Laser therapy for retinopathy in sickle cell disease

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness of various techniques of laser photocoagulation in SCD-related retinopathy.

Background

Description of the condition

Sickle cell disease (SCD) is common genetic disorder affecting millions of people worldwide. It is most endemic in tropical regions, mainly sub-Saharan Africa, India and the Middle East (Weatherall 2001). It has become a global issue due to the migration of population from these areas to Europe and other parts of the world, particularly over the last few decades (Roberts 2007). Sickle cell disease includes sickle cell anaemia (Hb SS), sickle cell-haemoglobin C disease (Hb SC), sickle cell-β thalassaemia (Sβ0 Thal and Sβ+ Thal) and other less prevalent double heterozygous conditions (Serjeant 2001). It is a systemic disease that affects almost all the organs and leads to neurological, cardiac, pulmonary, hepatic, renal, ophthalmic, musculoskeletal and dermatological manifestations (Ballas 2010).

The main pathophysiology associated with ophthalmic manifestations in SCD is vaso-occlusion that occurs in any vascular bed of ocular structures including conjunctiva, anterior segment, choroid, retina and optic nerve with potential visual impairment (Emerson 2005). Sight-threatening problems in SCD are mainly due to proliferative sickle retinopathy (PSR), which is secondary to occlusion of the peripheral retinal vasculature, which in turn leads to retinal ischemia and proliferation of new blood vessels with characteristic sea fans appearance. The incidence of PSR is more common in Hb SC disease and sickle cell-β thalassaemia, being approximately 33% and 14% respectively, compared to 3% in Hb SS (Lutty 1994). The incidence of PSR increases with age, it is relatively common between 15 and 29 years of age (Condon 1972), but there were reported studies in which PSR was detected in children as young as 7 to 13 years (Abiose 1978; Condon 1974a; Erachulu 2006). The peak prevalence of PSR in the HbSC genotype occurs earlier than in the SS type between 15 to 24 years in men and 20 to 39 years in women (Elagouz 2010). Goldberg and colleagues developed a classification of PSR according to the severity of fundus changes (Table 1) (Goldberg 1971).

Table 1. Classification of PSR
Table 1: Staging of proliferative sickle retinopathy (PSR)
Stage I            Peripheral arteriolar occlusion
Stage IIVascular remodelling, formation of arteriovenous anastomoses
Stage IIIPeripheral retinal neovascularization
Stage IVVitreous haemorrhage
Stage VRetinal detachment

Early stages of PSR may not need any intervention, as these early changes are quiescent or may even resolve due to auto-infarction. Spontaneous regression is seen in 32% of eyes with PSR without any blinding complications (Downes 2005). Regression of PSR is more common in the eyes of people with Hb SS disease, seen in 40% compared to 20% of Hb SC; and complete non-perfusion of PSR lesion is observed in 20% of SS and 7% of SC (Fox 1991). Although permanent visual loss is rare, incidence of visual loss among patients with SS and SC has been reported as 31 per 1000 eyes affected by PSR compared to 1.4 per 1000 eyes without PSR over a mean follow-up period of 6.9 years (Moriaty 1988). Visual loss in PSR is commonly due to vitreous haemorrhage and tractional retinal detachment (Moriaty 1988) and affects relatively younger patients indicating that early detection with timely effective treatment of stage III PSR is necessary to prevent such visual loss.

Description of the intervention

Various treatment options, such as diathermy, cryotherapy and transpupillary or transscleral diode laser photocoagulation, have been proven to be effective treatments of PSR (Condon 1974b; Goldbaum 1979; Seiberth 2001). Transpupillary laser photocoagulation is the safest and the preferred method among the available techniques, as cryotherapy is associated with adverse effects like retinal detachment (Goldbaum 1979). Transscleral diode laser coagulation is considered as an alternative in cases only when transpupillary laser coagulation is not applicable due to media opacities (Seiberth 2001).

