OGS PRESIDENT'S MESSAGE

The Association of International Glaucoma Societies (AIGS) recently held their 4th Consensus Meeting on intraocular pressure (IOP). Highlights of this meeting will be presented in the next issue of this e-journal. Similar to other areas of glaucoma, there is a great deal of new information about IOP. Assumptions that clinicians held as gospel are being challenged. For example, when is the IOP highest? Is diurnal variability important? Should one use a correction algorithm to compensate for corneal thickness? Besides corneal thickness, are there other biomechanical factors that affect IOP measurements? Does the wearing of contact lenses affect IOP measurements? The questions go on and on.

I graduated from New England College of Optometry in 1976. One memory is students having the option of which form of tonometry, noncontact or Goldmann, to perform as part of general examinations. For either test we had to move our patients to a separate area where the tonometers were located. The Goldmann tonometer was the instrument of choice with the perception that a precise Swiss instrument was being used. The noncontact tonometer was rarely used, in part because of concerns about accuracy as well as once a patient felt the cannon-like blast of air hit the eye, they were reluctant to use the instrument again. Times have changed. The noncontact tonometer has improved dramatically with the amount of air now hitting the eye being almost imperceptible and its accuracy similar to other tonometers, while the limitations of Goldmann tonometry are well known. The difference between the instruments has narrowed as our knowledge base has expanded. Target IOP is another example of a relatively new concept that has important clinical consequences. During my days in school, there was never any discussion about goals for therapy. Target IOP refers to a range of pressures that with therapy become reduced with the expectation that progression is unlikely to occur. Target IOPs are an educated guess that provide some structure early in the course of therapy. Only as we follow the patient over time will we learn if their condition is stable and whether the target IOP is appropriate. These examples are a few of the many new ideas in regards to IOP that are affecting the management of our patients. As part of the process of attending the Consensus meeting, I realized those ideas I once thought were sacrosanct are now being questioned. The need to keep an open mind is crucial if one wants to continue to be a good clinician.

Murray Fingeret, OD
President, Optometric Glaucoma Society
murrayf@optonline.net

EDITORIAL

Focus on Perimetry

A number of the articles in this 7th issue of our electronic journal focus on perimetry. There are three key reasons for visual field assessment; (i) to determine if deficits in visual function are present; (ii) to identify characteristic patterns of loss that aid differential diagnosis; and (iii) to determine whether existing defects are stable.

Traditionally, perimetry relates to the use of clinically-applied psychophysical tests. Although invaluable and useful for the substantial majority of patients, these subjective tests do have a number of drawbacks. One drawback is that threshold sensitivity values measured are not perfectly repeatable. This lack of repeatability is relatively mild in the normal field and, for a variety of reasons, increases when there is field damage; making discrimination between stable and progressive defects challenging. In this issue, our polls reflect this challenge well, demonstrating no consensus amongst respondents about how to compare sequential visual fields. Because of the large volume of numeric data contained in a single field, statistical tools can provide some help. One of these, Glaucoma Progression Analysis, is discussed in the Visual Field Review.

Another drawback of perimetry is that for a variety of reasons, some patients are simply unable to perform the test. In the past, such individuals may have forgone assessment or received crude and gross estimation of visual function, such as simple confrontation testing. However, there is potential for improving this situation as perimetric tools are being developed that permit objective visual field assessment. The most promising of these are introduced in this issue. In the next issue, the practicalities of these tests will be discussed to give context about how objective perimetry may compliment ‘traditional’ standard automated perimetry in the future.

Paul GD Spry, PhD, BSc, MCOptom DipGlauc
Editor-in-Chief
paul.spry@ubht.nhs.uk

Is IOP fluctuation an independent risk factor for glaucoma progression?

Bengtsson et al (1) have performed a stimulating additional analysis from the Early Manifest Glaucoma Trial (EMGT). The EMGT followed 255 patients with newly detected and previously untreated glaucoma who were randomized to two arms. One arm was subjected to IOP lowering treatment (360° trabeculoplasty and Betaxolol) while the other was observed in the same manner but without receiving treatment. The main EMGT outcome was that a significantly lower rate of glaucomatous progression was observed in the treated arm(2). In the current manuscript, the authors’ address another question of considerable importance to the management of patients with glaucoma, that being 'is IOP fluctuation a risk factor for glaucoma progression independent of the mean level of IOP?'

Within the follow-up period of the current study(1) (median 8 years, range 0.1 to 11.1 years), 68% of the cohort progressed (59% of treated, 76% of control patients) based on mild changes in standard automated perimetry results or ‘worsening of the disc’ as determined by masked graders. The mean follow-up IOP was 19.5 mmHg in progressors and 16.5 mmHg in non-progressors. The standard deviation of follow-up IOP measurements made during a stable management window (my term, not theirs) was used as an index of IOP fluctuation. The stable management window for a patient comprised all visits from the first post-randomization visit (at 3 months) until progression occurred, or until the most recent follow up visit if progression did not occur. The stable management window was used to prevent treatment effects from artificially inflating IOP fluctuation.

Two important lessons cry out to be heard at this point and a brief aside seems warranted. The first lesson is that study design can influence associations between variables: a flawed design may cause a strong but inaccurate correlation between two measures. The authors of the current paper avoided such a flaw by not including baseline IOP in the calculation of IOP fluctuation. If baseline IOP had been included in the calculation of IOP fluctuation then the treated group would have displayed higher fluctuation because a decrease in IOP occurred soon after commencing therapy. IOP fluctuation would thus no longer be an independent measure but would be correlated to randomization group (either treatment or no treatment) and randomization group is a significant risk factor for progression. The inclusion of baseline IOP in calculation of IOP fluctuation would therefore have resulted in IOP fluctuation being subject to this confounding factor. Similarly, if treatment were instituted or more aggressively pursued once progression occurred (68% of the cohort) and post progression IOPs had been included in the calculation of IOP fluctuation, then IOP fluctuation would have been confounded by progression. The authors wisely did not include post progression IOPs in their calculation of IOP fluctuation. The second lesson, one we should all keep in mind when reading studies that report correlations, is that correlation does not imply causation. There is a high correlation between the use of white mobility canes and blindness but using a white cane does not cause blindness. Always be on the lookout for spurious associations.

