Integrated versus non‐integrated orbital implants for treating anophthalmic sockets

Silvana Schellini; Regina El Dib; Leandro RE Silva; Joyce G Farat; Yuqing Zhang; Eliane C Jorge

doi:10.1002/14651858.CD010293.pub2

. 2016 Nov 7;2016(11):CD010293. doi: 10.1002/14651858.CD010293.pub2

Integrated versus non‐integrated orbital implants for treating anophthalmic sockets

Silvana Schellini ¹, Regina El Dib ², Leandro RE Silva ³, Joyce G Farat ³, Yuqing Zhang ⁴, Eliane C Jorge ^5,^✉

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6465188 PMID: 27820878

Abstract

Background

Anophthalmia is the absence of one or both eyes, and it can be congenital (i.e. a birth defect) or acquired later in life. There are two main types of orbital implant: integrated, whereby the implant receives a blood supply from the body that allows for the integration of the prosthesis within the tissue; and non‐integrated, where the implant remains separate. Despite the remarkable progress in anophthalmic socket reconstruction and in the development of various types of implants, there are still uncertainties about the real roles of integrated (hydroxyapatite (HA), porous polyethylene (PP), composites) and non‐integrated (polymethylmethacrylate (PMMA)/acrylic and silicone) orbital implants in anophthalmic socket treatment.

Objectives

To assess the effects of integrated versus non‐integrated orbital implants for treating anophthalmic sockets.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 7), Ovid MEDLINE, Ovid MEDLINE In‐Process and Other Non‐Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2016), Embase (January 1980 to August 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 8 August 2016.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs of integrated and non‐integrated orbital implants for treating anophthalmic sockets.

Data collection and analysis

Two authors independently selected relevant trials, assessed methodological quality and extracted data.

Main results

We included three studies with a total of 284 participants (250 included in analysis). The studies were conducted in India, Iran and the Netherlands. The three studies were clinically heterogenous, comparing different materials and using different surgical techniques. None of the included studies used a peg (i.e. a fixing pin used to connect the implant to the prosthesis). In general the trials were poorly reported, and we judged them to be at unclear risk of bias.

One trial compared HA using traditional enucleation versus alloplastic implantation using evisceration (N = 100). This trial was probably not masked. The second trial compared PP with scleral cap enucleation versus PMMA with either myoconjunctival or traditional enucleation (N = 150). Although participants were not masked, outcome assessors were. The last trial compared HA and acrylic using the enucleation technique (N = 34) but did not report comparative effectiveness data.

In the trial comparing HA versus alloplastic implantation, there was no evidence of any difference between the two groups with respect to the proportion of successful procedures at one year (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.95 to 1.09, N = 100, low‐certainty evidence). People receiving HA had slightly worse horizontal implant mobility compared to the alloplastic group (mean difference (MD) −3.35 mm, 95% CI −4.08 to −2.62, very low‐certainty evidence) and slightly worse vertical implant motility (MD −2.76 mm, 95% CI −3.45 to −2.07, very low‐certainty evidence). As different techniques were used – enucleation versus evisceration – it is not clear whether these differences in implant motility can be attributed solely to the type of material. Investigators did not report adverse events.

In the trial comparing PP versus PMMA, there was no evidence of any difference between the two groups with respect to the proportion of successful procedures at one year (RR 0.92, 95% CI 0.84 to 1.01, N = 150, low‐certainty evidence). There was very low‐certainty evidence of a difference in horizontal implant motility depending on whether PP was compared to PMMA with traditional enucleation (MD 1.96 mm, 95% CI 1.01 to 2.91) or PMMA with myoconjunctival enucleation (−0.57 mm, 95% CI −1.63 to 0.49). Similarly, for vertical implant motility, there was very low‐certainty evidence of a difference in the comparison of PP to PMMA traditional (MD 3.12 mm 95% CI 2.36 to 3.88) but no evidence of a difference when comparing PP to PMMA myoconjunctival (MD −0.20 mm 95% CI −1.28 to 0.88). Four people in the PP group (total N = 50) experienced adverse events (i.e. exposures) compared to 6/100 in the PMMA groups (RR 17.82, 95% CI 0.98 to 324.67, N = 150, very low‐certainty evidence).

None of the studies reported socket sphere size, cosmetic effect or quality of life measures.

Authors' conclusions

Current very low‐certainty evidence from three small published randomised controlled trials did not provide sufficient evidence to assess the effect of integrated and non‐integrated material orbital implants for treating anophthalmic sockets. This review underlines the need to conduct further well‐designed trials in this field.

