The myth of the glaucoma continuum

The myth of the glaucoma continuum

Paul Palmberg

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA

Introduction

According to Webster’s Dictionary, a myth is “a traditional story […] that serves to […] explain a practice, belief or natural phenomenon”, or something “having only an unverifiable existence”, or “an ill-founded belief held uncritically, especially by an interested group”.

I contend that just such a myth has developed around the belief that structural damage to the optic nerve always precedes functional loss. It began with several papers, published in the 1970’s, reporting that structural damage of the optic disc generally preceded visual field loss as detected by the Goldmann Kinetic Perim- etry.1-4 A mythical paradigm was adopted by many that this was always so.

The paradigm was updated by Quigley and then Weinreb with quantitative methods. Quigley and coworkers counted optic nerve fibers in autopsy specimens and correlated the results with the most recent Goldmann kinetic visual fields obtained before death, concluding that “Patients may lose up to 40% of their optic nerve fibers before damage can be detected” and “Patients may lose up to 90% of their nerve fibers before they notice symptoms.”5 Weinreb and coworkers compared the results of optic nerve imaging to automated visual field testing, concluded that structural changes usually precede functional changes by several years, and proposed the ‘Glaucoma Continuum’ (Fig. 1).6

According to the diagram of the Glaucoma Continuum, ganglion cell death precedes detectable retinal nerve fiber loss, which precedes loss detectable by selective functional testing such as Short Wavelength Automated Perimetry (SWAP), which precedes visual field loss detected by Standard Automated Perimetry (SAP) and finally blindness. The way the diagram represents the process, damage is already quite advanced before visual field loss is detectable. To be fair, the authors acknowledge that functional loss sometimes is detected before structural loss, and that both must be assessed, but the diagram ignores that possibility.

Address for correspondence: Paul Palmberg, MD, PhD, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, P.O. Box 018660, Miami, FL 33101, USA

Eye on the Bayou, New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology, pp. 83–88 Transactions of the 54th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 18-20, 2005

edited by Jonathan D. Nussdorf

© 2006 Kugler Publications, The Hague, The Netherlands

Fig. 1. The glaucoma continuum.

The consequences of adopting the glaucoma continuum

The widespread advocacy of the Glaucoma Continuum has had important consequences. It brought proper attention to looking for structural changes, which is certainly appropriate – a big plus. However, the misleading aspects of the diagram have been taken too literally by some ophthalmologists, leading to an inappropriate aggressiveness with medication and even surgery to treat ocular hypertension in the absence of either visual field or disc changes, for fear of ‘losing half of the optic nerve’ before field loss develops and an additional fear that ‘once damage occurs it is difficult to halt progression’.

It ain’t necessarily so

What is the current evidence regarding the validity of the dictum that structural change precedes functional change? There have been three modern tests of the hypothesis.

First, in the Ocular Hypertension Treatment Study (OHTS), damage was first detected by masked reading of serial stereophotography of the disc in 55% of cases, but first by confirmed visual field loss in 35% and both in 10% (Fig. 2).7 The earlier detection by disc change may in part be an artifact of the protocol, which required change on three visual fields over 12 months, whereas disc change could be confirmed on two examinations over 6 months. We will have to await further analysis of the OHTS results to clarify this. A more appropriate analysis would be to attribute the date of change to the first observation of a subsequently confirmed change.

Fig. 2. First POAG endpoint per participant.

A second test of the hypothesis was performed by Artes and Chauhan, who used Heidelberg Retinal Tomography (HRT) to detect changes in structure and both SAP and High-Pass Resolution Perimetry to follow function, and reported that change was detected first by structure two-thirds of the time and by function one-third of the time.8 There was little correlation of structural change and functional change at the first sign of change, as in the OHTS. The authors suggested that perhaps redundancy in receptor fields hides the initial loss of function, while perhaps sick cells malfunction without as yet dying.

The third test of the hypothesis was a widely misinterpreted study, in which Harwerth taught monkeys to do SAP and then created glaucoma with laser ablation of the trabecular meshwork. Monkeys were sacrificed at various stages of damage and the ganglion cell density and visual field loss were determined in corresponding areas of the retina (Fig. 3).9

The curve relating visual field sensitivity loss to the percent of ganglion cell loss was fairly flat with early cell loss, and then rose progressively with moderate to severe loss. This has been widely misinterpreted to mean that the first 50% of cell loss occurs with little loss of visual field, but in fact, just the opposite is true. What is generally missed is that the intercept on the visual field loss axis is at 6 dB, not 0 dB, and means that there was a quite significant loss of visual field sensitivity from the beginning in this model in which the intraocular pressure was raised abruptly, and that the flat portion of the curve represents the death of cells that had already lost their function. So, in this model, loss of function preceded loss of structure.