Given the favourable chances of spontaneous regression, indication for the treatment of PSR varies among clinicians. Treatment is usually indicated in cases with peripheral neovascularization of more than 60° of circumference. This is particularly the case in eyes with bilateral involvement, spontaneous vitreous haemorrhage, large and elevated sea fans, rapid progression of new blood vessels, or precious eye in which the fellow eye has been lost due to PSR (Emerson 2006). The aim of treatment is to induce regression in stage III PSR prior to complications to prevent visual loss (Goldberg 1983). The different types of laser mainly used to achieve these goals are white xenon arc or blue/green argon.

The specific methods of laser in PSR include feeder vessel coagulation and scatter laser coagulation, either localized or 360° peripheral scatter coagulation (Ballas 2012). Scatter laser photocoagulation is considered to be the preferred method for PSR (Castro 1999). There are two types of scatter laser photocoagulation, the first being sectoral or localised and the second being 360° or circumferential laser treatment. In sectoral ablation, laser burns are applied only to the localised area around new blood vessels whereas in circumferential or 360° scatter laser, burns are applied circumferentially to entire peripheral retina (Cruess 1983; Kimmel 1986). The latter is usually indicated in an unreliable patient (Ballas 2012). Laser therapy is most effective when peripheral lesions are diagnosed early before involving the central retina (Castro 1999).

How the intervention might work

Laser photocoagulation has been considered safe as well as effective in the treatment of PSR, as it maintains quality of life and preserves the vision by preventing vision-threatening complications in affected population (Goldbaum 1979; Goldberg 1983).

The mechanism of laser treatment in feeder vessel coagulation is to occlude the feeding vessels by applying direct, heavy laser burns to feeding arterioles leading to closure of neovascular fronds. Ocular media should be clear enough over the feeder vessels for successful photocoagulation (Goldbaum 1979). Both xenon arc and argon laser photocoagulation are used for feeder vessel coagulation; however, currently argon is more commonly used by clinicians as xenon has a higher complication rate compared to argon (Emerson 2005). Scatter laser coagulation has an indirect effect, as it destroys the ischemic retina responsible for production of vascular endothelial growth factor (VEGF) that triggers the proliferation of new blood vessels (Ballas 2012). This technique is primarily used to treat proliferative diabetic retinopathy. The fact that laser photocoagulation to ischemic retina results in regression of new blood vessels in eyes with proliferative diabetic retinopathy has led to this technique being adapted for treatment of PSR. To achieve this goal, blue/green argon laser burns are applied to the retina with laser setting of 500 um spot size and 0.1 second duration.

Studies have demonstrated that laser treatment for PSR has been accepted for several decades (Cruess 1983; Kimmel 1986; Rednam 1982). Timely, successful treatment avoids the need for surgical interventions with their potential complications and morbidities (Cohen 1986; Goldberg 1983).

Why it is important to do this review

Proliferative sickle retinopathy is a leading cause of visual impairment in patients with SCD. Cochrane systematic reviews of randomised controlled trials have been published for prophylaxis and treatment in other organs affected by SCD (Hirst 2012; Marti-Carvajal 2012), but none to date for ocular involvement. Cochrane systematic reviews evaluating the effects of laser photocoagulation in other proliferative retinopathies, such as neovascular age-related macular degeneration, have found that laser treatment slows the progression of visual loss in affected eyes (Virgili 2009). A Cochrane review for laser photocoagulation in diabetic retinopathy is currently ongoing (Dineen 2008). Despite the well-known clinical applications of laser photocoagulation in PSR, it is imperative to identify the treatment effect in people with SCD, given the potentially blinding complications of PSR if treatment is delayed.

Even though laser photocoagulation in PSR is a relatively simple and safe treatment, summarised safety and efficacy compared to placebo or other treatment options in patients with PSR is lacking. Furthermore, various techniques of laser photocoagulation have been practised among clinicians based on preference and facilities. It is therefore essential to perform a systematic review to evaluate the evidence for the effectiveness of different laser photocoagulation therapies in patients with PSR for preventing visual loss and ocular morbidity, along with their potential adverse effects.