Plain language summary

Integrated compared with non‐integrated orbital implants for treating anophthalmic sockets

What is the aim of this review?  The aim of this Cochrane Review was to find out if integrated orbital implants are better than non‐integrated orbital implants for treating anophthalmic sockets. Cochrane researchers collected and analysed all relevant studies to answer this question and found three studies.

Key messages  There is uncertainty as to the benefits and harms of integrated compared with non‐integrated orbital implants.  What was studied in the review?  'Anophthalmia' is the absence of the eye in the orbit. This can occur in childhood (because of problems with development) or it can happen during the course of life (due to an accident or other eye disease).

Doctors can put an implant in the orbit to fill the void left by the removal of the eye and this together with an external prosthesis can improve the patient's appearance. This orbital implant can be made of two types of materials – integrated or non‐integrated material. If the material is integrated, then new blood vessels can grow into the implant material. If the material is non‐integrated, then the orbital implant remains separate from the rest of the orbit's tissue.

The review authors looked to see if the type of implant material affected the success of the surgery or, in other words, if integrated implants can provide better results than non‐integrated implants. They were also interested in how much the external prosthesis could move better after surgery – using integrated or non‐integrated orbital implants. Also, the authors wanted to know if the type of orbital implant material can affect people's quality of life. Were there any adverse (harmful) effects of using integrated or non‐integrated orbital implants?

What are the main results of the review?  The type of material used for the orbital implant may not affect the success of the surgery (low‐certainty evidence). The review authors judged the evidence on prosthesis movement and adverse effects as providing very little certainty about the true effects. There was no information on quality of life.

How up‐to‐date is this review?  The Cochrane researchers searched for studies that had been published up to 8 August 2016.

Summary of findings

Summary of findings 1. Summary of findings.

Integrated versus non‐integrated orbital implants for treating anophthalmic sockets
Patient or population: people with anophthalmic sockets Intervention: integrated implants Comparison: non‐integrated implants
Outcomes	Comparison	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty (quality) of the evidence (GRADE)	Comment
Outcomes	Comparison	Risk with non‐integrated material	Risk with integrated material	Relative effect (95% CI)	No of participants (studies)	Certainty (quality) of the evidence (GRADE)	Comment
Proportion of successful procedures at 1 year and up to 5 years after surgery (no exposure/extrusion)	PP (scleral cap enucleation) versus PMMA (traditional and myoconjunctival enucleation)	960 per 1000	883 per 1000 (806 to 1000)	RR 0.92 (0.84 to 1.01)	150 (1)	⊕⊕⊝⊝ Low^a	—
	HA (traditional enucleation) versus alloplastic (evisceration)	960 per 1000	980 per 1000 (912 to 1000)	RR 1.02 (0.95 to 1.09)	100 (1)	⊕⊕⊝⊝ Low^b	—
Socket and prosthesis motility (horizontal)	PP (scleral cap enucleation) versus PMMA (traditional enucleation)	The mean socket and prosthesis motility (horizontal) score was 5.14 mm	The mean socket and prosthesis motility (horizontal) score in the intervention group was on average 1.96 mm more (1.01 mm more to 2.91 mm more)	—	100 (1)	⊕⊝⊝⊝ Very low^a,c	—
	PP (scleral cap enucleation) versus PMMA (myoconjunctival enucleation)	The mean socket and prosthesis motility (horizontal) score was 7.67 mm	The mean socket and prosthesis motility (horizontal) score in the intervention group was on average 0.57 mm less (1.63 mm less to 0.49 mm more)	—	100 (1)	⊕⊝⊝⊝ Very low^a,c	—
	HA (traditional enucleation) versus alloplastic (evisceration)	The mean socket and prosthesis motility (horizontal) score was 10.25 mm	The mean socket and prosthesis motility (horizontal) score in the intervention group was on average 3.35 mm less (4.08 mm less to 2.62 mm less)	—	100 (1)	⊕⊝⊝⊝ Very low^b,c	—
Socket and prosthesis motility (vertical)	PP (scleral cap enucleation) versus PMMA (traditional enucleation)	The mean socket and prosthesis motility (vertical) score was 2.68 mm	The mean socket and prosthesis motility (vertical) score in the intervention group was on average 3.12 mm more (2.36 mm more to 3.88 mm more)	—	100 (1)	⊕⊝⊝⊝ Very low^a,c	—
	PP (scleral cap enucleation) versus PMMA (myoconjunctival enucleation)	The mean socket and prosthesis motility (vertical) score was 6 mm	The mean socket and prosthesis motility (vertical) score in the intervention group was on average 0.20 mm less (1.28 mm less to 0.88 mm more)	—	100 (1)	⊕⊝⊝⊝ Very low^a,c	—
	HA (traditional enucleation) versus alloplastic (evisceration)	The mean socket and prosthesis motility (vertical) score was 8.45 mm	The mean socket and prosthesis motility (vertical) score in the intervention group was on average 2.76 mm less (3.45 mm less to 2.07 mm less)	—	100 (1)	⊕⊝⊝⊝ Very low^b,c	—
Any adverse outcomes (e.g. extrusions or migration, infections, ectropion)	PP (scleral cap enucleation) versus PMMA (traditional or myoconjunctival enucleation)	1 per 1000	18 per 1000 (1 to 325 per 1000)	RR 17.82 (0.98 to 324.67)	150 (1)	⊕⊝⊝⊝ Very low^a,c	Adverse outcomes not reported for HA versus alloplastic comparison
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HA: hydroxyapatite; PMMA: polymethylmethacrylate; PP: porous polyethylene; RR: risk ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

