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Amniotic Membrane Transplantation for the Ocular Surface

Policy Number: MP-624

Latest Review Date:   June 2019

Category:  Medical                                                               

Policy Grade:  C

DESCRIPTION OF PROCEDURE OR SERVICE:

The outermost layer of the cornea, the clear layer of the eye, has a surface that is composed of an epithelium, a thin layer of stratified squamous cells. The corneal epithelium has the ability to rapidly regenerate and this regeneration relies on stem cells located in the limbal epithelium (the junction zone between the corneal and conjunctival epithelia).

Corneal epithelial defects are a focal loss of the corneal epithelium. Persistent corneal epithelial defects refractory to conventional treatment remain a therapeutic challenge, often requiring surgical intervention. Symptoms associated with these defects can include pain, photophobia, tearing and a sensation of a foreign body in the eye. Corneal defects can be caused by:

  • Corneal dryness and systemic disorders leading to corneal dryness (e.g., Sjogren’s syndrome, Vitamin A deficiency, dry eye syndrome and thyroid eye disease)

  • Deficiency of the limbal cells or failure to regenerate epithelial cells

  • Ultraviolet burns (e.g., prolonged sun exposure off reflective surfaces, welding)

  • Exposure of eye (e.g., neurotrophic diseases causing incomplete eyelid closure, proptosis, restrictive eyelid diseases)

  • Mechanical trauma of the cornea (e.g., chemical exposure, foreign body in the lid/fornices/trichiasis/distichiasis, contact lens overuse, fingernail scratch)

Amniotic membrane transplantation (AMT) has been proposed as a treatment of ocular conditions. AMT is also being investigated for use in the restructuring of damaged ocular surfaces and as an aid in the healing of damaged ocular tissues. Ocular injuries due to trauma or disease damage the cornea and limbal epithelium. The corneal surface cannot regenerate if the damage to the epithelium is extensive. This results in ulcerations and loss of tissue to the extent of stem cell deficiency. This ulceration often fails to heal normally and can lead to vision loss. Amniotic membrane-covered surfaces are reported to induce rapid re-epithelialization in as little as 2 to 4 weeks, resulting in a smooth, wettable surface, with reduced inflammation, vascularization and scarring. This, in turn, allows for successful surface reconstruction.

Human Amniotic Membrane

Human amniotic membrane (HAM) consists of two conjoined layers, the amnion and chorion, and forms the innermost lining of the placenta. When prepared for use as an allograft, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated.  Many products available using amnion, chorion, amniotic fluid, and umbilical cord are being studied for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions.

Fresh amniotic membrane contains collagen, fibronectin, and hyaluronic acid, along with a combination of growth factors, cytokines, and anti-inflammatory proteins such as interleukin-1 receptor antagonist. There is evidence that the tissue has anti-inflammatory, antifibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause substantial immune response. It is believed that these properties are retained in cryopreserved HAM and dehydrated HAM products, resulting in a readily available tissue with regenerative potential. In support, one dehydrated HAM product has been shown to elute growth factors into saline and stimulate the migration of mesenchymal stem cells, both in vitro and in vivo.

Use of a HAM graft, which is fixated by sutures, is an established treatment for disorders of the corneal surface, including neurotrophic keratitis, corneal ulcers and melts, following pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Amniotic membrane products that are inserted like a contact lens have more recently been investigated for the treatment of corneal and ocular surface disorders.

Conservative therapy for neurotrophic keratitis may include 5 days of pressure patching, therapeutic contact lens, topical lubricants, and topical antibiotics.

Conservative therapy for corneal ulcers and melts may include 2 days of patching, therapeutic contact lens, and topical antimicrobial agents.

A persistent epithelial defect is one that failed to close completely after 5 days of conservative treatment or has failed to demonstrate a decrease in size after 2 days of conservative treatment. Conservative treatment of a persistent epithelial defect may include 5 days of the following: topical lubricants, topical antibiotics, therapeutic contact lens, or patching.

POLICY:

Effective for dates of service on or after June 26, 2019:

Amniotic membrane transplantation for the treatment of corneal conditions refractory to conventional treatment using grafts that are fixated using sutures, glue fixation, secured under a bandage contact lens, self-contained or unfixated (e.g., Prokera®, AmbioDisk™) may be considered medically necessary for any the following conditions:

  • Absence of iris;
  • Bullous keratopathy;
  • Conjunctivochalasis;
  • Corneal degeneration;
  • Corneal ectasia, corneal staphyloma, descemetocele or other corneal deformity;
  • Corneal ulceration or defect;
  • Corneal disorder due to contact lens or recurrent erosion of cornea;
  • Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment;
  • Following removal of conjunctival lesion(s);
  • Hereditary corneal dystrophies;
  • Neurotrophic keratoconjunctivitis;
  • Ocular burns;
  • Stevens-Johnsons Syndrome;
  • Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient;
  • Persistent Epithelial defects that do not respond to conservative therapy;
  • Pterygium;
  • Pseudopterygium

Amniotic membrane transplantation for the treatment of dry eye syndrome and any other conditions not listed above is not medically necessary and is considered investigational.

