Abstract
Scleral necrosis is a rare but severe complication caused by various etiologies. The main therapeutic approach is topical and systemic medical treatment. Surgical interventions may be indicated in unresponsive cases. These approaches, however, may fail to control the scleral necrosis. In addition, both medical and surgical treatment may lead to a number of ocular and systemic side effects, calling for noninvasive but effective treatment for the management of scleral necrosis. This review aims to summarize current studies investigating the role of topical erythropoietin in the treatment of scleral necrosis caused by various etiologies. Different electronic databases were extensively searched for relevant studies published until May 30, 2025, using the following keywords: “erythropoietin” AND “scleral necrosis” OR “necrotizing scleritis” OR “scleral ischemia.” The primary outcomes assessed were the indication for topical erythropoietin administration, with secondary outcomes including the efficacy and ocular and systemic safety of treatment with this medication. Seven studies reported the outcomes of the administration of topical erythropoietin for the treatment of scleral necrosis. Of which, two were experimental studies, two were single case reports, including three eyes of two patients, two were case series, including 11 eyes of 11 patients, and one was a nonrandomized case-control study, including 11 eyes of nine patients. Etiologies for scleral necrosis were chemical burns in 15 eyes, thermal burn in one eye, surgically-induced scleral necrosis in six eyes, and systemic autoimmune diseases in three eyes. The necrotic lesions were improved in all eyes 9–90 days after the initiation of treatment with topical erythropoietin. Regarding ocular safety, two eyes developed granulation tissue, which resolved after the cessation of the treatment. Corneal vascularization was observed in 16 eyes with limbal stem cell deficiency due to chemical/thermal burns. No intraocular vascularization or systemic adverse reactions were observed during treatment with topical erythropoietin. Topical administration of erythropoietin can be safe and effective for the management of scleral necrosis caused by various etiologies. However, more studies, including randomized clinical trials, are needed to establish the role of topical erythropoietin in the treatment of this rare but sight-threatening complication.
Plain language summary
This narrative review gathered current knowledge available in the literature regarding the role of erythropoietin eye drops in the treatment of scleral melting. This review includes the studies concentrating on outcomes of the local administration of erythropoietin in the melting of the white coat of the eye (sclera) due to different causes including ocular chemical injuries, ocular surgeries, and collagen vascular diseases, with a glance through the mechanisms of action of the drug in the eye. Topical erythropoietin showed promise as a treatment strategy in scleral melt. All patients completely recovered after the administration of erythropoietin eye drops. No cases had significant ocular or systemic adverse reactions. In conclusion, due to its neuroprotective, anti-inflammatory, and angiogenic properties, local administration of erythropoietin is a potential treatment option for treating scleral melt caused by various etiologies.
Keywords
Introduction
Erythropoietin is a glycoprotein hormone, primarily synthesized and released by renal cells in adults. The released hormone travels through the bloodstream to reach the bone marrow, where it stimulates the erythroid tissues and inhibits erythroid progenitors’ apoptosis. 1 Recent investigations demonstrate that erythropoietin and its receptors are present in several non-hematopoietic tissues such as retinal pigment epithelium, the inner segments of photoreceptors, inner nuclear layer, ganglion cells, and plexiform layers. 2 Erythropoietin can be a promising treatment option for a variety of ocular disorders due to its antiapoptotic, anti-inflammatory, anti-oxidant, and neuroprotective features. 3 There are several in vivo, in vitro, and clinical studies investigating the therapeutic effects of erythropoietin in ocular disorders, including retinopathy of prematurity, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal detachment, traumatic optic neuropathy, methanol optic neuropathy, optic neuritis, and scleral necrosis. 3 However, treatment with erythropoietin can be a double-edged sword due to its angiogenic features. 4 For example, during the early stage of diabetic retinopathy and retinopathy of prematurity, it has neuroprotective effects and can heal the breakdown of the blood-retinal barrier. 3 But in the advanced stage, erythropoietin can stimulate neovascularization caused by extreme hypoxia. 4 Erythropoietin can be administered locally or systematically. Systematic administration of erythropoietin can provoke hematopoiesis, increase hematocrit, and aggravate the risk of atherosclerosis, stroke, and cardiovascular complications. 5 Local administration of erythropoietin through different routes, including intravitreal, subretinal, subconjunctival, and retrobulbar injections as well as eye drops, eliminates the risk of systemic adverse reactions. 4
Scleral necrosis is a severe complication caused by various etiologies, such as infections, chemical and thermal burn injuries, surgical procedures, systemic autoimmune diseases, and vasculitis.6–10 Scleral necrosis weakens the integrity of the sclera, increasing the risk of scleral infection and perforation. 10 Medical and surgical interventions have been employed to treat scleral necrosis. Medical interventions include antibiotic eye drops, non-preserved artificial tears, and topical and systemic immunosuppressive agents.6–8 Surgical interventions, including conjunctival flap and tenonplasty, are frequently used to reestablish blood supply to the avascular area. 11 Patients suffering from extensive scleral thinning may benefit from procedures such as scleral patch grafting with conjunctival flap placement or amniotic membrane transplantation to improve the overall strength and stability of the eye.6,7,12,13 Although these therapeutic measures are effective, treatment of scleral necrosis still remains challenging. Systemic corticosteroids and immunosuppressants can cause a number of systemic side effects, especially in the elderly with age-related comorbidities. Furthermore, scleral necrosis might not respond to immunosuppressive therapy. 14 Surgical procedures are challenging during active ocular inflammation. The viable conjunctiva and Tenon’s capsule may not be adequate enough to entirely cover a large necrotic scleral area. In addition, flap retraction, symblepharon formation, and forniceal shortening are well-known complications after tenonplasty, necessitating a secondary surgical intervention. 15 These drawbacks call for noninvasive but effective measures to treat scleral necrosis. Recently, topical erythropoietin has been introduced as an innovative therapy for avascular scleral lesions.16–22 In this review, we aim to summarize current studies investigating the role of topical erythropoietin in the treatment of scleral necrosis caused by various etiologies.
