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Carroll C, Papaioannou D, Rees A, et al. The Clinical Effectiveness and Safety of Prophylactic Retinal Interventions to Reduce the Risk of Retinal Detachment and Subsequent Vision Loss in Adults and Children with Stickler Syndrome: A Systematic Review. Southampton (UK): NIHR Journals Library; 2011 Apr. (Health Technology Assessment, No. 15.16.)

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The Clinical Effectiveness and Safety of Prophylactic Retinal Interventions to Reduce the Risk of Retinal Detachment and Subsequent Vision Loss in Adults and Children with Stickler Syndrome: A Systematic Review.

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3Assessment of clinical effectiveness

Methods for reviewing effectiveness

A review of the evidence for clinical effectiveness has been undertaken systematically following the general principles recommended in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.29 English- and non-English-language studies were included (where translation is available) and there was no limit by date.

Identification of studies

A comprehensive search was undertaken in October 2009 to identify, systematically, both clinical effectiveness and adverse events literature pertaining to prophylactic retinal interventions to prevent RD in populations reported specifically to comprise participants with Stickler syndrome or populations that may include participants with Stickler syndrome. This search was performed by an information specialist (AR). Searches were not restricted by language or publication date. The MEDLINE search strategy is reported in Appendix 1.

The following electronic databases and online conference proceedings were searched from inception for published and unpublished research evidence:

  • MEDLINE (Ovid) 1950–October 2009
  • MEDLINE in process (Ovid) October 2009
  • EMBASE 1980–October 2009
  • Cumulative Index to Nursing and Allied Health Literature (via EBSCO) 1982–October 2009
  • The Cochrane Library including the following databases 1991–October 2009: Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) and NHS Economic Evaluation Database (NHS EED)
  • Biological Abstracts [via Thomson Reuters (formerly ISI) Web of Science®] 1969–October 2009
  • Science Citation Index (via ISI Web of Science) 1900–October 2009
  • UK Clinical Trials Research Network (UKCRN) and the National Research Register archive up to October 2009
  • Current Controlled Trials up to October 2009
  • Clinical Trials.gov up to October 2009
  • Annual Meeting of the Association for Research in Vision and Ophthalmology up to 2009.

All citations were imported into reference manager, version 12, software (Thomson Reuters, New York, NY, USA) and duplicates were deleted (AR). Titles and abstracts of all unique citations were then double-screened by two reviewers (CC and DP) using the inclusion criteria outlined below. Any disagreements concerning possible inclusion were resolved by discussion between the reviewers or with reference to the full paper itself. The full papers of all potentially relevant citations were retrieved so that an in-depth assessment concerning inclusion could be made. Again, both reviewers independently screened full papers for relevance and any disagreements concerning possible inclusion were resolved by discussion. In the event that published papers did not report potentially relevant data, corresponding authors were contacted by letter. If relevant data were made available by this route, they were included in the analysis.