The standard deviation of IOP during follow-up was 2.02 mmHg and 1.78 mmHg in progressors and non-progressors respectively and the authors concluded that IOP fluctuation was not a statistically significant independent risk factor for glaucomatous progression.

This finding is in conflict with the AGIS, where analyses have suggested that IOP fluctuation is an independent risk factor for glaucoma progression. In the AGIS, once a patient progressed, additional treatment / surgery was instituted with a consequent effect on IOP. Progressing patients underwent more IOP altering treatments, each one acting to increase variability in the set of IOP measurements for a patient. The authors of the current work suggest that including post progression IOP in the calculation of IOP fluctuation in the AGIS may have influence the findings of that study.

Two items deserve consideration in evaluating the current study. First, IOP was very stable during follow-up in both arms of the EMGT. We cannot be sure that IOP fluctuation wouldn’t have been a significant risk factor if it had been present to a greater degree. This situation is analogous to concluding that a trial drug is not effective because there is no difference between treated and control arms yet the treated arm received a pharmacologically ineffective dose. The second item of consideration is that quantification of IOP fluctuation reported in this study may not be representative of the true temporal IOP behavior. Twenty-four hour IOP monitoring was not performed in the EMGT study so IOP fluctuation throughout the diurnal cycle may still be an important risk factor for glaucoma progression. However, it was not addressed in this thought provoking manuscript.

Shaban Demirel BScOptom, PhD

References
1. Bengtsson B, Leske MC, Hyman L, Heijl A. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:205-9.
2. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Archives of Ophthalmology. 2002;120:1268-79.

Are Contrast Sensitivity Changes due to Normal Aging and Glaucomatous Damage Different for Magno and Parvocellular Mechanisms?

Using a novel stimulus design which supposedly assesses function of an achromatic subset of parvo and magno retinal ganglion cells (RGCs) (1) McKendrick et al. (2) examined contrast sensitivity alterations brought about by normal aging and by glaucoma. Clinical tests that claim to assess parvo (HRP, perhaps SAP) or magno (FDT) function generally have very different stimulus properties. The psychophysical approach used in this study was attractive because the parvo and magno stimuli were identical and only differed in their timing.

The effects of aging and glaucoma were addressed by testing young normals, older normals and older patients with glaucoma. All subjects were tested foveally and at one or two locations in the mid-periphery. In the glaucoma group, mid-peripheral testing was performed at one location within a defect identified on standard automated perimetry (SAP) and at one additional location that was considered ‘normal’ on SAP.

Some of the findings were as expected. For example, young normals performed better than older normals and foveal contrast sensitivity was better than in the mid-periphery for parvo and magno stimuli. Many visual tasks display these characteristics, which mirror the number of RGCs in younger vs. older and central vs. peripheral retina. Another non-contentious finding was that subjects with glaucoma had significantly worse contrast sensitivity than normal in visual field areas that were abnormal with SAP.

The more remarkable results of this study are at odds with previous evidence that magno RGCs and/or larger RGCs are selectively damaged early in glaucoma. In the SAP abnormal region of the visual field of glaucoma subjects the contrast sensitivity loss appeared similar for magno and parvo stimuli and did not seem worse for stimuli that would likely be processed by larger RGCs. When testing glaucomatous eyes at visual field regions that were normal on SAP, a significant reduction of contrast sensitivity was seen with the parvo stimulus. Contrast sensitivity measured with the magno stimulus in these SAP normal regions of glaucoma eyes, was not significantly reduced. The authors conclude that there is no evidence for selective loss of magno or parvo function with normal aging or due to glaucoma.

It’s interesting to note that most of the evidence supporting selective loss of RGC sub-types (usually magno cells or large cells) is anatomical/histological, i.e. structural in nature. Conversely, there is ample evidence in the literature on visual function in glaucoma that abnormalities exist for stimuli that are processed by parvo-, magno- and koniocellular RGCs. Reconciling this mismatch in the structure - function relationship might reveal much about the glaucomatous disease process.

Shaban Demirel BScOptom, PhD

References
1. Leonova A, Pokorny J, Smith VC. Spatial frequency processing in inferred PC- and MC-pathways. Vision Research. 2003;43:2133-9.
2. McKendrick AM, Sampson GP, Walland MJ, Badcock DR. Contrast sensitivity changes due to glaucoma and normal aging: low-spatial-frequency losses in both magnocellular and parvocellular pathways. Investigative Ophthalmology and Visual Science. 2007;48:2115-22.

OBJECTIVE PERIMETRY IN GLAUCOMA

Examination of the visual field is a mainstay of clinical care for all glaucoma patients and suspects. It is arguably the most important measurement of vision function made for diagnostic and management purposes. Despite continual improvements in the methodologies underlying perimetry including automation, faster and more accurate thresholding algorithms, sensitive and selective stimuli, visualization capabilities and software algorithms for evaluating progression, clinicians are routinely faced with the challenge of interpreting unreliable visual field results. There are many facets contributing to the problem of questionable reliability including patient performance issues such as fixation accuracy and stability, consistency of response criteria, anxiety, boredom and fatigue. Perhaps equally troubling is the physiological variability inherent to visual “thresholds”, which may even increase in disease states.