Methodology
The following electronic databases were extensively searched for studies published until May 30, 2025: PubMed, Scopus, Embase, Ovid Medline, ScienceDirect, Cochrane, Clinicaltrials.gov, and Google Scholar. Keywords used in the search queries included a combination of the following terms: “erythropoietin” AND “scleral necrosis” OR “necrotizing scleritis” OR “scleral ischemia.” Published articles including animal studies, case reports, case series, original articles, and reviews were considered eligible for our review. Relevant references mentioned in the retrieved articles were also evaluated. There were no language restrictions.
The search identified seven studies that met the criteria for inclusion in this review, including two experimental studies,16,17 two single case reports (three eyes of two patients),18,19 two case series (11 eyes of 11 patients),20,21 and one nonrandomized case-control study (11 eyes of nine patients). 22 Etiologies for scleral necrosis were chemical burns in 15 eyes, thermal burn in one eye, surgically-induced scleral necrosis in six eyes, and systemic autoimmune diseases in three eyes. The concentration of erythropoietin eye drops was 3000 IU/mL in six studies16–18,20–22 and 6000 IU/mL in one study, 19 and the medication was applied every 8 h in experimental studies16,17 and every 6 h in human studies (Table 1).18–22 Treatment with topical erythropoietin resulted in complete improvement of scleral necrosis in all eyes.
Summary of studies investigating the role of topical erythropoietin in the treatment of scleral necrosis.
Etiopathogenic mechanisms of scleral necrosis
Scleral necrosis is caused by a variety of etiologies such as infections, chemical/thermal burns, trauma, post-surgical state, and systemic autoimmune diseases. The exact pathogenesis of scleral necrosis is largely unidentified due to the lack of animal models, rarity of the disease, and limited human tissue available for research. Furthermore, the process that triggers ocular inflammation and systemic disorders has so far not been identified.
Infections
Infection constitutes roughly 5%–10% of all cases of scleral melt and necrosis.23,24 The presence of mucopurulent discharge and hypopyon suggests the possibility of an infectious etiology. Risk factors for infectious scleritis include accidental ocular trauma, infectious corneal ulcer, and ocular surgeries, with pterygium removal surgery being the most common.23,24 Several microorganisms can cause infectious scleritis, with bacteria more frequent than fungi. Pseudomonas aeruginosa is the most frequently isolated bacterium, but Mycobacterium spp., Streptococcus pneumoniae, Staphylococcus epidermidis, and Staphylococcus aureus have also been cultured.23,24 Fungal infectious scleritis carries the poorest prognosis and is most frequently caused by Scedosporium spp. and Aspergillus spp. 23
Ocular chemical burn-associated scleral necrosis
Ocular chemical burns are a medical emergency and account for approximately 7.7%–18% of all ocular injuries. 24 This condition has several causes; however, industrial accidents and injuries that occur at home are the most common causes. 24 Ocular chemical burns can result in various early and late complications, consisting of eyelid disorders, corneal epithelial defects, limbal stem cell deficiency, corneal haze, elevated intraocular pressure, uveitis, cataract, and visual loss. 25 Acidic and alkali materials lead to ocular damage through different mechanisms. Exposure to acids, such as sulfuric acid and acetic acid, leads to protein coagulation and contracture of the collagen fibers. 26 On the other hand, the hydroxyl ion in alkaline agents like ammonia, lye, and lime causes injury through saponification of the fatty acids, resulting in the easier penetration of alkalis to the eye compared to acids. 27
Damage to conjunctival and episcleral vasculature in severe chemical burns can lead to the necrosis of the sclera. The extension of scleral necrosis depends on several factors such as the type and concentration of the chemical agent, the interval from injury to the initiation of treatment, and the management administered during the acute phase. 22 Compared to acids, alkalis are more likely to be associated with scleral necrosis. 22 The scleral damage is worsened by cytokines and destructive enzymes released by inflammatory cells. 22
Surgically-induced scleral necrosis
Surgically-induced scleral necrosis is a rare complication of ocular surgeries involving the sclera, including pterygium excision, cataract surgery, strabismus surgery, intraocular injections, pars plana vitrectomy, scleral buckling, cryotherapy, trabeculectomy, and tube shunt implantation.23,24 The time interval from surgery to the onset of this complication varies from 1 day to more than 50 years postoperatively, but usually develops within 6 months of the procedure. 23 Women are affected more commonly than men, and the mean age at presentation is 62 years. 23 Several risk factors make the patient more vulnerable to developing post-surgical scleral necrosis, including multiple previous ocular surgeries, underlying systemic autoimmune diseases, the adjunctive use of mitomycin C, and excessive cautery.23,24 Surgically-induced scleral necrosis can develop in patients with a previous or subsequent diagnosis of autoimmune disease or those without a diagnosis of autoimmune disease. 28 Patients with an autoimmune background have a shorter interval from the first surgical procedure to the onset of scleral necrosis, more severe scleral inflammation, and a higher incidence of ocular complications compared to nonautoimmune patients. 28 Rheumatoid arthritis and granulomatosis with polyangiitis are the most frequent underlying diseases related to surgically-induced scleral necrosis. 23 This point highlights the importance of comprehensive history taking, including an exhaustive review of systems, before performing any ocular procedures that involve the sclera.