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^aDowngraded for risk of bias (−1) and indirectness (−1). The trial was poorly reported, and it was difficult to judge risk of bias for many domains. It was conducted in one specific setting, and it is unclear if the findings are generalisable to other settings. ^bDowngraded for risk of bias (−1) and indirectness (−1). The trial was poorly reported, and it was difficult to judge risk of bias for most domains. It was a quasi‐randomised study and probably not masked. It was conducted in one specific setting, and it is unclear if the findings are generalisable to other settings. ^cDowngraded for imprecision (−1): confidence intervals include clinically unimportant effect.

Background

Description of the condition

Anophthalmia is the absence of one or both eyes, and it can be congenital (i.e. a birth defect) or acquired later in life (such as by trauma, tumour, glaucoma, etc.).

Description of the intervention

History

The development of techniques for enucleation (the surgical removal of the eyeball leaving the eye muscles and orbital contents intact) and evisceration (the removal of the eye's contents) occurred almost concurrently with the development of the materials used in the manufacture of prostheses and implants for aesthetic and functional repair of the anophthalmic socket. The first implants were very light and made of a type of very thin glass (Tonkelaar 1991). Since the destruction of glass implant manufacturing plants during World War II, other types of non‐integrated (non‐porous) materials, such as silicone and polymethylmethacrylate (PMMA), have emerged and gained popularity. These types of implants still dominate the world market in anophthalmic socket repair.

Since 1987, the landscape of eye socket reconstruction has changed substantially, with integrated (porous) implants made of natural hydroxyapatite becoming widely available (Perry 1990). The BioEye (Hydroxyapatite Orbital Implant; Integrated Orbital Implants Inc., San Diego, CA, USA) is an implant built using natural hydroxyapatite and composed of calcium carbonate, the same mineral that forms the hard parts of bones. A hydrothermal reaction converts calcium carbonate into calcium phosphate during BioEye manufacture (Massry 1995). This material is extremely porous, allowing for vascular and fibrovascular ingrowth; thus, it can become "part of the patient's body" as an integrated implant (Flanagan 1990). Synthetic hydroxyapatites were introduced soon after natural hydroxyapatite in several countries (Jordan 1998), including Brazil (Jordan 2000; Schellini 2000).

Other biomaterials, such as porous polyethylene (Medpor; Porex Technologies Corporation, Fairburn, GA, USA), became available for the repair of anophthalmic sockets in mid‐1991 (Karesh 1994). Experimental research in Brazil also made use of similar materials, showing good results (Schellini 2000).

Different types of implants are used to reconstruct the anophthalmic cavity. These implants can be classified according to their shape (spherical, oval or conical), the material used (integrated or non‐integrated) and the surface type (smooth/non‐porous or porous). Non‐porous (non‐integrated) implants are most often composed of PMMA or silicone, while porous (integrated) implants are made of hydroxyapatite, porous polyethylene and composites (including bioceramics).

In 1995, a study from the USA reported that most American surgeons were using spheres made of natural hydroxyapatite (Hornblass 1995). By 2004, this preference had changed, with American surgeons preferring to use porous polyethylene implants without coupling pegs between the implant and the external prosthesis (Su 2004). A Canadian study in 2006 revealed that porous polyethylene implants were the most widely used prostheses in Canada (Jordan 2006). In Brazil, despite a lack of studies on anophthalmic socket implants, integrated implants are rarely used, most likely due to their higher cost; however, actually PMMA is still the preferred choice among 62.75% of Brazilian ophthalmologists (Schellini 2015; Sousa 2012).

Physicians originally considered that the use of pegs conferred advantages for integrated implants, enabling the anchoring of implants to the external prothesis. Nowadays, pegs have fallen out of use, as there have been observational reports of complications, although the evidence for this is scarce.