Objectives

To evaluate the effectiveness of various techniques of laser photocoagulation in SCD-related retinopathy.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and controlled clinical trials.

Types of participants

Children and adults diagnosed with SCD and PSR, irrespective of phenotype, age, gender, race, ethnic origin and setting.

Types of interventions

All types of laser photocoagulation to the retina compared to no intervention or to other forms of treatment such as cryotherapy or intravitreal antiVEGF injection.

Types of outcome measures

Primary outcomes
  1. Regression of PSR (change in number and size (in clock hours or in degrees of retinal circumference) of new blood vessels)

  2. Development of new PSR (proliferation of blood vessels at a new area after treatment)

Secondary outcomes
  1. Quality of life (using any validated measures)

  2. Change in visual loss associated with PSR (visual loss is defined by the deterioration of visual acuity of two lines or more with the Snellen chart)

  3. Change in leakage from new blood vessels (change in fundus fluorescein angiography (FFA) findings three months after treatment)

  4. Adverse effects, such as:

    1. retinal breaks;

    2. retinal detachment;

    3. retinal haemorrhage;

    4. choroidal haemorrhage;

    5. choroidal neovascularization.

We will tabulate all adverse effects related to laser photocoagulation for the treatment of PSR that are reported in the included studies.

Search methods for identification of studies

Electronic searches

We will identify relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

We will also search the following resources: Latin American and Caribbean Health Science Literature Database (LILACS) (http://lilacs.bvsalud.org/en/), WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and ClinicalTrials.gov (www.clinicaltrials.gov). We will not restrict the electronic searches for trials by date or language.

Searching other resources

We will handsearch the International Congress of Ophthalmology from 1980 to present day to identify unpublished studies. We will also search the reference lists of review articles for details regarding the relevant publication. We will contact organizations and researchers in the field of ophthalmology by email for information on ongoing trials.

Data collection and analysis

Selection of studies

Two review authors (KTM, SS) will independently assess trial eligibility by screening the titles and abstracts of all RCTs identified during the search process. Should we fail to ascertain relevant data from the title or abstract we will retrieve the full text of the study. If there is any unclear information in the published studies, or studies are published in abstract form only, we will contact the trial author(s) for further details. The same two authors will independently review full texts of all potential relevant studies and assess the eligibility according to the specific criteria for inclusions of studies. The review authors will be unmasked to the trial authors, institutions and study results during the assessment. We will try to resolve any disagreements by discussion and if necessary we will request the opinion of the third review author (HN). Should we fail to resolve the disagreement, we will add the study to the 'Studies awaiting classification' and we will contact the trial author(s) for further details. We will record the excluded studies in the 'Characteristics of excluded studies' table in RevMan 5.2 with reasons for exclusion (RevMan 2012).

Data extraction and management

Two review authors (KTM, SS) will independently extract data from eligible studies using standard data collection form for optimal reliability. We will check for any errors and inconsistencies and if there is any disagreement we will try to resolve by discussion and consensus. We will maintain a record regarding any disagreements related with extracted data. One review author (KTM) will then enter data into RevMan 5.2 (RevMan 2012) and a second review author (HN) will check for any errors or discrepancies.

We plan to extract the following data.

1. Participants' characteristics

  • Demographic data (age, sex, race)

  • Eligibilty (inclusion and exclusion criteria)

  • Total number in comparison group

  • Sickle cell types (SS, SC, Sβ-thalassemia)

  • Withdrawals or dropouts and losses to follow up with reasons

2. Method

  • Study design

  • Time and duration of study

  • Randomization

  • Allocation concealment method

  • Blinding of participants

3. Characteristics of PSR

  • Location in retinal quadrants (superotemporal, superonasal, inferotemporal, inferonasal)

  • Extent in number of clock hours or degree in circumference of the retina

  • Surface (raised or flat)

3. Interventions

  • Method of laser (feeder vessel coagulation, generalised scattered or focal scattered coagulation)

  • Types of laser (argon, xenon or other)

  • Laser setting (laser power or intensity, spot size, duration of laser photocoagulation)

  • Number of laser sessions

4. Outcome

  • Outcomes mentioned above

  • Time of assessment

  • Length of follow up

We plan to report our outcomes at up to one month, over one month to six month,over six months to one year and over one year. we will also consider additional follow-up data recorded at other time periods.