Pterygium excision surgery is the most common ocular surgery associated with scleral necrosis.21,29 Necrosis of the sclera that develops immediately after pterygium excision usually occurs in healthy individuals and is due to the surgical procedure itself, including improper placement of conjunctival grafts and damage to episcleral vessels secondary to excessive cauterization and application of mitomycin C.21,29 In scleral necrosis associated with other types of ocular procedures, such as strabismus surgery and cataract extraction, patients demonstrate an anomalous immunologic response to surgical trauma. 23 In fact, 50% of these cases have an underlying autoimmune disease, and in those with no history of an underlying disease, a systemic workup is necessary to rule out an occult condition.23,24 Surgical trauma in such eyes results in a delayed type III hypersensitivity reaction against exposed or modified autoantigens. This reaction includes antigen-antibody immune complex deposition, complement system activation, helper T-cell response, enzymatic destruction of scleral collagen, and vascular disruption. 23 Other proposed mechanisms include molecular mimicry/cross-reactivity and suppressor cell function loss. 23
Immune-mediated scleral necrosis
Approximately 50% of cases with scleritis are associated with a systemic autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, granulomatosis with polyangiitis, and polyarteritis nodosa.9,30,31 Immune-mediated scleral necrosis most commonly occurs during an exacerbation of the underlying systemic disease and is characterized by the presence of granulomatous inflammatory reaction, infiltration of IgG-positive plasma cells, macrophages, and T lymphocytes, perivascular depositions of IgG antibodies, and the invasion of vessel walls by neutrophils with fibrinoid necrosis. 32 These findings indicate that both adaptive and innate immunity, as well as cell-mediated and humoral immunity, may be involved in the pathogenesis of immune-mediated scleral necrosis.32,33 Two possible mechanisms have been suggested for this complication. The first mechanism is ischemia, which is caused by focal occlusive vasculitis due to the deposition of immune complexes in vessel walls and subsequent complement activation. 9 The second mechanism is the destruction of scleral tissue secondary to an imbalance between matrix metalloproteinases and their inhibitors.9,33 Tumor necrosis factor alpha and interleukin-1 alpha are potent inducers of matrix metalloproteinase-3 and -9 production by human scleral fibroblasts. 9 The level of these pro-inflammatory cytokines was reported to be elevated in eyes with necrotizing scleritis. 32 Furthermore, TIMP-1, the natural inhibitor of matrix metalloproteinases, was reported to be less expressed in the necrotic areas of the sclera.9,32
Medical treatment of scleral necrosis
Scleral necrosis is a sight-threatening complication and requires early diagnosis and appropriate therapeutic measures. Treatment should be tailored to an individual case on the basis of the etiology, patient age and sex, severity of the scleral necrosis, and associated underlying autoimmune and other systemic diseases. 23 Identifying the underlying etiology is crucial for choosing appropriate treatment, which is chiefly medical, especially in surgically-induced and autoimmune-related scleral necrosis (Figure 1). However, surgical intervention may be indicated due to severe scleral thinning or perforation.
Algorithmic approach for medical treatment of patients with scleral necrosis caused by different etiologies.