With the increased use of integrated implants, studies have observed complications in 10% to 22% of patients, including conjunctival dehiscence, implant exposure or extrusion, and the necessity to remove the implant (Buettner 1992; Goldberg 1994; Nunery 1993; Rubin 1994; Shields 1992; Shields 1994). These complication rates are based on the longest periods of observation in the individuals who received the implants. Several reports have been published on the lack of success of integrated implants, and these failures have been related to the failure of the surgical technique, the use of external prostheses that create too much pressure against the surface of the implant (Shields 1994), and the use of uncoated spheres (Rubin 1994). This research led to the conclusion that hydroxyapatite spheres had a higher risk of failure than spheres made of silicone (Nunery 1993).

Thus, despite the remarkable progress in anophthalmic socket reconstruction and the development of various types of implants, there are still uncertainties about the real roles of integrated and non‐integrated orbital implants in anophthalmic socket treatment.

Enucleation surgery

Enucleation surgery refers to removing the entire eyeball, that is, without cutting into or dissecting the globe. It consists of the following steps.

Determination of general or local anaesthesia.
A 360° conjunctival peritomy (the conjunctiva is separated from the sclera with scissors close to the limbus).
Identification and sectioning of the extrinsic ocular rectus muscle and sectioning of the optic nerve.
Removal of the entire eye and the inspection of Tenon's capsule.
Determination of the implant size.
Insertion of the orbital implant.
If necessary, wrapping of the implant to be attached to the extrinsic ocular rectus muscles.
Suturing of Tenon's fascia.
Suturing of the conjunctiva (attaching the upper conjunctiva to the lower conjunctiva).

Evisceration surgery

Evisceration surgery removes the eye's contents but leaves the scleral shell, Tenon's capsule, the orbital fat and the extraocular muscles intact. The operation consists of the following steps.

Determination of general or local anaesthesia.
A 360° peritomy (the conjunctiva is separated from the sclera using scissors).
Penetration into the anterior chamber using a no. 11 scalpel blade and enlargement of the corneo‐scleral opening with scissors.
Removal of the eye contents using an ocular evisceration spoon.
Evaluating the size of the implant to be placed into the scleral shell.
Suturing of the sclera and Tenon's fascia.
Suturing of the conjunctiva (attaching the upper conjunctiva to the lower conjunctiva).

How the intervention might work

The main factors that favour the use of integrated implants are the mobility of the external prosthesis and the presence of immune cells within implants that receive a blood supply from the host, allowing for the integration of the prosthesis with the host's tissue, which in turn results in a lower risk of migration and implant extrusion (Flanagan 1990; Rubin 1994). In contrast, the non‐integrated implants contain no unique apparatus for attachments to the extraocular muscles and do not allow in‐growth of organic tissue into their inorganic substance.

Enucleation surgery is used in cases of intraocular tumours, in patients at risk of sympathetic ophthalmia and in cases of severe atrophy of the scleral layer (phthisis bulbi). Evisceration surgery is used in cases of virulent endophthalmitis. However, both enucleation and evisceration surgeries are used for painful and blind eyes, and there are different arguments as to whether these techniques should be the procedure of choice. Both procedures should include implant placement to replace the lost volume and to restore the facial aesthetics. The implants can be non‐integrated (PMMA, silicone) or integrated (i.e. hydroxyapatite, polyethylene or composites).

Why it is important to do this review

Various autologous tissues, such as bone, fat and dermis, have been used to restore anophthalmic sockets, as have organic and alloplastic materials, including acrylics, silicone, hydroxyapatite and porous polyethylene. The high incidence of complications has prompted new research aiming to identify the gold standard material. However, the best technique in the management of anophthalmic sockets is currently unclear, and there is variation in trends around the world. A systematic review of integrated and non‐integrated orbital implants would be useful to patients, ophthalmologists and other professionals involved in providing eye care to evaluate the efficacy of procedures and to reduce complications.

Objectives

To assess the effects of integrated versus non‐integrated orbital implants for treating anophthalmic sockets.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which investigators determined allocation to treatment by alternation, use of alternate medical records, date of birth, or other predictable methods). This decision was due to our anticipation of not finding many trials in this area.

Types of participants

Participants were people affected by anophthalmia, regardless of age or sex. We also considered patients who had an implant rejection.

Types of interventions

We included the following interventions in this review.

Intervention group: porous/integrated materials (hydroxyapatite, porous polyethylene, composites).
Comparator: non‐porous/non‐integrated materials (polymethylmethacrylate (PMMA)/acrylic and silicone).

We also planned to investigate composite integrated/non‐integrated implants such as the Gutthoff implant as per our published protocol (Schellini 2013).

We considered both the enucleation and evisceration reconstruction of the anophthalmic socket.

Types of outcome measures

Primary outcomes

The primary outcomes for this review were:

the proportion of successful procedures at one year and up to five years after surgery; and
the proportion of successful procedures after five years.