These problems, in part, have served as kindling for the development of various modes of “objective perimetry”. The main aim is to remove the subjective component from patient responses during the otherwise taxing task of testing thresholds topographically. For example, if we can obtain the requisite information (i.e. status of retinal ganglion cell and optic nerve function) without influence from a patient’s higher brain centers, we might avoid the confounding effects of shifting response criteria (e.g. false positives, false negatives and variable threshold values). Moreover, by measuring parameters other than thresholds, we might also avoid some of the sources of physiological noise due to neuronal behavior around threshold.

Although there are far too many objective measures of vision function to cover in this brief review, there are two particular techniques worthy of mention because they are both capable of being applied topographically (i.e. to be used for perimetry) and have both progressed to relatively advanced stages of development. These two techniques are known as “pupil perimetry” and “multifocal visual evoked potentials (mfVEP)”, respectively.

Randy Kardon and colleagues at the University of Iowa have been chiefly responsible for continued development of pupil perimetry (1-3). Using infrared imaging to monitor pupil size, they are able to measure and evaluate pupil responses (contraction amplitude and latency) to focal spot stimuli positioned at standard visual field locations (e.g. the 76 locations of a 30-2 pattern). They have shown that defects measured by pupil perimetry match those measured by standard psychophysical threshold perimetry in patients with ischemic and compressive optic neuropathy, but not in primary open-angle glaucoma (1,2). There are differences between the topographical profiles of pupil sensitivity and visual sensitivity within the same normal eyes (3) which may explain some of the discrepancy in glaucomatous eyes. This suggests that defects measured by pupil perimetry offer not only a rapid, objective measure of the visual field but perhaps also a complementary measure to standard psychophysical perimetry. Further research is needed to assess the reliability of pupil perimetry and its capability for detecting progression.

The mfVEP technique was first shown to be capable of mapping glaucomatous visual field defects by Sasha Klistorner, Stuart Graham and colleagues in Sydney Australia (4). They have continued to develop methodological improvements and to demonstrate the feasibility of the mfVEP technique to be used as a method of objective perimetry (4-8). Similarly, Don Hood, Xian Zhang and colleagues at Columbia University in NY have made vital contributions to development of mfVEP recording procedures, analytical methods and software for visualization of results (9). Collectively, their work shows that the performance of the mfVEP in glaucoma diagnosis is on par with that for standard automated perimetry (SAP) and/or confocal scanning laser tomography. (4-12). The work of our own group at the Devers Eye Institute in Portland, OR, in conjunction with the Hood lab supports the same conclusion; namely that the mfVEP is able to objectively detect visual field loss with high sensitivity and specificity (13,14) and that the mfVEP and SAP have similar diagnostic capability in glaucoma and high-risk ocular hypertension (15). The repeatability of the mfVEP is also at least as good as SAP, if not slightly better (16-19), which suggests that potential for detecting progression of glaucomatous functional loss may be equal (or better) using mfVEP. Longitudinal studies are underway to address this question.

Brad Fortune, OD, PhD

References
1. Kardon RH, Kirkali PA, Thompson HS. Automated pupil perimetry. Pupil field mapping in patients and normal subjects. Ophthalmology. 1991;98:485-495; discussion 495-496.
2. Kardon RH. Pupil perimetry. Curr Opin Ophthalmol. 1992;3:565-570.
3. Hong S, Narkiewicz J, Kardon RH. Comparison of pupil perimetry and visual perimetry in normal eyes: decibel sensitivity and variability. Invest Ophthalmol Vis Sci. 2001;42:957-965.
4. Klistorner AI, Graham SL, Grigg JR, Billson FA. Multifocal topographic visual evoked potential: improving objective detection of local visual field defects. Invest Ophthalmol Vis Sci. 1998;39:937-950.
5. Klistorner A, Graham SL. Objective perimetry in glaucoma. Ophthalmology. 2000;107:2283-2299.
(6). Goldberg I, Graham SL, Klistorner A. Multifocal objective perimetry in the detection of glaucomatous field loss. Am J Ophthalmol. 2002;133:29-39.
7. Graham SL, Klistorner AI, Goldberg I. Clinical application of objective perimetry using multifocal visual evoked potentials in glaucoma practice. Arch Ophthalmol. 2005;123:729-739.
8. Balachandran C, Graham SL, Klistorner A, Goldberg I. Comparison of objective diagnostic tests in glaucoma: Heidelberg retinal tomography and multifocal visual evoked potentials. J Glaucoma. 2006;15:110-116.
9. Hood DC, Greenstein VC. Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma. Prog Ret Eye Res. 2001;22:201-251.
10. Thienprasidhi P, Greenstein VC, Chen C, et al. Multifocal visual evoked potential responses in glaucoma patients with unilateral hemifield defect. Am J Ophthalmol. 2003;136:34-40.
11. Hood DC, Thienprasiddhi P, Greenstein VC, et al. Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci. 2004;45:492-498.
12. Thienprasiddhi P, Greenstein VC, Chu DH, et al. Detecting early functional damage in glaucoma suspect and ocular hypertensive patients with the multifocal VEP technique. J Glaucoma. 2006;15:321-327.
13. Fortune B, Goh K, Demirel S, et al. Detection of glaucomatous field loss using Multifocal VEP. In: IPS Proceedings 2002/2003. The Hague: Kugler Publications; 2004: 251-260.
14. Fortune B, Zhang X, Hood DC, Demirel S, Johnson CA. Normative ranges and specificity of the multifocal VEP. Doc Ophthalmol. 2004;109:87-100.
15. Fortune B, Demirel S, Zhang X, et al. Comparing Multifocal VEP and Standard Automated Perimetry in High-Risk Ocular Hypertension and Early Glaucoma. Invest Ophthalmol Vis Sci. 2007;48:1173-1180.
16. Chen CS, Hood DC, Zhang X, Karam EZ, Liebmann JM, Ritch R, Thienprasiddhi P, Greenstein VC. Repeat reliability of the multifocal visual evoked potential in normal and glaucomatous eyes. J Glaucoma. 2003;12:399-408.
17. Fortune B, Demirel S, Zhang X, Hood DC, Johnson CA. Repeatability of normal multifocal VEP: implications for detecting progression. J Glaucoma. 2006;15:131-141.
18. Bjerre A, Grigg JR, Parry NRA, Henson DB. Test-retest variability of multifocal visual evoked potential and SITA standard perimetry in glaucoma. Invest Ophthalmol Vis Sci. 2004;45:4035-4040.
19. Klistorner A, Graham SL. Intertest variability of the mfVEP amplitude: reducing its effect on the interpretation of sequential tests. Doc Ophthalmol. 2006;111:159-167.