Infectious scleral necrosis
Treatment of infectious scleral necrosis includes the empirical administration of broad-spectrum topical fortified and systemic antibiotics after smear and cultures are obtained.23,24 Nevertheless, specific treatment should be initiated once the smear and culture determine a specific microbial pathogen and its antibiogram profile. 23 Suggested empirical treatment that is effective against Pseudomonas aeruginosa includes frequent topical gatifloxacin 0.3% and fortified cefazolin (50 mg/mL) combined with a systemic fluoroquinolone.23,24 Ceftazidime and amikacin are excellent alternatives for Pseudomonas aeruginosa. 23 Infectious scleral necrosis caused by atypical mycobacteria and Nocardia responds well to amikacin. 23 Management of fungal scleritis includes frequent topical amphotericin-B 0.15%, voriconazole 1%, or natamycin 5% along with systemic antifungals such as oral voriconazole (200 mg), ketoconazole (200 mg), or itraconazole (100 mg) twice daily, or intravenous amphotericin-B (100 mg) once. 23
If infectious scleral necrosis develops after scleral buckling or strabismus surgery, infected materials should be removed before improvement can be successfully achieved.23,24 Some pathogens, such as Aspergillus species, Streptococcus pneumoniae, and Pseudomonas aeruginosa, can penetrate deep into the scleral lamellae. 23 Therefore, surgical debridement may be needed to eradicate these microorganisms when medical therapy fails. 23 Debridement provides samples for smear and culture, removes toxins and enzymes that aggravate scleral necrosis, and enhances the penetration of drugs into the sclera, thus improving outcomes and reducing the duration of hospitalization. 24 Surgical debridement is most effective when performed extensively and early in the course of treatment. 23 In eyes that need extensive debridement, however, a scleral patch graft may be required to preserve globe integrity. 23
Chemical burn injury-associated scleral necrosis
The acute phase of chemical burn requires urgent measures to minimize ocular damage. The affected eye should be copiously irrigated with lactated Ringer’s solution, balanced salt solution, or normal saline until a neutral pH is reached.34,35 In addition, any foreign bodies retained in the conjunctival fornices should be removed. After copious irrigation, the aims of medical treatment are to prevent infection, reduce inflammation, and facilitate epithelialization of the ocular surface. 24 Aggressive lubrication of the ocular surface with non-preserved artificial tears and biologic solutions, including autologous serum, platelet-rich plasma, and umbilical cord blood serum, is essential to enhance conjunctival and corneal epithelization after a burn injury. 22 Topical corticosteroids are administered frequently for 2 weeks to reduce ocular inflammation. Subconjunctival injection of corticosteroid is controversial. 24 Topical or systemic ascorbate (vitamin C) is crucial for collagen synthesis by fibroblasts and can reduce the risk of scleral melt and perforation. 24 Topical ascorbate 10% every 2 h is administered in combination with 500 mg of oral ascorbate every 6 h during the first 4 weeks. 24 Oral minocycline and doxycycline inhibit matrix metalloproteinases, thereby reducing scleral necrosis. 24 A surgical intervention may be indicated in severe scleral necrosis after chemical burn injuries, with no response to medical therapy.
Surgically-induced scleral necrosis
After ruling out infection, the management of surgically-induced scleral necrosis should be based on the association with autoimmune diseases and the severity of scleral inflammation and thinning. 28 Topical treatments include antibiotic eye drops, ocular lubricants, and topical anti-inflammatory medications such as corticosteroids and tacrolimus. 23 Subconjunctival corticosteroid injections should be avoided as they have been associated with scleral melt. 23 Topical treatment is frequently inadequate because the underlying mechanisms frequently necessitate more aggressive systemic treatment. Eyes with nonautoimmune surgically induced scleral necrosis and mild inflammation are managed with systemic non-steroidal anti-inflammatory drugs. Celecoxib (200–400 mg/day) is used as first-line therapy in these cases due to its safety profile. Oral prednisolone 1 mg/kg per day is prescribed for eyes unresponsive to two different non-steroidal anti-inflammatory drugs and those with moderate to severe inflammation at baseline.23,28 Rapidly progressive cases with impending risk of scleral perforation require intravenous methylprednisolone, 1 g per day for three days, followed by oral corticosteroid taper.28,29 Nevertheless, patients should be offered systemic immunosuppressive therapy if inflammation persists or worsens to avoid prolonged steroid use side effects. A combination of systemic corticosteroids and immunosuppressive therapy is usually required in cases of surgically-induced scleral necrosis with an underlying autoimmune disease (see below).23,28,29 Adjunctive therapies include matrix metalloproteinase inhibitors such as topical N-acetylcysteine 10% or 20% every 6 h, medroxyprogesterone acetate 0.5%–1% once or twice per day, and oral tetracycline (250 mg every 6 h). 24
Autoimmune-mediated scleral necrosis
Although idiopathic nodular scleritis or diffuse anterior scleritis may respond well to systemic non-steroidal anti-inflammatory drugs, autoimmune-mediated scleral necrosis, especially that associated with an underlying autoimmune disease, requires systemic immunosuppressive agents in addition to systemic corticosteroids to obtain disease control. 31 Surgical intervention in this situation is challenging because any surgical procedure can worsen the ocular surface inflammation, resulting in the failure of the procedure.
