Evaluation of macular ganglion cell analysis compared to retinal nerve fiber layer thickness for pre-perimetric glaucoma diagnosis.

The National Program for Control of Blindness survey, 2001, found glaucoma to be one the most common causes of irreversible blindness in India.[1] Long-term, randomized control studies have established that glaucomatous neuropathy can be stabilized in a large percentage of patients; however, some continue to progress despite therapy.[234] Therefore, accurately diagnosing preperimetric glaucoma would enable an ophthalmologist to start treatment at an appropriate time, and prevent/delay the occurrence of visual field loss.

Studies have looked for perimetric strategies such as blue on yellow and motion detection to look for preperimetric or very early signs of Glaucoma, but found shortcomings due to subjectivity, interindividual variability, effect of nuclear sclerosis, etc. The advent of objective imaging, especially optical coherence tomography (OCT), in glaucoma was welcomed, hoping that it would enable the diagnosis of preperimetric or early glaucoma. An average of retinal nerve fiber layer (RNFL), measurements in groups of patients having early glaucoma showed a statistical difference in RNFL assessment, compared to healthy controls. Yet, it was not possible to extrapolate this to an individual patient due to interindividual variability in optic nerve head (ONH) size and shape in patients as well as in measurements by different instruments, leading to difficulty in interpretation, when used alone. Histopathology in experimental glaucoma models has shown substantial ganglion cell loss in the perifoveal and parafoveal regions.[56] Improved spectral domain OCTs with additional postprocessing of scans, has made it possible to delineate individual layers in the retina, of which RNFL, ganglion cell layer (GCL), and inner plexiform layer (IPL) are significantly affected in glaucoma. Compared to RNFL measurements around the optic nerve head, assessment at the macular area shows less inter-subject anatomic variability, and also has a greater number of ganglion cells, so that small changes can be definitively diagnosed.

Oddone et al., in a systematic review of published studies, to find out the relative diagnostic accuracy of RNFL versus different macular measurements for glaucoma, observed that the sensitivity summary of most parameters for both RNFL and macular ganglion cell complex (GCC) was between 0.65 and 0.75, making each of these unsatisfactory as a single parameter to be used in clinical setting. A meta-analysis looking at different OCT instruments and differing GCC parameters showed that OCT RNFL parameters are still preferable to macular measurements for diagnosis of manifest glaucoma, though differences may be small [Table 1].[78910]

Table 1

Relative diagnostic odds ratio for ganglion cell complex and ganglion cell inner plexiform layer studies in diagnosing manifest glaucoma

Kansal et al. reported a meta-analysis of 5 OCT devices and found a diagnostic accuracy of RNFL and segmented macular regions (ganglion cell IPL [GCIPL], GCC) scans to be similar, and higher than total macular thickness.[11] More diagnostically favorable areas under the receiver operating characteristic curves were demonstrated in patients with increased glaucoma severity. Kim et al.[12] have suggested that a larger macular grid 3 mm × 6 mm has better diagnostic ability for early glaucoma.

GCIPL, GCCIPL, thickness on high definition OCT has been evaluated in the diagnosis of preperimetric and early glaucoma and found that the diagnostic ability of GCCIPL in preperimetric glaucoma was less than ONH and RNFL parameters, while it was similar in perimetric glaucoma.[131415]

However, macular parameters such as the GCC may be more reliable in certain clinical settings, for example, in pathological myopia (with disc tilting and peripapillary atrophy), optic disc size variability or deformation like ONH hypoplasia or coloboma, the conditions which lower the accuracy of peripapillary RNFL.[1617] Macular pathology that causes abnormal thickening of the inner retina such as macular edema or retinal fibrosis will interfere with GCC measurements. This prevents accurate comparison with the normative database, as well as interfering with detection of change over time.

Pierro et al.[18] found that the definition of the GCC across manufacturers varies, with most considering the GCC to be made up of the IPL + GCL + nerve fiber layer (NFL) (Optovue; Nidek) while Carl Zeiss Meditec uses only IPL + GCL and ignores the NFL, and Topcon gives three different maps with varying combinations of IPL/GCL/NFL. Depending on the OCT machine used, average GCC thickness is approximately 95–100 μ. As the technique is new, along with a lack of standardization between OCT units, it is difficult to compare GCC instruments to each other, or to existing glaucoma instruments in terms of sensitivity and specificity for glaucoma detection and diagnosis.[2] Tan et al. noted that more than one-third of their scans on glaucomatous eyes had to be excluded from segmentation analysis owing to poor quality scans related to speckle noise and uneven tissue reflectivity.[10]

The ganglion cell analysis, GCA, published in this issue, done in early glaucomatous eyes, glaucoma suspects, ocular hypertensives and normal eyes, also shows that analyzing GCA, a combination of GCL and IPL, is not better than RNFL measurements in the detection of preperimetric glaucoma.[19]

Most importantly, there is no standard accepted definition of preperimetric glaucoma itself, making diagnostic evaluations arbitrary. Further, to know the difference between the diagnostic accuracy of RNFL versus GCC or GCCIPL, direct comparative or randomized studies are needed to obviate the heterogeneity in the sensitivity analysis of recent studies.

About the author

Prof Ramanjit Sihota, MD, FRCS, FRCOphth, heads the Glaucoma Research Facility and Clinical Services at Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.

Prof Sihota has won the World Glaucoma Association Research Recognition Award 2011, and numerous national and international awards for research in glaucoma. She has spearheaded the National Task Force in Glaucoma, which is currently operational across India. She has also taken a lead in rationalizing the treatment of Primary Angle Closure Disease in South East Asia. She is a past president of the Glaucoma Society of India, which she has fondly nurtured to become one of the most impactful professional ophthalmic organizations in India.

Prof Sihota is a powerful teacher and leaves an indelible influence on her residents in training. Her edited version of the legendary book “Parsons' Diseases of the Eye” is very widely followed by the students of ophthalmology.

Prof Sihota is an astute and a compassionate clinician, a consummate surgeon an insightful academician, a teacher par excellence, and an opinion-leader in glaucoma. IJO is proud to have her on the Editorial Board and as a Guest Editor.