We considered a successful procedure as involving no need for secondary reconstruction of the anophthalmic socket or implant extrusion. We also considered implant removal and implant exposure needing implant removal as an implant extrusion.

Secondary outcomes

Secondary outcomes for this review were:

Horizontal and vertical socket and prosthesis motility measured by evaluating the prosthesis excursion in different eye gaze positions or any validated measurement aiming to measure the impact of motility function loss;
degree of vascularisation measured by magnetic resonance imaging (MRI);
sphere size before and after surgery;
cosmetic effect (self‐reported);
quality of life measures: any validated measurement scale aiming to measure the impact of visual function loss on quality of life of participants;
economic data: we planned to perform comparative cost analysis if data were available; and
adverse events: any adverse outcomes as reported in trials, particularly extrusions or migration, infections, ectropion, ptosis, significant inflammatory responses or exposures.

We wanted to measure the secondary outcome measures at one year or more after surgery.

Search methods for identification of studies

Electronic searches

See appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), Embase (Appendix 3), LILACS (Appendix 4), ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We handsearched the reference lists of the identified relevant studies for additional citations. We also contacted specialists in the area and the main authors of included trials about unpublished data as well as pharmaceutical companies for further details of published and unpublished trials.

Data collection and analysis

Selection of studies

Two authors (RED and EJC) independently screened the trials identified by the literature search. We obtained full copies of all potentially or definitely relevant articles. We resolved disagreements by discussion and consulted each other for quality assurance of the processes. We documented reasons for exclusion for any study we rejected after viewing full copies in the 'Characteristics of excluded studies' table.

Data extraction and management

Two authors (RED and EJC) independently extracted data. We resolved any discrepancies by discussion. We used a standard data extraction form to record the following information: characteristics of the study (design, methods of randomisation), participants, interventions and outcomes (types of outcome measures, adverse events). One author (ECJ) entered all data into RevMan 5 (RevMan 2014). The second author (RED) independently checked the data entered.

Assessment of risk of bias in included studies

We assessed risk of bias using the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used the following six separate criteria: random sequence generation, allocation concealment, masking (blinding), incomplete outcome data, selective reporting and other types of bias. See Table 2 for further information on each parameter.

1. Risk of bias criteria.

Random sequence generation	Was the allocation sequence adequately generated, for example with random number tables or computer‐generated random numbers? We assessed trials as being at low risk of bias (the method used is either adequate or unlikely to introduce confounding), uncertain risk of bias (there is insufficient information to assess whether the method used is likely to introduce confounding) or high risk of bias (the method used (e.g. quasi‐randomised trials) is improper and likely to introduce confounding).
Allocation concealment	Was allocation adequately concealed in a way that would not allow either the investigators or the participants to know or influence allocation to an intervention group before an eligible participant was entered into the study (for example using central randomisation or sequentially numbered, opaque, sealed envelopes held by a third party)? We judged trials to be at low risk of bias (the method used (e.g. central allocation) is unlikely to induce bias in the final observed effect), uncertain risk of bias (there is insufficient information to assess whether the method used is likely to induce bias in the estimate of effect) or high risk of bias (the method used (e.g. open random allocation schedule) is likely to induce bias in the final observed effect).
Masking (blinding)	We judged the possibility of masking being done on both participants and outcome assessors. We did not consider masking of personnel as this is not feasible in these trials. Were the participants and study outcome assessors masked from knowledge of which intervention a participant received? We judged trials to be at low risk of bias (the outcome measurement is not likely to be influenced by lack of masking), uncertain risk of bias (there is insufficient information to assess whether the type of masking used is likely to induce bias in the estimate of effect) or high risk of bias (the outcome or the outcome measurement is likely to be influenced by lack of masking).
Incomplete outcome data	Were incomplete outcome data adequately addressed? Incomplete outcome data essentially include: attrition, exclusions and missing data. If any withdrawals occurred, were they described and reported by treatment group with reasons given? We recorded whether or not there were clear explanations for withdrawals and dropouts in the treatment groups. An example of an adequate method to address incomplete outcome data is the use of an intention to‐treat analysis (ITT). We judged trials to be at low risk of bias (the underlying reasons for missing data are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data), uncertain risk of bias (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias in the estimate of effect), or high risk of bias (the crude estimate of effects (e.g. complete case estimate) clearly was biased due to the underlying reasons for missing data, and the methods used to handle missing data are unsatisfactory).
Selective reporting	Are reports of the study free from any suggestion of selective outcome reporting? This was interpreted as no evidence that statistically non‐significant results might have been selectively withheld from publication, for example selective under‐reporting of data or selective reporting of a subset of data. We judged trials to be at low risk of bias (the trial protocol is available and all of the trials prespecified outcomes that are of interest in the review have been reported or similar), uncertain risk of bias (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting), or high risk of bias (not all of the trials prespecified primary outcomes have been reported or similar).
Other sources of bias	Was trial funded from parties that might not have conflicting interests (e.g. an antibacterial agent manufacturer), or any academic, professional, financial or other benefits to the person responsible for the trial were independent of the direction or statistical significance of trial results? We assessed trials as being at low risk of bias (if trial funding did not come), unclear risk of bias (if the source of funding was not clear, or if it was unclear whether the person responsible for the trial stands to benefit according to the direction or statistical significance of trial results) or high risk of bias (if the trial’s source of funding had a conflict of interest, or if any academic, professional, financial or other benefits to the person responsible for the trial are dependent on the direction or statistical significance of trial results).