Clear communication between the rheumatologist and ophthalmologist is crucial to select appropriate immunosuppressive agents. Oral prednisolone is typically started at 1 mg/kg per day, up to 60–80 mg daily. 36 As the inflammation wanes, the dose of the drug should be tapered to decrease adverse reactions. The first-line immunosuppressive therapy is frequently oral methotrexate or mycophenolate mofetil. 36 Methotrexate can be administered subcutaneously or intravenously in patients with gastrointestinal complications due to the oral use of the drug.32,36 Mycophenolate mofetil is useful in treating autoimmune-associated scleral necrosis and may be preferred to azathioprine due to its more rapid effect and less severe side effect profile.32,36 Systemic calcineurin inhibitors, including cyclosporine A and tacrolimus, can be administered in scleral necrosis. 36 Treatment with cyclosporine A entails regular evaluation of renal function and blood pressure, and its application may be limited in the elderly secondary to such adverse reactions. Cyclophosphamide, an alkylating agent, is frequently prescribed for the management of ANCA-positive scleral necrosis (polyarteritis nodosa, micro-polyarteritis nodosa, and granulomatosis with polyangiitis). Cyclophosphamide suppresses both humoral and cellular immunity by diminishing the numbers of B cells, T cells, and antibody production. 36 Compared to oral administration, short-term use of the intermittent intravenous pulse protocol is suggested to improve the induction of disease remission and decrease drug toxicity. 36 The initial dose of cyclophosphamide is 2 mg/kg per day, which can be increased to 3 mg/kg per day.32,36
Two types of biological agents have been commonly used for the management of autoimmune-associated scleral necrosis, including tumor necrosis factor alpha inhibitors and anti-CD20. Inhibitors of tumor necrosis factor alpha include golimumab, etanercept, adalimumab, infliximab, and certolizumab.31,36 Infliximab, a chimeric human-murine monoclonal antibody, is effective in granulomatosis with polyangiitis-induced scleral necrosis and surgically-induced scleral necrosis, especially when treatment with other immunosuppressive agents fails.31,36 A clinical response occurs after 13 weeks of treatment with infliximab, and repeated monthly injections may be necessary to maintain remission. 36 Etanercept is a humanized, recombinant antibody that acts as a free tumor necrosis factor scavenger; it binds both tumor necrosis factor alpha and beta, blocking their interaction with the cell surface receptors. 36 Compared to infliximab, etanercept is less effective in inflammatory eye diseases. In patients with rheumatoid arthritis, both etanercept and infliximab have been reported to cause paradoxical ocular inflammation, including uveitis and scleritis, with etanercept being associated with a higher rate of uveitis than infliximab. 36 There are limited data on the role of certolizumab, adalimumab, and golimumab for the treatment of scleral necrosis, and their use is typically only considered when other biologic agents cannot be utilized. 36
Rituximab is a chimeric human-murine monoclonal antibody, which is directed at CD20 in mature B cells. 36 It induces a sustained B cell depletion for up to 6 months, with CD20-positive cells attaining their pretreatment levels within 12 months after the drug discontinuation. 36 In addition, rituximab can produce IgG-opsonized cells that attach to macrophages and avert their pathogenic interactions with tissue-associated immune complexes. Treatment with rituximab is beneficial for refractory necrotizing scleritis with an inadequate response to methotrexate or tumor necrosis factor alpha inhibitors, especially ANCA-positive scleral necrosis (polyarteritis nodosa, micro-polyarteritis nodosa, and granulomatosis with polyangiitis). 36 The therapeutic regimen includes two intravenous infusions of rituximab (1 g) separated by 2 weeks, repeated every 3–6 months. 36 Compared to cyclophosphamide, rituximab results in less reproductive adverse reactions in female patients, such as acute ovarian failure, amenorrhea, and infertility. 32 Other side effects are typically transient and related to the infusion of rituximab. 36
Surgical treatment of scleral necrosis
Surgical intervention is required in 5%–10% of eyes with severe scleral necrosis that is unresponsive to medical therapy. 36 They include procedures to restore adequate blood supply, such as conjunctival autografts, tenonplasty, and mucous membrane graft.12,13,37 For cases with severe scleral melting, scleral patch graft along with conjunctival flap or amniotic membrane transplantation can increase the structural integrity of the globe. Nonetheless, transplanted tissue might undergo melt as well if they are performed in the absence of systemic immunosuppression. Therefore, immunosuppressive therapy is still necessary postoperatively to control ocular inflammation and underlying systemic autoimmune disease. All elective ophthalmic procedures should be postponed until the inflammation is brought under control for at least three months.
Conjunctival flaps
A conjunctival flap can provide vascular supply to the necrotic sclera and decrease ischemia and inflammation.24,29 It is easy to create a conjunctival flap, with no need for additional grafting. Conjunctival flap alone, however, is not effective in very thin or perforated sclera as it does not add tectonic support.24,29
Tenonplasty
Tenon’s capsule is vascularized with a muscle-rich venous network and numerous arteriovenous anastomoses. Tenonplasty is frequently used in eyes with severe scleral necrosis when a healthy conjunctiva is not available.24,29 In this case, a tenon flap is prepared to provide a reliable source of blood supply to the necrotic area. In case of severe scleral thinning and uveal exposure, this procedure should be combined with a scleral patch graft to increase the structural support of the eye.24,29
Mucous membrane graft
When the healthy Tenon’s capsule is not adequate enough to cover the necrotic sclera entirely, a mucous membrane graft, which is composed of a rich vascular network, can be used. In cases with severe scleral thinning, oral mucosal grafts may not provide sufficient structural support. 24
Scleral and corneal graft
Scleral patch graft combined with tenonplasty or amniotic membrane transplantation can restore the integrity of the eye when scleral necrosis is associated with severe scleral melt.23,24 In contrast to scleral grafts, corneal grafts do not need amniotic membrane transplantation or conjunctival flaps. 24 In addition, the cornea is thicker and has a denser lamellar construction than sclera; therefore, corneal grafts provide better tectonic capacity and reduce the risk of remelting. Unfortunately, corneal patch graft can result in a poor cosmetic outcome due to its transparency. 23
New treatment perspectives for scleral necrosis
Future directions could include topical preparation of existing non-corticosteroid immunosuppressive medications. This strategy maximizes drug concentration in the sclera and eliminates its systemic side effects. In addition, the use of nanoparticles and iontophoresis enhances drug delivery for scleritis treatment. Current clinical trials investigate the role of DNA or RNA vaccination to treat rheumatoid arthritis, which can be the truly innovative next steps in the treatment of autoimmune-induced scleral necrosis. Recently, topical erythropoietin has been introduced for the management of scleral necrosis associated with chemical burns, ocular surgery, and systemic autoimmune diseases.
