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نقش بستن چشم در مدیریت محرومیت محرک آمبلیوپی

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چکیده

پیشینه

محرومیت محرک آمبلیوپی (stimulus deprivation amblyopia; SDA) به دلیل انسداد مسیر عبور نور، ثانویه به وضعیتی مانند کاتاراکت (آب مروارید)، ایجاد می‌شود. انسداد مانع از تشکیل یک تصویر روشن روی شبکیه چشم می‌شود. SDA می‌تواند در برابر درمان مقاوم بوده، و منجر به پیش‌آگهی ضعیف بینایی شود. SDA احتمالا كمتر از 3% از كل موارد آمبلیوپی را تشکیل می‌دهد، اگرچه تخمین‌های دقیق برای شیوع آن نامشخص است. در کشورهای با درآمد بالا، بیشتر افراد مبتلا زیر یک سال سن دارند؛ در کشورهایی با درآمد پائین و متوسط، افراد احتمالا در سنین بالاتری با تظاهرات این وضعیت مراجعه می‌کنند. پایه اصلی درمان، اصلاح انسداد (به‌عنوان مثال، برداشتن آب مروارید) و سپس بستن چشمی است که دید بهتری دارد، اما رژیم‌های درمانی متفاوت و اجرای آن‌ها دشوار است، و به‌طور مرسوم این باور وجود دارد که درمان منجر به نتایج ناامید کننده‌ای می‌شود.

اهداف

ارزیابی اثربخشی بستن چشم برای SDA در تلاش برای ایجاد پیامدهای درمانی واقع‌گرایانه و بررسی شواهدی از هرگونه اثر دوز‐پاسخ و ارزیابی تاثیر طول مدت درمان، شدت، و عامل ایجاد کننده بر اندازه و جهت اثر درمان.

روش‌های جست‌وجو

ما CENTRAL (2018، شماره 12)، را که شامل پایگاه ثبت کارآزمایی‌های گروه چشم و بینایی در کاکرین است؛ Ovid MEDLINE؛ Embase.com؛ و پنج بانک اطلاعاتی دیگر را جست‌وجو کردیم. هیچ محدودیتی را از نظر تاریخ یا زبان در جست‌وجوهای الکترونیکی اعمال نکردیم. بانک‌های اطلاعاتی را برای آخرین بار در تاریخ 12 دسامبر 2018 جست‌وجو کردیم.

معیارهای انتخاب

ما برنامه‌ریزی کردیم تا کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) و کارآزمایی‌های بالینی کنترل‌ شده را با حضور شرکت‌کنندگان مبتلا به SDA یک‐طرفه با حدت بینایی بدتر از 0.2 LogMAR یا معادل آن وارد کنیم. هیچ محدودیتی را برای ورود به مطالعه بر اساس سن، جنسیت، قومیت، بیماری‌های همزمان، مصرف دارو، یا تعداد شرکت‌کنندگان تعیین نکردیم.

گردآوری و تجزیه‌وتحلیل داده‌ها

ما از روش‌شناسی استاندارد کاکرین استفاده کردیم.

نتایج اصلی

هیچ کارآزمایی‌ای را شناسایی نکردیم که معیارهای ورود تعیین‌شده را در پروتکل برای ورود به این مرور داشته باشد.

نتیجه‌گیری‌های نویسندگان

هیچ شواهدی را از RCTها یا کارآزمایی‏‌های شبه‐تصادفی‏‌سازی‏ شده در مورد اثربخشی هرگونه درمانی برای SDA پیدا نکردیم. برای ارزیابی ایمنی و اثربخشی بستن چشم، مدت زمان درمان، سطح بینایی که به‌صورت واقعی می‌توان به‌دست آورد، تاثیر سن بر شروع این وضعیت و بزرگی نقص بینایی، رژیم درمانی مطلوب بستن چشم و عوامل مرتبط با پیامدهای رضایت‌بخش و غیر‐رضایت‌بخش بودن استفاده از مداخلات مختلف برای SDA، نیاز به انجام RCTهایی در این زمینه وجود دارد.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

خلاصه به زبان ساده

درمان آمبلیوپی ناشی از انسداد بینایی

هدف از انجام این مرور چه بود؟
ما شواهد موجود را در مورد درمان بستن چشم در مدیریت محرومیت محرک آمبلیوپی (stimulus deprivation amblyopia; SDA) با توجه به میزان بینایی در پایان دوره درمان بررسی کردیم.