 

 Effective for dates of service May 6, 2016- June 25, 2019:

Amniotic membrane transplantation for the treatment of corneal conditions refractory to conventional treatment using grafts that are fixated using sutures, glue fixation, secured under a bandage contact lens, self-contained or unfixated (e.g., Prokera®) may be considered medically necessary for any the following conditions:

  • Absence of iris;

  • Bullous keratopathy;

  • Conjunctivochalasis;

  • Corneal degeneration;

  • Corneal ectasia, corneal staphyloma, descemetocele or other corneal deformity;

  • Corneal ulceration or defect;

  • Corneal disorder due to contact lens or recurrent erosion of cornea;

  • Following removal of conjunctival lesion(s);

  • Hereditary corneal dystrophies;

  • Neurotrophic keratoconjunctivitis;

  • Ocular burns;

  • Stevens-Johnsons Syndrome;

  • Pterygium;

  • Pseudopterygium

Amniotic membrane transplantation for the treatment of dry eye syndrome and any other conditions not listed above is considered not medically necessary and investigational.

KEY POINTS:

 

The most recent literature update was performed through November 27, 2018.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice

Amniotic membrane obtained from cesarean deliveries is cryo-preserved and can be applied to the ocular surface, either sutured or unsutured. Studies support that amniotic membrane-covered surfaces often demonstrate rapid re-epithelialization and reduced inflammation and scarring which promotes successful ocular surface reconstruction. Most of the available studies were with patients with symptomatic bullous keratopathy with intractable pain and poor visual potential. Many studies have been conducted outside the United States, were of very small sample size, and not randomized or controlled for the most part (due to the nature of the injuries and treatment).

HAM Graft for Ophthalmologic Conditions

Sutured and self-retained HAM has been evaluated for a variety of ophthalmologic conditions. Traditionally, the amniotic membrane has been fixed onto the eye with sutures or glue or placed under a bandage contact lens for a variety of ocular surface disorders. Several devices have been reported that use a ring around a HAM allograft that allows it to be inserted under topical anesthesia similar to insertion of a contact lens. Sutured HAM transplant has been used for many years for the treatment of ophthalmic conditions. Many of these conditions are rare, leading to difficulty in conducting RCTs. Therefore, clinical input was sought to determine the most appropriate use of sutured and non-sutured HAM. The following indications apply to both sutured and self-retained HAM unless specifically noted.

Neurotrophic Keratitis with Ocular Surface Damage or Inflammation that does not respond to Conservative Treatment

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have neurotrophic keratitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have neurotrophic keratitis?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have neurotrophic keratitis with ocular surface damage or inflammation that does not respond to conservative treatment.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: tarsorrhaphy or bandage contact lens.

Outcomes

The general outcomes of interest are eye pain and epithelial healing.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

Khokhar et al (2005) reported on an RCT of 30 patients (30 eyes) with refractory neurotrophic corneal ulcers who were randomized to HAM transplantation (n=15) or conventional treatment with tarsorrhaphy or bandage contact lens. At the 3-month follow-up, 11 (73%) of 15 patients in the HAM group showed complete epithelialization compared with 10 (67%) of 15 patients in the conventional group. This difference was not significantly significant.

Suri et al (2013) reported on 11 eyes of 11 patients with neurotrophic keratopathy that had not responded to conventional treatment. The mean duration of treatment prior to Prokera insertion was 51 days. Five of the 11 patients (45.5%) were considered to have had a successful outcome.

Clinical input recommended HAM for neurotrophic keratitis that did not respond to conservative therapy. Input recommended non-sutured HAM as the preferred initial treatment "because it can be performed rapidly in an office setting, avoiding the delay associated with scheduling a procedure in an outpatient surgical facility."

Section Summary: Neurotrophic keratitis with Ocular Surface Damage and Inflammation that does not respond to Conservative Therapy

An RCT of 30 patients showed no benefit of sutured HAM graft compared to tarsorrhaphy or bandage contact lens. Based on clinical input, HAM might be considered for patients who did not respond to conservative therapy. Clinical input indicated that non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.

Corneal Perforation When There is Active Inflammation after Corneal Transplant Requiring Adjunctive Treatment

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have active inflammation after a corneal transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have corneal perforation when there is active inflammation after corneal transplant?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have corneal perforation when there is active inflammation after a corneal transplant.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy.

Outcomes

The general outcomes of interest are eye discomfort and reduction in inflammation.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

No evidence was identified for this indication.

