Journal of Ophthalmic and Vision Research

: 2016  |  Volume : 11  |  Issue : 1  |  Page : 108--111

Recurrent corneal perforation due to chronic graft versus host disease; a clinicopathologic report

Mehrdad Mohammadpour1, Siamak Maleki1, Hassan Hashemi2, Amir Houshang Beheshtnejad1,  
1 Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
2 Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran

Correspondence Address:
Mehrdad Mohammadpour
Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, Tehran 13366


Purpose: To describe a case of chronic graft versus host disease (GVHD) leading to severe dry eye and recurrent corneal perforation in both eyes, its stepwise management and histopathological reports. Case Report: A 22-year-old woman with a history of thalassemia and subsequent high-dose chemotherapy followed by allogeneic bone marrow transplant (BMT) was referred to Farabi Eye Hospital. Despite aggressive medical and surgical intervention, corneal vascularization in her right eye progressed and led to corneal perforation. Cyanoacrylate glue was applied to seal the perforation, however it recurred. Multilayer amniotic membrane transplantation (AMT) was performed to seal the corneal perforation, which was effective for a short period. Subsequently, the corneal perforation recurred and penetrating keratoplasty was performed. After a few months deep vascularization and descemetocele occurred in the fellow left eye and the patient finally underwent therapeutic lamellar keratoplasty. Conclusion: Patients with GVHD are at risk of severe dry eye and subsequent corneal vascularization. Recurrent and recalcitrant corneal perforation resistant to cyanoacrylate glue and multilayer AMT may occur. Proper systemic and ocular management alongside close collaboration with the hematologist is strongly recommended to control the condition.

How to cite this article:
Mohammadpour M, Maleki S, Hashemi H, Beheshtnejad AH. Recurrent corneal perforation due to chronic graft versus host disease; a clinicopathologic report.J Ophthalmic Vis Res 2016;11:108-111

How to cite this URL:
Mohammadpour M, Maleki S, Hashemi H, Beheshtnejad AH. Recurrent corneal perforation due to chronic graft versus host disease; a clinicopathologic report. J Ophthalmic Vis Res [serial online] 2016 [cited 2020 Aug 13 ];11:108-111
Available from:

Full Text


Patients who undergo bone marrow transplantation (BMT) are at risk of developing graft versus host disease (GVHD).[1] GVHD which occurs within the first 100 days of transplantation is termed 'acute' and those developing after 100 days are called 'chronic'. Of patients with chronic GVHD, 60 to 90% have ocular involvement. The most frequent finding in these patients is dry eye (up to 90%).[2] The presence of ocular GVHD has no association with age, gender, or specific conditioning regimens.[3] Chronic GVHD may cause irreparable damage to the cornea including ulceration, thinning and melting.[4]

Herein, we describe a case of corneal vascularization and perforation secondary to chronic GVHD and its stepwise management, as well as the results of histopathological evaluation.

 Case Report

A 22-year-old woman with a history of thalassemia was referred to our clinic for decreased vision and ocular discomfort. She had received high-dose chemotherapy followed by allogeneic bone marrow transplantation (BMT) and had been prescribed frequent lubricants as well as topical antibiotics at another center.

Upon admission, the patient complained of foreign body sensation and painful sore gritty eyes. Corrected visual acuity was 3/10 and 7/10 in the right and left eyes, respectively. The diagnosis was severe dry eye secondary to chronic GVHD. Despite aggressive medical and surgical interventions such as topical cyclosporine and steroids, blepharorrhaphy, and upper and lower punctal occlusion, she experienced worsening of the condition followed by further deterioration of vision in her right eye. A significant decrease in tear meniscus, blepharitis and development of superficial corneal vascularization were noted during follow-up. Corneal vascularization progressed and led to corneal perforation. Slit lamp examination revealed a small Seidel-positive corneal perforation approximately 1.5 mm × 1 mm in size in her right eye [Figure 1]. Bandage contact lens (BCL) was applied as a temporary management and the patient was admitted. Cyanoacrylate glue was applied to seal the perforation site but was ineffective. Multilayer amniotic membrane transplantation (AMT) was performed to seal the corneal perforation [Figure 2]. The corneal perforation was sealed for 3 weeks following resorption of the AMT [Figure 3]. However, corneal perforation recurred six months later [Figure 4]. Penetrating keratoplasty (PK) together with a deep subconjunctival and intrastromal bevacizumab injection in the donor cornea were performed simultaneously in the right eye [Figure 5]. The corneal bottom was sent for histopathologic and bacteriologic evaluations which revealed corneal vascularization, inflammation, stromal edema and stromal degeneration [Figure 6]. Bacteriologic evaluations were negative.{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}{Figure 6}