Assessment of risk of bias in included studies

Two review authors (KT, SM) will independently assess the risk of bias in the included studies according to the criteria listed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will follow the domain-based assessment for risk of bias in included studies and resolve any disagreements by discussion. We will evaluate the following six domains: sequence generation (randomisation); concealment of allocation; blinding of participants, personnel and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. For each domain we will assign one of the three risk of bias judgements: 'low risk'; 'unclear risk'; or 'high risk' of bias. We will resolve any disagreement by discussion and if necessary we will confer with a third author (HN). We will record results on the above six domains in the relevant risk of bias tables in RevMan (RevMan 2012).

1. Random sequence generation

  • Low risk of bias - if the sequence generation was randomised using computer generated random number, random number table, cards shuffling, coin tossing or envelopes.

  • High risk of bias - if non-random procedure using date of birth, date of admission, hospital or out-patient number for sequence generation.

  • Unclear risk of bias - if the method used to generate sequence of generation is not clearly mentioned.

2. Concealment of allocation

  • Low risk of bias - if allocation of participants was done by using methods such as cental allocation or sequentially numbered opaque or sealed envelopes.

  • High risk of bias - if allocation sequence was known to investigators who assigned the participants using methods such as open random allocation schedule or non-opaque envelopes.

  • Unclear risk of bias - if there is insufficient information to assess allocation concealment.

3. Blinding of participants, personnel and outcome assessors

  • Low risk of bias - if the blinding was done to participants, personnel or clinicians delivering treatment and outcome assessor with sufficient information for methods of blinding.

  • High risk of bias - if there is absent or incomplete blinding.

  • Unclear risk of bias - if there is an insufficient description provided on blinding.

4. Incomplete outcome data

  • Low risk of bias - if the number and reasons for withdrawal or dropouts in all intervention groups were described or no attrition.

  • High risk of bias - if the number and reasons for withdrawal or dropouts were not stated.

  • Unclear risk of bias - if there is insufficient information regarding withdrawals or dropouts.

5. Selective outcome reporting

  • Low risk of bias - if expected outcomes of study were reported.

  • High risk of bias - if one or more expected outcomes were not reported.

  • Unclear risk of bias - if there is insufficient information to judge.

6. Other sources of bias

  • Low risk of bias - free of other sources of bias.

  • High risk of bias - if there are other sources of bias that lead to high risk of bias.

  • Unclear risk of bias - if there is insufficient information to judge.

Measures of treatment effect

For dichotomous data, we plan to calculate the risk ratio (RR) with 95% confidence intervals (CIs) for each outcome. For continuous data, if the outcomes are measured by the same scale within the studies, we will use the mean difference (MD) and corresponding CIs. If different scales are used to measure the same outcome we will use the standardized mean difference (SMD) and corresponding 95% CIs.

Unit of analysis issues

We will assess all included studies to determine the unit of analysis reported, which may be the eye or the patient. If the unit of analysis reported in studies is the eye, rather than patient, we will attempt to extract the data for both individual eyes and for the participant, depending on the design of the selected studies. We will perform separate analyses on results in the eyes and in the patients if necessary.