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Firstly, we copied information that was relevant for making a judgment on a criterion from the original publication into an assessment table. If study authors provided additional information, we entered it in the table along with an indication that this was unpublished information. Two review authors (RED and ECJ) independently made a judgment as to whether the risk of bias for each criterion was low, uncertain, or high. We resolved disagreements by discussion.

When we classified trials as being at low risk of bias in sequence generation, allocation concealment, masking, incomplete data and selective outcome reporting, we considered them to be trials at low risk of bias. If the protocol was available, we compared the pre‐specified outcomes with the outcomes reported in the Results to assess selective reporting bias. Otherwise, we used the primary trial report to compare outcomes listed in the Methods section with those in the Results.

We recorded this information for each included trial in 'Risk of bias' tables in RevMan 5 (RevMan 2014) and summarised the risk of bias for each study in a summary 'Risk of bias' figure and graph.

Measures of treatment effect

Binary outcomes

For dichotomous data (proportion of successful procedures and adverse outcomes), we used the risk ratio (RR) as the effect measure with 95% confidence intervals (CIs).

Continuous outcomes

For continuous data (socket motility and prosthesis motility, degree of vascularisation, sphere size, cosmetic effect, and quality of life), we presented the results as mean differences (MDs) with 95% CIs. When pooling data across studies we would have estimated the MD if different trials measured the outcomes in the same way. We would have used the standardised mean difference (SMD) to combine trials that measure the same outcome but used different methods.

Unit of analysis issues

The unit of analysis was each participant, as only a minority would be anophthalmic in both eyes.

Dealing with missing data

An intention‐to‐treat analysis (ITT) considers data from all trial participants allocated to an intervention whether they received the intervention or not. We planned to impute an outcome for a dropout rate of 5%. For each trial we planned to report whether or not the investigators stated if the analysis was performed according to the ITT principle. If participants were excluded after allocation, we planned to report any details provided in full.

Furthermore, we planned to perform the analysis on an ITT basis whenever possible (Newell 1992). Otherwise, we adopted the available case analysis.

We attempted to contact study authors for missing data if necessary.

Assessment of heterogeneity

We quantified inconsistency among the pooled estimates using the Chi² test for heterogeneity. This illustrates the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2003). I² = [(Q ‐ df )/Q] x 100% test, where Q is the Chi² statistic and df its degrees of freedom. We assessed heterogeneity between the trials by visual examination of the forest plot to check for overlapping CIs, using the Chi² test for heterogeneity with a 10% level of significance, and the I² statistic. We classified heterogeneity using the following I² values.

0 to 40%: might not be important.
30% to 60%: may represent moderate heterogeneity.
50% to 90%: may represent substantial heterogeneity.
75% to 100%: considerable heterogeneity.

Assessment of reporting biases

Apart from assessing the risk of selective outcome reporting (see Assessment of risk of bias in included studies), we would have assessed the likelihood of potential publication bias using funnel plots had there been at least 10 trials. If small studies in a meta‐analysis showed larger treatment effects, we would have considered other causes including selection biases, poor methodological quality, heterogeneity, artefactual causes and chance.

Data synthesis

We ana lysed data as described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). If three or more studies had been included in a meta‐analysis, we would have used the random‐effects model, and if there were substantial heterogeneity, we would have investigated the source of heterogeneity by conducting a subgroup analysis. As there were fewer than three studies, we described the clinical characteristics of the included studies in tables.

Subgroup analysis and investigation of heterogeneity

In the case of excessive clinical heterogeneity (I² > 50%), we would have used subgroup analyses to pool the results. Subgroup analyses are secondary analyses in which the participants are divided into groups according to shared characteristics, and outcome analyses are conducted to determine if any significant treatment effect occurs according to that characteristic. If data had permitted, we would have carried out the following subgroup analyses, as we hypothesised that the effect of the interventions might be different due to variations in the surgical techniques, type or size of material used, and age.

