POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

Original Issue Date (Created): 7/9/2002 Most Recent Review Date (Revised): 7/21/2015

Effective Date: 12/1/2015

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Corneal Transplant

Corneal transplantation may be considered medically necessary for patients with the following conditions:

 Aphakic corneal edema  Chemical injuries

 Complications of transplanted organ  Congenital opacities

 Corneal degenerations  Ectasias/thinnings  Keratoconus

 Mechanical complication of corneal graft  Mechanical trauma, non-surgical

 Microbial /post-microbial keratitis

 Non-infectious ulcerative keratitis or perforation  Other causes of corneal opacification/distortion  Primary corneal endotheliopathies

 Pseudophakic corneal edema  Regraft related to allograft rejection  Regraft unrelated to allograft rejection  Stromal corneal dystrophies

 Viral/post-viral keratitis

Corneal transplantation for indications other than those listed in this policy (e.g., astigmatism, correction of refractive errors) is considered not medically necessary.

Endothelial Keratoplasty

Endothelial keratoplasty (Descemet’s stripping endothelial keratoplasty [DSEK] or Descemet’s stripping automated endothelial keratoplasty [DSAEK], Descemet’s membrane endothelial

POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND

RATIONALE DEFINITIONS BENEFIT VARIATIONS

DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

keratoplasty [DMEK] or Descemet’s membrane automated endothelial keratoplasty [DMAEK]) may be considered medically necessary for the treatment of endothelial dysfunction, including but not limited to the following conditions:

 ruptures in Descemet’s membrane  endothelial dystrophy

 aphakic and pseudophakic bullous keratopathy  iridocorneal endothelial (ICE) syndrome  corneal edema attributed to endothelial failure  failure or rejection of a previous corneal transplant

Femtosecond laser-assisted corneal endothelial keratoplasty (FLEK) or femtosecond and excimer lasers-assisted endothelial keratoplasty (FELEK) are considered investigational. There is

insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure.

Endothelial keratoplasty is not medically necessary when endothelial dysfunction is not the primary cause of decreased corneal clarity.

Policy guidelines

Endothelial keratoplasty should not be used in place of PK for conditions with concurrent endothelial disease and anterior corneal disease. These situations would include concurrent anterior corneal dystrophies, anterior corneal scars from trauma or prior infection, and ectasia after previous laser vision correction surgery. Clinical input suggested that there may be cases where anterior corneal disease should not be an exclusion, particularly if endothelial disease is the primary cause of the decrease in vision. EK should be performed by surgeons who are adequately trained and experienced in the specific techniques and devices used.

Keratoprostheses

The Boston Keratoprosthesis (Boston KPro) may be considered medically necessary for the treatment of corneal blindness under the following conditions:

 The cornea is severely opaque and vascularized; AND

 Best-corrected vision is ≤20/400 in the affected eye and ≤20/40 in the opposite eye; AND

 The patient has had one or more prior failed corneal transplants AND

 No end-stage glaucoma or retinal detachment is present; AND

 The patient has one of the following indications: o Multiple corneal transplant graft failures

o Stevens-Johnson syndrome o Ocular cicatricial pemphigoid

o Autoimmune conditions with rare ocular involvement o Ocular chemical burns

o An ocular condition unlikely to respond favorably to primary corneal transplant surgery (e.g., limbal stem cell compromise or post herpetic anesthesia)

Patients should be expected to be able to be compliant with postoperative care.

Note: Implantation of a keratoprosthesis is considered a high-risk procedure associated with numerous complications and probable need for additional surgery. Therefore, the likelihood of regaining vision and the patient’s visual acuity in the contralateral eye should be taken into account when considering the appropriateness of this procedure. Treatment should be restricted to centers experienced in treating this condition and staffed by surgeons adequately trained in techniques addressing implantation of this device.

A permanent keratoprosthesis for all other conditions is considered investigational. All other types of permanent keratoprostheses are considered investigational.

There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with these procedures.

Cross-references:

MP-1.044 Corneal Surgery to Correct Refractive Errors and Phototherapeutic Keratoplasty

MP-6.031 Gas Permeable Scleral Contact Lens and Therapeutic Soft Contact Lens

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[N] = No product variation, policy applies as stated

[Y] = Standard product coverage varies from application of this policy, see below

[N] Capital Cares 4 Kids [N] Indemnity

[N] PPO [N] SpecialCare

[N] HMO [N] POS

[N] SeniorBlue HMO [Y] FEP PPO*

* Refer to FEP Medical Policy Manual MP-9.03.22 Endothelial Keratoplasty and MP 9.03.01 Keratoprosthesis. The FEP Medical Policy manual can be found at:

http://bluewebportal.bcbs.com/landingpagelevel3/504100?docId=23980

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Corneal Transplant

Corneal transplants are also referred to as keratoplasty. This surgical procedure is usually performed under local anesthesia in an outpatient setting and involves implantation of a cornea from a donor eye. This is the most common organ transplant procedure in the United States. There are two major types of corneal transplants, lamellar keratoplasty and penetrating keratoplasty (PK).

Endothelial Keratoplasty

Endothelial keratoplasty (EK), also referred to as posterior lamellar keratoplasty, is a form of corneal transplantation in which the diseased inner layer of the cornea, the endothelium, is replaced with healthy donor tissue. Specific techniques include Descemet’s stripping endothelial keratoplasty, Descemet’s stripping automated endothelial keratoplasty, or Descemet’s membrane endothelial keratoplasty.

The cornea, a clear, dome-shaped membrane that covers the front of the eye, is a key refractive element of the eye. Layers of the cornea consist of the epithelium (outermost layer); Bowman’s layer; the stroma, which comprises approximately 90% of the cornea; Descemet’s membrane; and the endothelium. The endothelium removes fluid from the stroma and limits entry of fluid as well, thereby maintaining the ordered arrangement of collagen and preserving the cornea’s transparency. Diseases that affect the endothelial layer include Fuchs’ endothelial dystrophy, aphakic and pseudophakic bullous keratopathy (corneal edema following cataract extraction), and failure or rejection of a previous corneal transplant.

The established surgical treatment for corneal disease is penetrating keratoplasty (PK), which involves the creation of a large central opening through the cornea and then filling the opening with full-thickness donor cornea that is sutured in place. Visual recovery after PK may take 1 year or more due to slow wound healing of the avascular full-thickness incision, and the procedure frequently results in irregular astigmatism due to the sutures and the full-thickness vertical corneal wound. PK is associated with an increased risk of wound dehiscence,

endophthalmitis, and total visual loss after relatively minor trauma for years after the index procedure. There is also risk of severe, sight-threatening complications such as expulsive suprachoroidal hemorrhage, in which the ocular contents are expelled during the operative procedure, as well as postoperative catastrophic wound failure.

A number of related techniques have been, or are being, developed to selectively replace the diseased endothelial layer. One of the first endothelial keratoplasty (EK) techniques was termed

deep lamellar endothelial keratoplasty (DLEK), which used a smaller incision than PK, allowed more rapid visual rehabilitation, and reduced postoperative irregular astigmatism and suture complications. Modified EK techniques include endothelial lamellar keratoplasty,

endokeratoplasty, posterior corneal grafting, and microkeratome-assisted posterior keratoplasty. Most frequently used at this time are Descemet’s stripping endothelial keratoplasty (DSEK), which uses hand-dissected donor tissue, and Descemet’s stripping automated endothelial keratoplasty (DSAEK), which uses an automated microkeratome to assist in donor tissue dissection. A laser may also be utilized for stripping in a procedure called femtosecond laser-assisted corneal endothelial keratoplasty (FLEK) or femtosecond and excimer lasers-laser-assisted endothelial keratoplasty (FELEK). These techniques include some donor stroma along with the endothelium and Descemet’s membrane, which results in a thickened stromal layer after

transplantation. If the donor tissue comprises Descemet’s membrane and endothelium alone, the technique is known as Descemet’s membrane endothelial keratoplasty (DMEK). By eliminating the stroma on the donor tissue and possibly reducing stromal interface haze, DMEK is

considered to be a potential improvement over DSEK/DSAEK. A variation of DMEK is Descemet’s membrane automated EK (DMAEK). DMAEK contains a stromal rim of tissue at the periphery of the DMEK graft to improve adherence and increase ease of handling of the donor tissue.