VISUAL FIELD REVIEW

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Detecting Glaucoma Progression

The identification of visual field progression in glaucoma remains a challenging issue. In the past, practitioners could make use of the Glaucoma Change Probability (GCP) analysis on the Humphrey Field Analyzer. However, GCP did not take into account the importance of confirming suspected visual field defect progression and was not designed to be used with SITA (Standard or Fast), so something new was needed.

The Glaucoma Progression Analysis (GPA) software has been introduced for use with both SITA tests and allows the original full threshold fields to be used only as baseline tests. GPA is based on the variability established by repeat visual field testing 4-times over a month and was validated in the Early Manifest Glaucoma Trial (EMGT).

On follow-up, the GPA program compares each point in the pattern deviation map to the average of two baseline determinations for that same patient. It is necessary for baselines to be reliable as future point-wise comparison determines whether any of the changes are within or outside the variability characterized by the GPA.

The GPA program flags field locations that fall beyond the 95% confidence limit for variability with an unfilled triangle (). However, it extends this logic so that if change is confirmed at this same location on the next visit (2 successive tests) the triangle becomes larger and half-filled. Further confirmation at the next visit (3 successive tests) returns a fully filled triangle (). Points that show a high level of loss are flagged as "out of range" with an X, because the fluctuation of these points makes meaningful judgments of progression impossible.

Furthermore, the GPA software allows a summary printout to be shown with the most recent single field result. Here a summary box appears to the lower right portion of the printout that gives the dates of the baseline and follow-up fields and identifies progressing fields with a summary explanation. The descriptor is for "possible progression" when 3 or more locations lie outside the expected variability on 2 successive tests or as "likely progression", if they lie outside expectation on 3 successive tests. The GPA affords practitioners a high level of sophistication in monitoring patients who have been diagnosed as having glaucoma.

I will demonstrate the issues developed in the previous section on this case provided kindly by Dr Murray Fingeret. This 82 year old patient underwent a 24-2 SITA Standard visual field examination on July 27, 2005. He has a history of primary open angle glaucoma, first diagnosed on October 9, 1996. The Glaucoma Progression Analysis (GPA) data are for the gentlemen’s left eye. The single field printout for the 2005 visit (Figure 1) is annotated with "Likely Progression", indicating that at least 3 points (pattern deviation plots) have worsened beyond the 95th percentile on 3 consecutive tests, compared to his own baseline. The first page of the GPA printout (Figure 2) shows the two baseline fields and a plot of the mean deviation (MD) for the entire series of fields. In this case, 9 fields have been performed over a 9-year period with the MD getting worse over time. Using a regression equation, the MD slope of -0.81 dB per year, is statistically worse than that expected. This change in MD is largely due to the development of a cataract in this eye. Looking at the single field printout (Figure 1), the cataract-related diffuse loss is evident on the total deviation plot (lower left) with local change shown in the pattern deviation (lower right). The GPA analysis printouts for fields performed between May 2003 and July 2005 (Figures 3-5) show a series of points progressively worsening when compared to baseline: open triangles indicate changes found on this exam only; half-filled triangles indicate points that have changed on both of 2 successive fields; and filled triangles show points that have changed on all of 3 successive fields. Figure 5 shows the latest result obtained in July 2005 - here 5 points have changed on all of 3 exams in a row being the first evidence for “Likely Progression” in the field and indicating that the management of this patient needs to be reviewed.

Algis Vingrys BScOptom, PhD

Axenfeld’s Anomaly

The subject of this case is a 46 year-old Hispanic female who was seen initially for a complaint of reduced vision. Medical and ocular histories were noncontributory and she was not taking any medications. There was a strong family history of glaucoma including her father, an aunt and a sister. A review of systems specifically ruled out migraine, prednisone use, Raynaud’s phenomenon or systemic hypotony.

Best-corrected visual acuity was 20/20 and 20/60 in the right and left eyes, respectively. There was a 2+ relative afferent pupillary defect in the left eye. Applanation tonometry was 28 and 41 mm Hg in the right and left eyes, respectively.

Figure 1. Gonioscopy of the left eye. Note the prominent Schwalbe’s line as well as iris abnormalities.

At slit-lamp examination, there was a prominent and anteriorly displaced Schwalbe’s line (posterior embryotoxon), visible as a white line deep within the cornea, adjacent but anterior to the limbus. Gonioscopy revealed anterior chamber abnormalities including numerous iridocorneal adhesions varying in size from small threads to broader bands (Figure 1). Adhesions arose from the central areas of the iris that attach to the cornea at or just anterior to Schwalbe’s line.