پیام‌های کلیدی
هیچ شواهدی از کارآزمایی‌های تصادفی‌سازی و کنترل‌ شده (کارآزمایی‌هایی که در آنها شرکت‌کنندگان به‌طور تصادفی به یک گروه درمان یا گروه دیگر اختصاص داده می‌شوند) در مورد تاثیرات درمان بستن چشم بر SDA وجود ندارد.

چه چیزی در این مرور مورد بررسی قرار گرفت؟
آمبلیوپی یا «تنبلی چشم» زمانی رخ می‌دهد که بینایی در اوایل دوران کودکی به‌طور طبیعی رشد نمی‌کند و توسعه نمی‌یابد. SDA نوعی آمبلیوپی است که به دلیل انسداد بینایی در چشم (به‌عنوان مثال به دلیل وجود لنز غیرشفاف یا افتادگی پلک) ایجاد می‌شود. چشم‌پزشکان این نوع از آمبلیوپی را دشوارترین نوع بیماری چشم برای درمان می‌دانند. اگرچه حدود 1% تا 5% از افراد، مبتلا به نوعی از آمبلیوپی هستند، SDA كمتر شایع است، و تقریبا 3% از كل افراد مبتلا به هر نوعی را از آمبلیوپی متاثر می‌سازد. SDA معمولا زمانی تشخیص داده می‌شود که والدین، قبل از تولد یک سالگی کودک، وجود مردمک سفید یا افتادگی پلک را مشاهده می‌کنند. SDA اغلب پس از درمان علت آن تشخیص داده می‌شود و اصلاح انکسار (به‌عنوان مثال عینک زدن) تجویز می‌شود.

هدف از درمان SDA، بهبود بینایی در چشم آسیب‌دیده و ایجاد استریوپسیس (stereopsis)، یعنی دید «سه‐بعدی» و درک عمق است. برای اطمینان از اینکه چشم مبتلا تا حد امکان بینایی خود را به‌دست می‌آورد، درمان ممکن است چندین ماه طول بکشد. هم‌چنین، مشارکت در ورزش و اشتغال در آینده ممکن است تحت تاثیر دید ضعیف در یک چشم یا از بین رفتن دید سه‐بعدی قرار بگیرد. یک روش درمانی معمول، بستن یا پوشاندن چشم سالم، اغلب با کمک پچ چسبی، به ‌منظور اجبار به استفاده از چشم مبتلا به آمبلیوپی است. از آنجا که کودکان خردسال، بستن چشم را گیج‌کننده یا ناراحت‌کننده می‌دانند، ممکن است اجرای آن برای والدین دشوار باشد.

نتایج اصلی این مرور چه هستند؟
ما هیچ کارآزمایی تصادفی‌سازی و کنترل‌شده‌ای را پیدا نکردیم که اثربخشی بستن چشم را برای SDA ارزیابی کرده باشد. بنابراین، قبل از اینکه اطلاعاتی را به دست بیاوریم که برای تصمیم‌گیری در مورد درمان نیاز داریم، انجام مطالعات پژوهشی بیشتر با طراحی خوب در مورد SDA مورد نیاز است.

این مرور تا چه زمانی به‌روز‌رسانی شده‌ است؟
نویسندگان مرور برای یافتن مطالعاتی که تا دسامبر 2018 منتشر شده بودند، به جست‌وجو پرداختند.

Authors' conclusions

Implications for practice

It is not possible to draw reliable conclusions from the data available from non‐randomized studies since the study designs either did not compare treatment strategies or were subject to significant bias in the selection of participants for particular treatments. In addition, the variation between studies in treatment delivery and outcome measurement prevents any meaningful comparison or combination of results.

The general trend in practice, based on the proportion of papers we found reporting this treatment, favors an intensive occlusion therapy regimen to attain better visual outcomes. It is important to acknowledge that we did not systematically search for these papers and therefore they may represent a biased sample. It is currently difficult to objectively advise parents or formulate evidence‐based guidelines for the management of stimulus deprivation amblyopia (SDA). Realistic expectations remain uncertain from the treatment for SDA and optimization of treatment regimens.