EK involves removal of the diseased host endothelium and Descemet’s membrane with special instruments through a small peripheral incision. A donor tissue button is prepared from

corneoscleral tissue after removing the anterior donor corneal stroma by hand (e.g., DSEK) or with the assistance of an automated microkeratome (e.g., DSAEK) or laser (FLEK or FELEK). Several microkeratomes have received clearance for marketing through the U.S. Food and Drug Administration (FDA) 510(k) process. Donor tissue preparation may be performed by the surgeon in the operating room, or by the eye bank and then transported to the operating room for final punch out of the donor tissue button. To minimize endothelial damage, the donor tissue must be carefully positioned in the anterior chamber. An air bubble is frequently used to center the donor tissue and facilitate adhesion between the stromal side of the donor lenticule and the host posterior corneal stroma. Repositioning of the donor tissue with application of another air bubble may be required in the first week if the donor tissue dislocates. The small corneal incision is closed with one or more sutures, and steroids or immunosuppressants may be provided either topically or orally to reduce the potential for graft rejection. Visual recovery following EK is typically achieved in 4-8 weeks, in comparison with the year or more that may be needed following PK.

Eye Bank Association of America (EBAA) statistics show the number of EK cases in the United States increased from 1,429 in 2005 to 23,409 in 2012. The EBAA report estimates that approximately 1/2 of corneal transplants performed in the U.S. were endothelial grafts. As with any new surgical technique, questions have been posed about long-term efficacy and the risk of complications. EK-specific complications include graft dislocations, endothelial cell loss, and rate of failed grafts. Long-term complications include increased intraocular pressure, graft

rejection, and late endothelial failure. Also of interest is the impact of the surgeon’s learning curve on the risk of complications.

Keratoprostheses

A keratoprosthesis is an artificial cornea that is intended to restore vision to patients with severe bilateral corneal disease (such as prior failed corneal transplants, chemical injuries, or certain immunologic conditions) for whom a corneal transplant is not an option.

The cornea, a clear, dome-shaped membrane that covers the front of the eye, is a key refractive element of the eye. Layers of the cornea consist of the epithelium (outermost layer); Bowman’s layer; the stroma, which comprises approximately 90% of the cornea; Descemet’s membrane; and the endothelium. The established surgical treatment for corneal disease is penetrating keratoplasty (PK), which involves making a large central opening through the cornea and then filling the opening with full-thickness donor cornea. In certain conditions, such as Stevens-Johnson syndrome; cicatricial pemphigoid; chemical injury; or prior failed corneal transplant, survival of transplanted cornea is poor. The keratoprosthesis has been developed to restore vision in patients for whom a corneal transplant is not an option.

Keratoprosthetic devices consist of a central optic held in a cylindrical frame. The

keratoprosthesis replaces the section of cornea that has been removed, and, along with being held in place by the surrounding tissue, may be covered by a membrane to further anchor the prosthesis. A variety of biologic materials are being investigated to improve the integration of prosthetic corneal implants into the stroma and other corneal layers.

Autologous keratoprostheses use a central polymethylmethacrylate (PMMA) optic supported by a skirt of either tibia bone or the root of a tooth with its surrounding alveolar bone. The most common is the osteo-odonto keratoprosthesis (OOKP), which uses osteodental lamina derived from an extracted tooth root and attached alveolar bone that has been removed from the

patient’s jaw. Insertion of the OOKP device requires a complex staged procedure, in which the cornea is first covered with buccal mucosa. The prosthesis itself consists of a PMMA optical cylinder, which replaces the cornea, held in place by a biological support made from a canine tooth extracted from the recipient. A hole is drilled through the dental root and alveolar bone, and the PMMA prosthesis is placed within. This entire unit is placed into a subcutaneous ocular pocket and is then retrieved 6 to 12 months later for final insertion.

Hydroxyapatite, with a similar mineral composition to both bone and teeth (phosphate and calcium), may also be used as a bone substitute and as a bioactive prosthesis with the orbit. Collagen coating and scaffolds have also been investigated to improve growth and

biocompatibility with the cornea epithelial cells, which form the protective layer of the eye. Many of these materials and devices are currently being tested in vitro or in animal models. Regulatory Status

A keratoprosthesis is a Class II U.S. Food and Drug Administration (FDA) device intended to provide a transparent optical pathway through an opacified cornea, in an eye that is not a

reasonable candidate for a corneal transplant. Two permanent keratoprostheses have received 510(k) marketing clearance by FDA. The Dohlman-Doane Keratoprosthesis, also referred to as the Boston Keratoprosthesis (KPro), is manufactured under the auspices of the Harvard Medical School-affiliated Massachusetts Eye and Ear Infirmary. The Boston type I KPro uses an optic between a central stem and a back plate. The Boston type II prosthesis is a modification of the type I prosthesis and is designed with an anterior extension to allow implantation through surgically closed eyelids. The AlphaCor, previously known as the Chirila keratoprosthesis (Chirila KPro) marketed by Argus Biomedical was cleared for marketing by FDA in 2002. The AlphaCor prosthesis consists of a PMMA device with a central optic region fused with a surrounding sponge skirt; the device is inserted in a 2-stage surgical procedure. According to the 510(k) summary, the AlphaCor keratoprosthesis was shown to be substantially equivalent to the Dohlman-Doane Type I Keratoprosthesis. Both devices are indicated as permanent

implantable keratoprostheses for eyes that are not corneal transplant candidates and are made of materials that have been proven to be biocompatible.

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Endothelial Keratoplasty Literature Review

The most recent review was performed through July 29, 2014.

Descemet’s Stripping Endothelial Keratoplasty (DSEK) and Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK)

A 2009 review, performed by the American Academy of Ophthalmology’s (AAO) Ophthalmic Technology Assessment Committee, of the safety and efficacy of DSAEK identified one level-I study (randomized controlled trial [RCT] of precut vs. surgeon dissected) along with 9 level-II (well-designed observational studies) and 21 level-III studies (mostly retrospective case series). (1) Although more than 2,000 eyes treated with DSAEK were reported on in different

publications, most were reported by one research group with some overlap in patients. The main results from this evidence review are as follows:

 DSAEK-induced hyperopia ranged from 0.9 to 1.5 diopters (D), with minimal induction of astigmatism (ranging from 0 to 0.6 D).

 The reporting of visual acuity was not standardized in the studies reviewed. The average best-corrected visual acuity (BCVA) ranged from 20/33 to 20/66, and the percentage of patients seeing 20/40 or better ranged from 38% to 100%.

 The most common complication from DSAEK in the studies reviewed was posterior graft dislocation (mean 14%; range 0–82%), with a lack of adherence of the donor posterior lenticule to the recipient stroma, typically occurring within the

first week. It was noted that this figure may be skewed by multiple publications from one research group with low complication rates. Graft dislocation required additional surgical procedures (rebubble procedures) but did not lead to sight-threatening vision loss in the articles reviewed.

 Endothelial graft rejection occurred in an average 10% of patients (range, 0– 45%); most were reversed with topical or oral immunosuppression, with some cases progressing to graft failure. Primary graft failure, defined as unhealthy tissue that has not cleared within 2 months, occurred in 5% of patients (range 0– 29%). Iatrogenic glaucoma occurred in an average of 3% of patients (range 0– 15%) due to a pupil block induced from the air bubble in the immediate postoperative period or delayed glaucoma from topical corticosteroid adverse effects.