Dealing with missing data

For each selected study we will assess the percentage of dropouts, withdrawals or losses to follow up. If the reasons for any missing data are well documented in the studies, we will conduct the analysis based on participants with complete data. If there is no reported reason for missing data in the studies, we will contact the author(s) for clarification. If reasons for missing data are not reported, we will perform a sensitivity analysis to document the impact of missing data. We will carefully evaluate important numerical data, from eligible and randomised patients as well as the intention-to-treat population. To conduct an intention-to-treat analysis, we will extract data from the allocated treatment group, regardless of their compliance. We plan to contact author(s) for further information if we find any eligible studies only published in abstract form or presented at meetings or conferences.

If statistical information (such as standard deviations) is missing from the studies, we plan to calculate these by using other relevant data such as P values and CIs.

Assessment of heterogeneity

We will use the Chi² test to evaluate statistical heterogeneity between the studies. If the P value is less than 0.1, we will consider this as statistically significant. We will use the I² statistic to quantify heterogeneity and interpret the values of this as follows: 0% to 40% as not significant heterogeneity; 30% to 60% as moderate heterogeneity; 50% to 90% as substantial heterogeneity; 75% to 100% as considerable heterogeneity (Deeks 2011) .

Assessment of reporting biases

Two review authors (KTM, SS) will perform comprehensive searches to minimise publication and reporting bias. Within the studies, we will consider selective outcome reporting as part of the risk of bias assessment. We aim to identify any selective outcome reporting by comparing the study protocols or trial registries with the final reports. We will also use our clinical judgement to decide if outcomes that we would expect to be measured, are reported. If study protocols are not availablewe will compare the 'Methods' section to the 'Results' section of full published paper to ensure that all the outcomes which were measured, were reported. If we have at least 10 trials, we plan to use a funnel plot to assess publication bias, if any asymmetry is detected we will also explore other causes.

We will identify and exclude duplicate publications by comparing following criteria from studies; author names, location and setting, specific details of interventions, numbers of participants, date and duration of study.

Data synthesis

We will perform statistical analyses using RevMan 5.2 (RevMan 2012). We will use the fixed-effect model for combining data if there is an absence of significant heterogeneity, both statistical and clinical, amongst included studies. We will use a random-effects model if substantial or considerable heterogeneity is identified (I² value of 50% or more).

Subgroup analysis and investigation of heterogeneity

If there is statistically significant heterogeneity identified for the primary outcome, we will conduct subgroup analyses as follows:

  1. different types of laser photocoagulation (argon, xenon);

  2. different methods of laser photocoagulation (feeder vessel coagulation, sectoral scattered coagulation, circumferential scattered coagulation);

  3. types of sickle cell disease (SS, SC disease, SβThal).

Sensitivity analysis

If there are 10 or more studies included, we plan to perform a sensitivity analysis to determine the robustness of the results regarding the risk of bias. We will repeat the meta-analyses after excluding studies with an overall high risk of bias. We will also explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect.

Acknowledgements

We would like to acknowledge Miss Tracey Remmington, Managing Editor for Cochrane Cystic Fibrosis and Genetic Disorder Group (CFGD) for her assistance throughout the development of this protocol. We thank Mrs Natalie Hall, Trial Search Co-ordinator for (CFGD) for running electronic searches. We are grateful to Editors of CFGD group for their comments on the protocol. We also like to express our gratitude to Prof Datuk Abdul Razzak, Cheif Executive of Melaka Manipal Medical College, Prof Jaspal Singh Sahota, Dean of Melaka Manipal Medical College and Prof Adinegara Bin Lufti Abas, Deputy Dean of Melaka Manipal Medical college for their support and encouragement in writing this protocol.

Contributions of authors

Roles and responsibilities Who will undertake the task?
Protocol stage: draft the protocol KTM, HN
Review stage: select which trials to include (2 + 1 arbiter) KTM, SS
Review stage: extract data from trials (2 people) KTM, SS
Review stage: enter data into RevMan KTM, HN
Review stage: carry out the analysis SM
Review stage: interpret the analysis KTM, SM
Review stage: draft the final review KTM, HN
Update stage: update the review KTM, SS

Declarations of interest

None known.

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