Implications for research

There is a clear and pressing need for randomized controlled trials (RCTs) to evaluate the effects of interventions for SDA. Occlusion therapy is usually considered the mainstay of treatment for SDA. Some may argue that withholding this treatment from children in an RCT may be unethical. But use of occlusion therapy is not supported by evidence from RCTs, and results in significant stress for both the children and their parents. Because there is a lack of evidence about whether the treatment is effective and safe, it should be ethical to randomize children to no occlusion therapy or an alternative treatment in a trial. It is important to acknowledge that there are practical challenges to setting up a randomized trial for SDA; due to the low numbers, a multicenter study would be required. In addition, many years of follow‐up, for example to age seven, would be required to determine long‐term, post‐treatment visual acuity outcomes. Nevertheless, such a study would provide extremely valuable evidence for the management of this condition.

Unsuccessful treatment ultimately results in the same outcome as no treatment, that is, reduced sight in one eye and loss of stereopsis. Exposure to treatment also carries the potential for harm. Thus, future studies on treatment for SDA should report treatment effect and accurately measure any potential physical, emotional, or psychological harm.

The following are specific questions that need to be addressed in prospective randomized studies (with appropriate stratification to study any subgroup analyses).

  • What is the safety and effectiveness of the interventions, including occlusion or patching for SDA?

  • What is the appropriate duration of treatment for SDA?

  • What is the level of vision that can realistically be achieved; what are the effects of age at onset and magnitude of visual defect?

  • What is the optimum occlusion regimen?

  • What are potential adverse effects from treatments for SDA?

  • What are the factors associated with satisfactory and unsatisfactory outcomes with various interventions for SDA?

Background

Description of the condition

The term 'amblyopia' refers to bluntness of vision and is derived from the Greek words "amblys" (meaning blunt) and "ops" (meaning eye). Clinically, amblyopia denotes a reduction in vision in the absence of any retinal anomaly or any disorder of the afferent visual pathways (Duke‐Elder 1973). Amblyopia typically affects only one eye but it sometimes affects both eyes. Amblyopia is usually classified according to its cause:

  • strabismic, caused by squint (eye misalignment);

  • anisometropic, caused by unequal refractive (focusing) error;

  • meridional, caused by astigmatism (irregular corneal curvature);

  • ammetropic, caused by high refractive error in both eyes;

  • stimulus deprivation, caused by an obstruction in the visual pathway.

Mixed amblyopia, which is a result of more than one cause, is typically due to a combination of strabismic and anisometropic amblyopia. This review is focused on interventions for stimulus deprivation amblyopia (SDA), also called amblyopia ex anopsia. Other Cochrane Reviews have evaluated interventions for strabismic and anisometropic (refractive) amblyopia (Taylor 2011; Taylor 2012).

Pathophysiology

Visual experiences in early life determine the organization of the portion of the adult brain that processes visual stimuli (Wiesel 1963). The time within which abnormal visual input can lead to a disruption of the normal pattern of development is called the 'critical period' (Hockfield 1998). There are several critical periods, each associated with different visual functions (Harwerth 1990), which probably reflect development of different parts of the brain. These critical periods can be considered as a continuum from extreme sensitivity to almost no sensitivity to external stimuli. Amblyopia begins to develop in these critical periods at young ages when the brain and the visual system are immature and connections between neurons are still being formed and stabilized. During the critical period, most amblyopia is reversible, usually until the child is 10 years old (AAO 2002). The critical period varies considerably among children and depends on the type of amblyopia.

Etiology

People with SDA lose vision from disuse or lack of formation of clear retinal images, most commonly as a result of one of the following:

People with SDA may have either otherwise healthy eyes or other co‐existing conditions, such as microphthalmos (small eye), coloboma (incomplete formation of the eye), optic nerve hypoplasia (underdeveloped optic nerve), or retinal abnormalities. Co‐existing conditions often limit the visual prognosis. It is difficult to discern whether the visual loss is due to SDA or other co‐existing conditions in the eye.

The most commonly reported cause of SDA is congenital or infantile cataract in one eye. Stimulus deprivation secondary to the cataract continues until the cataract is removed and optical correction is provided. Even after optical correction, the affected eye may continue to be anisometropic and anisekonic (forming unequal image sizes) (Enoch 1983). The early insult to the visual system is believed to make this type of amblyopia particularly severe and resistant to treatment. Visual prognosis has been reported to be poor (Kanski 1994; Taylor 1997).

Epidemiology

The prevalence of amblyopia in the general population ranges from 1% to 5% (Brown 2000; Hillis 1983). In European children, the prevalence ranges from 1% to 2.5% (Kvarnstrom 2001; Newman 2000). Amblyopia accounts for 29% of unilateral blindness in Copenhagen (Buch 2001), and as much as 8.3% of bilateral blindness in India following childhood cataract surgery (Dandona 2003). SDA accounts for less than 3% of people with amblyopia (Hillis 1983).