Inclusion and exclusion criteria

Population

Children (up to the age of 18 years) and adults diagnosed with type 1 or type 2 Stickler syndrome or ‘Wagner–Stickler’ syndrome with non-ocular features. There are no universally agreed diagnostic criteria for Stickler syndrome, but it is expected that study participants would demonstrate the presence of a typical vitreous phenotype (type 1 or 2) and/or COL2A1/COL11A1 mutation. Criteria of diagnosis were recorded. The protocol originally stated that individuals with Wagner–Stickler syndrome were to be excluded (see Appendix 6). It is recognised that Wagner and Stickler syndromes are quite distinct genetically, and in terms of systemic features.10,17,19,30,31 For example, Wagner syndrome is accepted to have only ocular abnormalities and no other systemic features.10,17,19,30 However, Stickler syndrome has a highly variable degree of systemic features (a subgroup has been identified with no or very few systemic features).1720 The differences between the two syndromes have become clinically apparent only in recent years, so, despite the previously ‘confusing’ nomenclature of ‘Wagner–Stickler’ syndrome,17 studies of this population have also been included in this review if their study samples exhibit non-ocular symptoms (i.e. consistent with Stickler syndrome). This is because there is little published research evaluating primary prophylaxis in populations specifically diagnosed with Stickler syndrome, and study samples diagnosed with Wagner–Stickler syndrome may be composed of individuals diagnosed with Stickler syndrome, in part at least. Clinical advice was divided on the relevance of including these studies, but the majority opinion was that they offered some interesting supporting but not pivotal information, as long as the issues regarding the reported diagnosis of these populations in these studies were highlighted. Any studies of Wagner–Stickler patients with non-ocular symptoms have therefore not been presented as pivotal evidence but are alluded to as supporting evidence only. Children form a possible relevant subgroup, as the risk of RD, although life-long, has been reported to be highest between the ages of 10 and 30 years in Stickler syndrome populations. Individuals with conditions or syndromes other than Stickler syndrome or Wagner–Stickler syndrome with non-ocular features, but who have a predisposition to RD, e.g. retinopathy of prematurity or Marfan syndrome, were excluded.

Interventions

Any intervention aimed at the primary prevention of RD. Interventions must involve surgical procedures or settings, such as the use of a sterile environment or anaesthesia.

Comparators

No prophylactic treatment (there is no defined usual care for this population).

Settings

Secondary care.

Outcomes

Primary outcome

Retinal detachment in the eye(s) exposed to prophylactic intervention.

Secondary outcomes

  1. Adverse events relating to the intervention.
  2. Blindness (by self-assessment, or being registered or legally blind).
  3. Time to RD.
  4. Presence and type of lesions or retinal tears (as these may constitute a precursor for RD).

Study design

Any study design with a control or comparator group.

Data extraction strategy

Data were extracted independently from all included studies by two reviewers (CC and DP) using a data extraction form developed for this review and piloted on two studies (see Appendix 2). Any discrepancies between extractions were resolved by discussion and referral to the full paper.

Quality assessment strategy

Assessment of study quality was undertaken using an appropriate study design checklist, in this case the Critical Appraisal Skills Programme checklist for cohort studies.32 A copy of the full checklist is included in Appendix 3. The critical appraisal of study quality was again conducted for each study independently by two reviewers (CC and DP) and any discrepancies resolved by discussion. The aim of the quality assessment process was to address issues regarding the appropriate recruitment of the sample, controlling for possible confounders (including comparability of groups), the length of follow-up, and the preciseness and external validity of the results. Studies were not excluded on the basis of their assessed quality. The purpose of this appraisal was to assess both the internal validity of the included studies and the potential risk of bias across studies included in the review.

Methods of analysis/synthesis

Data were tabulated and, given the small number of studies identified (two pivotal studies33,34 and two supporting studies3638) and the heterogeneity of the evaluated interventions, a narrative synthesis rather than a meta-analysis was performed. The relative risk or risk ratio (RR) measure of relative effect was not reported in any of the published papers and also has not been reported in the main body of this report. This is because of the high risk of bias found in both studies33,34 (see Quality assessment below), especially concerning the comparability of treatment and control groups, which would adversely affect the reliability and validity of any such estimates of effect.35 The between-group differences reported in the published papers are therefore the only statistical results reported here.

Results

Quantity and quality of research available

The search of electronic databases identified 1444 unique citations. One hundred and twenty-two full papers were retrieved after double-screening to determine whether they were relevant to this review. After double-screening of the full papers, only two studies explicitly satisfied all of the inclusion criteria: Ang et al.33 and Leiba et al.34 A further two studies (three papers)3638 were identified as being of potential relevance as supporting studies because the study population had Wagner–Stickler syndrome. The diagnostic criteria described in these two studies included non-ocular features, and so were possibly consistent with a diagnosis of Stickler rather than Wagner syndrome. No additional relevant papers were identified from either reference tracking (two potential papers were unattainable, but appeared to concern Wagner syndrome patients only)39,40 or contact with expert advisors.