Figure 2. Fundus pictures of the right and left eyes. There is significant cupping and nasalization of the central retinal vessels with comparatively greater pallor on the left side.

Figure 3a.

Figure 3b.

Figure 4.

Figure 2 shows the optic nerve head appearances at presentation. The optic discs are large in diameter and have bilateral advanced glaucomatous optic neuropathy, with significant cupping and nasalization of the central retinal vessels in both eyes with comparatively greater pallor on the left side. There is end stage visual field loss in the left eye, with defects present in both hemifields in the right eye (Figure 3). The structural evaluation with GDx Retinal Nerve Fiber Analyzer (Carl Zeiss Meditec, Dublin, CA) mirrors the visual field with damage greater in the left eye (Figure 4).

Figure 5. Child 1 (male age 6) at diagnosis. Note disc asymmetry with larger C/D in the right eye.

Figure 6. Child 1. The corresponding visual fields show greater damage in the right eye.

Figure 7. Child 1 (male age 6), GDx. Although the patient’s age is below threshold for the normative database, there is evidence of thinned RNFL greater in the right eye.

A diagnosis of Axenfeld’s anomaly was made. Axenfeld's anomaly is a congenital disorder associated with iridocorneal dysgenesis and is a variant of Axenfield-Reiger syndrome. This group of conditions are thought to have a genetic basis, with autosomal dominant inheritance, although variable penetrance. Axenfeld’s anomaly is characterized by posterior embryotoxon with iridocorneal adhesions. Posterior embryotoxon has also been reported to occur in up to 15% of normals in whom it is usually only visible in the nasal and temporal corneal quadrants, unlike the usual 360° appearance of the anomaly. It is the anterior chamber angle dysgenesis reducing aqueous outflow facility that is responsible for the increased IOP and resulting glaucomatous damage. Hypoplasia of the anterior iris stroma accompanies some cases, but more severe defects are not usually present. This case is especially unusual because glaucoma development in Axenfeld’s anomaly is rare.

Other variants of Axenfeld-Reiger syndrome include Axenfeld’s syndrome (AS, often also called Reiger’s anomaly) which differs from the anomaly because it is usually bilateral, has greater iris involvement, such as marked atrophy, and hole formation. Glaucoma development in AS is more common, with up to 50% of patients affected. The third group is Reiger’s syndrome which has the same ocular signs as Axenfeld’s syndrome/Reiger’s anomaly but also has associated non-ocular signs including dental and facial malformations.

Figure 8. Child 2 (male age 4) at diagnosis.

Figure 9. Child 2 (male age 4) at diagnosis. Note the nasal defects in the right visual field.

Figure 10. Child 2 (male age 4) at diagnosis. RNFL appears to be relatively normal. Note: database comparisons are not applicable due to the patient’s age.

The patient was managed with betoptic bid OU (diagnosis was made prior to prostaglandin analogue availability). Iopidine bid and Trusopt were added later. The visual fields remained stable in both eyes over time but the OS field became increasingly unreliable. IOP has remained in the mid-teens OD and in the high teens to low 20’s OS. In view of the degree of glaucoma in the left eye, the patient was offered surgery. A left trabeculectomy augmented with mitomycin C was performed and IOP was significantly lowered as a result.

The subject of this report has two offspring. Their data are presented in Figures 5-7 and 8-10, respectively. At diagnosis, the siblings were ages 6 and 4, respectively. Note that the optic discs, visual field results and RNFL analysis all show abnormalities, consistent with the autosomal dominant genetic basis of this disorder.

It is critical to look carefully with gonioscopy when anterior chamber abnormalities are suggested at slit-lamp observation. In addition, it is important given the mechanism of genetic transmittance to examine offspring of patients with any of the Axenfeld-appearing anomalies.

Robert E. Prouty, OD, FAAO, Leo Semes, OD, FAAO

References
1. Mandal AK, Walton DS, John T, Jayagandan A. Mitomycin C-augmented trabeculectomy in refractory congenital glaucoma. Ophthalmology. 1997 Jun;104(6):996-1001; discussion 1002-3.
2. Shields MB, Buckley E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol. 1985; 29: 387-409.
3. Lines MA, Kozlowski K, Walter MA. Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet. 2002; 11:1177-84.
4. Amendt BA, Semina EV, Alward WL. Rieger syndrome: a clinical, molecular, and biochemical analysis.Cell Mol Life Sci. 2000; 57: 1652-66.
5. Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol. 2000; 130: 107-15.

 

OGS MEMBER RESEARCH PROFILE

Many OGS members are research-active, performing relevant and highly topical work that helps improve our understanding of glaucoma and provides an evidence-base for clinical practice. We would like to tell you about the work of these individuals and for this issue we have asked founder OGS member Ronald S. Harwerth, OD, PhD, to profile the work of his laboratory. Dr Harwerth is the John and Rebecca Moores Professor of Optometry and Chair of the Department of Vision Sciences in the College of Optometry at the University of Houston, Houston, Texas.

The overall goal of the research on glaucoma that is being conducted in my laboratory is to gain a better understanding of the relationships between standard clinical measures of glaucomatous neuropathy and the underlying pathological losses of retinal ganglion cells. The motivation for these investigations is that clinicians must make their management decisions from the results of either subjective testing, e.g., standard automated perimetry (SAP), or objective testing, e.g., optical coherence tomography (OCT) because, without an established biological marker of glaucoma, the diagnosis and assessment must rely on ophthalmic measures of structure and/or function.