Clinical input indicated that "both sutured and non-sutured HAM reduces inflammation and promotes epithelial healing. It is, therefore, a useful adjunct in addition to corneal transplantation in those patients with active inflammation and perforation."

Section Summary: Corneal Perforation When There is Active Inflammation after Corneal Transplant Requiring Adjunctive Treatment

No evidence was identified for this indication. Clinical input supported the use of HAM to reduce inflammation and promote epithelial healing with active inflammation following corneal transplant.

Bullous Keratopathy in Patients Who are not Candidates for a Curative Treatment (e.g., Endothelial or Penetrating Keratoplasty)

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have bullous keratopathy is to provide a treatment option that is an alternative to or an improvement on existing therapies. Bullous keratopathy is characterized by stromal edema and epithelial and subepithelial bulla formation.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have bullous keratopathy and are not candidates for a curative treatment?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have bullous keratopathy who are not candidates for curative treatment.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: stromal puncture.

Outcomes

The general outcomes of interest are eye discomfort and epithelial healing

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

Dos Santos Paris et al (2013) published an RCT that compared fresh HAM with stromal puncture for the management of pain in patients with bullous keratopathy. Forty patients with pain from bullous keratopathy who were either waiting for a corneal transplant or had no potential for sight in the affected eye were randomized to the two treatments. Symptoms had been present for approximately two years. HAM resulted in a more regular epithelial surface at up to 180 days follow-up, but there was no difference between the treatments related to the presence of bullae or the severity or duration of pain. Because of the similar effects on pain, the authors recommended initial use of the simpler stromal puncture procedure, with the use of HAM only if the pain did not resolve.

Clinical input recommended HAM as a palliative measure in patients who are not candidates for curative treatment (e.g., endothelial or penetrating keratoplasty) Input recommended HAM as a reasonable alternative to stromal puncture.

Section Summary: Bullous Keratopathy in Patients Who are not Candidates for a Curative Treatment and who are Unable to Remain Still for Stromal Puncture

An RCT found no advantage of sutured HAM over the simpler stromal puncture procedure for the treatment of pain from bullous keratopathy. Based on clinical input, non-sutured HAM could be used as an alternative to stromal puncture.

Partial Limbal Stem Cell Deficiency with Extensive Diseased Tissue Where Selective Removal Alone is not sufficient

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have LSCD is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have partial LSCD?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have LSCD with extensive diseased tissue where selective removal alone is not sufficient.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: limbal stem cell transplants.

Outcomes

The general outcomes of interest are visual acuity and corneal epithelial healing.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Review of Evidence

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

No RCTs were identified on HAM for LSCD.

Keirkhah et al (2008) reported on the use of HAM in 11 eyes of 9 patients who had LSCD. Patients underwent superficial keratectomy to remove the conjunctivalized pannus followed by HAM transplantation using fibrin glue. An additional Prokera patch was used in seven patients. An improvement in visual acuity was observed in all but two patients. Pachigolla et al (2009) reported a series of 20 patients who received a Prokera implant for ocular surface disorders; 6 of the patients had limbal stem cell deficiency with a history of chemical burn. (REF) Following treatment with Prokera, 3 of the 6 patients had a smooth corneal surface and improved vision to 20/40.The other 3 patients had final visual acuity of 20/400, counting fingers, or light perception.

Clinical input recommended HAM for patients with LSCD in conjunction with superficial keratectomy, noting that due to the rarity of this disease, it is unlikely that RCTs will ever be performed. Input also noted that "comparisons to limbal stem cell transplants are unlikely to be performed because of the risks of systemic immune suppression.”

Section Summary: Partial LSCD with Extensive Diseased Tissue Where Selective Removal Alone is not sufficient

No RCTs were identified on HAM for LSCD. Improvement in visual acuity has been reported for some patients who have received HAM in conjunction with removal of the diseased limbus. Clinical input noted the limitations of performing an RCT and supported the use of HAM for this indication.

Moderate or Severe Stevens - Johnson syndrome

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have Stevens-Johnson syndrome is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have moderate or severe Stevens-Johnson syndrome?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have moderate or severe Stevens-Johnson syndrome.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy alone (antibiotics, steroids, or lubricants).

Outcomes

The general outcomes of interest are visual acuity, tear function, and corneal clarity.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

One RCT from India by Sharma et al (2016) assigned 25 patients (50 eyes) with acute ocular Stevens-Johnson syndrome to c-HAM plus medical therapy (antibiotics, steroids, or lubricants) or medical therapy alone. The c-HAM was prepared locally and applied with fibrin glue rather than sutures. Application of c-HAM in the early stages of Stevens-Johnson syndrome resulted in improved visual acuity (p=0.042), better tear breakup time (p=0.015), improved Schirmer test results (p<0.001), and less conjunctival congestion (p=0.03). In the c-HAM group at 180 days, there were no cases of corneal haze, limbal stem cell deficiency, symblepharon, ankyloblepharon, or lid-related complications. These outcomes are dramatically better than those in the medical therapy alone group, which had 11 (44%) cases with corneal haze (p=0.001), 6 (24%) cases of corneal vascularization and conjunctivalization (p=0.03), and 6 (24%) cases of trichiasis and metaplastic lashes. Clinical input recommended HAM for moderate-to-severe Stevens-Johnson noting that the severity of the disease and its infrequency makes it unlikely that a large RCT will be performed.” Sutured HAM would be preferred to prevent lid-related complications, but non-sutured HAM “is still helpful in emergency settings when the patient condition does not allow for surgical intervention.”