In subsequent examinations, despite full medical/surgical treatment such as frequent lubrication with preservative-free artificial tears, topical cyclosporine and steroids, autologous serum, lateral tarsorrhaphy, and punctual occlusion; deep corneal stromal vascularization and descemetocele developed in the fellow left eye and the patient underwent therapeutic lamellar keratoplasty.

At this stage, her hematologist was consulted and asked to intensify the immunosuppression. The dosage of systemic mycophenolate mofetil, prednisolone acetate, and cyclosporine were increased to 2 g daily, 50 mg daily, and 150 mg daily, respectively. After intensifying the systemic regimen, the dry eye improved significantly, and the dosage was gradually tapered to 1 g daily, 10 mg daily, and 50 mg daily for mycophenolate mofetil, prednisolone acetate, and cyclosporine A, respectively. With maximum ocular and systemic treatment, the graft remained clear during the subsequent three years [Figure 7].{Figure 7}


Patients with GVHD can develop severe dry eye that may lead to epithelial thinning and corneal erosions.[5] If not treated properly, progressive corneal vascularization may occur and visual acuity may be affected.[6] Subsequently, subtle perforations may develop in patients with GVHD.[7] When patients develop subtle corneal defects associated with GVHD, they require careful monitoring because serious complications, such as corneal vascularization and perforation, may ensue. It has been shown that bevacizumab may be considered for management of intrastromal corneal vascularization.[8] Therefore, we administered a deep intrastromal bevacizumab injection during PK in the right eye since the patient had developed progressive stromal vascularization.

Sterile corneal perforations in the paracentral region of the cornea are uncommon after BMT.[9] Such perforations are rare but should be noted as a grave complication. Suzuki et al presented a similar case. Although the exact process of perforation was unclear, the sequence of events that might lead to corneal ulceration have been postulated to be severe dry eye due to sicca syndrome, which is a complication of chronic GVHD.[10] Severe dry eye, chronic sterile conjunctivitis, scleritis, corneal ulcer and perforation, cataracts, central serous chorioretinopathy, multifocal choroiditis, and uveitis are among other complications reported in patients with GVHD.[9],[10],[11],[12],[13],[14],[15],[16]

Ocular surface involvement includes loss of or significant reduction in the amount of conjunctival goblet cells, and conjunctival and corneal epithelial keratinization and squamous metaplasia.[11],[12] Mild peripheral corneal vascularization may be seen in GVHD patients with dry eyes; however, progressive neovascularization has also been reported in this condition.[6] One possible mechanism for progressive corneal vascularization in such cases is an immune-mediated limbitis, which may cause partial stem cell deficiency because of altered conditions in the microenvironment of stem cells. Limbal stem cell dysfunction together with severe dry eye may compose a vicious cycle, eventually leading to corneal neovascularization.[17]

The conjunctiva and lacrimal gland are two sites with the most prevalent histopathological changes in chronic ocular GVHD which predominantly consist of keratinization. One of the main causes of severe dry eye in chronic ocular GVHD is involvement of the lacrimal glands. CD34+ fibroblasts play an important role in the pathogenesis of lacrimal gland fibrosis.[18] There is a relationship between dry eye syndrome and chronic GVHD activity in other organs. However, in some patients, such as ours, dry eye syndrome is the only manifestation of chronic GVHD.[19]

Current therapies for dry eye related to chronic GVHD include tear supplements (artificial tears and autologous serum), nonspecific immunosuppressants (steroidal and non-steroidal topical or systemic preparations) and punctal plugs. Other recent treatment modalities include cyclosporine A, tacrolimus and retinoic acid.[20],[21]

In summary, sterile corneal ulceration may develop following BMT, leading to thinning and perforation of the cornea. Special attention should be paid to the diagnosis and management of dry eye before corneal neovascularization develops. Collaboration with the hematologist is mandatory for management of ocular complications caused by GVHD, especially dry eye–induced morbidities. Therapy consists of intensive management of dry eye and sufficient systemic immune suppression to control the systemic disease.