The specific ongoing investigations have involved studies of experimental glaucoma in macaque monkeys that are followed by studies of patients with clinical glaucoma. In this manner, methods and procedures that were developed with experimental glaucoma are verified, or modified, by patient-based results. The use of experimental glaucoma has many advantages for the initial investigations of structure-function relationships, such as, the ability to make repeated measures of visual defects over the full time course of glaucomatous neuropathy, an in-animal control because experimental glaucoma is a unilateral treatment, and prime tissue for the analysis of the histologic correlates of glaucoma. On the other hand, there are many important differences between clinical and experimental glaucoma, such as, differences in IOP levels and the time course of defective vision, anatomical differences in their eyeballs, and effects of normal aging on retinal ganglion cell populations that, thereby, necessitate a phase of transformative research.

By and large, the current results of the studies have demonstrated that both SAP and OCT measures can be translated into common parameters that are related to the residual population of retinal ganglion cells. However, in presentations at the 2007 ARVO meeting (IOVS 2007;48;E-abstract 491 & 492) we reported that translational procedures for the two clinical measures involve different variables. For SAP, the density of retinal ganglion cells underlying a given test field location is a function of only the visual sensitivity and eccentricity at the test location, without involving age-dependent or stage-dependent variables. In contrast, the density of the axons of retinal ganglion cells in a given region of the nerve fiber layer is a function of both age-dependent and stage-dependent variables, but without an eccentricity-dependent variable. Thus, both clinical measures may be used in analyses that provide an accurate and reasonably precise evaluation of a patient’s retinal ganglion cells. In general, the collaborative work of many investigators in my laboratory has shown that SAP measures of visual sensitivity and OCT measures of retinal nerve fiber layer thickness are concordant measures of ganglion cell populations in normal eyes or in eyes with glaucomatous neuropathy. These studies improve our understanding of the neuronal relationships for the measurements and demonstrate that the combined results of the two tests should provide important information to aid clinicians in their decision-making for the diagnosis or assessment of progression of glaucoma.

 

MEETING NEWS

Selective laser Trabeculoplasty
The 6th International Glaucoma Symposium (IGS) was held at the Megaron Athens International Conference Centre in Athens, Greece, from 28th-31st March 2007. This year is a busy one for international glaucoma meetings, with the forthcoming World Glaucoma Congress (WGC) due in Singapore in July. Indeed, both the IGS and WGC meetings will be the last of their type, as their organisers have together agreed to merge them into one biennial global glaucoma meeting. The first of these new joint meetings will be held in North America during 2009.

This IGS was aimed squarely at individuals directly involved in glaucoma practice: most presentations had a clinical slant. Sessions fell into two categories, those based on submitted abstracts and those sponsored by commercial organisations. One such session, "Selective Laser Trabeculoplasty - an Emerging Primary Therapy for Open-angle Glaucoma" featured speakers invited by the session sponsor. To those like myself who had little or no exposure to SLT, it provided a useful overview and introduction to the subject.

The first speaker, Dr MA Latina is involved in research and commercial development of SLT. He explained that SLT differs from the long-established argon laser trabeculoplasty (ALT) because it does not cause photo-thermal coagulation of the trabecular meshwork(TM) beams and leaves no gonioscopically visible coagulation craters. He explained that SLT does not cause mechanical damage because laser pulses are very short (3ns) and have low energy, so that it is absorbed by individual trabecular cells, and its therapeutic effect is achieved by impacting the biology of these cells.

The second speaker in this session, Dr J Alvarado, presented further information on the biological, biochemical and physiological mechanisms implicated in the therapeutic effect of SLT. A series of observations and experiments were presented suggesting that two connected pathways contribute to IOP reduction after SLT. It was postulated that when individual trabecular meshwork endothelial cells (TMEs) are damaged by exposure to SLT, they release both specific cytokines and chemokines. The first pathway is cytokine-mediated and consists of increased permeability of Schlemm’s canal endothelium, promoting transendothelial aqueous flow. The second pathway is chemokine-mediated recruitment of additional monocytes within the TM. Dr Alvarado explained that on average 15,000 monocytes are present physiologically in the TM, but that this increases to around 75,000 after SLT. These additional cells do not block the meshwork, but are thought to somehow improve meshwork efficiency. Interestingly, a number of studies have found a small but statistically significant degree of treatment effect in the untreated fellow eye where SLT is performed unilaterally and Dr Alvarado hypopthesised that increased monocyte activity may provide the explanation for this observation.

To date, there are many published clinical trials of SLT. Few of these have used a prospective, longitudinal randomised controlled trial (RCT) design, and the final presentation of the session was from the first author of one of the few RCTs available in the literature, Mrs M Nagar. This RCT had compared a variety of SLT 'doses' (90°, 180° or 360° treatment) with latanoprost monotherapy. Average IOP was lower throughout the study’s one year duration with medical treatment than any of the SLT treatment groups. In terms of achieving target IOP, significantly fewer patients treated with 90° and 180° SLT achieved IOP reductions of 20% or 30% from baseline, whilst 360° SLT and latanoprost were not significantly different in this regard, latanoprost achieving these reductions in 90% and 78% of patients respectively, compared with 82% and 52% for 360° SLT. Patient age, sex, race, pre-treatment IOP, OHT or OAG status, laser power settings or total energy delivered did not appear to predict those achieving 20% or 30% IOP reductions. Not surprisingly, many of the patients randomised to SLT treatment experienced transient adverse events (discomfort/pain, uveitis, or IOP spikes). This RCT provides encouraging data on SLT effectiveness and apparent dose-dependency. Further high-quality research on the duration of IOP response to SLTs and the effectiveness of repeat treatments will help determine the place of this treatment in our armamentarium.

Paul GD Spry, PhD BSc, MCOptom DipGlauc

Reference
1. Nagar M, Ogunyomade A, O'Brart DP, Howes F, Marshall J. A randomised, prospective study comparing selective laser trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open angle glaucoma. Br J Ophthalmol; 2005: 89(11): 1413-7.

