Figure 2: Slit-lamp photograph showing the meibomian gland dysfunction, thickened palpebral margins, and telangiectasias

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Two years later, the patient returned to our service with a history of bilateral cataract surgery performed in other institution. He complained of photophobia in OD. The patient had a UCVA of counting fingers at 1 m in OD and 20/70 in OS. Slit-lamp examination revealed bilateral pseudophakia, pupils round and reactive to light. The right eye examination showed ciliary injection and conjunctival hyperemia, stromal corneal opacity, 3 mm × 4 mm paracentral descemetocele, and a corneal perforation measuring 1 mm × 1 mm [Figure 3]a. The left eye examination revealed the corneal opacity previously described. The assessment in this visit was as follows: corneal esthesiometry OS (mm) central 40, temporal 40, nasal 45, superior 40, inferior 40, niTBUT (4.7 s), OSDI score (68.2, 11 answered questions), and SICCA ocular staining score 6. This time, the patient was managed with 0.5% moxifloxacin in OD and oral doxycycline 100 mg/day. Systemic workup and laboratory tests including rheumatoid factor, cyclic citrullinated peptide antibodies, antinuclear antibodies, and C-reactive protein were within normal limits. The patient also had an extensive clinical and physical assessment with a neurologist and an endocrinologist, who did not report any sign or symptom associated with peripheral neuropathy or any other neurological abnormality. Subsequently, a tectonic keratoplasty using a sclerocorneal graft was performed without complications [Figure 3]b. The topical treatment was continued using 0.5% moxifloxacin four times a day, 3% trehalose four times a day, and loteprednol etabonate 0.5% in dose reduction. The 7-day postoperative evaluation demonstrated mild conjunctival hyperemia, sclerocorneal graft in situ, negative Seidel sign, adequate anterior chamber depth, and intraocular pressure of 13 mmHg. The remainder of the examination was unremarkable.
Figure 3: (a) Slit-lamp photograph of the right eye with paracentral descemetocele and corneal perforation measuring 1 mm × 1 mm. (b) Slit-lamp photograph of the right eye with the sclerocorneal graft in situ with 8 interrupted 10-0 nylon sutures

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  Discussion Top

Neurotrophic keratopathy is a degenerative disease caused by partial or total loss of the sensitive corneal nerve fibers. Any process damaging the trigeminal nerve plexus is a risk factor for this pathology.[3] According to the Mackie classification, there are three stages. Stage 1 is distinguished by corneal punctate keratopathy and reduced tear film rupture time. Stage 2 is characterized by the presence of a persistent epithelial defect. Stage 3 involves stromal damage with frank ulceration and perforation.[5]

Rosacea is a chronic disease characterized by endothelial vascular dysfunction, edema, and skin inflammation. The main ophthalmologic findings are meibomian gland dysfunction, blepharitis, telangiectasias, superficial punctate keratopathy, and corneal infiltrates or ulcerations.[2]

The initial pachymetry of our patient demonstrated reduced corneal thickness previous to the ulceration. Yildrim et al. reported that central corneal thickness is significantly reduced in ocular rosacea patients compared to controls. This could be explained by the increased levels of inflammatory cytokines detected in the tear fluid of patients with ocular rosacea. Those molecules cleave the epithelial basal membrane and are responsible for the stromal melting, especially the matrix metalloproteinase-8 (MMP-8). This MMP has collagenase activity against collagen type I, the most abundant type in the human cornea, and type III. Besides the reduced tear secretion and blink rate caused by neurotrophic keratopathy, the contact time between MMP-8 and the ocular surface was long enough to allow the epithelial defect to introduce more proteases into the stroma and finally cause melting.[6] The existence of a pro inflammatory basal status on the ocular surface induced by ocular rosacea plus the chronic imbalance of neurotrophic factors associated with diabetes mellitus,[7] are the possible mediators for corneal stromal thinning and perforation in our patient.

Regarding the corneal hypoesthesia in this patient, it is well known that diabetic patients show decreased basal epithelial and endothelial cell density, reduced anterior stromal keratocyte counts, and corneal nerve alterations (sub-basal nerve plexus), observing a clear association between the duration of type 2 diabetes and progression of sub-basal nerve plexus loss.[8] The latter is directly associated with a measurable loss of sensitivity and epithelial healing, thus representing a common etiology of neurotrophic keratopathy and possibly the main responsible for the corneal hypoesthesia in our patient. Although no direct association between ocular rosacea and corneal hypoesthesia has been observed, complex neurovascular and neuroimmune interactions (involving substances such as calcitonin gene-related peptide and substance P) have been implicated in the pathophysiology of ocular rosacea.[9] The high prevalence of dry eye, as well as the alterations in corneal nerve morphology and inflammatory cell response leading to sensitivity abnormalities and hypoesthesia[8] in patients with ocular rosacea (as it was in our case), presents a challenge in the assessment of corneal and conjunctival sensitivity since the pathophysiological and neuroimmune pathways involved are often intertwined.[10] Hence, in our patient, the longstanding course of type 2 diabetes and the evaporative severe dry eye associated with blepharitis and rosacea are thought to be responsible for the alteration in corneal sensitivity response, observed clinically as hypoesthesia.