 Endothelial cell loss, which provides an estimate of long-term graft survival, was an average 37% at 6 months and 42% at 12 months. This percentage of cell loss was reported to be similar to that observed with penetrating keratoplasty (PK). The technology assessment concluded that DSAEK appears to be at least equivalent to PK in terms of safety, efficacy, surgical risks, and complication rates, although long-term results are not yet available. The evidence also indicated that endothelial keratoplasty (EK) is superior to PK in terms of refractive stability, postoperative refractive outcomes, wound- and suture-related complications, and risk of intraoperative choroidal hemorrhage. The reduction in serious and occasionally catastrophic adverse events associated with PK has led to the rapid adoption of EK in place of PK for the treatment of corneal endothelial failure.

It was noted that the specific techniques are still evolving; the authors identified the following future research needs:

“Future research should be directed at assessing better surgical techniques for increasing endothelial cell survival with endothelial procedures, whether this represents new surgical techniques and/or new instrumentation…. Both new surgical techniques such as Descemet’s membrane endothelial keratoplasty and new insertion techniques must be validated by basic laboratory ex vivo studies and large, well-designed cohort or randomized controlled studies and/or long-term prospective studies demonstrating complication rates and long-term endothelial cell survival.”

A number of studies included in the AAO review were from Chen and colleagues at the Devers Eye Institute. One of the publications reported 6-month clinical outcomes from 100 of the first 150 consecutive eyes treated by DSAEK at this tertiary care center during 2005 and 2006. (2) Fifty eyes were not available for 6-month follow-up due to illness, death, or

residence out of state. Preoperatively, every patient had a diagnosis of endothelial dysfunction with clinically evident stromal edema; BCVA averaged 20/86, and uncorrected visual acuity (UCVA) averaged 20/155. Cataract surgery (n=51) was concurrently performed if the patient

had visually significant cataract or mild cataract with expectation of progression and minimal remaining accommodative amplitude. At 6-month follow-up, all grafts were clear, and there were no primary graft failures. There was an average gain of greater than 4 Snellen lines with an average BCVA of 20/38. Eighty-five percent of eyes had better visual acuity than they had preoperatively, and 81% obtained vision of 20/40 or better. When patients were excluded due to other possible causes of visual loss such as macular or glaucomatous damage, BCVA improved from 20/60 to 20/30 (n=74), with an average gain of 3 Snellen lines. Eighty-eight percent of eyes in this group had better visual acuity at 6 months than they had preoperatively, and 97% of eyes had obtained a vision of 20/40 or better. The reporting of results on visual acuity did not distinguish between patients who had received concurrent cataract surgery and those whose improvements could be attributed entirely to DSAEK.

Searches of the MEDLINE database, performed to identify additional reports published after the AAO technology assessment, have identified case reports on complications (e.g., epithelial ingrowth and adverse effects of the bubbles), as well as a number of papers on DSEK/DSAEK technique. Chen and colleagues reported the effect of training on outcomes following DSAEK. (3) Of 327 consecutive cases performed at their tertiary care centers during 2005–2007, 235 were performed by the attending corneal surgeon, and 92 were performed by the corneal fellows. Loss to follow-up at 6 months (36% to 37%) was due to illness, death, or residence out of state. For the 208 patients who returned for the 6-month assessment, 91% of those treated by the attending surgeon and 69% of those treated by fellows had also undergone concurrent phacoemulsification for visually significant cataract at the time of DSAEK. There were no graft failures in either group, and all grafts were clear at the 6-month assessment. Dislocations and endothelial cell loss were similar in the 2 groups of patients (2% vs.1% dislocations, respectively, and mean cell loss of 32% and 35%, respectively). Patients from both groups gained approximately 4 Snellen lines, with a 6-month average best corrected visual acuity of 20/37 and 20/36. Vision of 20/40 or better was obtained by 78% of patients treated by attending surgeons and 90% of patients treated by fellows. Vision of 20/20 or better was obtained by 14% of patients treated by attending surgeons and 3% treated by fellows. Longer-term graft survival has been reported in a retrospective analysis from the Cornea Research Foundation of America and Price Vision Group. (4) A total of 453 cases were identified (out of 835 performed) that had received DSEK by a single surgeon between 2003 and 2007 and had at least 1-year follow-up. Most cases (n=342) had no preexisting glaucoma, while 65 had medically managed glaucoma and 46 had undergone prior glaucoma surgery with either a shunt or trabeculectomy. With graft failure defined as persistent corneal edema resulting in irreversible loss of optical clarity, 1-year graft survival was similar (96% to 100%) in the 3 groups. Kaplan-Meier analysis showed 5-year graft survival to be 96% in eyes with no prior glaucoma, 90% in eyes with medically managed preexisting glaucoma, and 48% in eyes with prior glaucoma surgery (p<0.001). In a multivariate model, prior glaucoma surgery and a prior rejection episode were significant risk factors for corneal endothelial failure.

Three-year outcomes after DSAEK were reported from the Devers Eye Institute in 2012. (5) This retrospective analysis included 108 patients who underwent DSAEK for Fuchs’

endothelial dystrophy or pseudophakic bullous keratopathy and had no other ocular

comorbidities. BCVA was measured at 6 months, and 1, 2, and 3 years. BCVA after DSAEK was found to improve over the 3 years of the study. For example, the percentage of patients who reached a visual acuity of 20/20 or greater was 0.9% at baseline, 11.1% at 6 months, 13.9% at 1 year, 34.3% at 2 years, and 47.2% at 3 years. Ninety-eight percent of patients reached a visual acuity of 20/40 or greater by 3 years.

Descemet’s Membrane Endothelial Keratoplasty (DMEK) and Descemet’s Membrane Automated Endothelial Keratoplasty (DMAEK)

Reviews suggest that by eliminating the stroma on the donor tissue, DMEK/DMAEK may reduce stromal interface haze and provide better visual acuity outcomes than DSEK/DSAEK. (6, 7) Current literature is limited to large case series and retrospective comparisons. Tourtas et al. reported a retrospective comparison of 38 consecutive patients/eyes that underwent DMEK versus 35 consecutive patients/eyes that had undergone DSAEK. (8) Only patients with Fuchs’ endothelial dystrophy or pseudophakic bullous keratopathy were included in the study. After DMEK, 82% of eyes required rebubbling. After DSAEK, 20% of eyes required rebubbling. BCVA in the 2 groups was comparable at baseline (DMEK, 0.70 logMAR and DSAEK, 0.75 logMAR). At 6-month follow-up, mean visual acuity improved to 0.17 logMAR after DMEK and 0.36 logMAR after DSAEK. This difference was statistically significant. At 6 months following surgery, 95% of DMEK-treated eyes reached a visual acuity of 20/40 or better and 43% of DSAEK-treated eyes reached a visual acuity of 20/40 or better. Endothelial cell density decreased by a similar amount after the 2 procedures (41% after DMEK and 39% after DSAEK).

In 2013, Van Dijk et al. reported outcomes of their first 300 consecutive eyes treated with DMEK. (9) Indications for DMEK were Fuchs’ dystrophy, pseudophakic bullous keratopathy, failed PK, or failed EK. Of the 142 eyes (64%) evaluated for visual outcome at 6 months, 79% reached a BCVA of 20/25 or more and 46% reached a BCVA of 20/20 or more. Endothelial cell density measurements at 6 months were available in 251 eyes, with an average cell density of 1,674 cells/mm2, a decrease of 34.6% from preoperative donor cell density. The major postoperative complication in this series was graft detachment requiring rebubbling or regraft, which occurred in 10.3% of eyes. Allograft rejection occurred in 3 eyes (1%). Twenty eyes (6.7%) had an elevation of intraocular pressure. Except for 3 early cases that may have been prematurely regrafted, all but 1 eye with an attached graft cleared in 1-12 weeks.

