Oclusión para la ambliopía por privación de estímulo
Resumen
Antecedentes
La ambliopía por privación de estímulo (APE) se desarrolla debido a una obstrucción al paso de la luz secundaria a un trastorno como la catarata. La obstrucción impide la formación de una imagen clara en la retina. La APE puede ser resistente al tratamiento, lo cual da lugar a un pronóstico visual deficiente. La APE probablemente constituye menos del 3% de todos los casos de ambliopía, aunque no se conocen los cálculos precisos de la prevalencia. En los países de ingresos altos, la mayoría de los pacientes se presentan con menos de un año de edad; en los países de ingresos bajos y medios, es probable que los pacientes sean mayores en el momento de la presentación. La base del tratamiento es la corrección de la obstrucción (por ejemplo, la extirpación de la catarata) y luego la oclusión del ojo con mejor visión, pero los regímenes varían, pueden ser difíciles de ejecutar y tradicionalmente se cree que producen resultados desalentadores.
Objetivos
Evaluar la efectividad del tratamiento de oclusión para la APE en un intento de establecer resultados de tratamiento realistas y examinar la evidencia de cualquier efecto de respuesta a la dosis y evaluar el efecto de la duración, la gravedad y el factor causal en el tamaño y la dirección del efecto del tratamiento.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL (2018, número 12), que contiene el Registro Cochrane de Ensayos de Ojos y Visión (Cochrane Eyes and Vision Trials Register); Ovid MEDLINE; Embase.com; y en otras cinco bases de datos. No hubo ninguna restricción de fecha o idioma en las búsquedas electrónicas. La última vez que se buscó en las bases de datos fue el 12 de diciembre de 2018.
Criterios de selección
Se planeó incluir ensayos controlados aleatorizados (ECA) y ensayos clínicos controlados de participantes con APE unilateral con una agudeza visual inferior a 0,2 LogMAR o equivalente. No se especificó ninguna restricción para la inclusión basada en la edad, el sexo, el origen étnico, las comorbilidades, el uso de fármacos o el número de participantes.
Obtención y análisis de los datos
Se utilizó la metodología Cochrane estándar.
Resultados principales
No se identificaron ensayos que cumplieran los criterios de inclusión especificados en el protocolo de esta revisión.
Conclusiones de los autores
No se encontró evidencia de ECA o ensayos cuasialeatorizados sobre la efectividad de ningún tratamiento para la APE. Se necesitan ECA para evaluar la seguridad y la efectividad de la oclusión, la duración del tratamiento, el nivel de visión real que puede lograrse, los efectos de la edad al comienzo de la enfermedad y la magnitud del defecto visual, el régimen de oclusión óptimo y los factores asociados con resultados satisfactorios e insatisfactorios con el uso de diversas intervenciones para la APE.
PICO
Resumen en términos sencillos
Tratamiento para la ambliopía causada por obstrucción en la visión
¿Cuál es el objetivo de la revisión?
Se examinó la evidencia disponible con respecto al tratamiento de oclusión para la ambliopía por privación de estímulo (APE) en lo que se refiere a la visión al final del tratamiento.
Mensajes clave
Falta evidencia de ensayos controlados aleatorizados (ensayos en los que los participantes se asignan al azar a un grupo de tratamiento u otro) con respecto a los efectos del tratamiento de oclusión para la APE.
¿Qué se estudió en la revisión?
La ambliopía u “ojo perezoso” ocurre cuando la visión no se desarrolla normalmente en la primera infancia. La APE es un tipo de ambliopía que se produce debido a la obstrucción de la visión en el ojo (por ejemplo, por una lente turbia o un párpado caído). Los oftalmólogos consideran que este tipo de ambliopía es el más difícil de tratar. Aunque alrededor del 1% al 5% de las personas presentan algún tipo de ambliopía, la APE es mucho menos común, y afecta alrededor del 3% de todos los pacientes con cualquier tipo de ambliopía. Generalmente, la APE se diagnostica después de que los padres observan una pupila de color blanco o un párpado caído antes del primer cumpleaños del niño. La APE se diagnostica a menudo después de que se haya tratado la causa y se prescriba la corrección refractiva (por ejemplo, el uso de gafas).