Physiologic roles of erythropoietin in the eye
Before birth, erythropoietin plays a major role in the development of visual function. A recent study found that the level of erythropoietin mRNA in the fetal retina and the vitreous humor is directly correlated with gestational age. 38 Another study revealed that erythropoietin, alongside signal transducer activator-of-transcription (STAT)-5, erythropoietin receptor, and pro-apoptotic protein Bcl-2-associated X (Bax) expressions are present during the organogenesis of the eye, spanning the development of the lens and retina. 38 Erythropoietin plays a role in promoting eye development by exerting antiapoptotic effects. When erythropoietin binds to its receptor, it triggers JAK2 phosphorylation, leading to dimerization and subsequent activation of various tyrosine residues that provide docking sites for MAPK, NF-κB, STAT, and PI3-K/Akt. The phosphorylated STAT and MAPK molecules relocate to the nucleus and stimulate the expression of antiapoptotic Bcl-xl and Bcl-2, which are regulators of the Bcl-2 family that prevent cell apoptosis. 39 In the PI3-K/Akt pathway, activation involves phosphorylation, which inhibits caspase activity by preventing the leakage of cytochrome C from the mitochondria. This action ultimately reduces DNA degradation and the activity of inflammatory cells. In addition, JAK2 phosphorylation results in the recruitment and activation of the cytoplasmic I-κB kinase (IKK) complex by NF-κB. Subsequently, the complex phosphorylates I-κB, marking it for ubiquitylation and proteasomal degradation. The released NF-κB then moves into the nucleus. 40
Junk et al. 41 suggested that the effect of erythropoietin on the PI3-K/Akt, MAPK, and NFκB signal transduction pathways stimulates the production of antiapoptotic factors (Bcl-2 and Bcl-xl) and encourages the transcription of neuroprotective genes, including superoxide dismutase and inhibitors of apoptosis. Xie et al. 42 have shown that administering exogenous erythropoietin via intravitreal injection reduced caspase-3 activity and increased the expression of Bcl-xl, providing a clear explanation of the protective effect of erythropoietin in the eye.
Treatment of experimentally-induced scleral necrosis with topical erythropoietin in animal models
Feizi et al. 16 showed that topical erythropoietin effectively healed experimentally-induced scleral necrosis in rabbit eyes (Figure 2). Treatment with topical erythropoietin resulted in complete improvement of scleral necrosis after 28 days, whereas control eyes had a delay mean healing time of 62.5 days. 16 The experiment suggested that erythropoietin exerts its effects through decreasing the inflammatory reaction, preventing apoptosis, stimulating fibroblast activity, and increasing angiogenesis. The rabbit eyes exhibited no complications related to topical erythropoietin, including corneal epithelial defects or corneal and intraocular neovascularization. Another animal safety study explored the probable angiogenic adverse effect of topical erythropoietin on the cornea. 17 After inducing alkali-burn injury, rabbits were categorized into two groups: the control group and the experimental group that received erythropoietin eye drops for 30 days. 17 After day 60, the rabbits were euthanized, and the eyes were enucleated immediately. No significant difference was observed between the two groups in macroscopic and microscopic corneal angiogenesis, indicating that topical erythropoietin did not induce corneal neovascularization when corneal limbal stem cells were intact at the time of treatment with erythropoietin. 17 However, this medication induced corneal angiogenesis when topically applied in rabbit eyes with corneal epithelial defects. 43
Effect of topical erythropoietin on experimentally induced scleral necrosis in a rabbit eye. (a) Photograph shows an area of avascular sclera immediately after the induction of scleral necrosis. (b) The healing response is evident after 14 days of treatment with topical erythropoietin, characterized by the proliferation of epithelium and vascular tissue over the necrotic area, resulting in a reduction in the lesion size. (c) The avascular lesion heals completely 24 days after treatment with topical erythropoietin. (d) Photograph shows the rabbit eye 40 days after the discontinuation of topical erythropoietin. The treated area is covered by a normal-looking conjunctiva, with no evidence of corneal vascularization.