Presentation

Routine health checks of babies and toddlers are carried out by a variety of healthcare personnel (e.g. pediatricians, nurses) and provide an opportunity for detection of the causative factors (e.g. ptosis, cataract) associated with SDA. SDA itself is not likely to be noticed, but parents may detect the signs associated with causes of SDA such as leukocoria (white pupils) in children with congenital cataracts or droopy eyelid (ptosis). Children may also present with squint (misalignment) as a result of poor vision in one eye. In high‐income countries, most people with SDA present for treatment while they are under the age of one year (Mein 1991).

Diagnosis

There are four main steps in the diagnosis of SDA.

  • Visual acuity testing: testing young children largely relies on objective observations that are limited by cognition and concentration. Qualitative methods (e.g. assessing fixation preference) may be used, however quantitative tests (e.g. preferential looking) are more precise. Preferential looking tests rely on the observation that infants prefer to look at patterned rather than plain surfaces (Fanz 1958). Children look at a striped panel when they can discern it. A Snellen equivalent can then be computed using the degree of visual angle subtended by the stripes in the panel. In older children, testing methods are more objective and rely on the child's identification of pictoral or letter optotypes in Snellen, decimal, or logMAR notation.

  • External and internal eye exam to identify any co‐existing conditions: the exam must focus on identifying lesions such as optic nerve hypoplasia that could lead to inappropriate or unsuccessful treatment of the condition.

  • Cycloplegic refraction and corrective prescription when indicated: amblyopia can be diagnosed only after correcting any significant refractive error.

  • Rechecking visual acuity with any prescribed refractive correction in place: some improvement in visual acuity can be expected with refractive correction alone. There should be a period of adjustment to spectacles before retesting. Traditionally, this adjustment period has been four to six weeks, but studies on refractive and strabismic amblyopia show this period as 24 weeks (Moseley 2002).

Definitions of amblyopia vary largely as there is little evidence as to what constitutes normal vision at different ages based on successful performances on many commonly used tests. Amblyopia may be defined by comparing both eyes (interocular difference) or by looking at monocular visual acuity alone. We have elected to define amblyopia as vision worse than 6/9 on a Snellen‐based test (0.2 LogMAR or its equivalent) in one eye in the presence of an amblyogenic factor. Assuming that the fellow eye has normal vision, that is 6/6 or logMAR 0.0, this definition means that the difference in vision between the two eyes is greater than 0.2 log MAR.

Description of the intervention

Visual loss due to SDA can be difficult to quantify due to the limitations of the visual acuity tests available for young children but is believed to be severe in most cases. The aim of treatment is to maximize visual recovery without adversely affecting acuity in the better‐seeing eye. The rationale for treatment is two‐fold, to provide a good second eye should the better‐seeing eye ever be visually compromised; and to maximize stereopsis (binocular co‐operation between the eyes). Untreated or unsuccessfully treated amblyopia may affect adult life. For people with amblyopia, the lifetime risk of serious visual impairment due to loss or damage of the better‐seeing eye is estimated to be between 1.2% and 3.3% (Rahi 2002). In addition, there are implications for employment prospects and, therefore, income. The number of jobs barred to people with reduced vision increases with the severity of the deficit (Adams 1999). Furthermore, stereopsis is required to participate in many sports and for some jobs.

Stages of treatment

  • The first stage is to correct any factor degrading the quality of the visual image (e.g. infantile cataract extraction, ptosis repair). In cases of early unilateral deprivation, correction should be undertaken in the first eight to 12 weeks of life (Birch 1986; Birch 1988; Gregg 1992; Kanski 1994; McCulloch 1994; Taylor 1997).

  • The second stage is to provide necessary refractive correction to maximize the quality of visual stimulation received by the child's amblyopic eye. Intraocular implants, contact lenses, or both may be used after cataract surgery.

  • The third stage is occlusion therapy. Occlusion of the unaffected eye forces the use of the amblyopic eye to stimulate the formation of functional connections in the brain (Boothe 2000).