A review of the first 50 consecutive cases from another group in Europe suggests that a greater number of patients achieve 20/25 vision or better with DMEK. (10) Of the 50 consecutive eyes, 10 (20%) required a secondary DSEK for failed DMEK. For the remaining 40 eyes, 95% had a BCVA of 20/40 or better, and 75% had a BCVA of 20/25 or better. Donor detachments and primary graft failure with DMEK were problematic, and the ultimate success of DMEK will depend on the reliability of graft adherence and demonstrated improvement in visual

acuity outcomes in comparison with DSAEK. In 2011, this group reported on the learning curve of DMEK, with their first 135 consecutive cases retrospectively divided into 3 subgroups of 45 eyes. (11) Graft detachment was the most common complication and decreased with experience. In their first 45 cases, a complete or partial graft detachment occurred in 20% of cases, compared with 13.3% in the second group and 4.4% in the third group. Clinical outcomes in eyes with normal visual potential and a functional graft (n=110) were found to be similar in the 3 groups, with an average endothelial cell density of 1,747 cells and 73% of cases achieving a BCVA of 20/25 or better at 6 months.

A North American group reported 3-month outcomes from a prospective consecutive series of 60 cases of DMEK in 2009, and in 2011, they reported 1-year outcomes from these 60 cases plus an additional 76 cases of DMEK. (12, 13) Preoperative BCVA averaged 20/65 (range of 20/20 to counting fingers). Sixteen eyes were lost to follow-up and 12 grafts (8.8%) had failed. For the 108 grafts that were examined and found to be clear at 1 year, 98% achieved BCVA of 20/30 or better. Endothelial cell loss was 31% at 3 months and 36% at 1 year. Although visual acuity outcomes appeared to be improved over a DSAEK series from the same investigators, preparation of the donor tissue and attachment of the endothelial graft were found to be more challenging. A 2012 cohort study by this group found reduced transplant rejection with DMEK. (14) One patient (0.7% of 141) in the DMEK group had a documented episode of rejection compared with 54 (9% of 598) in the DSEK group and 5 (17% of 30) in the PK group.

The same group of investigators reported a prospective consecutive series of their initial 40 cases (36 patients) of DMAEK (microkeratome dissection and a stromal ring) in 2011. (15) Indications for EK were Fuchs’ endothelial dystrophy (87.5%), pseudophakic bullous

keratopathy (7.5%), and failed EK (5%). Air was reinjected in 10 eyes (25%) to promote graft attachment; 2 grafts (5%) failed to clear and were successfully regrafted. Compared with a median BCVA of 20/40 at baseline (range, 20/25-20/400), median BCVA at 1 month was 20/30 (range, 20/15 -20/50). At 6 months, 48% of eyes had 20/20 vision or greater and 100% were 20/40 or greater. Mean endothelial cell loss at 6 months relative to baseline donor cell density was 31%.

Femtosecond Laser-Assisted Corneal Endothelial Keratoplasty (FLEK)

In 2009, Cheng et al. reported a multicenter randomized trial from Europe that compared FLEK with PK. (16) Eighty patients with Fuchs’ endothelial dystrophy, pseudophakic bullous keratopathy, or posterior polymorphous dystrophy, and best spectacle-corrected visual acuity lower than 20/50, were included in the study. In the FLEK group, 4 of the 40 eyes did not receive the treatment due to significant preoperative events and were excluded from the analysis. Eight eyes failed (22% of 36), and 2 patients were lost to follow-up due to death in the FLEK group. Only 1 patient was lost to follow-up in the PK group due to health issues. At 12 months postoperatively, refractive astigmatism was lower in the FLEK group than the PK group (86% vs. 51%, respectively, with astigmatism <3.0D [Latin oculus dexter]), but there was greater hyperopic shift. Mean best corrected visual acuity was better following PK than

FLEK at 3-, 6-, and 12-month follow-up. There was greater endothelial cell loss in the FLEK group (65%) than the PK group (23%). With the exception of dislocation and need for

repositioning of the FLEK grafts in 28% of eyes, the percentage of complications were similar in the 2 groups. Complications in the FLEK group were due to pupillary block, graft failure, epithelial ingrowth, and elevated intraocular pressure, whereas complications in the PK group were related to the sutures and elevated intraocular pressure.

A small retrospective cohort study from 2013 found a reduction in visual acuity when the endothelial transplant was prepared with laser (FLEK: 0.48 logMAR, n=8) compared with microtome (DSAEK: 0.33 logMAR, n=14). (17) There was also greater surface irregularity with the laser-assisted EK.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. 2009

In response to requests, input was received through physician specialty societies (3 reviewers representing 3 associated organizations) and 2 academic medical centers while this policy was under review in 2009. Clinical input supported DSEK and DSAEK as the standard of care for endothelial failure, due to improved outcomes in comparison with PK.

2013

In response to requests, input was received through 3 physician specialty societies (2 reviewers) and 3 academic medical centers while this policy was under review in 2013. Clinical input uniformly considered DMEK and DMAEK to be medically necessary

procedures, while the majority of input considered FLEK and FELEK to be investigational. Input was mixed regarding the exclusion of patients with anterior corneal disease. Additional indications suggested by the reviewers were added as medically necessary.

Summary

Endothelial keratoplasty, and particularly Descemet’s stripping endothelial keratoplasty (DSEK), Descemet’s stripping automated endothelial keratoplasty (DSAEK), Descemet’s membrane endothelial keratoplasty (DMEK) and Descemet’s membrane automated

endothelial keratoplasty (DMAEK), are relatively new procedures. Femtosecond laser-assisted corneal endothelial keratoplasty (FLEK) and femtosecond and excimer lasers-assisted

endothelial keratoplasty (FELEK) have been reported as alternative ways to prepare the donor endothelium. The literature and clinical input available at this time indicates that endothelial keratoplasty reduces the serious complications associated with penetrating keratoplasty. Specifically, visual recovery occurs much earlier, and because endothelial keratoplasty (EK)

maintains an intact globe without a sutured donor cornea, astigmatism and the risk of severe, sight-threatening complications such as expulsive suprachoroidal hemorrhage and

postoperative catastrophic wound failure are eliminated. These improvements appear to have resulted in rapid acceptance of this procedure with a trend toward intervention at an earlier stage of endothelial disease.

Long-term graft survival with these new techniques is presently unknown. However, current procedures result in acceptable short-term survival, and additional surgical intervention can be performed with a low risk of visual loss. Due to the marked reduction in serious complications compared to the alternative, DSEK/DSAEK has become the preferred approach for endothelial dysfunction among corneal surgeons. DMEK/DMAEK have also become accepted approaches to EK, due to a reduction in stromal haze and improvement in visual acuity. Therefore, these techniques may be considered medically necessary.

FLEK and FELEK have not been shown to have improved outcomes compared to existing techniques; therefore, these techniques are considered investigational.

EK will continue to evolve as techniques are modified in an attempt to improve donor tissue adherence and increase endothelial survival. Randomized controlled studies and/or long-term prospective studies will be needed to adequately evaluate these new procedures.

Practice Guidelines and Position Statements

In 2009, the Health Policy Committee of the American Academy of Ophthalmology (AAO) published a position paper on endothelial keratoplasty, stating that the optical advantages, speed of visual rehabilitation, and lower risk of catastrophic wound failure have driven the adoption of EK as the standard of care for patients with endothelial failure and otherwise healthy corneas. (18)

The AAO position paper was based in large part on a comprehensive review of the literature on Descemet’s stripping automated endothelial keratoplasty (DSAEK) by the American Academy of Ophthalmology’s Ophthalmic Technology Assessment Committee. (1) The Technology Assessment Committee concluded that “the evidence reviewed suggests DSAEK appears safe and efficacious for the treatment of endothelial diseases of the cornea. Evidence from retrospective and prospective DSAEK reports described a variety of complications from the procedure, but these complications do not appear to be permanently sight threatening or detrimental to the ultimate vision recovery in the majority of cases. Long-term data on endothelial cell survival and the risk of late endothelial rejection cannot be determined with this review.” “DSAEK should not be used in lieu of PK for conditions with concurrent endothelial disease and anterior corneal disease. These situations would include concurrent anterior corneal dystrophies, anterior corneal scars from trauma or prior infection, and ectasia after previous laser vision correction surgery.”