 

CLINICAL QUESTIONS AND ANSWERS

If you would like us to answer a clinical question, please send it to paul.spry@ubht.nhs.uk with "OGS question" as the subject. The questions can concern anything related to glaucoma, for example, analysis of an optic nerve image, optic disc, a challenging case or side effect of a medication. We welcome your questions and we will try to address as many as possible in each issue.

Figure 1.

Figure 2.

Question: Last year, I took nerve head pictures of a 32 year old male with a family history of glaucoma (figure 1). Tensions were 15 mmHg OU, threshold visual fields were normal and he had normal thickness corneas. When the pictures were repeated one year later (figure 2) I observed that the cup-to-disc ratio had reduced. Why did the c/d get smaller?

Tony Litwak, OD, answers: The difference in the appearance of cupping in the two photos is most likely the color hue differences between the photos. In my experience, true reversal of optic cupping is a very rare event.

There are a couple of instances where a "pseudo-reversal" of cupping may occur. If the IOP is very high (>40) and you bring it down rapidly, there can be the appearance of a reversal of cupping. I would postulate that the change represents a physical change in the size of the ganglion cell axon (a localized decompression of the axon) rather than the regeneration of axons.

The most common setting in which I have witnessed a decrease in optic cupping is when a patient undergoes filtering surgery for glaucoma. In cases where the IOP drops into the low single digits (hypotony), there may be a pseudo-appearance of an increase in neuro-retinal rim tissue. I believe this represents a pressure gradient shift in the axo-plasmic flow with the intracranial pressure (in the CSF encompassing the optic nerve) becoming greater than the IOP. This results in a backup of the retrograde axo-plasmic flow and swelling of the ganglion cell axons. In this case, a patient with advanced cupping will appear to have less cupping because of the swollen axons when the eye becomes hypotonous. This change in the optic nerve appearance can be dramatic. I have seen patients with .95 cupping appear to have a .3 cup after filtering surgery. Unfortunately this does not represent a regeneration of the axons and when the IOP increases above 8-10 mmHG, the advanced cupping will revert to its pre-surgical appearance.

Douglas R. Anderson, MD, answers: My first guess would be the possibility that the IOP was not the same at the time the pictures were taken in this young person, so the disc is more filled in with one picture than the other. We have certainly seen such shrinkage of the cup when a patient is treated, mainly in young patients like this one. I have seen changes of this magnitude with IOP changes of, say, 10 mm Hg in young people. It happens almost instantly, and while it is not often done, when you relieve the IOP in surgery and look at the optic nerve, the cup will already be filled in. More often people MIGHT look the next day to observe it. We saw reversal fairly often in CIGTS and in OHTS we have seen smaller cups in the follow-up photos fairly often too, and although we are masked we assume they were in the treated group.

It is important to recognise this guess is speculative: we are talking about a rarely observed phenomenon; photos like these are not commonplace. So, this individual may be very different from others in terms of optic nerve head elastic properties, but also the IOP may have been more different than usual (because of major cycloplegic response, for example) between the two photos. Interesting photos to look at to remind us of individual differences, but perhaps not something to generalize to all patients as a typical or frequent event.

Douglas R. Anderson, M.D. is Professor of Ophthalmology and Douglas R. Anderson Chair in Ophthalmology at Dept of Ophthalmology, Univ. of Miami Leonard M. Miller School of Medicine, Bascom Palmer Eye Institute.

Brad Fortune OD, PhD and Claude Burgoyne, MD, answer: In our opinion this pair of photographs demonstrates true change of optic disc architecture. In making this judgment we first assessed the size of the optic disc in both photographs, which appears to be stable. The appearance of architectural change can sometimes be due to magnification changes secondary to changes in the eye size, refractive components of the eye or camera optics. We see no evidence for this, nor do we see evidence that a physical contraction of Bruch’s membrane opening (BMO, the clinically visible optic disc margin)(1) has occurred. Contraction of the BMO would induce the appearance of a smaller cup because the existing prelaminar tissues would then need to pass through a smaller opening.

There is a decrease in the size of the central cup and an increase in the amount of rim tissue for 360 degrees. There are numerous features that suggest the presence of physical change. The most salient of these are the following: 1) the vessel crossing the cup near the inferotemporal rim bifurcates into branches that extend toward approximately the 3 and 4 o’clock positions of the disc edge; the length of these branches visible within the cup is nearly twice as long in the first (earlier) photograph as compared with their visibility in the later photograph. 2) Note that the tortuous branch emanating from the primary superior temporal retinal artery crosses over the superior temporal vein, then across the superotemporal rim tissue of the disc; as it curls superiorly toward the edge of the disc, its position approximately bisects the thickness of the superotemporal rim in the second photo, whereas in the first photo, its position relative to the thickness of the rim clearly shows that the superotemporal rim is thinner at that earlier time. 3) The branch vein draining the superior retina crosses under the superior temporal artery near the 11 o’clock position of the neuroretinal rim just before it joins the vein draining the superior temporal retina to become the large superior branch vein visible within the cup; the amount of rim tissue at 11 o’clock masking this large branch vein within the cup is clearly greater in the later photo.

A change in the angle of photographic axis (that which creates parallax during photography) could not simultaneously produce these effects at all positions around the border between the rim tissue and cup edge (though it could possibly contribute to such effects along just one border). Similarly, the difference in color balance between the two photographs cannot explain the change in cup size. Because this change appears to be in the rim and real, we do not agree with the use of the terms cupping reversal or pseudo-cupping reversal. The first emphasizes a central empty space and suggests an improvement in a pathophysiologic process. The second suggests that the phenomenon is not real. We do not believe that either is the case.