Types of anophthalmic reconstructions (enucleation and evisceration).
Different implant sizes (small, medium, and large, approximating the volume of a 16 mm, 18 mm and 20 mm sphere).
Different types of non‐integrated and integrated materials.
Different ages: adults (aged 18 to 65 years) versus older adults (66 to 70 years) versus children and adolescents (17 years old or younger).

Sensitivity analysis

Had there been an adequate number of studies, we would have performed a sensitivity analysis to assess methodological decisions and the robustness of the results. We would have included the following factors in the sensitivity analysis, separating studies according to:

trials with low risk of bias versus those with high risk of bias; and
rates of withdrawal for each outcome (greater than 5%).

Summary of findings and assessment of the certainty of the evidence

We used the principles of the GRADE system to assess the quality of the body of evidence associated with specific outcomes (the proportion of successful procedures at one year or more after surgery; the proportion of successful procedures after five years and; socket and prosthesis motility; cosmetic effect; any adverse outcomes and quality of life) in our review and construct a 'Summary of findings' table using the GRADE software (GRADEpro 2015). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The assessment of the quality of a body of evidence considers within‐study risk of bias (methodologic quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.

Results

Description of studies

Results of the search

The electronic searches yielded a total of 407 references (Figure 1). The Cochrane Information Specialist removed 69 duplicate records, and we screened the remaining 338 reports. We rejected 259 records after reading the abstracts and obtained the full‐text reports of 79 references for further assessment. We identified three studies that met the inclusion criteria (Colen 2000; Shome 2010; Tari 2009). We assessed and excluded a further 76 references; see Characteristics of excluded studies for details.

Included studies

See Characteristics of included studies and Table 3.

2. Clinical characteristics of the included studies.

Study ID	No of participants randomised	Material		Technique used	Mean follow‐up period (months)
Colen 2000	34	Integrated	Hydroxyapatite	Enucleation	3^a
Colen 2000	34	Non‐integrated	Acrylic	Enucleation	3^a
Shome 2010	150	Integrated	Porous polyethylene	Enucleation	PP: 15.6
Shome 2010	150	Non‐integrated	Polymethylmethacrylate	Enucleation (myoconjunctival or traditional)	Traditional: 16.4 Myoconjuntival: 17.3
Tari 2009	100	Integrated	Hydroxyapatite	Enucleation	13.16
Tari 2009	100	Non‐integrated	Alloplastic	Evisceration	11.56

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^aAbsolute number.

We included three trials with a total of 284 participants (Colen 2000; Shome 2010; Tari 2009).

Design

Colen 2000 was a multicentre randomised clinical trial, while Tari 2009 was a single‐centre randomised clinical trial, and Shome 2010, a randomised trial did not report whether it took place in one or more centres.

Participants

Tari 2009 took place in Tehran University Eye Research Center, Tehran, Iran. The quadrisection group consisted of 50 participants: 35 men and 15 women with a mean age of 42.32 years. The HA group consisted of 50 participants: 41 men and 9 women with a mean age of 39.56 years. The reason(s) for operation in the quadrisection group were: a painful blind eye (n = 36), cosmetic unacceptability (n = 9) and endophthalmitis (n = 8). In the other group, there were 36 participants who had a painful blind eye; 6 cited cosmetic unacceptability; 5, acute trauma; and three were attributed to the other group.

Shome 2010 took place in Hyderabad, India; however, authors did not specify the institution, nor did they report the age, sex or health status details of the 150 participants.

Colen 2000 was a multicentre trial in the Rotterdam Eye Hospital, Rotterdam, and in the University Medical Center, Utrecht, Netherlands. The hydroxyapatite group consisted of 14 participants: seven men and seven women with a mean age of 64.0 years. In this group, six participants had the implant on the right side and eight on the left side. The acrylic group consisted of 16 participants: nine men and seven women with a mean age of 57.8 years. In this group, nine participants had the implant on the right side and seven on the left side. Thirty‐four participants were eligible for the study, and 30 were ana lysed. All participants had intraocular melanoma.

Interventions

Colen 2000 studied hydroxyapatite (integrated group) (n = 14) and acrylic implants (non‐integrated group) (n = 16). All participants underwent the enucleation technique. The follow‐up was three months.

Shome 2010 compared PMMA (non‐integrated group) (n = 50) versus PMMA myoconjunctival (non‐integrated group) (n = 50) versus integrated porous polyethylene (integrated group) (n = 50). The mean follow‐up of the participants was 16.4 months in the traditional PMMA group, 17.3 in the myoconjunctival PMMA group, and 15.6 in the porous polyethylene group.