The United Kingdom’s National Institute for Health and Clinical Excellence released guidance on corneal endothelial transplantation in 2009. (19) The studies reviewed used DLEK, DSEK,

and DSAEK. Additional data reviewed from the U.K. Transplant Register showed lower graft survival rates after EK than after penetrating keratoplasty (PK); however, the difference in graft survival between the two procedures was noted to be narrowing with increased experience in EK use. The guidance concluded that “current evidence on the safety and

efficacy of corneal endothelial transplantation (also known as endothelial keratoplasty [EK]) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and consent.” The Committee noted that techniques for this procedure continue to evolve, and thorough data collection should continue to allow future review of outcomes.

Keratoprosthesis

The most recent literature review was performed through January 13, 2015.

Assessment of efficacy for therapeutic interventions involves a determination of whether the intervention improves health outcomes. The optimal study design for a therapeutic intervention is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as

noncomparability of treatment groups, the placebo effect, and variable natural history of the condition.

The keratoprosthesis is intended for the relatively small number of patients with severe corneal damage who have lost vision and for whom a corneal transplant is not expected to result in satisfactory outcomes. This generally refers to the population of patients who have failed 1 or more corneal transplants and who therefore have very limited options to prevent blindness. Because this is considered to be a salvage procedure with no acceptable alternative treatment, comparative studies are limited/lacking. The available literature primarily consists of

retrospective case series. This literature review examines the types of devices currently being tested in humans, focusing on reports that allow assessment of integration within the eye, durability, visual outcomes, and adverse events following implantation.

Osteo-Odonto Keratoprosthesis

A systematic review from 2012 included 8 case series describing surgical outcomes and

complication rates of the osteo-odonto-keratoprosthesis (OOKP).1 Sample sizes ranged from 4 to 181 eyes. (The 2 largest series follow. The study by Hughes et al described next was not included in the systematic review.) At 5 years, the anatomic survival rate was 87.8% (range, 67%-100%), and at 20 years, the anatomic survival rate was 81.0% (3 studies; range, 65%-98%). About half of the patients obtained visual acuity better than 6/18. Visual acuity in the other patients was not described.

The largest series is by Falcinelli et al in 2005, who reported on OOKP in 181 patients.2 At a median follow-up of 12 years, survival analysis estimated that 18 years after surgery, the probability of retaining an anatomically intact OOKP was 85% with reasonable visual acuity. In 2008, investigators from Spain published a retrospective review of 227 patients who

underwent OOKP (n=145), or osteokeratoprosthesis (OKP; n=82) using tibial bone in patients who lacked canine teeth to assemble the prosthesis.3 A second publication in 2011 from the same study examined the impact of clinical factors on long-term functional and anatomic outcomes.4 The primary diagnosis was chemical or thermal burn (48%), Steven-Johnson syndrome or Lyell syndrome (13%), cicatricial pemphigoid (11%), trachoma (11%), and 17% other or not assignable. The mean preoperative decimal best-corrected visual acuity (BCVA) was 0.00062 (range, light perception to 0.10). (On the decimal visual acuity scale, 0 = no light perception, 0.00001 = light perception, 0.0001 = light projection, and 0.001 = counting fingers.) Functional survival was defined as BCVA of 0.05 or more, and anatomic survival was defined as retention of the keratoprosthesis lamina. Mean follow-up was 8.4 years for OOKP and 3.5 years for OKP. Anatomic success at 10 years was estimated to be 66% for OOKP and 47% for OKP. Functional success at 10 years was estimated to be 38% for OOKP and 17% for OKP. The best functional survival was in the Stevens-Johnson group, followed by chemical burn and trachoma. The least favorable prognosis was for the thermal burn group.

Complications included extrusion of the keratoprosthesis (28%), retinal detachment (16%), uncontrolled glaucoma (11%), infection (9%), retroprosthetic membrane (5%), and vitreous hemorrhage (3%). In cases without complications, functional survival was 57% at 5 years and 42% at 10 years.

Hughes et al reported vitreoretinal complications of the OOKP in a retrospective review of 35 cases performed at 1 hospital in England between 1996 and 2005.5 Original diagnoses were

Stevens-Johnson syndrome in 15 patients, chemical injury in 5, mucous membrane pemphigoid in 3, and topical medication toxicity in 3. Follow-up at a mean 57 months (range, 13-105 months) revealed 9 vitreoretinal complications in 8 patients (23%). These included vitreous hemorrhage (n=3), rhegmatogenous retinal detachment (n=3), retinal detachment complicating endophthalmitis after lamina resorption and optic extrusion (n=2), and intraoperative choroidal hemorrhage (1 patient). Retinal detachment with loss of vision occurred in 5 of the 8 patients. A 2009 publication of 36 patients treated at the same hospitals between 1996 and 2006 (likely to be an overlap of the patients reported by Hughes et al5) estimated that the probability of

retaining visual acuity was 53% at 5 years and 44% at 9 years.6 In addition to the vitreoretinal

complications causing loss of vision, resorption of the bony lamina to the extent of causing visual or anatomic compromise occurred in 7 cases (19%).

Boston Keratoprosthesis (KPro or Dohlman-Doane)

One of the largest studies on the Boston Keratoprosthesis (Boston KPro) is a prospective series of 265 eyes (265 patients) from 18 medical centers, published by the Boston Type 1

to development of retroprosthetic membranes. Most eyes (85.4%) had undergone an average of 2.2 (range, 1-8) penetrating keratoplasties before keratoprosthesis implantation. The remaining eyes (14.6%) were considered to be at high risk for penetrating keratoplasty failure and had received a primary keratoprosthesis. At a mean of 17.8 months of follow-up, retroprosthetic membranes had formed in 31.7% of eyes. The mean time to development of retroprosthetic membranes was 216.7 days (range, 7 days to 4 years). Risk factors were found to be the indication for the keratoprosthesis, specifically, infectious keratitis had a hazard ratio of 3.20, and aniridia had a hazard ratio of 3.13.

A 2013 report from the Boston Type 1 Keratoprosthesis Study Group assessed retention of the device in 300 eyes of 300 patients.8 At a mean duration of follow-up of 17.1 months (range, 1 week to 6 years), 93% of the keratoprostheses were retained. The probability of retention was 94% at 1 year and 89% at 2 years. Mean survival time was 3.8 years. Risk factors for

keratoprosthesis loss were autoimmune disease, ocular surface exposure, and number of prior failed penetrating keratoplasties.

An earlier report from the Boston Type 1 Keratoprosthesis Study Group was published in 2006.9 Thirty-nine surgeons were encouraged to mail standardized pre- and postoperative reports on their patients to a central collection site. Seventeen sites (44%) provided data on 133 patients (136 eyes). The number of patients with BCVA of 20/200 increased from 3.6% to 57%; 19% had postoperative vision of 20/40 or better. Postoperative complications were reported in 109 patients, with 35 occurrences of retroprosthetic membrane and 21 cases of high intraocular pressures. A limitation of this report is potential bias in the voluntary submission of data. In a small (N=24) prospective study, Cortina and Hallak found that quality of life measured by the National Eye Institute Visual Function Questionnaire‒25 significantly improved following Boston KPro implantation (from a score of 44.6 preoperatively to 70.0 at a mean 6-month follow-up).10 Retrospective series of the Boston type I KPro have been reported from a number of U.S. institutions.