Topical erythropoietin in the management of chemical burn-induced scleral necrosis
The results of a study demonstrate the effectiveness of treatment with topical erythropoietin in expediting conjunctival epithelialization and vascularization of the necrotic area in five eyes with scleral necrosis induced by thermal (one eye) or chemical (four eyes) burns. 21 The interval from injury to the initiation of topical erythropoietin varied from 10 to 39 days in these five eyes. Treatment with topical erythropoietin led to the complete healing of the avascular areas after 10 to 62 days, consequently obviating the need for surgical intervention in the acute phase of the injury. 21 A recent study enrolled 16 cases with scleral necrosis secondary to chemical burns within 6 weeks of injury. 22 Eleven eyes of nine cases were treated with topical erythropoietin, started 0 to 37 days (mean, 16.6 ± 15.2 days) after chemical injuries, in addition to conventional treatment. 22 The authors also included a historical control group (seven eyes of seven cases) who just received conventional medical treatment, including lubricating ointment every 6 h per day, non-preserved artificial tears every 3 h per day, platelet-rich plasma every 3 h per day, topical chloramphenicol every 6 h per day, topical betamethasone every 3 h per day for 2 weeks, oral doxycycline 100 mg every 12 h per day, and oral vitamin C 500 mg every 6 h per day. 22 The necrotic lesions completely healed in all cases, 9–90 days (mean, 30.7 ± 23.2 days) after the initiation of topical erythropoietin, eliminating the need for surgical interventions for scleral necrosis (Figure 3). 22 In contrast, conventional treatment failed to heal the necrotic lesions in the control group, necessitating reconstructive procedures such as conjunctival advancement, tenonplasty, and mucous membrane graft. 22
A 23-year-old male presents 30 days after chemical burn in his right eye. He received conventional medical treatment in addition to amniotic membrane transplantation before his presentation, which failed to improve the condition. (a) Diffuse slitlamp photograph shows extensive scleral necrosis, total limbal stem cell deficiency, and corneal haziness at the time of presentation. (b) Scleral necrosis completely heals after 34 days of treatment with topical erythropoietin, 6000 IU/mL every 6 h, in addition to levofloxacin eye drops every 6 h, non-preserved artificial tears every 3 h, topical non-preserved methylprednisolone every 8 h, and oral doxycycline 100 mg every 12 h.
Topical erythropoietin in the management of surgically-induced scleral necrosis
Recently, topical erythropoietin has been used for the management of post-surgical scleral necrosis (Figure 4). Feizi and Javadi 20 used topical erythropoietin in three eyes of three patients who presented with surgically-induced scleral necrosis 17 to 46 days (mean, 33.0 ± 14.7 days) after pterygium excision surgery. Treatment with topical antibiotics, lubricating eye drops/ointments, and topical and systemic corticosteroids was unsuccessful to improve the necrotic lesions. The eyes were then started on topical erythropoietin in combination with lubricating eye ointments every 8 h per day, non-preserved artificial tears every 3 h per day, and chloramphenicol 0.5% eye drops every 8 h per day. Healing response was observed within 1 week after the initiation of the medication and characterized by progressive scleral re-epithelialization and vascularization, with a decrease in the surrounding inflammation. 20 The necrotic scleral lesions healed completely in all three eyes 28 to 57 days (mean, 34.3 ± 20.3 days) after treatment with topical erythropoietin. 20 In another report, a 37-year-old man developed surgically induced scleral necrosis after pterygium removal. 21 The patient underwent free conjunctival autograft for the management of scleral necrosis; however, the conjunctival graft melted out within 17 days postoperatively. Topical erythropoietin was started 41 days after initial surgery, which resulted in complete improvement of scleral necrosis within 33 days. 21 Yadgari et al. 18 reported a case of surgically-induced scleral necrosis, managed successfully with topical erythropoietin. Scleral necrosis developed after performing glaucoma device implantation surgery in a 35-year-old diabetic woman with a history of multiple ocular surgeries. 18 The administration of topical erythropoietin along with lubricants and topical antibiotics led to complete improvement of the necrotic part of the sclera after 2 weeks. 18 In another report, a 44-year-old female developed conjunctival dehiscence over a scleral patch graft, which was performed to cover an exposed glaucoma drainage device tube. 21 Several treatments, including normobaric oxygen therapy, lubrication, oral acetazolamide, oral vitamin C, and wound re-suturing, failed to heal the lesion. Treatment with topical erythropoietin for 35 days resulted in the complete coverage of the scleral patch graft with normal conjunctival tissue. 21
A 76-year-old female complains of ocular pain, redness, and reduced visual acuity in her left eye 55 days after combined trabeculectomy and phacoemulsification surgery. (a) Diffuse slitlamp photograph shows scleral necrosis at the site of trabeculectomy, with corneal epithelial defects and corneal stromal infiltration around the site of a releasable suture. (b) An improvement in scleral necrosis and corneal infiltration is observed 6 days after treatment with fortified cefazoline and gentamicin eye drops every 3 h and topical erythropoietin 3000 IU/mL every 6 h. (c) The necrotic scleral lesion completely improves after 20 days of treatment with topical erythropoietin.