In vivo confocal microscopy (IVCM) is a noninvasive imaging technique that gives qualitative histologic-like resolution used in the assessment of the ocular surface and eyelids. It specifically serves as a tool to evaluate structural and histologic alterations in the cornea and conjunctiva (such as attenuation or absence of the sub-basal nerve plexus) and to classify the meibomian gland dysfunction based on the degree of inflammation and fibrosis of the glands.[11] In this case, IVCM assessment would have been really helpful to determine the damage or alterations observed in the sub-basal nerve plexus and therefore to determine the main etiology of the corneal hypoesthesia since significant alterations (decrease in nerve diameter and density) are observed in dry eye disease, while patients with ocular rosacea often exhibit mild or insignificant changes in the sub-basal plexus.[8] Unfortunately, the availability of confocal microscopes is often limited to research ophthalmological centers; therefore, it was not possible to use this imaging technique.

Krysik et al. in 2007, after reviewing 247 cases, reported that there is no standard surgical technique to treat corneal perforations and concluded that treatment must be individualized. Tectonic keratoplasty is helpful to restore globe integrity, and in this case, we opted for this approach due to the small size of the defect.[12]

During the second visit, a severe central corneal thinning (descemetocele) was observed in the examination of the OD; hence, it was scheduled for an emergency graft surgery. Unfortunately, at the time of the visit, our eye bank did not have corneal tissue for optic or tectonic transplantation and a sclerocorneal ring for tectonic purposes was the only available tissue. Therefore, despite the unfavorable visual prognosis in comparison with a clear corneal graft, and considering the impending corneal perforation, we decided to use the sclerocorneal tissue. The option of a temporal tarsorrhaphy immediately after the tectonic graft to enhance epithelial and stromal healing was heavily discussed. However, despite the imminent corneal perforation, proper eyelid position and eyelid closure prompted us to defer tarsorrhaphy to a second surgical time if needed.

Evidence shows that a daily dose of 100 mg doxycycline reduces MMP-8 concentrations to levels found in healthy individuals after 4–8 weeks of treatment. Moreover, the tear film rupture time was increased. Therefore, oral tetracyclines reduce ocular surface inflammation, preventing corneal thinning and perforation.[13]

The corneal perforation could be explained by the superposition of both disorders (neuropathic keratopathy and ocular rosacea), which lead to dry eye syndrome and chronic inflammation of the ocular surface. Further treatment in this patient should be aggressive, focusing on the control of the inflammatory response associated with ocular rosacea, the meibomian gland dysfunction, and the collagenolytic degradation of the corneal stroma. Topical macrolides (erythromycin ointment or azithromycin eye drops), periodical use of topical steroids, frequent lubrication of the ocular surface, cytoprotective/epithelialization enhancement drugs such as trehalose, and oral tetracyclines can be used. If extensive corneal collagen degradation of the stroma is observed or dry eye control cannot be achieved, the use of an amniotic membrane, blood derivatives, and/or tarsorrhaphy can be considered. Future surgical intervention to restore corneal transparency (penetrating optical keratoplasty) should be discussed with the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002;46:584-7.  Back to cited text no. 1
Rodriguez-Garcia A. Ocular rosacea: Recent advances in pathogenesis and therapy. In: Vega JP, editor. Advances in Dermatology Research. Hauppauge: Nova Biomed Sci Pub.; 2015. p. 175-99.  Back to cited text no. 2
Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol 2014;8:571-9.  Back to cited text no. 3
Labetoulle M, Baudouin C, Calonge M, Merayo-Lloves J, Boboridis KG, Akova YA, et al. Role of corneal nerves in ocular surface homeostasis and disease. Acta Ophthalmol 2019;97:137-45.  Back to cited text no. 4
Mastropasqua L, Nubile M, Lanzini M, Calienno R, Dua HS.In vivo microscopic and optical coherence tomography classification of neurotrophic keratopathy. J Cell Physiol 2019;234:6108-15.  Back to cited text no. 5
Yildirim Y, Olcucu O, Agca A, Karakucuk Y, Alagoz N, Mutaf C, et al. Topographic and biomechanical evaluation of corneas in patients with ocular rosacea. Cornea 2015;34:313-7.  Back to cited text no. 6
Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye (Lond) 2006;20:837-9.  Back to cited text no. 7
Al-Aqaba MA, Dhillon VK, Mohammed I, Said DG, Dua HS. Corneal nerves in health and disease. Prog Retin Eye Res 2019;73:100762.  Back to cited text no. 8
Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert J, Mess C, et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc 2011;15:53-62.  Back to cited text no. 9
Örnek N, Karabulut AA, Örnek K, Onaran Z, Usta G. Corneal and conjunctival sensitivity in rosacea patients. Saudi J Ophthalmol 2016;30:29-32.  Back to cited text no. 10
Randon M, Aragno V, Abbas R, Liang H, Labbé A, Baudouin C.In vivo confocal microscopy classification in the diagnosis of meibomian gland dysfunction. Eye 2019;33:754-60.  Back to cited text no. 11
Krysik K, Dobrowolski D, Lyssek-Boron A, Jankowska-Szmul J, Wylegala EA. Differences in surgical management of corneal perforations, measured over six years. J Ophthalmol 2017;2017:1582532.  Back to cited text no. 12
Määttä M, Kari O, Tervahartiala T, Peltonen S, Kari M, Saari M, et al. Tear fluid levels of MMP-8 are elevated in ocular rosacea-treatment effect of oral doxycycline. Graefes Arch Clin Exp Ophthalmol 2006;244:957-62.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]


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