El objetivo del tratamiento de la APE es mejorar la visión del ojo afectado y proporcionar una estereopsis, es decir, una visión "tridimensional" y una percepción de profundidad. El tratamiento puede durar varios meses para asegurar que el ojo afectado gane la mejor visión posible. Además, la participación en los deportes y el futuro empleo puede verse afectada por la mala visión en un ojo o la pérdida de la visión tridimensional. Un tratamiento común es ocluir o cubrir el ojo no afectado, a menudo con un parche adhesivo, para forzar el uso del ojo ambliópico. Debido a que en los niños pequeños la oclusión es confusa o incómoda, para los padres puede ser difícil implementar el tratamiento de oclusión.
¿Cuáles son los principales resultados de la revisión?
No se encontraron ensayos controlados aleatorizados que evaluaran la efectividad del tratamiento de oclusión para la APE. Por lo tanto, se necesitan estudios de investigación bien diseñados de la APE con objeto de obtener la información necesaria para tomar decisiones de tratamiento.
¿Cuál es el grado de actualización de la revisión?
Los autores de la revisión buscaron estudios que se habían publicado hasta diciembre de 2018.
Authors' conclusions
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:
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strabismic, caused by squint (eye misalignment);
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anisometropic, caused by unequal refractive (focusing) error;
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meridional, caused by astigmatism (irregular corneal curvature);
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ammetropic, caused by high refractive error in both eyes;
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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:
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unoperated infantile cataract (opacity of the lens);
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ptosis (droopy eyelids) (Dray 2002; Gusek‐Schneider 2000);
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hemangioma (blood‐rich swelling on the lid) (Schulz 1982);
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obstruction in the vitreous (clear gel that fills the eye), for example due to bleeding (Ferrone 1994);
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aphakia (absence of the natural lens);
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occlusion prescribed to treat amblyopia of the other eye (Awaya 1973; Von Noorden 1973; Von Noorden 1981).
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.
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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.
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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.
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Cycloplegic refraction and corrective prescription when indicated: amblyopia can be diagnosed only after correcting any significant refractive error.
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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
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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).
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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.
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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.
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CAM visual stimulator: uses rotating high‐contrast square wave gratings to stimulate the amblyopic eye.
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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.
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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.
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Unrestricted age, gender, ethnicity, co‐morbidity, and medication use.
Types of interventions
We planned to include trials evaluating the following interventions:
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total occlusion by adhesive patch;
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total occlusion by occlusive contact lens;
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pleoptic treatment;
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partial occlusion (i.e. Bangerter filters);
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CAM visual stimulation.
We planned to examine the following comparisons:
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total occlusion versus no occlusion;
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any method of total occlusion compared to another;
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total occlusion plus pleoptic treatment versus total occlusion alone;
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total occlusion plus CAM visual stimulator versus total occlusion alone;
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full‐time occlusion (more than six hours/day) versus part‐time occlusion (less than six hours/day);
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different durations of partial occlusion, for example two hours/day versus six hours/day;
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any partial occlusion compared to another;
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any total occlusion compared to any partial occlusion;
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any partial occlusion compared to no occlusion.
Types of outcome measures
Primary outcomes
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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.
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Normal = better than or equal to 0.2 logMAR, 6/9 Snellen, or its equivalent.
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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
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Visual acuity in the amblyopic eye at seven years of age or older.
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Proportion of the amblyopia deficit corrected (Stewart 2003).
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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.
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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).
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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.
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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).
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MEDLINE Ovid (1946 to 12 December 2018) (Appendix 2).
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Embase.com (1947 to 12 December 2018) (Appendix 3).
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PubMed (1948 to 12 December 2018) (Appendix 4).
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Latin American and Caribbean Health Science Information Database (LILACS) (1982 to 12 December 2018) (Appendix 5).
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metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com; searched March 2012) (Appendix 6).
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 12 December 2018) (Appendix 7).
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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.
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Participants:
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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;
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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;
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adjustment period to spectacle correction.
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Intervention: method of occlusion, regimens, use of CAM or pleoptics.
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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:
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random sequence generation (selection bias);
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allocation concealment (selection bias);
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masking of outcome assessors (detection bias);
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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;
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selective outcome reporting (reporting bias);
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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:
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participants with and without co‐existing ocular pathology (that might be expected to limit visual prognosis);
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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:
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outcomes measured on uncrowded vision tests;
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studies where any risk of bias item has been graded as 'high risk';
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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.
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.