How the intervention might work

Occlusion regimen

Protocols and practices for occlusion therapy vary considerably. Typically, occlusion therapy ranges in duration from one hour to more than six hours (full‐time). Factors affecting the prescribed amount of occlusion include the level of visual deficit, the age of the child, and the likely waiting time to the next appointment. Follow‐up is recommended at intervals of one week per year of age during periods of aggressive patching (Simon 1987). Occlusion may be stopped when visual acuity becomes equal in the two eyes or if no progress has been made after three months of good compliance with occlusion (Pratt‐Johnson 2001). Children may require monitoring until they reach the age of visual maturity (approximately seven years of age) to ensure that amblyopia does not recur. Some periods of maintenance occlusion may be required during that time (Mein 1991).

The following have been used as additions to occlusion therapy, but are not currently popular clinically.

  • CAM visual stimulator: uses rotating high‐contrast square wave gratings to stimulate the amblyopic eye.

  • Pleoptics: employs after‐images to encourage foveal fixation and normal projection in the amblyopic eye.

Types of occlusion

Atropine penalization and optical penalization (patching or use of lenses to reduce the acuity) are forms of occlusion that encourage use of the amblyopic eye by diminishing visual form. These treatments for amblyopia were evaluated in another Cochrane Review, which showed that atropine penalization is as effective as conventional occlusion (Li 2009). Total occlusion has some disadvantages in terms of discomfort, but it is relatively easy to control the dosage of treatment and is without the more complex adverse effects of alternatives such as occlusive contact lenses.

Measuring outcomes

In order to quantify amblyopia, visual acuity must be measured. Qualitative methods for assessing vision in preverbal children are based on the observation of their fixation patterns. These methods are often unreliable and require highly trained examiners (Wright 1986; Zipf 1976). Visual acuity assessed using an age‐appropriate test is the most commonly used outcome to evaluate treatment for amblyopia (Fulton 1978; Sebris 1987). Tests vary in the use of optotypes (pictures, letters, or symbols), presented with or without crowding. Crowded visual acuity tests are harder to perform but are more sensitive to amblyopia than uncrowded tests.

Developmental changes in young children complicate the evaluation of actual change in visual acuity before and after treatment. Alternative methods of measuring change have been suggested (Schmidt 1994; Stewart 2003), but we aimed to compare post‐treatment visual acuity levels (defining restoration of normal visual acuity as better than or equal to 6/9 on Snellen, or 0.2 LogMAR, or its equivalent).

Factors affecting outcome

Compliance with therapy is critical for successful treatment but often can be difficult to achieve. Young children can become distressed by being restricted to reduced visual acuity and from the discomfort of wearing an adhesive patch. It has been suggested that, if possible, compliance should be monitored to measure its effect on the response to treatment. Devices to objectively measure compliance have been developed (Awan 2005; Stewart 2005), but are not in common use; typically clinicians depend on parental reports. Other factors believed to affect treatment success are the duration of visual deprivation, age at onset, and timing of initiation of therapy (Maurer 1989); early onset of amblyopia, long duration of the condition, and late initiation of therapy are associated with worse visual prognosis.

Harm from occlusion therapy

Potential adverse effects from occlusion therapy include inducing amblyopia in the occluded eye, skin allergies, infections or corneal abrasions from contact lens wear, diplopia (double vision), and psychological effects on the parents and children (e.g. distress).

Why it is important to do this review

The reported success of treatment for SDA varies. Studies have reported good levels of vision following early treatment (Gregg 1992; McCulloch 1994), but there is a lack of standardization and poor agreement among experts as to the optimum amount of occlusion needed to achieve a good visual outcome. Commencing occlusion therapy in infants with very poor vision can be harrowing for the parents and stressful for the child. Realistic treatment goals are often poorly defined. It is thus necessary to establish the most effective occlusion regimen(s) for SDA and to define the degree of improvement that can reasonably be expected from this treatment.

Objectives

To evaluate the effectiveness of occlusion therapy for SDA in an attempt to establish realistic treatment outcomes and to examine evidence of any dose–response effect and assess the effect of the duration, severity, and causative factor on the size and direction of the treatment effect.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomized and quasi‐randomized trials, with no restriction on the number of participants in the trials.

Types of participants

We planned to include trials that recruited participants with the following characteristics.

  • Unilateral SDA, defined as best‐corrected visual acuity (BCVA) in the affected eye worse than 6/9 Snellen, or its equivalent, after treatment for the causative factor had been undertaken and ensuing refractive error had been corrected. We also planned to report other co‐existing amblyogenic factors.

  • Unrestricted age, gender, ethnicity, co‐morbidity, and medication use.