Tari 2009 compared evisceration plus quadrisection of sclera with alloplastic implantation (non‐integrated group) (n = 50) versus enucleation with HA (integrated group) (n = 50). The mean follow‐up was 11.6 months for quadrisection and 13.2 months for HA.

Outcomes

Colen 2000 evaluated motility, saccadic gain and saccadic symmetry.

Shome 2010 measured implant and prosthesis movement as well as implant displacement and exposure.

Tari 2009 evaluated the presence or absence of exposure or extrusion and deep superior sulcus deformity along with implant motility.

Excluded studies

We excluded 76 studies after obtaining full‐text reports, as they did not meet the inclusion criteria. See the Characteristics of excluded studies for study names and the reasons for exclusion.

Risk of bias in included studies

See: Figure 2; Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We classified Colen 2000 and Shome 2010 as being at unclear risk of bias for random sequence allocation due to the lack of information reported in the papers. However, Tari 2009 used an alternative method to randomise participants, and we judged the risk of bias to be high. With regard to allocation concealment, only Colen 2000 reported the use of an envelope to mask the randomisation (low risk of bias) while Shome 2010 and Tari 2009 did not report this domain (unclear risk of bias).

Blinding

The masking of personnel does not apply for the clinical question under study, so we did not evaluate it in this review.

Only Colen 2000 reported that participants were unaware of the type of implant (low risk of bias), while Shome 2010 and Tari 2009 did not report information related to this domain (unclear risk of bias).

In both Colen 2000 and Shome 2010, the investigators who recorded the outcomes were unaware of the type of implant, so we assessed these studies as being at low risk of detection bias.

Incomplete outcome data

With regard to incomplete outcome data, in Colen 2000 there was only 11.77% of dropouts and in Tari 2009 all participants completed the study (low risk of bias). Shome 2010 did not report on the number of participants completing the study (unclear risk of bias).

Selective reporting

There was no evidence of selective reporting in any of the included studies (low risk of bias) (Colen 2000; Shome 2010; Tari 2009).

Other potential sources of bias

There was no evidence of any conflict of interest in Shome 2010 and Tari 2009 (low risk of bias), and Colen 2000 did not report on it (unclear risk of bias).

Effects of interventions

See: Table 1

Please see Table 4 and Table 1.

3. Clinical outcome.

Study ID	Type of material (surgical technique)		Proportion of successful procedures at 1‐5 years after surgery (no exposure/extrusion)	Adverse outcomes (i.e.infection or migration)	Horizontal implant motility (mm)	Vertical implant motility (mm)
Study ID	Integrated	Non‐integrated	RR (95% CI)	RR (95% CI)	MD (95% CI)	MD (95% CI)
Colen 2000	HA (enucleation)	Acrylic (enucleation)	—	—	—	—
Shome 2010	PP (enucleation)	PMMA traditional (enucleation)	0.92 ( 0.84 to 1.01) N = 150	17.82 (0.98 to 324.67) N = 150	1.96 (1.01 to 2.91) N = 100	(3.12 (2.36 to 3.88) N = 100
Shome 2010	PP (enucleation)	PMMA myoconjunctival (enucleation)	0.92 ( 0.84 to 1.01) N = 150	17.82 (0.98 to 324.67) N = 150	−0.57 ( −1.63 to 0.49) N = 100	(−0.20 (−1.28 to 0.88) N = 100
Tari 2009	HA (enucleation)	Alloplastic (evisceration)	1.02 (0.95 to 1.09) N = 100	—	−3.35 ( −4.08 to −2.62) N = 100	(−2.76 (−3.45 to −2.07) N = 100

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HA: hydroxyapatite; MD: mean difference; PMMA: polymethylmethacrylate; PP: porous polyethylene; RR: risk ratio.

We were unable to pool data from Shome 2010 and Tari 2009 in a meta‐analysis because of the different surgical techniques used (evisceration versus enucleation) and due to the heterogeneity among the clinical outcomes ana lysed.

We did not include Colen 2000 in the meta‐analysis as it did not report comparative effectiveness data. The authors compared vertical versus horizontal saccades gain, symmetry and curvilinearity between the operated and fellow eye instead of comparing it between both the intervention and comparator groups.

Proportion of successful procedures at one year and up to five years after surgery (no exposure/extrusion)

We found no statistically significant difference in the proportion of participants needing secondary reconstruction of the anophthalmic socket, implant extrusion or implant removal in the groups receiving integrated versus non‐integrated implants at one year or more after surgery. We compared HA versus alloplastic evisceration in one trial (RR 1.02, 95% CI 0.95 to 1.09, P = 0.56, Tari 2009; N = 100), and in another single trial, we compared both PMMA traditional and myoconjunctival versus porous polyethylene (RR 0.92, 95% CI 0.84 to 1.01, P = 0.07, Shome 2010; N = 150).