Section Summary: Moderate or Severe Stevens - Johnson syndrome

The evidence on HAM for the treatment of Stevens-Johnson syndrome includes 1 RCT with 25 patients (50 eyes) that found improved symptoms and function with HAM compared to medical therapy alone. Clinical input indicated that large RCTs are unlikely due to the severity and rarity of the disease, supported the use of HAM for moderate or severe Stevens-Johnson.

Persistent Epithelial Defects and Ulcerations that does not Respond to Conservative Therapy

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have persistent epithelial defects and ulcerations is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have persistent epithelial defects and ulcerations that do not respond to conservative therapy?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have persistent epithelial defects that do not respond to conservative therapy.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used for persistent epithelial defects and ulceration: medical therapy alone (e.g. topical lubricants, topical antibiotics, therapeutic contact lens, or patching).

Outcomes

The general outcomes of interest are epithelial closure

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

Bouchard and John (2004) reviewed the use of amniotic membrane transplantation in the management of severe ocular surface disease. They noted that c-HAM has been available since 1995, and has become an established treatment for persistent epithelial defects and ulceration refractory to conventional therapy. However, there was a lack of controlled studies due to the rarity of the diseases and the absence of standard therapy. They identified 661 reported cases in the peer-reviewed literature. Most cases reported assessed the conjunctival indications of pterygium, scars and symblepharon, and corneal indications of acute chemical injury and post infectious keratitis. Clinical input recommended HAM for persistent epithelial defects that do not respond to conservative therapy (e.g., topical lubricants and/or antibiotics, therapeutic contact lens, or patching), noting that “the uncommon nature of the diseases associated with persistent epithelial defects and the lack of a standard therapeutic regimen account for the lack of RCTs.”

Section Summary: Persistent Epithelial Defects and Ulceration that does not respond to Conservative Therapy

No RCTs were identified on persistent epithelial defects and ulceration. Clinical input noted the difficulty in conducting RCTs for this indication and supported the use of amniotic membrane for persistent epithelial defects and ulceration that does not respond to conservative therapy.

Severe Dry Eye Disease with Ocular Surface Damage and Inflammation that does not respond to Conservative Therapy

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have severe dry eye is to provide a treatment option that is an alternative to or an improvement on existing therapies. Dry eye disease involves tear film insufficiency with the involvement of the corneal epithelium. Inflammation is common in dry eye disease, which causes additional damage to the corneal epithelium.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have severe dry eye with ocular surface damage and inflammation?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have severe dry eye with ocular surface damage and inflammation.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical management consisting of artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications.

Outcomes

The general outcomes of interest are the pain, corneal surface regularity, and vision, which may be measured by the Report of the International Dry Eye WorkShop score (DEWS). The DEWS assess nine domains with a score of one to four including discomfort, visual symptoms, tear breakup time, corneal signs and corneal staining. Corneal staining with fluorescein or Rose Bengal indicates damaged cell membranes or gaps in the epithelial cell surface. A DEWS of two to four indicates moderate-to-severe dry eye disease.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

The Prokera c-HAM device was evaluated in a 2016 series by Cheng et al. The senior author of the study (S.C.G. Tseng) holds the patent on Prokera. This retrospective review assessed ten patients treated with the self-retained device for moderate-to-severe dry eye disease. In this study, these ten patients had moderate-to-severe dry eye syndrome despite conventional medical treatment. The c-HAM device was placed in 15 eyes (one eye at a time) for a mean of 4.9 days (range, 2-8 days), after which the c-HAM was either dissolved or cloudy. Treatment resulted in symptomatic relief for a mean of 4.2 months (range, 0.3 to 6.8 months) after a single treatment. Symptomatic improvement was accompanied by statistically significant reductions of Ocular Surface Disease Index scores, use of topical medications, conjunctival hyperemia, corneal staining (all p<0.001), and a trend toward improved visual acuity (p=0.06).