Srikumaran et al reported mean follow-up of 46.7 months (range, 6 weeks to 8.7 years) on 139 eyes of 133 patients who had received a Boston KPro prosthesis at 1 of 5 tertiary referral centers in the United States.11 Twenty-seven percent of eyes underwent a primary KPro procedure while 73% had experienced a prior donor graft failure. Postoperatively, visual acuity improved to at least 20/200 in 70% of eyes. The probability of maintaining visual acuity of at least 20/200 was 50% and device retention was estimated at 67% at 7 years. The 7-year cumulative incidence of complications was 49.7% for retroprosthetic membrane formation, 21.6% for glaucoma surgery, 18.6% for retinal detachment, and 15.5% for endophthalmitis.

Outcomes

In 2010, Dunlap et al reported a retrospective analysis from 122 patients (126 eyes) at 2 centers who received a Boston type I keratoprosthesis between 2004 and 2007.12 For most patients, the affected eye had a visual acuity of less than 20/400, and the other eye did not have better vision. Of the 126 eyes, 112 had a history of multiple failed corneal grafts, and 14 received the

keratoprosthesis as a primary procedure due to the presence of limbal stem cell deficiency or the presence of significant ocular surface diseases. Following implantation, 22 eyes (17.4%) did not have improved vision and 8 eyes (6.3%) lost vision, leaving 76% of eyes with improved vision. At 3-month follow-up, 54% of eyes had 20/200 vision or better, with 18% achieving 20/40 or better. In approximately 45% of the eyes, visual acuity remained less than 20/400. The

percentage of patients with improved visual outcomes was noted to be lower than in other published studies, due in part to the presence of comorbid conditions, which included glaucoma and retinal detachment.

In 2009, Bradley et al reported outcomes from all of the 30 eyes (28 patients) who had

previously received a Boston type I keratoprosthesis at their institution; 6 of the eyes had been included in the multicenter study described earlier.13 Preoperative diagnoses were failed graft (26 eyes [87%]), chemical injury (3 eyes [10%]), and Stevens-Johnson syndrome (1 eye [3%]). Each eye had undergone an average of 2.6 prior corneal transplants (range, 0-7). Twenty eyes (66%) had preoperative glaucoma. Preoperative BCVA ranged from 20/150 to light perception (<20/200 in 83% of eyes). At an average follow-up of 19 months (range, 1-48 months) anatomic retention of the initial keratoprosthesis was 83%, with 5 failures (corneal melting in 4 eyes, infectious keratitis in 1 eye). The number of patients with BCVA of 20/200 or better increased from 14% preoperatively to 77% postoperatively; 23% of patients achieved postoperative vision of 20/40 or better. In the 16 eyes followed up for at least 1 year, 12 (75%) achieved BCVA better than 20/200 and 4 (25%) achieved BCVA better than 20/40. The most common nonsurgical complication was retroprosthetic membrane formation (43% of eyes), followed by increased intraocular pressure (27%), corneal melt (17%), infectious keratitis (17%),

endophthalmitis (10%), progression of glaucoma (7%), choroidal effusion or hemorrhage (7%), vitreous hemorrhage (3%), iris prolapse (3%), sterile vitritis (3%), posterior capsular opacity (3%), high myopic refraction (3%), hyphema (3%), and phthisis bulbi (3%). Keratoprosthesis replacement was performed at least once in 5 eyes (17% of patients).

Harissi-Dagher and Dohlman performed a retrospective study of 30 eyes (30 patients) with severe ocular trauma (6 mechanical trauma, 21 chemical burns, 3 thermal burns) implanted with a Boston KPro type I prosthesis at the Massachusetts Eye and Ear Infirmary since 1990.14 Patients were followed up for an average of 35 months (range, 1-108 months). Anatomic success (retention of the prosthesis) was achieved in 5 of 5 of the mechanical trauma patients, 14 of 17 of the chemical burn patients, and 3 of 3 of the thermal burn patients. In addition to repeat KPro implantation in 3 patients (2 with early models), repair procedures for leaks were performed in 8 chemical burn eyes. Preoperative visual impairment was near total, with visual acuity ranging

from counting fingers to light perception. Postoperatively, 80% of patients achieved BCVA of 20/400 or better, and 53% achieved BCVA of 20/60 or better. There was some attrition in visual acuity over time, primarily from progression of glaucoma in eyes with chemical burns. The authors noted that glaucoma progression is difficult to control in these patients because of damage to the trabecular meshwork and to the retinal ganglion cell layer and nerve fiber layer and that damage to the eye behind the cornea cannot always be diagnosed until the medium (e.g., opaque cornea) is cleared. Aquavella et al reported on a case series of 25 patients who received a Dohlman-Doane device.15 With a follow-up time ranging from 2 to 12 months, 20 of the 25 patients had a visual acuity of 20/400 or better, with 12 patients achieving better than 20/40 vision. There were no dislocations or extrusions, and no reoperations were required within the 2- to 12-month follow-up.

Indications

A 2009 study reported expanding indications and outcomes from a consecutive series of 50 eyes of 49 patients implanted with the Boston type I keratoprosthesis and a donor cornea.16 In addition to the single patient with bilateral prostheses, 31% of patients had good preoperative vision (visual acuity of 20/40 or better) in the contralateral eye. Patients had to meet the following criteria to be considered a candidate for keratoprosthesis implantation: visually significant corneal opacification (BCVA ≤20/200); poor candidacy for repeat corneal

transplantation because of a history of 2 or more failed transplantations, extensive corneal limbal stem cell failure with or without corneal vascularization and scarring, or both; and adequate visual potential for meaningful visual restoration. Exclusion criteria included: adequate potential for a successful outcome after penetrating keratoplasty; the presence of a comorbid ocular condition associated with a minimal chance of recovering meaningful vision, such as a chronic retinal detachment or near end-stage glaucoma; the presence of comorbid ocular conditions associated with an unacceptably high risk of postoperative complications, such as inadequate eyelid function, severe ocular surface desiccation, ocular surface keratinization, recalcitrant intraocular inflammation, patient inability or unwillingness to comply with the routine

postoperative regimen, or a combination thereof. Of the 50 eyes that underwent implantation of the Boston KPro, 42 had a history of prior corneal transplantation, varying between 1 and 5 prior transplantations (mean, 2.3). Preoperative visual acuity was 20/200 or worse in all eyes, with vision of counting fingers, hand movements, or light perception in 42 eyes (88%). Glaucoma was present in 38 eyes (76%) undergoing keratoprosthesis implantation, and tube shunt implantation was performed simultaneously with keratoprosthesis implantation in 45% of the eyes with preexisting glaucoma. A total of 57 Boston type I KPros were implanted in 50 eyes. Two eyes were excluded due to the early death of 1 patient and replacement of the type I KPro with a type II KPro in another patient. Nine of the 57 keratoprostheses implanted were removed, resulting in a retention rate of 84% during an average follow-up of 17 months (range, 3-49 months). Three of the 9 were removed in the first 6 months after surgery, and 5 were removed

between 1 and 2 years after surgery. The final postoperative vision was improved over the preoperative vision in 38 eyes (79%), unchanged in 9 eyes (9%), and decreased

in 1 eye (2%; from counting fingers preoperatively to light perception postoperatively). The percentage of eyes with postoperative visual acuity of 20/100 or better was 67% of 45 eyes followed up for at least 6 months (90% follow-up), 75% of 28 eyes (56%) followed up to 1 year, 69% of 13 eyes (26%) at 2 years, and all of the 7 eyes (14%) followed up for at least 3 years. In 38 eyes (76%), 1 or more postoperative complications developed. The most common

postoperative complications were retroprosthetic membrane formation (44% of eyes) and persistent epithelial defects (38% of eyes). This detailed report provides information on visual outcomes and complications in a well-described patient population. The major limitation of this study is the small number of subjects who were followed up for more than 6 months.