Topical erythropoietin in the management of systemic collagen vascular diseases associated with scleral necrosis
A 69-year-old female developed necrotizing scleritis due to rheumatoid arthritis. 21 She received frequent lubrication, topical betamethasone, and systemic immunosuppressive therapy, including oral prednisolone, subcutaneous adalimumab, and intravenous cyclophosphamide, which effectively controlled scleritis. 21 However, she did not recover from scleral necrosis, and her condition progressed to severe scleral thinning. After 19 days of treatment with topical erythropoietin, the vascularized conjunctiva entirely covered the necrotic area. 21 A 52-year-old male exhibited bilateral anterior necrotizing scleritis with significant scleral thinning and positive c-ANCA with no underlying autoimmune diseases. 19 The ocular condition was refractory to betamethasone eye drops, oral prednisolone 50 mg per day, oral methotrexate 20 mg per week, and intravenous cyclophosphamide 2 g once. 19 Complete improvement in scleral necrosis was achieved after treatment with topical erythropoietin and intravenous rituximab (Figure 5). 19 These two cases indicate that topical erythropoietin may be effective in the management of scleral necrosis in cases with collagen vascular diseases, while appropriate treatment of underlying autoimmune diseases is started.
A 52-year-old male exhibits anterior necrotizing scleritis with significant scleral thinning in his right eye and positive c-ANCA. (a) Diffuse slitlamp photograph demonstrates multiple areas of scleral necrosis, severe scleral thinning, and uveal show which are unresponsive to betamethasone eye drops, oral prednisolone 50 mg per day, oral methotrexate 20 mg per week, and intravenous cyclophosphamide 2 g once. (b) Complete improvement in scleral necrosis is achieved after treatment with topical erythropoietin, 6000 IU/mL every 6 h, and intravenous rituximab.
Ocular and systemic safety of treatment with topical erythropoietin
Treatment with topical erythropoietin was well tolerated and did not cause ocular burning sensations. Topical erythropoietin applied for chemical burn and surgically induced scleral necrosis caused the formation of granulation tissue in three eyes, which resolved after the discontinuation of the medication.20–22 Vascularization of the intraocular structures, such as the iris and retina, was not reported. Treatment with topical erythropoietin did not lead to corneal vascularization in eyes with normal limbal stem cells, such as those with scleral necrosis associated with ocular surgeries and autoimmune diseases. However, this treatment resulted in corneal neovascularization in the sectors of the cornea that lack normal limbal stem cells due to chemical/thermal burns (16 eyes).21,22 In the case of limbal stem cell deficiency, corneal vascularization is an advantageous response that eliminates the likelihood of corneal ulcer and perforation while waiting for limbal stem cell transplantation. Other adverse reactions, such as reduced visual acuity, corneal epitheliopathy, or elevated intraocular pressure, have not been reported after treatment with this medication. With respect to systemic safety, no side effects, including alterations in fasting blood glucose levels, hematological indices, or blood pressures, have been reported after topical administration of erythropoietin.20–22
Contraindications
There are some ocular and systemic contraindications for the local administration of erythropoietin. Hematological and solid malignancies, conjunctival and intraocular malignant melanoma, and ocular surface squamous neoplasia should be considered as contraindications for topical erythropoietin, as it may accelerate tumor growth through stimulating angiogenesis, inhibiting apoptosis, and enhancing cell proliferation. There is a report of an 87-year-old male who developed scleral necrosis after excisional biopsy of his conjunctival well-differentiated squamous cell carcinoma. 44 The scleral necrosis completely healed after 21 days of treatment with topical erythropoietin. After four months, while the patient was under surveillance, the ocular surface squamous neoplasia recurred with evidence of invasion into the anterior chamber and ciliary body (Figure 6). 44 The authors believed that topical erythropoietin could be linked to tumor recurrence and intraocular invasion in this case. 44
An 87-year-old male presents with scleral necrosis after excisional biopsy of his conjunctival well-differentiated squamous cell carcinoma. (a) Diffuse slitlamp photograph shows surgically-induced scleral necrosis on the nasal side adjacent to the limbus. (b) The scleral necrosis completely heals after 21 days of treatment with topical erythropoietin. (c) After 4 months, the ocular surface squamous neoplasia recurs with evidence of invasion into the anterior chamber angle.
Other contraindications include a history of high systemic blood pressure, thromboembolic events, polycythemia, uncontrolled intraocular pressure, and ocular conditions that predispose to abnormal intraocular vascularization, including retinal vascular occlusion and proliferative diabetic retinopathy. 3 Since improvement of scleral necrosis by topical erythropoietin takes 30 days, on average, severe scleral thinning or perforation should be considered another contraindication for this treatment.
This review has a number of limitations. First, only a few studies with small sample sizes evaluated the role of topical erythropoietin in the management of scleral necrosis. Second, the included studies are single case reports and case series, with only one nonrandomized case-control study identified. There are currently no randomized clinical trials or sufficient case-control studies to support the use of erythropoietin for scleral necrosis, mainly due to the rarity of this complication. The results of this review, however, indicate that topical erythropoietin could be a promising option in treating scleral necrosis caused by a variety of etiologies with no safety concerns. Multicenter randomized clinical trials are needed to establish the role of topical erythropoietin in the treatment of this rare but sight-threatening complication.