John et al (2017) reported on an RCT with 20 patients with moderate-to-severe dry eye disease who were treated with Prokera c-HAM or maximal conventional treatment. The c-HAM was applied for an average of 3.4 days (range, 3-5 days), while the control group continued treatment with artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications. The primary outcome was an increase in corneal nerve density. Signs and symptoms of dry eye disease improved at both one-month and three-month follow-ups in the c-HAM group but not in the conventional treatment group. For example, pain scores decreased from 7.1 at baseline to 2.2 at 1 month and 1.0 at 3 months in the c-HAM group. In vivo confocal microscopy, reviewed by masked readers, showed a significant increase in corneal nerve density in the study group at three months, with no change in nerve density in the controls. Corneal sensitivity was similarly increased in the c-HAM group but not in controls.

The treatment outcomes in the DRy Eye Amniotic Membrane study (McDonald et al [2018]) was a retrospective series of 84 patients (97 eyes) with severe dry eye despite maximal medical therapy who were treated with Prokera self-retained c-HAM. A majority of patients (86%) had superficial punctate keratitis. Other patients had filamentary keratitis (13%), exposure keratitis (19%), neurotrophic keratitis (2%), and corneal epithelial defect (7%). Treatment with Prokera for a mean of 5.4 days (range, 2 to 11) resulted in an improved ocular surface and reduction in the DEWS score from 3.25 at baseline to 1.44 at 1 week, 1.45 at 1 month and 1.47 at 3 months (p=0.001). Ten percent of eyes required repeated treatment. There was no significant difference in the number of topical medications following c-HAM treatment.

Summary: Severe Dry Eye with Ocular Surface Damage and Inflammation that does not respond to Conservative Therapy

The evidence on HAM for severe dry eye with ocular surface damage and inflammation includes an RCT with 20 patients and a retrospective series of 84 patients (97 eyes). Placement of self-retained HAM for 2 to 11 days reduced symptoms and restored a smooth corneal surface and corneal nerve density for as long as 3 months.

Moderate or Severe Acute Ocular Chemical Burns

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have acute ocular burns is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or self-retained HAM improve the net health outcome in patients who have moderate or severe acute ocular chemical burns?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have moderate or severe acute ocular chemical burn.

Interventions

The therapy being considered is sutured or non-sutured HAM.

Comparators

The following therapies are currently being used: medical therapy (e.g. topical antibiotics, lubricants, steroids and cycloplegics, oral vitamin C, doxycycline)

Outcomes

The general outcomes of interest are visual acuity, corneal epithelialization, corneal clarity, and corneal vascularization.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

An RCT of 100 patients with chemical or thermal ocular burns was published by Tandon et al (2011). Half of the patients (n=50) had moderate ocular burns and the remainder (n=50) had severe ocular burns. All but eight of the patients had alkali or acid burns. Patients were randomized to HAM transplantation plus medical therapy or medical therapy alone. Epithelial healing, which was the primary outcome, was improved in the group treated with HAM, but there was no significant difference between the two groups for the final visual outcome, symblepharon formation, corneal clarity or vascularization.

Use of the Prokera self-retained implant was reported by Kheirkhah et al (2008) in a series of 5 patients with acute alkaline burns.

A 2012 Cochrane review evaluated the evidence on HAM graft for acute ocular burns. Included in the review was a single RCT from India of 68 patients with acute ocular burns who were randomized to c-HAM plus medical therapy or to medical therapy alone. In the subset of 36 patients with moderate ocular burns treated within seven days, 13 (65.0%) of 20 control eyes and 14 (87.5%) of 16 AMT-treated eyes had complete epithelialization by 21 days. There was a trend (p=0.09) toward a reduced relative risk of failure of epithelization in the treatment group. Mean logarithm of the minimum angle of resolution (logMAR) final visual acuities were 0.06 in the treatment group and 0.38 in the control group. In the subset of patients with severe ocular burns treated within seven days, one (5.9%) of 17 AMT-treated eyes and one (6.7%) of 15 control eyes were epithelialized by day 21. There was no significant difference in final visual acuity, which was 1.77 logMAR in the treated eyes and 1.64 in the control group (p=NS). The risk of bias was considered high because of differences between the groups at baseline and because outcome assessors could not be masked to treatment. Reviewers determined that conclusive evidence supporting the treatment of acute ocular surface burns with AMT is lacking.

Clinical input recommended HAM for acute ocular chemical burn, noting that “ocular chemical burns represent a diverse array of clinical conditions and severity, making high-quality RCTs difficult or impossible to perform.”

Section Summary: Moderate or Severe Acute Ocular Chemical Burns

Evidence includes an RCT of 100 patients with acute ocular chemical burns who were treated with HAM transplantation plus medical therapy or medical therapy alone. Patients in the HAM group had a faster rate of epithelial healing, without a significant benefit for other outcomes. Clinical input was in support of HAM for acute ocular chemical burn.

Corneal Perforation When Corneal Tissue is not Immediately Available

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have corneal perforation when corneal tissue is not immediately available is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured HAM improve the net health outcome in patients who have corneal perforation?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have corneal perforation when corneal tissue is not immediately available.