Types of interventions

We planned to include trials evaluating the following interventions:

  • total occlusion by adhesive patch;

  • total occlusion by occlusive contact lens;

  • pleoptic treatment;

  • partial occlusion (i.e. Bangerter filters);

  • CAM visual stimulation.

We planned to examine the following comparisons:

  • total occlusion versus no occlusion;

  • any method of total occlusion compared to another;

  • total occlusion plus pleoptic treatment versus total occlusion alone;

  • total occlusion plus CAM visual stimulator versus total occlusion alone;

  • full‐time occlusion (more than six hours/day) versus part‐time occlusion (less than six hours/day);

  • different durations of partial occlusion, for example two hours/day versus six hours/day;

  • any partial occlusion compared to another;

  • any total occlusion compared to any partial occlusion;

  • any partial occlusion compared to no occlusion.

Types of outcome measures

Primary outcomes

  • Best‐corrected visual acuity (BCVA) of the amblyopic eye, assessed by an age‐appropriate test 12 months after cessation of occlusion therapy.

Although the two are not directly equivalent, we planned to convert Snellen data into the logMAR equivalent for ease of interpretation and analysis.

We planned to dichotomize the outcomes as follows.

  • Normal = better than or equal to 0.2 logMAR, 6/9 Snellen, or its equivalent.

  • Residual deficit = worse than 0.2 logMAR units.

Where possible, we planned to compare the proportions of children with the outcomes specified versus without.

Secondary outcomes

  • Visual acuity in the amblyopic eye at seven years of age or older.

  • Proportion of the amblyopia deficit corrected (Stewart 2003).

  • Any measure of stereoacuity (three‐dimensional (3‐D) vision).

Cost data

We planned to summarize the comparative costs of the treatment methods described in the included trials.

Adverse effects

We planned to summarize adverse effects related to treatment that were reported in the included trials.

  • Severe: occlusion amblyopia, contact lens‐related problems (e.g. infection, corneal abrasions), adverse psychological effects (e.g. distress), treatment cessation due to poor compliance or failure to attend follow‐up visits, or diplopia (double vision).

  • Minor: allergy to patches.

Quality of life measures

We planned to summarize any data on quality of life measures of both the parents and child, as described in the reports of the included trials.

Follow‐up

We planned to include in our analyses data from trials with a minimum post‐treatment follow‐up of six months. For trials that did not meet this criterion, we planned to include the trials in our qualitative synthesis but exclude them from any meta‐analyses.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for randomized controlled trials (RCTs) and controlled clinical trials. There were no restrictions on language or year of publication. Electronic databases were last searched on 12 December 2018.

  • Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 12) (which contains the Cochrane Eyes and Vision Trials Register), in the Cochrane Library (searched 12 December 2018) (Appendix 1).

  • MEDLINE Ovid (1946 to 12 December 2018) (Appendix 2).

  • Embase.com (1947 to 12 December 2018) (Appendix 3).

  • PubMed (1948 to 12 December 2018) (Appendix 4).

  • Latin American and Caribbean Health Science Information Database (LILACS) (1982 to 12 December 2018) (Appendix 5).

  • metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com; searched March 2012) (Appendix 6).

  • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 12 December 2018) (Appendix 7).

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 12 December 2018) (Appendix 8).

Searching other resources

We did not conduct any manual searches for this review. In updates of this review, we will search the Web of Science for any articles that cited reports of trials included in this review. In addition, we also will handsearch references cited in reports of trials included in this review.

Data collection and analysis

Selection of studies

Two review authors independently assessed the titles and abstracts of all reports identified by the electronic searches as per the 'Criteria for considering studies for this review'. The review authors were aware of the report authors, institutions, and trial results during this assessment.

We classified each abstract as definitely include, unsure, or definitely exclude. We retrieved full‐text articles for abstracts classified as definitely include and unsure. Two review authors independently screened the full‐text articles and classified them as included, awaiting clarification, or excluded. A third review author resolved any disagreements at each stage. We contacted the authors of studies classified as awaiting assessment for further clarification. The Characteristics of excluded studies table lists the details of full‐text articles classified by both review authors as excluded.

Methods for future updates

If any randomized or quasi‐randomized trials are identified in future updates of this review, we will adopt the following methods.

Data extraction and management

Two review authors will independently extract data from the reports of the included trials. We will resolve discrepancies through discussion. We will contact the trial investigators about any missing data. One review author will enter data into Review Manager 5 and a second review author will verify the entered data (Review Manager 2014).