Fig. 3. The correlation of ganglion cell loss to VF loss in Harwerth’s monkeys. In this acute model of glaucoma a 6 dB depression of field preceded cell loss, not a 50% loss of cells before a loss of function.

Alleviating fear about loss of a substantial portion of the optic nerve before loss is detected, or that once field loss is present that progression would be difficult to halt

With the use of Optical Coherence Tomography, it is unlikely that more than 20% of optic nerve fibers would be lost without the loss being detected, and rarely is more than 25-30% thinning of the retinal nerve fiber layer noted by OCT without corresponding loss on SAP. Furthermore, the Collaborative Initial Glaucoma Treatment Study (CIGTS)10 demonstrated that with aggressive lowering of IOP (35%) no net visual field loss occurred in 5 years in initially diagnosed cases. The Advanced Glaucoma Intervention Study (AGIS)11 demonstrated that with lowering of IOP to the low normal range no net visual field progression occurred in 8 years. There is no need to be overly aggressive when no detectable functional loss is present.

Future Studies of Structure and Function in Glaucoma

Improvements in our ability to measure both structure and function in glaucoma are currently undergoing validation. The newest versions of Optical Coherence Tomography (OCT) have been shown to have a 3 micron-resolution,12 far outperforming current HRT, OCT and Laser Polarimetry. Improved tests of function include SWAP and Frequency Doubling Technology (FDT), which have the advantage of isolating the function of sub-groups of retinal ganglion cells, and the Pattern Visual Evoked Potential (PVEP) and the Pattern-Electroretinogram (PERG). The latter two may be compared to a stress electrocardiogram, in that the retina is

exposed to rapidly alternating black and white stripes, presumably stressing the metabolic ability of the retinal ganglion cells to fire repeatedly. The PERG test has demonstrated a reversible loss of function in some ocular hypertensives in whom no structural loss (by OCT) or conventional functional loss (by SAP) is detected. The depression of the PERG amplitude reverted to normal in several subjects in whom the pressure was lowered medically, with a time course of several days to a few weeks.13 Such reversal might be a sign of adequate IOP control, suggesting the use of PERG as an ‘axon screamometer’,14 useful in determining an appropriate target pressure for an individual.

Conclusions

The myth of the Glaucoma Continuum as it is sometimes presented has overstated the case for structural change preceding functional change. Functional changes can occur before structural ones, especially with recent, acute IOP changes. While the stress on monitoring structure has been constructive, it should not cause us to ignore monitoring function. Furthermore, with current methods of monitoring optic nerve structure and function, no more than a quarter of the tissue is likely to be lost before we can detect it, and clinical studies show conclusively that glaucoma damage can be halted in the great majority of cases with adequate treatment. Therefore, there is no need to fear that glaucoma damage once started would be difficult to stop, nor to be overly aggressive in trying to prevent the first detectable damage.

References

1.Reed RM, Spaeth GL: Transactions of the American Ophthalmological Society 78:255, 1974

2.Sommer A, Pollack I, Maumenee AE: Arch Ophthalmol 97:1444, 1979

3.Shiose Y: Glaucoma 1:41, 1979

4.Grant WM, Burke JF: Why do some people go blind from glaucoma? Ophthalmol 89:991998, 1982

5.Quigley HA, Addicks EM, Green WR: Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 2:100:135-146, 1982

6.Weinreb RN, Friedman DS, Fechtner RD, et al: Risk assessment in the management of patients with ocular hypertension. Am J Ophthalmol 138:458-467, 2004 (Review)

7.Kass MA, Heuer DK, Higginbotham EJ, et al: The Ocular Hypertension Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 120:701-713, 2002

8.Artes PH, Chauhan BC: Longitudinal changes in the visual field and optic disc in glaucoma. Prog Retin Eye Res 24:333-354, 2005

9.Harwerth RS, Carter-Dawson L, Shen F, Smith EL, 3rd, Crawford ML: Ganglion cell losses underlying visual field defects from experimental glaucoma. Invest Ophthalmol Vis Sci 40:2242-2250, 1999

10.Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmol 108:1943-1953, 2001

11.The AGIS Investigators. The Advanced Glaucoma Intervention Study: 7. The relationship

between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429-440, 2000

12.Wojtkowski M, Srinivasan V, Fujimoto JG, et al: Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmol 112:1734-1746, 2005

13.Ventura LM, Porciatti V : Restoration of retinal ganglion cell function in early glaucoma after intraocular pressure reduction: a pilot study. Ophthalmology 112:20-27, 2005

14.Palmberg P: Discussion of Ventura and Porciatti, AAO 2004.