Interventions

The therapy being considered is sutured HAM.

Comparators

The following therapies are currently being used: conservative management.

Outcomes

The general outcomes of interest are eye pain.

Timing

Changes in symptoms may be measured in days, while changes in the ocular surface would be measured at one to three months.

Setting

The setting is outpatient care by an ophthalmologist for self-retained HAM or in a surgical suite for sutured HAM.

Review of Evidence

No RCTs were identified on corneal perforation.

Clinical input noted that multiple layers of HAM have been shown to promote healing of corneal perforation and recommended sutured HAM for tectonic support when corneal tissue is not immediately available.

Section Summary: Corneal Perforation When Corneal Tissue is not Immediately Available

The standard treatment for corneal perforation is corneal transplantation. Based on clinical input, sutured HAM may be used as a temporary measure when corneal tissue is not immediately available.

Following Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

Clinical Context and Therapy Purpose

The purpose of HAM in patients who have pterygium repair is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: does the use of sutured or glued HAM improve the net health outcome in patients who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft (e.g., extensive, double, or recurrent pterygium)?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are patients who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Interventions

The therapy being considered is sutured or glued HAM.

Comparators

The following therapies are currently being used: conjunctival autograft.

Outcomes

The general outcomes of interest are a recurrence of pterygium.

Timing

Pterygium recurrence would be measured at one to three months.

Setting

The setting is in a surgical suite for pterygium repair.

Review of Evidence

RCTs have been reported on the use of amniotic membrane following pterygium repair. The American Academy of Ophthalmology (2013) published a technology assessment on options and adjuvants for pterygium surgery. Reviewers identified four RCTs comparing conjunctival or limbal autograft procedure with amniotic membrane graft, finding that conjunctival or limbal autograft was more effective than HAM graft in reducing the rate of pterygium recurrence. A 2016 Cochrane review of 20 RCTs (total n=1866 patients) arrived at the same conclusion. Clinical input recommended sutured or glued HAM for pterygium repair when there was insufficient healthy tissue to create a conjunctival autograft (e.g., extensive, double, or recurrent pterygium).

Section Summary: Following Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

Systematic reviews of RCTs have been published that found that conjunctival or limbal autograft is more effective than HAM graft in reducing the rate of pterygium recurrence. Based on clinical input, sutured or glued HAM may be considered when there is insufficient healthy tissue to create a conjunctival autograft (e.g., extensive, double, or recurrent pterygium).

Summary of Evidence

Neurotrophic Keratitis with Ocular Surface Damage and Inflammation That Does Not Respond to Conservative Therapy

For individuals who have neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy who receive HAM, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. An RCT of 30 patients showed no benefit of sutured HAM graft compared to tarsorrhaphy or bandage contact lens. Based on clinical input, HAM might be considered for patients who did not respond to conservative therapy. Clinical input indicated that non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Corneal Ulcers and Melts That Does Not Respond to Initial Medical Therapy

For individuals who have corneal ulcers and melts that does not respond to initial medical therapy who receive HAM, the evidence is limited. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. Corneal ulcers and melts are uncommon and variable and RCTs are not expected. Based on clinical input, HAM might be considered for patients who did not respond to conservative therapy. Clinical input indicated that non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Corneal Perforation When There is Active Inflammation after Corneal Transplant Requiring Adjunctive Treatment

For individuals who have corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment who receive HAM, the evidence is limited. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. No comparative evidence was identified for this indication. Clinical input supported the use of HAM to reduce inflammation and promote epithelial healing with active inflammation following corneal transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Bullous Keratopathy as a Palliative Measure in Patients Who are not Candidates for a Curative Treatment (e.g., endothelial or penetrating keratoplasty)

For individuals who have bullous keratopathy and who are not candidates for curative treatment (e.g., endothelial or penetrating keratoplasty) who receive HAM, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. An RCT found no advantage of sutured HAM over the simpler stromal puncture procedure for the treatment of pain from bullous keratopathy. Based on clinical input, non-sutured HAM could be used as an alternative to stromal puncture. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Partial Limbal Stem Cell Deficiency with Extensive Diseased Tissue Where Selective Removal Alone is not sufficient

For individuals who have partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient who receive HAM, the evidence is limited. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. No RCTs were identified on HAM for limbal stem cell deficiency. Improvement in visual acuity has been reported for some patients who have received HAM in conjunction with removal of the diseased limbus. Clinical input noted the limitations of performing an RCT and supported the use of HAM for this indication. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Moderate or Severe Stevens - Johnson syndrome