Use of the Boston KPro has been reported in children and in patients with herpetic keratitis, autoimmune disease, aniridia, atopic keratoconjunctivitis, medication toxicity, and other corneal dystrophies.17 The device has a lower retention rate when used for highly inflammatory,

cicatricial, and autoimmune ocular disorders. Also reported is use of the KPro as a primary treatment in eyes considered to have little or no chance of success with penetrating

keratoplasty.18 The most common preoperative diagnosis was primary or secondary limbal stem cell disease (71.4%), including chemical/thermal injury (28.6%), aniridia (23.8%), and Stevens-Johnson syndrome (4.8%). Retention rate of the keratoprosthesis was 90.5% at a mean follow-up of 14.6 months (range, 6-36.3 months).

Complications

Longer term vision outcomes and complications with the Boston type I KPro was reported by Greiner et al in 2011.19 Included in the series were all of the 40 eyes of 35 patients who received a Boston KPro between 2004 and 2010 at their institution. Preoperative diagnoses included failed corneal transplants (47.5%), chemical injury (25%), and aniridia (12.5%). Preoperative visual acuity ranged from 20/150 to light perception and was 20/400 or less in 38 eyes (95%). Follow-up evaluations were performed at 1, 3,6, 9, and 12 months and then annually, with a mean duration of follow-up of 33.6 months (range, 5-72 months). Of 36 eyes followed for at least 1 year, 32 (89%) achieved postoperative BCVA of 20/200 or more. The percentage of eyes that retained BCVA of 20/200 or more was 59% (19/32) at 1 year, 59% (16/27) at 2 years, 50% (7/14) at 3 years, and 29% (2/7) at 4 years or longer. The most common reason for vision loss (54% of the 13 eyes when BCVA ≥20/200 was not retained) was end-stage glaucoma.

Other complications included glaucoma drainage device erosion (22.5%), retroprosthetic membrane formation (55%), endophthalmitis (12.5%), and corneal melt (15%). In a separate publication, this group of investigators reported that of 25 eyes implanted with both the Boston type I KPro and glaucoma drainage devices, conjunctival breakdown occurred in association with 10 implants in 9 eyes.20 The authors note that glaucoma continues to be one of the most difficult postoperative management challenges in patients with a Boston type I keratoprosthesis.

Posterior segment complications were reported by Goldman et al in 2013.21 Of 83 eyes (93 procedures) with follow-up of at least 6 months (range, 6-84 months), 38 eyes (40.9%) had at least 1 postoperative posterior segment complication, which included retinal detachment (16.9%), choroidal detachment (16.9%), and sterile vitritis (14.5%). Visual acuity was worse in eyes that experienced posterior segment complications compared with eyes that did not. Pujari et al reported outcomes from 29 eyes of 26 patients who received the Boston type II

keratoprosthesis between 2000 and 2009 at the Massachusetts Eye and Ear Infirmary.22 The type II keratoprosthesis is a modification of the original prosthesis, with an anterior extension to allow implantation through surgically closed eyelids and is generally reserved for patients with

significant symblepharon or ankyloblepharon, ocular surface keratinization, and absence of normal lid function. Preoperative diagnoses were mucous membrane pemphigoid (51.7%), Stevens-Johnson syndrome/toxic epidermal necrolysis (41.4%), and other ocular surface disease (6.9%). In patients who had more than 1 year of follow-up (mean of 3.7 years), loss of visual acuity was found to occur due to retinal detachment (17.4%), end-stage glaucoma (8.7%), choroidal detachment (8.7%), endophthalmitis (4.3%), and unknown (21.7%). Fourteen eyes (48.3%) required treatment for retroprosthetic membranes. Of the total of 29 eyes, 12 (41.4%) either underwent reimplantation of the device or experienced partial or total extrusion of the keratoprosthesis during follow-up, corresponding to a hazard rate of 0.11 per person-year.

Other Devices

Studies suggest that with the AlphaCor device, thinning or “melting” of the anterior corneal surface can lead to loss of biointegration.23,24 This complication appears most prevalent in patients with ocular herpes, therefore the AlphaCor device is contraindicated in these patients. In 1 study, the percentage of eyes with visual acuity of better than 20/200 was 42% at an average 30-month follow-up.23 No additional studies with the AlphaCor were identified in literature updates.

The BIOKOP device is similar in concept to the AlphaCor device in that a microporous polymer is used to promote host tissue integration. However, the results with this device have been disappointing. In 1 case series of 11 patients with 5-year follow-up, the authors concluded that the BIOKOP keratoprosthesis was only able to restore vision for a short postoperative period.25 Limited success was due to instability of the device and postoperative complications.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 specialty society and 4 academic medical centers while this policy was under review in 2009. Reviewers generally supported a limited role for the Boston KPro in selected patients. Some reviewers recommended use without first

attempting a transplant in specific conditions that have a poor prognosis for corneal transplant; however, other input indicated that this is controversial. Some reviewers recommended use only in patients who have limited visual acuity in the contralateral eye. Overall, input indicated that the Boston Keratoprosthesis is reserved for cases in which no other alternative (ie, corneal transplantation) is available for treatment of corneal opacification.

Summary of Evidence

Successful development of a keratoprosthesis requires durable clarity, retention, and

bioincorporation. The published literature reveals ongoing modifications of the design of the keratoprosthesis, both in terms of the optics and the techniques used for anchoring the optic in place, the surgical technique, and the postoperative management. Randomized trials are unlikely due to very limited indications for this device and a lack of alternative treatments. Patients can serve as their own controls because the comparison of pre- and postoperative visual acuity has some validity given the predictable clinical course and relative lack of confounding factors. As a result, case series with pre- and postcomparisons are the primary type of evidence available; these types of studies are likely to remain small due to the low volume of the procedure.

Some large case series focus on the use of the osteo-odonto-keratoprosthesis (OOKP) in Europe. The OOKP device is not widely used in the United States. Anatomic retention with the OOKP appears good, but restoration of vision is not well-reported. Based on the literature and clinical input, the Boston KPro is the most widely used and accepted keratoprosthesis in the United States at this time. Anatomic retention and visual success of this device at long term are uncertain, but short-term visual outcomes with the Boston KPro show improvement in a substantial percentage of patients. This remains a high-risk procedure that is associated with numerous complications (e.g., growth of retroprosthetic membranes) and a probable need for additional surgery. Complications with other designs of keratoprostheses appear to be worse than those associated with the Boston KPro. Therefore, given the available evidence, the clinical input, and the absence of alternative treatment options, the Boston KPro may be considered medically necessary for patients with corneal opacification who have failed corneal

transplantation or who have a condition not amenable to good outcomes from corneal transplant.

Practice Guidelines and Position Statements

The U.K.’s National Institute for Clinical Excellence concluded in 2004 that, “Current evidence on the safety and efficacy of insertion of hydrogel keratoprosthesis does not appear adequate for this procedure to be used without special arrangements for consent and for audit or research.”26

U.S. Preventive Services Task Force Recommendations

Medicare National Coverage

There is no Medicare national coverage policy. Medicare has established an Ambulatory

Payment Classification 0293 for level V anterior segment eye procedures that includes CPT code 65770(keratoprosthesis) and a HCPCS code for the prosthesis (C1818 - integrated

keratoprosthesis OR L8609 - artificial cornea).27

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APHAKIA is a condition in which part or all of the crystalline lens of the eye is absent, due to a congenital defect or because it has been surgically removed, as in the treatment of cataracts. CORNEA is the transparent anterior portion of the sclera (the fibrous outer layer of the eyeball); it is a key refractive element of the eye. Layers of the cornea consist of the epithelium

(outermost layer); Bowman’s layer; the stroma, which comprises approximately 90% of the cornea; Descemet’s membrane; and the endothelium.