We will extract the following data from the included trials.

  • Participants:

    • numbers of participants in the trial, age at onset of SDA and age at initiation of treatment for SDA, duration of stimulus deprivation, cause of stimulus deprivation, visual acuity before treatment, and details about refractive correction;

    • concomitant ocular pathology that may limit visual outcome (e.g. coloboma, optic nerve hypoplasia, retinal dystrophy). Data from studies including such participants will be included in subgroup analyses;

    • adjustment period to spectacle correction.

  • Intervention: method of occlusion, regimens, use of CAM or pleoptics.

  • Outcomes: test(s) used; length of follow‐up; whether, when, and how compliance was assessed.

Assessment of risk of bias in included studies

Two review authors will independently assess the sources of systematic bias in trials according to methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We will evaluate reports of included trials for the following domains:

  • random sequence generation (selection bias);

  • allocation concealment (selection bias);

  • masking of outcome assessors (detection bias);

  • incomplete outcome data (attrition bias) – number of participants lost to follow‐up and the methods used to account for losses to follow‐up in the analyses;

  • selective outcome reporting (reporting bias);

  • other sources of bias.

Two review authors will grade each of the risk of bias domains as 'high risk', 'low risk', or 'unclear risk' of bias. A third review author will resolve any disagreements between the first two authors. We will not assess masking of participants and care providers because it is not feasible with interventions for SDA. We will contact authors of reports of included trials for any details that are not described in the published reports. We will use available information to assess the potential for risk of bias whenever the trial authors do not respond within four weeks of our communication.

Measures of treatment effect

For dichotomous outcomes, we will calculate odds ratios for rarer outcomes or risk ratios for more frequent outcomes. We will calculate mean differences for continuous outcomes. We will use standardized mean differences for outcomes measured using difference scales. We will report 95% confidence intervals (CIs) for all summary effect estimates.

Unit of analysis issues

People with SDA mostly present with unilateral disease. Consequently, we expect one eye per individual to be the unit of analysis in trials of interventions for SDA. We will refer to available statistical resources such as the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019) or the Cochrane Eyes and Vision Group for advise with any unit of analysis issues in data analysis.

Dealing with missing data

We will contact authors of reports for trials included in our review about any missing data. When the trial authors are unable to provide any details then we will include the trial in our qualitative analysis and omit it from meta‐analyses for the outcomes with missing data. We will not impute data, rather we will use the available‐case data and note the limitations with this method.

Assessment of heterogeneity

We will examine forest plots for overlap of 95% CIs of effect estimates for visual assessment of heterogeneity between effect estimates of the included trials. We will calculate the I2 statistic and use the Chi2 test for heterogeneity.

Data synthesis

If we find no evidence of statistical or clinical heterogeneity across included trials, we will combine the results from the trials in meta‐analyses using a fixed‐effect model. If there is statistical heterogeneity in the absence of clinical heterogeneity, we will compute a summary measure using a random‐effects model. In the case where we find substantial statistical (I2 greater than 50%) or clinical heterogeneity, we will not combine the study results and instead will present our findings in a tabulated or narrative summary.

Subgroup analysis and investigation of heterogeneity

When sufficient data are available and trials are stratified prior to randomization, we will explore the following subgroups:

  • participants with and without co‐existing ocular pathology (that might be expected to limit visual prognosis);

  • participants with SDA associated with a unilateral congenital cataract versus any other unilateral etiology.

Sensitivity analysis

We will conduct sensitivity analyses, when appropriate, to determine the size and direction of effect when excluding the following:

  • outcomes measured on uncrowded vision tests;

  • studies where any risk of bias item has been graded as 'high risk';

  • unpublished studies or industry‐funded studies.

Results

Description of studies

Results of the search

Details of the results of previous searches were published in the 2014 version of this review (Antonio‐Santos 2014). In brief, no eligible studies were identified from 824 records searched in 2004, additional 53 reports in 2007, and 954 titles and abstracts and 256 trial registries identified through electrical searches in 2013. The latest electronic search of the databases as of 12 December 2018 yielded 1376 unique records (Figure 1). After 1376 titles and abstracts were screened, 1286 records were excluded and full‐text reports of 90 records were obtained for further review. Of them, 76 records (75 studies) were excluded with reasons (Characteristics of excluded studies table). The most common reasons for exclusion after full‐text review were because they were not randomized or quasi‐randomized trials; participants did not have SDA; or both. Twelve records (12 studies) were awaiting classification due to lack of information to judge eligibility (Characteristics of studies awaiting classification table).