Seventy full papers were double-screened and excluded because they clearly failed to satisfy one or more of the criteria relating to the population, intervention or outcomes (these studies are listed in Appendix 4). The full papers of three citations were not available for screening.4143 A total of 44 further papers were excluded because they evaluated primary prophylactic surgical interventions for RD but did not provide sufficient details to be certain that there were no Stickler syndrome patients within the study population. These studies are listed in Appendix 5. Eight of these studies stated that a family history of RD was either an indication for prophylactic intervention or a characteristic of the study population.4451 Details of the screening and inclusion process are provided in the PRISMA flow diagram (Figure 1).

FIGURE 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

The reviewers therefore contacted the authors of these eight papers4451 to ascertain whether there were any Stickler syndrome patients in their study sample (November 2009) and the results of any intervention for this subgroup. However, at the time of this report, only four authors had communicated with the review team, and all reported either that there was no known Stickler syndrome patients in their samples4547 or that the data were no longer available to determine whether or not Stickler patients had been included.48 The total number of studies therefore included in the principal analysis was two controlled cohort studies of prophylactic surgical interventions in type 1 Stickler syndrome populations. Details of two studies (three papers)3638 of cohorts with comparator groups evaluating prophylactic surgical interventions in ‘Wagner–Stickler’ syndrome populations are also summarised as supporting evidence.

Summary of studies

Two studies were identified that assessed primary prophylactic surgical interventions in populations diagnosed with type 1 Stickler syndrome (Table 1).33,34 The diagnostic criteria applied in both studies were consistent with Stickler syndrome. In both studies, the diagnosis was confirmed ‘where possible’ with genetic analysis, but this does not appear to have been applied to all participants.

TABLE 1. Study characteristics.

TABLE 1

Study characteristics.

In the Ang et al. study,33 the intervention was 360° cryotherapy on the post-oral retina to prevent progression to RD of the posterior flap of giant retinal tears (GRTs). The study by Leiba et al.34 evaluated circumferential or focal laser treatment. The circumferential treatment consisted of confluent laser burns 360° around the peripheral retina, with four to eight laser burns applied circumferentially at the junction between the posterior border of the lesions and the unaffected retina. In the focal treatment, small localised lesions of lattice degeneration or isolated breaks were encircled by three to six rows of laser burns. The Ang et al.33 study was conducted in the UK and the Leiba et al.34 study in Israel. Both studies employed retrospective case review of data from a cohort exposed to the intervention and a cohort of controls. In both studies, bilateral and unilateral prophylaxis was performed. In the Leiba et al.34 study, the control group does not appear to have received any specific form of prophylaxis. However, in the study by Ang et al.,33 an unknown number of procedures of laser retinopexy or ‘treating isolated areas of lattice more posteriorly’ may have been performed on members of the control group. The length of follow-up for the intervention groups ranged from 1 to 33 years in the Ang et al.33 study and from 1 to 15 years in the Leiba et al.34 study. There was no reported length of follow-up for the controls in either study.

Quality assessment

Both the Ang et al.33 and Leiba et al.34 studies recruited relevant populations diagnosed with type 1 Stickler syndrome, although confirmatory genetic analysis appears to have been used only ‘where possible’ in the study by Ang et al.33 Therefore, the diagnosis was made by clinical criteria only, and not confirmed by mutation analysis, for an unknown number of participants in the intervention and control groups in the Ang et al.33 study. However, the clinical examination used in this study, i.e. to identify the relevant membranous vitreous phenotype, has been shown to have a high degree of sensitivity in predicting the results of genetic analysis.30 Neither study justified the size of the sample (204 in Ang et al.33 and 22 in Leiba et al.34) or considered its implications in analysis, although the Ang et al.33 study does evaluate the largest published sample of any study of prophylactic interventions in Stickler syndrome or other potentially relevant populations. The intervention and outcome (RD) appear to be measured accurately in both studies (although an unknown number of participants in the control group in the Ang et al.33 study may have been exposed to some form of prophylaxis). It is unclear in both studies whether possible participants had been excluded.