MYOPIA is an error in refraction in which light rays are focused in front of the retina, enabling

the person to see distinctly for only a short distance.

STROMA refers to the supporting tissue or the matrix of an organ.

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The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member’s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member’s benefit information or contact Capital for benefit information.

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Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member’s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law.

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Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Investigational; therefore not covered:

HCPCS

Code Description

L8609 Artificial cornea

Investigational; therefore not covered:

CPT Codes®

0289T 0290T

Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.

Covered when medically necessary:

CPT Codes®

65710 65730 65750 65755 65756 65757 65770

Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.

HCPCS Code Description C1818 Integrated keratoprosthesis ICD-9- PCS Codes Description

11.61 Lamellar keratoplasty with autograft 11.62 Other lamellar keratoplasty

11.64 Other penetrating keratoplasty 11.69 Other corneal transplant 11.73 Keratoprosthesis ICD-10-CM Procedure codes Description

08R8X7Z Replacement of Right Cornea with Autologous Tissue Substitute, External Approach 08R9X7Z Replacement of Left Cornea with Autologous Tissue Substitute, External Approach 08U8X7Z Supplement Right Cornea with Autologous Tissue Substitute, External Approach 08U9X7Z Supplement Left Cornea with Autologous Tissue Substitute, External Approach

08R8XKZ Replacement of Right Cornea with Nonautologous Tissue Substitute, External Approach 08R9XKZ Replacement of Left Cornea with Nonautologous Tissue Substitute, External Approach 08U8XKZ Supplement Right Cornea with Nonautologous Tissue Substitute, External Approach 08U9XKZ Supplement Left Cornea with Nonautologous Tissue Substitute, External Approach 08R837Z Replacement of Right Cornea with Autologous Tissue Substitute, Percutaneous Approach 08R937Z Replacement of Left Cornea with Autologous Tissue Substitute, Percutaneous Approach 08U807Z Supplement Right Cornea with Autologous Tissue Substitute, Open Approach

08U837Z Supplement Right Cornea with Autologous Tissue Substitute, Percutaneous Approach 08U907Z Supplement Left Cornea with Autologous Tissue Substitute, Open Approach

08U937Z Supplement Left Cornea with Autologous Tissue Substitute, Percutaneous Approach 08R83KZ Replacement of Right Cornea with Nonautologous Tissue Substitute, Percutaneous

ICD-10-CM Procedure codes

Description

08R93KZ Replacement of Left Cornea with Nonautologous Tissue Substitute, Percutaneous Approach

08U80KZ Supplement Right Cornea with Nonautologous Tissue Substitute, Open Approach

08U83KZ Supplement Right Cornea with Nonautologous Tissue Substitute, Percutaneous Approach 08U90KZ Supplement Left Cornea with Nonautologous Tissue Substitute, Open Approach

08U93KZ Supplement Left Cornea with Nonautologous Tissue Substitute, Percutaneous Approach 08R83JZ Replacement of Right Cornea with Synthetic Substitute, Percutaneous Approach

08R8XJZ Replacement of Right Cornea with Synthetic Substitute, External Approach 08R93JZ Replacement of Left Cornea with Synthetic Substitute, Percutaneous Approach 08R9XJZ Replacement of Left Cornea with Synthetic Substitute, External Approach 08U80JZ Supplement Right Cornea with Synthetic Substitute, Open Approach

08U83JZ Supplement Right Cornea with Synthetic Substitute, Percutaneous Approach 08U8XJZ Supplement Right Cornea with Synthetic Substitute, External Approach 08U90JZ Supplement Left Cornea with Synthetic Substitute, Open Approach

08U93JZ Supplement Left Cornea with Synthetic Substitute, Percutaneous Approach 08U9XJZ Supplement Left Cornea with Synthetic Substitute, External Approach

ICD-9-CM Diagnosis Code*

Description

053.21 Herpes zoster keratoconjunctivitis 054.42 Dendritic keratitis 054.43 Herpes simplex disciform keratitis 055.71 Measles keratoconjunctivitis 077.1 Epidemic keratoconjunctivitis 098.43 Gonococcal keratitis 370.00 Corneal ulcer, unspecified

370.01 Corneal ulcer, Marginal corneal ulcer 370.02 Corneal ulcer, Ring corneal ulcer 370.03 Corneal ulcer, Central corneal ulcer 370.04 Corneal ulcer, Hypopyon ulcer

ICD-9-CM Diagnosis Code*

Description

370.05 Corneal ulcer, Mycotic corneal ulcer 370.06 Corneal ulcer, Perforated corneal ulcer 370.07 Corneal ulcer, Mooren's ulcer

370.50 Interstitial keratitis, unspecified 370.52 Diffuse interstitial keratitis

370.54 Interstitial keratitis, Sclerosing keratitis 370.55 Interstitial keratitis, Corneal abscess 370.59 Interstitial keratitis, Other

370.60 Corneal neovascularization, unspecified 370.61 Localized vascularization of cornea

370.62 Corneal neovascularization, Pannus (corneal) 370.63 Deep vascularization of cornea

370.64 Corneal neovascularization, Ghost vessels (corneal)

370.8 Other forms of keratitis 370.9 Unspecified keratitis 371.00 Corneal opacity, unspecified

371.01 Corneal opacity, Minor opacity of cornea 371.02 Corneal opacity, Peripheral opacity of cornea 371.03 Corneal opacity, Central opacity of cornea 371.04 Corneal opacity, Adherent leucoma 371.05 Corneal opacity, Phthisical cornea 371.10 Corneal deposit, unspecified

371.11 Corneal deposit, Anterior pigmentations 371.12 Corneal deposit, Stromal pigmentations 371.13 Corneal deposit, Posterior pigmentations 371.14 Corneal deposit, Kayser-Fleischer ring

371.15 Corneal deposit, Other deposits associated with metabolic disorders 371.16 Corneal deposit, Argentous deposits

371.20 Corneal edema, unspecified 371.21 Idiopathic corneal edema 371.22 Secondary corneal edema 371.23 Bullous keratopathy

371.24 Corneal edema due to wearing of contact lenses 371.30 Corneal membrane change, unspecified 371.31 Folds and rupture of Bowman's membrane 371.32 Folds in Descemet's membrane

ICD-9-CM Diagnosis Code*

Description

371.33 Rupture in Descemet's membrane 371.40 Corneal degeneration, unspecified 371.41 Senile corneal changes

371.42 Recurrent erosion of cornea 371.43 Band-shaped keratopathy

371.44 Other calcerous degenerations of cornea 371.45 Keratomalacia NOS

371.46 Nodular degeneration of cornea 371.48 Peripheral degenerations of cornea 371.49 Corneal degeneration, Other 371.50 Corneal dystrophy, unspecified 371.51 Juvenile epithelial corneal dystrophy 371.52 Other anterior corneal dystrophies 371.53 Granular corneal dystrophy 371.54 Lattice corneal dystrophy 371.55 Macular corneal dystrophy 371.56 Other stromal corneal dystrophies 371.57 Endothelial corneal dystrophy 371.58 Other posterior corneal dystrophies 371.60 Keratoconus, unspecified

370.61 Keratoconus, stable condition 370.62 Keratoconus, acute hydrops 371.70 Corneal deformity, unspecified 371.71 Corneal ectasia

371.72 Descemetocele 371.73 Corneal staphyloma

694.61 Benign mucous membrane pemphigoid , With ocular involvement 695.13 Stevens-Johnson syndrome

743.41 Congenital anomaly of corneal size and shape 743.42 Congenital corneal opacity, interfering with vision 743.43 Other congenital corneal opacity 921.3 Contusion of eyeball

996.51 Mechanical complication due to corneal graft

996.69 Infection and inflammatory reaction due to other internal prosthetic device, implant, and graft 996.79 Other complications due to other internal prosthetic device, implant, and graft 996.8 Complications of Transplanted Organ