For individuals who have moderate or severe Stevens-Johnson syndrome who receive HAM, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. The evidence on HAM for the treatment of Stevens-Johnson includes one RCT with 25 patients (50 eyes) that found improved symptoms and function with HAM compared to medical therapy alone. Clinical input indicated that large RCTs are unlikely due to the severity and rarity of the disease, supported the use of HAM for moderate or severe Stevens-Johnson syndrome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Persistent Epithelial Defects and Ulceration That Do Not Respond to Conservative Therapy

For individuals who have persistent epithelial defects that do not respond to conservative therapy who receive HAM, the evidence is limited. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. No RCTs were identified on persistent epithelial defects and ulceration. Clinical input noted the difficulty in conducting RCTs for this indication and supported the use of amniotic membrane for persistent epithelial defects and ulcerations that do not respond to conservative therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Severe Dry Eye with Ocular Surface Damage and Inflammation That Does Not Respond to Conservative Therapy

For individuals who have severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy, who receive HAM, the evidence includes an RCT and a large case series. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. The evidence on HAM for severe dry eye with ocular surface damage and inflammation includes an RCT with 20 patients and a retrospective series of 84 patients (97 eyes). Placement of self-retained HAM for 2 to 11 days reduced symptoms and restored a smooth corneal surface and corneal nerve density for as long as 3 months.

Moderate or Severe Acute Ocular Chemical Burns

For individuals who have moderate or severe acute ocular chemical burn who receive HAM, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. Evidence includes an RCT of 100 patients with acute ocular chemical burns who were treated with HAM transplantation plus medical therapy or medical therapy alone. Patients in the HAM group had a faster rate of epithelial healing, without a significant benefit for other outcomes. Clinical input was in support of HAM for acute ocular chemical burn. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Corneal Perforation When Corneal Tissue is not Immediately Available

For individuals who have corneal perforation when corneal tissue is not immediately available who receive sutured HAM, the evidence is limited. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. The standard treatment for corneal perforation is corneal transplantation. Based on clinical input, sutured HAM may be used as a temporary measure when corneal tissue is not immediately available. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Pterygium Repair When There is Insufficient Healthy Tissue to Create a Conjunctival Autograft

For individuals who have pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft who receive HAM, the evidence includes RCTs and systematic reviews of RCTs. The relevant outcomes are symptoms, morbid events, functional outcomes, and QOL. Systematic reviews of RCTs have been published that found that conjunctival or limbal autograft is more effective than HAM graft in reducing the rate of pterygium recurrence. Based on clinical input, sutured or glued HAM may be considered when there is insufficient healthy tissue to create a conjunctival autograft (e.g., extensive, double, or recurrent pterygium). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Clinical Input

In 2019, clinical input was sought to help determine whether the use of human amniotic membrane graft either without or with suture fixation for several ophthalmic conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice.

Respondents

Clinical input was provided by the following specialty societies and physician members identified by a specialty society or clinical health system:

  • American Academy of Ophthalmology (AAO)

  • Mark Latina, MD, Ophthalmology, Tufts University School of Medicine, identified by Massachusetts Society of Eye Physicians and Surgeons

Clinical input provided by the specialty society at an aggregate level is attributed to the specialty society. Clinical input provided by a physician member designated by a specialty society or health system is attributed to the individual physician and is not a statement from the specialty society or health system. Specialty society and physician respondents participating in the Evidence Street® clinical input process provide a review, input, and feedback on topics being evaluated by Evidence Street. However, participation in the clinical input process by a specialty society and/or physician member designated by a specialty society or health system does not imply an endorsement or explicit agreement with the Evidence Opinion published by BCBSA or any Blue Plan.

 

 

Practice Guidelines and Position Statements

Tear Film and Ocular Surface Society

The Tear Film and Ocular Surface Society (2017) published the DEWS [Dry Eye Workshop] II management and therapy report. The report evaluated the evidence on treatments for dry eye and provided a treatment algorithm for dry eye disease management. The full report is available at:

https://www.tearfilm.org/dettreports-tfos_dews_ii_report/32_30/eng/

 

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Absence of iris; Amniotic membrane transplantation; AMT; dry eye syndrome; keratopathy; bullous keratopathy; conjunctivochalasis; corneal degeneration; corneal ectasia; corneal staphyloma; descemetocele; other corneal deformity; corneal ulceration; corneal defect; corneal disorder due to contact lens or recurrent erosion of cornea; conjunctival lesion removal; hereditary corneal dystrophies; neurotrophic keratoconjunctivitis; ocular burns; pterygium; pseudopterygium; Stevens-Johnsons Syndrome; SJS; Prokera

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Human amniotic membrane products and amniotic fluid products are included in these regulations.

In 2003, Prokera™ was cleared for marketing by FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). FDA determined that this device was substantially equivalent to the Symblepharon Ring. The Prokera™ device is intended “for use in eyes in which the ocular surface cells have been damaged, or underlying stroma is inflamed and scarred.”