The risk of RD is life-long,2 so the longer the follow-up, the better. The Ang et al.33 study had a mean follow-up for both intervention groups of between 11 and 15 years, which is substantial. However, there is no reported follow-up for the control group. The follow-up of the intervention group in the Leiba et al.34 study was as much as 15 years, but was also as little as 1 year, which may not be long enough to demonstrate effectiveness reliably. However, the follow-up for three patients in the intervention group (6 of the 10 eyes) was between 8 and 15 years, which is more reliable. The length of follow-up for the control group was not reported. Neither Ang et al.33 nor Leiba et al.34 reported the relative risk [or confidence intervals (CIs)] of experiencing the outcome when exposed to the intervention compared with the control. Both studies reported only whether there was a significant difference in rates of RD between the intervention and control groups. There was therefore no estimate of effect. Also, Leiba et al.34 did not report the test used to determine a statistically significant difference between the two groups. The external validity of the Ang et al.33 study was good in comparison with Leiba et al.:34 the population and setting were highly applicable to the decision problem, being type 1 Stickler syndrome patients, compared with Leiba et al.'s34 consideration of a single family group of individuals with type 1 Stickler syndrome.

The results of both studies are subject to a high risk of bias. Both were retrospective cohort studies and so were limited by the bias inherent in that design.52 The study reported by Ang et al.33 had a number of strengths, including sample size, length of follow-up for the intervention groups and the reporting of data on the principal confounding factor of age. However, the control group presents a number of major problems. It does not represent a homogeneous group in terms of being exposed either to a single comparator intervention or to no intervention at all: an unknown number in the sample appear to have received some sort of prophylaxis that was not cryotherapy. The study correctly reports the potential confounding factor of age, but does not control for this in the results or analysis. The rate of RD in the control group is high in comparison with the intervention groups and is also higher than reported elsewhere for other Stickler syndrome populations not exposed to prophylaxis (but unconfirmed as type 1 only, and therefore potentially not at the highest risk of RD, unlike most if not all of the type 1 individuals in the Ang et al.33 study): 73% per patient compared with 57%–61% per patient reported in surveys.2,8,20 There is also a substantial difference between the intervention groups and the control group in terms of ‘follow-up’: the former has a maximum of 33 years with a mean of between 11 and 15 years, while there is no reported ‘follow-up’ at all for the latter, the controls. This further adversely affects the reliability of any comparison of event data between intervention and control groups. Also, the mean age of the controls was 49 years (range 5–92 years), the mean age of the bilateral prophylaxis group was 21 years (3–61 years) and the mean age of the unilateral group was 36 years (2–75 years). Given that age and, consequently, follow-up are both recognised to be important confounders, i.e. the likelihood of RD increases over time, with age, then the likelihood of the control group having experienced the outcome is inherently much higher than for the intervention groups. The relative effect of the intervention on the outcome of RD may therefore have been exaggerated when compared with the control group based on the event data reported in this study. It is also unclear whether the study was sufficiently powerful to generate a reliable effect size for the primary outcome. The risk of bias in this study was therefore high.

Leiba et al.34 considered the potential confounding factors of age at first RD and the presence or absence of RD in the primary eye. Differences between intervention and control groups were not reported, although only those participants who were considered eligible for treatment actually received prophylaxis; the control group may therefore have had a different (possibly higher) level of risk of RD. The control group in the Leiba et al.34 study is homogeneous as the subjects all appear to have received no form of prophylaxis at all. However, this study had more weaknesses than Ang et al.:33 the reported follow-up was shorter (a minimum of 1 year and a maximum of 15 years); the sample was much smaller and narrower (i.e. from a single pedigree); and the mean age of the intervention and control groups was not reported, although the data reported enable the comparison to be made that 9/10 individuals in the control group experienced an RD before the age of 30 years, and 5/6 patients exposed to prophylaxis received the treatment before 30 years of age. The risk of bias in this study was therefore also high.