Study flow diagram.

Study flow diagram.

Two records (two studies) were classified as ongoing (Characteristics of ongoing studies table). NCT02236351, started in 2014, enrolled 156 children under seven years old with strabismus, anisometropia, or deprivation amblyopia. These children were randomized to pinched patch or standard patch groups. NCT02687581, started in 2016, enrolled 81 children aged from three to eight years with amblyopia associated with strabismus, anisometropia, or both. This trial is comparing 12‐hour intermittent occlusion therapy glasses with six‐hour eye patch. We will include findings from these two trials once they are publicly available.

Risk of bias in included studies

Despite two ongoing studies, we found no randomized or quasi‐randomized trials eligible for inclusion in the review.

Effects of interventions

None of the studies identified in our searches were eligible for inclusion, highlighting a significant gap in existing evidence for the treatment of SDA.

Discussion

We found no RCTs that had evaluated the effects of occlusion or any other treatment for SDA, highlighting a gap in the evidence and the need for rigorous studies to address this question. Because SDA is generally accepted to be more severe and resistant to treatment compared with amblyopia due to other causes, participants with SDA have been excluded from existing RCTs (Kanski 1994; Taylor 1997).

Because of co‐existing pathology, the young age of afflicted children, and limitations of clinical tests, it is difficult to quantify the degree of visual deficit, determine how much of it is attributable to amblyopia, and assess responses to treatment. Success with treatment for SDA is also affected by compliance and the stress for the parents and the child associated with using occlusion therapy.

Existing evidence on the effects of interventions for SDA is derived largely from non‐randomized studies of children with SDA caused by unilateral congenital cataract. Although current practice favors aggressive patching in early life, its effectiveness is supported only by a few case‐series (Birch 1988; Drummond 1989; Lundvall 2002; Mayer 1989; Robb 1987). Findings from these studies indicate wide variability in the patching regimen employed and the proportion of children who responded to treatment. Less‐intense occlusion regimens, while being easier to execute, have been advocated because they promote more binocular interaction and stereoacuity. Some of the less intensive occlusion regimens examined in previous studies include occlusion for one hour/day per month of age for the first six months of life (Brown 1999), and patching for six hours and 12 hours a day (Stewart 2007).

Occlusion regimens and treatment outcomes

Current practice generally favors aggressive patching for SDA in early life based on the knowledge that the visual system is much more sensitive to change at this age. Mayer 1989 reported a negative correlation between the number of hours patched and the interocular difference in acuity when treating SDA due to congenital cataract. In non‐randomized studies of SDA, the definition of intensive or aggressive patching varied from a minimum of six hours/day to as much as 100% of waking hours. The definition of success also varied across the different studies. Birch 1988 reported that 53% of people achieved a visual acuity of 20/80 (6/24) or better. Lundvall 2002 found that 20% attained visual acuity of 0.1 (6/7.5) or better, Drummond 1989 reported that 43% achieved better than 20/50 (6/9), and Robb 1987 found 46% achieved visual acuity of at least 20/70 (6/18). This brief summary of some previous studies highlights the different ways in which results can be categorized. These and other dissimilarities in study methodologies make it impossible to compare results among these studies meaningfully. Less‐intense occlusion regimens are easier to execute and have been advocated because they are expected to promote more binocular interaction and stereoacuity. One study reported good visual and binocular results with occlusion of one hour/day per month of age for the first six months of life in children with congenital cataract (Brown 1999). Nevertheless, most studies of less‐intense occlusion regimens have been conducted in children with strabismic or anisometropic amblyopia, or both, and results are probably not generalizable to children with SDA.

Compliance

As with other types of amblyopia, treatment for SDA appears to rely on good compliance to achieve a satisfactory outcome. Studies on refractive and strabismic amblyopia have used objective methods to monitor how long occlusion is actually worn (Awan 2005; Loudon 2002; Stewart 2005). These show that the prescribed amount of occlusion is not always achieved. Unfortunately, compliance in treating SDA is often difficult to achieve due to the severity of the visual acuity deficit. While it is not surprising that a treatment that visually compromises a child by means of an adhesive patch is not easy to deliver, justification of adoption or rejection of a treatment must carefully consider evidence of harm alongside evidence of benefit. In a culture where justifying an intervention is increasingly required, the current absence of clear evidence of effectiveness in this area is concerning.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.