Financial Support and Sponsorship


Conflicts of Interest

There are no conflicts of interest.


1Anderson NG, Regillo C. Ocular manifestations of graft versus host disease. Curr Opin Ophthalmol 2004;15:503-507.
2Hessen M, Akpek EK. Ocular graft-versus-host disease. Curr Opin Allergy Clin Immunol 2012;12:540-547.
3Westeneng AC, Hettinga Y, Lokhorst H, Verdonck L, van Dorp S, Rothova A. Ocular graft-versus-host disease after allogeneic stem cell transplantation. Cornea 2010;29:758-763.
4Franklin RM, Kenyon KR, Tutschka PJ, Saral R, Green WR, Santos GW. Ocular manifestations of graft-vs-host disease. Ophthalmology 1983;90:4-13.
5Jabs DA, Hirst LW, Green WR, Tutschka PJ, Santos GW, Beschorner WE. The eye in bone marrow transplantation. II. Histopathology. Arch Ophthalmol 1983;101:585-590.
6Mohammadpour M. Progressive corneal vascularization caused by graft-versus-host disease. Cornea 2007;26:225-226.
7Jack MK, Jack GM, Sale GE, Shulman HM, Sullivan KM. Ocular manifestations of graft-v-host disease. Arch Ophthalmol 1983;101:1080-1084.
8Hashemian MN, Zare MA, Rahimi F, Mohammadpour M. Deep intrastromal bevacizumab injection for management of corneal stromal vascularization after deep anterior lamellar keratoplasty, a novel technique. Cornea 2011;30:215-218.
9Tranos PG, Forbes J, Jagger J. Corneal perforation in chronic graft-versus-host disease. Eye (Lond) 2001;15(Pt 1):111-113.
10Suzuki M, Usui T, Kinoshita N, Yamagami S, Amano S. A case of sterile corneal perforation after bone marrow transplantation. Eye (Lond) 2007;21:114-116.
11Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, et al. Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease. Bone Marrow Transplant 2004;33:1031-1035.
12Sanders JE. Chronic graft-versus-host disease and late effects after hematopoietic stem cell transplantation. Int J Hematol 2002;76 Suppl 2:15-28.
13Kim RY, Anderlini P, Naderi AA, Rivera P, Ahmadi MA, Esmaeli B. Scleritis as the initial clinical manifestation of graft-versus-host disease after allogenic bone marrow transplantation. Am J Ophthalmol 2002;133:843-845.
14Saito T, Shinagawa K, Takenaka K, Matsuo K, Yoshino T, Kiura K, et al. Ocular manifestation of acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. Int J Hematol 2002;75:332-334.
15Cheng LL, Kwok AK, Wat NM, Neoh EL, Jon HC, Lam DS. Graft-vs-host-disease-associated conjunctival chemosis and central serous chorioretinopathy after bone marrow transplant. Am J Ophthalmol 2002;134:293-295.
16Alvarez MT, Hernáez JM, Ciancas E, Figueroa MS. Multifocal choroiditis after allogenic bone marrow transplantation. Eur J Ophthalmol 2002;12:135-137.
17Mohammadpour M, Javadi MA. Keratitis associated with multiple endocrine deficiency. Cornea 2006;25:112-114.
18Riemens A, te Boome L, Imhof S, Kuball J, Rothova A. Current insights into ocular graft-versus-host disease. Curr Opin Ophthalmol 2010;21:485-494.
19Couriel DR. Ancillary and supportive care in chronic graft-versus-host disease. Best Pract Res Clin Haematol 2008;21:291-307.
20Ogawa Y, Kuwana M. Dry eye as a major complication associated with chronic graft-versus-host disease after hematopoietic stem cell transplantation. Cornea 2003;22 7 Suppl: S19-S27.
21Ogawa Y, Okamoto S, Mori T, Yamada M, Mashima Y, Watanabe R, et al. Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant 2003;31:579-583.