Assessment of effectiveness

No estimates of effect were reported in the published papers or calculated by the authors of this report (owing to the high risk of bias in the two studies33,34). The papers themselves appear to test for and report only between-group differences (see Table 2). The Ang et al.33 study reported a statistically significant difference between groups both for eyes [χ2 = 119.2, degrees of freedom (df) = 1, p < 0.001] and for patients (χ2 = 37, df = 1, p < 0.001), and the Leiba et al.34 study reported a statistically significant difference between intervention and control groups for RD (p < 0.0025), but the test used was not reported and it is unclear whether this was for eyes or patients. Relative estimates of effect (relative risks), calculated by the authors of this report and based on the event data reported by these studies, are not reported in the main body of the report because their validity is affected by the high risk of bias within the included studies. However, these relative risks are reported in Appendix 8.

TABLE 2. Reported outcomes.

TABLE 2

Reported outcomes.

Neither study reported details of any retinal tears or lesions which did not lead either to an RD or to further surgery. Only Leiba et al.34 reported data on blindness due to RD: the intervention group had only one RD and no resulting blindness; 10 members of the control group experienced RD in one or both eyes (18 eyes), and 16 of these 18 eyes proceeded to blindness post RD surgery (time to failure not reported). Only two eyes had not re-detached by the time of the study (duration of follow-up not reported).

Subgroups: children

Only Leiba et al.34 performed a subgroup analysis based on age. The study reported that 0/6 eyes treated prophylactically in children aged ≤ 13 years detached compared with 1/4 eyes treated prophylactically in children aged ≥ 13 years. The findings of this study may also indicate an increase in the likelihood of RD in adolescence and young adulthood. In the control group, who did not receive any prophylaxis, the retina detached in 6/13 (46%) eyes in children aged ≤ 13 years, but detached in 9/15 (60%) in adolescents and adults aged ≥ 13 years. However, this sample is very small.

Safety

None of the studies reported any serious or long-term adverse events or complications associated with cryotherapy, focal or circumferential laser treatment or scleral buckling. Only minor and temporary complications were reported by any of the studies. For cryotherapy, Ang et al.33 reported transient epiphora, lid swelling and temporary accommodative paresis, but no cases of choroidal haemorrhage, macular pucker or unexplained loss of vision. However, the study did not report the number of patients experiencing any complications, so the proportion of patients experiencing these or any other complications, and the duration of any side effects, is unknown. Leiba et al.34 reported that there were no ocular complications associated with the laser prophylaxis performed and visual acuity was unaffected.

Supporting studies

There are two studies (three papers), by Monin et al.36,37 and Fritsch et al.,38 reporting evaluations of primary prophylactic interventions in populations diagnosed as having ‘Wagner–Stickler’ syndrome (Tables 3 and 4). Both studies reported that all participants in their sample had ‘Wagner–Stickler’ syndrome, although the diagnostic criteria were not reported in the study by Monin et al.36,37 However, in this study by Monin et al., as well as being diagnosed with Wagner–Stickler syndrome, a number of participants had either a ‘family history’ of RD or ‘systemic abnormalities (cleft palate)’ in addition to ocular abnormalities stated as being consistent with Wagner or Stickler syndrome.36 In the study by Fritsch et al.,38 in addition to ocular abnormalities, all participants had non-ocular symptoms, which may be suggestive of Stickler rather than Wagner syndrome. However, neither chromosome nor genetic analysis was performed in either study to clarify diagnosis. It therefore cannot be stated categorically that the populations in these studies had Stickler syndrome. However, the reported, published diagnosis of Wagner–Stickler syndrome for these patients, and the greater consistency of symptoms with Stickler rather than Wagner syndrome, suggest that there are reasons to consider that these studies may provide possible relevant supporting evidence to this review. They have therefore been included, but are not considered as principal evidence.