This appears to be an increase in the volume of rim tissue at the level of Bruch’s membrane opening (BMO), which is likely due to a shift in the dynamics of laminar cribrosa position and pore architecture, neural canal expansion/compression and axoplasmic flow within the retinal ganglion cell axons at the level of the neural canal. It is possible that this is a fixed change due to new connective tissue synthesis by optic nerve head astrocytes, but there is no increase in pallor to suggest this. We emphasize the rim tissue because that is where the active (and we suspect dynamic) process has occurred, i.e., not a contraction of the canal opening and not contraction of an empty space.

Regarding the physiologic and/or pathophysiologic mechanism(s) underlying the change in the rim tissue, it is difficult to know the relative importance of each possible contributor because we are lacking other potentially relevant clinical data such as IOP, CSF pressure, medications at the time of each photograph and status of the fellow eye. We are also as yet unable to measure those aspects of optic nerve head connective tissue and vascular architecture that underlie most dynamic changes in the appearance of the optic disc.

If pre and post event imaging of the lamina had suggested an anterior shift within the canal, accompanied by a diminution in laminar pore size, we would be more comfortable ascribing the expansion of rim tissue to a change in laminar architecture with the possible addition of axonal swelling due to relative (but not necessarily pathphysiologic) block of axoplasmic flow. In this case, a primary change in the relationship between IOP, CSF and translaminar tissue pressure would be expected. In the setting of a stable lamina (position and thickness), we would need to invoke processes within RGC axons and/or astrocytes to explain the observed increase in prelaminar rim tissue. It is hoped that future adaptations of technologies such as optical coherence tomography (OCT) will enable imaging of deeper structures within the optic nerve head. Eventually these or other modalities may allow the assessment of not just architecture, but cellular function within the lamina cribrosa.

A few words of caution are warranted. We have seen rim expansion, without frank optic disc edema, be the presenting sign of psuedotumor cerebri in two patients with large central cups. One had frank glaucoma with clearly damaged rim tissue and visual field loss. The other (similar to this patient) had an enlarged central cups, but full rims and normal visual fields. Both had a suspicious body habitus, but only one had frank symptoms. Both had elevated CSF pressures upon CSF tap. Visual field testing, if not yet performed, is strongly recommended. Serial disc examinations, initially at frequent intervals to detect acute changes, are warranted.

Brad Fortune and Claude Burgoyne, Devers Eye Institute, Portland, OR, USA

Reference
1. Downs JC, Yang H, Girkin C, Sakata L, Bellezza A, Thompson H, and Burgoyne CF. Three Dimensional Histomorphometry of the Normal and Early Glaucomatous Monkey Optic Nerve Head: Neural Canal and Subarachnoid Space Architecture. Invest Ophthalmol Vis Sci. 2007; in press.

POLL RESULTS FROM VOLUME 2, ISSUE 2

CLICK HERE TO VOTE IN THIS ISSUE'S READER SURVEY! Survey results will be presented and discussed in the next issue! Identity of voters remains anonymous.

Our recent poll results are available and are included for your review. Thank you to all who participated.

When asked what method was their primary way of determining visual field progression, 30% of respondents reported comparing a visual field to its preceding field. Thirty-two percent make use of available statistical analyses. Twenty-five percent compare follow up visual fields to an established baseline to determine if the field has worsened.

Judging progression of visual fields is a particularly challenging aspect of patient care. The lack of consensus as to what constitutes progression is further evidence of this. The variability of subjective responses, true for any psychophysical test, as well as the reproducibility of the test itself, contribute to this intertest variability or long-term fluctuation. The degree of this variability will be different for different patients and at different stages of disease or vision loss. Comparison to a single visual field limits the clinician’s ability to reliably identify change. Roughly 1/3 of respondents use a statistical analysis to identify change. These require attention to select an appropriate baseline and identification of meaningful change on follow-up. It is safe to say that visual field progression would wisely be confirmed on repeat testing and interpreted within the clinical context.

More than half (51%) of respondents expect to increase their use of visual fields, whereas roughly 1/3 expect this to stay about the same. Eleven percent thought visual fields would be replaced to some degree by imaging technology. These technologies could reasonably make us less likely to repeat unreliable visual field tests - especially if more objective methods become available for clinical use. We may have the opportunity to decrease the frequency of field testing as we use other modalities to monitor our glaucoma patients, provided the relationship between the tests and visual function is known. This current and emerging technology may supplement the information derived from visual field testing and potentially lessen our dependence on visual field interpretation in the future. Stay tuned.

John McSoley, OD

NEWS ITEMS

Optometry and Vision Science will be having a feature issue on glaucoma, with guest editors Brad Fortune, William Hare, Allison McKendrick and Bob Weinreb. The deadline for submission is October 1st, 2007. All papers will be peer-reviewed and may be submitted at http://ovs.edmgr.com. Click Here to view the OVS call for papers.

Click Here to go to the AIGS Website to Register.

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Editor in Chief Paul Spry PhD MCOptom Associate Editors Brad Fortune, OD, PhD Shaban Demirel, BScOptom, PhD Algis Vingrys BScOptom, PhD

Editorial Board Douglas Anderson MD Paul Artes PhD MCOptom Dick Bennett OD Murray Fingeret, OD Ron Harwerth, PhD Chris Johnson, PhD Tony Litwak, OD John McSoley, OD Ron Melton, OD Bruce Onofrey, OD, RPh Leo Semes, OD Randall Thomas, OD Thom Zimmerman, MD, PhD   Art/Production Director Joe Morris Project Coordinator Janice Miller

 

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