AmnioClip (FORTECH GmbH) is a ring designed to hold the amniotic membrane in the eye without sutures or glue fixation. A mounting device is used to secure the amniotic membrane within the AmnioClip. The AmnioClip currently has CE approval in Europe.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

65778

 Placement of amniotic membrane on the ocular surface; without sutures

65779

  ; single layer, sutured

65780

 Ocular surface reconstruction; amniotic membrane transplantation, multiple layers

 

REFERENCES:

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  12. Georgiadis NS, Terzidou CD. Epiphora caused by conjunctivochalasis: treatment with transplantation of preserved amniotic membrane. Cornea. 2001; 20: 619-21.
  13. Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic epidermal necrolysis using amniotic membrane: A review of 10 consecutive cases. Opthalmology. 2011; 118(5):908-14.
  14. Hanada K, Shimazaki J, Shimmura S, et al. Multilayered amniotic membrane transplantation for severe ulceration of the cornea and sclera. Am J Ophthalmol. 2001; 131(3): 324-31.
  15. Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin glue in the management of corneal ulcers and perforation: a review of 33 cases. Cornea 2005; 24(4): 369-77.
  16. Honavar S, Bansai A, Sangwan V, et al. Amniotic membrane transplantation for ocular surface reconstruction in Stevens-Johnson syndrome. Ophthalmology. 2000; 107(5):975-79.
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  18. John TT, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. Aug 15 2017; 2017:6404918.
  19. John TT, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol, 2017 Sep 13;2017:6404918.
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  21. Kheirkhah A, Blanco G, Casas V, et al. Surgical strategies for fornix reconstruction based on symblepharon severity. Am J Ophthalmol. 2008; 146(2): 266-75.
  22. Kheirkhah A, Casas V, Blanco G, et al. Amniotic membrane transplantation with fibrin glue for conjunctivochalasis. Am J Ophthalmol. 2007; 144(2): 311-13.
  23. Kheirkhah A, Casas V, Esquenazi S, et al. New surgical approach for superior conjunctivochalasis. Cornea. 2007; 26(6): 685-91.
  24. Kheirkhah A, Johnson DA, Paranjpe DR, et al. Temporary sutureless amniotic membrane patch for acute alkaline burns. Arch Ophthalmol. 2008; 126:1059-66.
  25. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea. Aug 2005; 24(6):654-660.
  26. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea, 2005 Jul 15;24(6).
  27. Kim HK, Park HS. Fibrin glue-assisted augmented amniotic membrane transplantation for the treatment of large noninfectious corneal perforations. Cornea. 2009; 28(2): 170-76.
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  29. McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the Dry Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018 Apr 9;12:677-681.
  30. Meller D, Maskin SL, Pires RTF, et al. Amniotic membrane transplantation for symptomatic conjunctivochalasis refractory to medical treatments. Cornea. 2000; 19(6):796-803.
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  33. Paridaens D, Beekhuis H, van Den Bosch W, et al. Amniotic membrane transplantation in the management of conjunctival malignant melanoma and primary acquired melanosis with atypia. Br J Ophthalmol. 2001; 85: 658-61.
  34. Paris Fdos S, Goncalves ED, Campos MS, et al. Amniotic membrane transplantation versus anterior stromal puncture in bullous keratopathy: a comparative study. Br J Ophthalmol. Aug 2013; 97(8):980-984.
  35. Parolini O, Soncini M, Evangelista M, et al. Amniotic membrane and amniotic fluid-derived cells: potential tools for regenerative medicine? Regen Med. Mar 2009;4(2):275-291.
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  46. Suri K, Kosker M, Raber I, et al. Sutureless Amniotic Membrane ProKera for Ocular Surface Disorders. Short-Term Results. Eye Contact Lens. 2013;39:341-347
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  48. Tandon R, Gupta N, Kalaivani M, et al. Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns. Br J Ophthalmol. 2011; 95(2): 199-204.
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POLICY HISTORY:

Medical Policy Group, February 2016 (6):  Newly adopted policy.

Medical Policy Administration Committee, March 2016

Available for comment March 4 through May 5, 2016

Medical Policy Group, May 2016 (3): Updated literature review and clarified/expanded policy statement indications; updated Key Words & References

Medical Policy Administration Committee, May 2016

Medical Policy Panel, May 2017

Medical Policy Group, July 2017 (3): 2017 Updates on Description, Key Points, Governing Bodies, Key Words & References; clarified policy statements with types of grafts approved to coincide with coding and moved regulatory language to Governing Bodies section – no change in intent

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (3):  2018 Updates to Key Points & References; no change in policy statements.

Medical Policy Panel February 2019

Medical Policy Group, June 2019 (6) Updates to Description, Key Points, Practice Guidelines and References. Policy statement updated to include coverage for :Partial limbal stem cell deficiency, Persistent Epithelial defects and corneal perforation after corneal transplant.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.