TABLE 3. Study characteristics (Wagner–Stickler syndrome).

TABLE 3

Study characteristics (Wagner–Stickler syndrome).

TABLE 4. Reported outcomes (Wagner–Stickler syndrome).

TABLE 4

Reported outcomes (Wagner–Stickler syndrome).

In the Monin et al.36,37 study, only participants who had already experienced RD in the primary eye were included; prophylaxis was performed on the fellow eye (i.e. the eye that had not experienced a detachment). The study was conducted in France. There were three intervention groups, each exposed to different forms of primary prophylaxis: argon laser photocoagulation; scleral buckling; and a group exposed to four different interventions: focal cryotherapy, focal or circular laser photocoagulation, or vitrectomy. No group was designated as the primary intervention group or as controls. This study employed retrospective case review of data from cohorts exposed to the various interventions. Follow-up was reported to range from 3 to 67 months. In the study by Fritsch et al.,38 participants received either bilateral or unilateral prophylaxis. This was a cohort study conducted in France. It is unclear whether the study was prospective or retrospective. Groups in the cohort were exposed to one of the following interventions: focal laser treatment or cryotherapy, and scleral buckling or focal laser treatment with scleral buckling. Follow-up was reported to range from 2 to 8 years.

Monin et al.36,37 reported that scleral buckling appeared to be effective as none of the seven participants exposed to this unilateral intervention in the fellow eye had experienced an RD at follow-up (9 months to 3 years) (Table 4).37 However, 5 of 10 individuals exposed to unilateral argon laser photocoagulation had an RD in the fellow eye in the follow-up period, as did all four individuals exposed to cryotherapy, focal or circular laser photocoagulation, or vitrectomy. The mean age at first RD was 8 years in the laser group failures, 11 years for the laser group ‘successes’ and 16 years for the successful scleral buckling group participants. The age at first RD may therefore be a confounding factor. In the Fritsch et al.38 study, none of the individuals exposed to cryotherapy (number unknown), focal laser treatment (number unknown), scleral buckling (n = 2) or focal laser treatment with scleral buckling (n = 2) experienced an RD. Monin et al.36,37 reported lid swelling and chemosis immediately post operation for scleral buckling, as well as a single case of longer-term sero-haemorrhagic choroid detachment, which spontaneously resolved. The Fritsch et al.38 study did not report any complications with any intervention.

Both the Monin et al.36,37 and Fritsch et al.38 studies had a high risk of bias. They appear to be retrospective cohort studies and had very small samples (22 and 26 respectively); it is unclear if some possible participants had been excluded and the diagnosis itself may be flawed. There is no justification of the sample size in either study. In the absence of clearly reported diagnostic or treatment criteria, it is not possible to determine whether the populations in the treatment groups in the study by Monin et al.36,37 are in fact all the same. Fritsch et al.38 was a cohort study with comparator groups, but did not report the exact number of participants exposed to either focal laser treatment or cryotherapy in the principal group. The effect of each of the reported interventions therefore could not be determined. Neither Monin et al.36,37 nor Fritsch et al.38 reported any differences between groups. The follow-up in both studies (maximum 8 years) is almost certainly insufficient to demonstrate effect. Neither study performed any analysis on the results or calculated an estimate of effect. Fritsch et al.38 reported that no participant experienced the outcome of interest. This seems unlikely given the population and length of follow-up (up to 8 years): Monin et al.36,37 evaluated similar interventions in a similar population over a shorter length of time and reported a high incidence of RD in two of the three intervention groups. The external validity of both studies is limited because the populations were diagnosed as Wagner–Stickler syndrome rather than Stickler syndrome (although reported symptoms suggest a majority may have had Stickler syndrome) and neither was conducted in the UK, and techniques may differ by location.

© 2011, Crown Copyright.

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Bookshelf ID: NBK99330

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