Major ReviewPlus Disease
Introduction
The revised indications for the treatment of retinopathy of prematurity (ROP) resulting from the Early Treatment of ROP (ETROP) randomized trial have resulted in a significant change in clinical practice.9 The presence of plus disease has now become the primary indication for laser treatment. Although zones and stages of ROP are noted, they have become of secondary importance in determining whether laser treatment is needed. The ETROP study found that the presence of plus disease should play a pivotal role in the treatment decision process.10, 12 The new clinical algorithm calls for treatment of type 1 ROP, including eyes with plus disease having any ROP in zone I, or stage 2 or 3 ROP in zone II. Type 1 also includes eyes without plus disease with stage 3 ROP in zone I, but this scenario is relatively uncommon. Continued observation is recommended for the remaining prethreshold eyes, designated as type 2 ROP (eyes without plus disease having stage 1 or 2 ROP in zone I or stage 2 or 3 ROP in zone II). The purpose of this article is to review the history and pathophysiology of plus disease and to discuss the application of new technology to improve its diagnosis.
Section snippets
History of Plus Disease
Even before the term plus disease was coined, the prognostic importance of markedly dilated and tortuous vessels in the posterior pole was recognized. Owens and Owens were the first to describe the course of ROP, including its early stages of development.30 The first detectable abnormality was a slight dilation of the retinal arteries and veins. This dilatation gradually increased and was more marked in the veins, which nearly tripled their normal size. As the vessels increased in size, the
Pathologic Basis of Plus Disease
The progressive changes in posterior pole vessels that lead to plus disease usually occur in a predictable fashion. These vascular changes may occur gradually from biologic causes or more quickly as a result of flow mechanics. Vessels may be gradually remodeled over time in response to factors such as vascular endothelial growth factor (VEGF). Flow mechanics can change the appearance of vessels abruptly, as is seen when vessels appear thinner while an eye is undergoing scleral depression. Of
Plus Disease Predicting Visual and Structural Outcomes
Palmer et al found that the median onset of plus disease in the CRYO-ROP trial was 36.3 weeks postconceptional age, with 95% of infants of all birth weights who developed plus disease doing so by 42.9 weeks postconception.31 Plus disease typically occurs in eyes with advanced ROP and often portends a poor visual outcome.8, 39, 41
Even before the ETROP study, the presence of plus disease was known to be one of the most important prognostic indicators in ROP, and it was more predictive of poor
Recognition of Plus Disease
As early observers suggested and later studies confirmed, plus disease is a reliable sign of the possibility of serious ROP elsewhere in the eye.7, 13, 35 However, in addition to the inherent challenge of performing indirect ophthalmoscopy on a moving infant that may have poorly dilated pupils, recognition of plus disease has, because of its subjective nature, proven to be an imperfect and sometimes difficult task, and it remains one of the least robust aspects of ROP diagnosis.33 Certainly,
Quantification of Plus Disease
Several investigators have sought to objectively quantify these vascular morphologic changes both clinically and using semiautomated methods.4, 20, 40, 46 In order for blood vessels to be measured, they must first be extracted from an image using a process known as segmentation. Methods of segmentation include vessel tracking, neural networking, and morphologic processing.32 After segmentation, relevant vessels must be identified (either by the computer or its operator) and tortuosity and/or
Conclusion
Findings of the ETROP study clearly point to plus disease as the primary factor for determining when ROP should be treated with laser. Even with treatment, a significant number of eyes with plus disease go on to have poor visual and structural outcomes. There is a growing understanding that there exists a spectrum of retinal vessel dilation and tortuosity, and plus disease is on the severe end of this spectrum. This observation raises the possibility that eyes requiring treatment are really not
Method of Literature Search
The authors performed a Medline search using an Ovid database (1950 to October 2008) using plus disease as the search term. The literature search was not limited to the English language, although no translation was required. Inclusion or exclusion of articles was based on relevance to the subject. The reference lists of these articles were reviewed and additional articles were reviewed and included when considered appropriate. A meeting abstract and articles in press were included in an attempt
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The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, USA.