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Clinical characteristics of newly diagnosed primary, pigmentary and pseudoexfoliative open-angle glaucoma in the Collaborative Initial Glaucoma Treatment Study
  1. David C Musch1,2,
  2. Takayuki Shimizu2,3,
  3. Leslie M Niziol1,
  4. Brenda W Gillespie4,
  5. L Frank Cashwell5,
  6. Paul R Lichter1
  1. 1Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA
  2. 2Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
  3. 3National Center for Global Health and Medicine, Tokyo, Japan
  4. 4Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
  5. 5Wake Forest University Eye Center, Winston-Salem, North Carolina, USA
  1. Correspondence to Dr David C Musch, University of Michigan, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA; dmusch{at}umich.edu

Abstract

Background/aims Three types of open-angle glaucoma (OAG)—primary, pigmentary and pseudoexfoliative—are frequently encountered. The aim of this study was to compare demographic, ocular and systemic medical information collected on people with these three OAG types at diagnosis, and determine if the OAG type affected the prognosis.

Methods Information on 607 participants of the Collaborative Initial Glaucoma Treatment Study was accessed. Descriptive statistics characterised their demographic, ocular and medical status at diagnosis. Comparisons were made using analysis of variance and χ2 or Fisher's exact tests. Multinomial, mixed and logistic regression analyses were also performed.

Results Relative to people with primary OAG, those with pigmentary OAG were younger, more likely to be white, less likely to have a family history of glaucoma, and were more myopic. Those with pseudoexfoliative OAG were older, more likely to be white, more likely to be women, less likely to have bilateral disease, and presented with higher intraocular pressure (IOP) and better visual acuity. The type of glaucoma was not associated with IOP or visual field progression during follow-up.

Conclusion Characteristics of newly diagnosed enrollees differed by the type of OAG. While some of these differences relate to the pathogenesis of OAG type, other differences are noteworthy for further evaluation within population-based samples of subjects with newly diagnosed OAG.

  • Angle
  • clinical trial
  • epidemiology
  • genetics
  • glaucoma
  • intraocular pressure

https://doi.org/10.1136/bjophthalmol-2012-301820

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    Introduction

    In 2004, open-angle glaucoma (OAG) was estimated to affect 2.22 million people in the USA, and the authors estimated that by 2020, there will be more than three million people with OAG in the USA.1 While primary open-angle glaucoma (POAG) is the most common type of OAG encountered in the USA,2 a number of other OAG types exist, including pigmentary open-angle glaucoma (PIGM) and pseudoexfoliative OAG.

    POAG is defined as a group of ocular diseases that cause characteristic, progressive changes in the optic nerve head, visual field loss, or both.2 These changes may be associated with elevated intraocular pressure (IOP), but can often occur with IOPs below the population mean. The term ‘primary’ indicates that there is no overt cause such as trauma, inflammation, excessive anterior chamber pigment dispersion, or pseudoexfoliation of the lens capsule underlying this glaucoma. Risk factors commonly associated with POAG include elevated IOP, older age, African descent and a family history of POAG.3–7

    PIGM characteristically develops in young myopic patients with pigment dispersion syndrome, which is characterised by melanin pigment liberation from the iris pigment epithelium. Sugar8 noted a predominance of male patients and patients with myopia among 137 cases of PIGM he reviewed, a finding that Lichter and Shaffer9 also noted in 102 patients with PIGM they reviewed. They also reported an association of younger age at diagnosis with higher degrees of myopia.

    Pseudoexfoliation syndrome (PXS) has been termed the most common ‘identifiable’ cause of OAG.10 PXS results in the deposition and accumulation of exfoliative material on the lens, iris and other intraocular surfaces. While not all people with PXS develop glaucoma, those who develop pseudoexfoliative glaucoma (PEXG) tend to have a higher IOP at diagnosis than those with POAG, so that achieving success in treating PEXG can be more difficult than in treating POAG.11

    In this study, we used the data collected during the Collaborative Initial Glaucoma Treatment Study (CIGTS)12 to compare the three types of OAG (primary, pigmentary and pseudoexfoliative) that were included in the enrolment criteria for the CIGTS. Our aim is to describe differences in subjects who presented with these three types of OAG, using information obtained on patients when they were newly diagnosed with OAG, and to determine if these different OAG types responded differently to treatment.

    Materials and methods

    CIGTS investigators at 14 clinical centres in the USA enrolled 607 OAG patients between October 1993 and April 1997. Eligibility criteria included being newly diagnosed with one of three types of OAG in one or both eyes: POAG, PIGM, or PEXG, an age between 25 and 75 years, and lack of previous treatment for glaucoma. Details on these criteria have been described.12 The objective of CIGTS was to determine whether patients with newly diagnosed OAG demonstrated better control of their glaucoma by initial treatment with topical medication(s) or by immediate filtration surgery. In the present study, we analysed the baseline data that CIGTS investigators gathered at the study participants' baseline visits at the clinical centres. A study eye was designated at baseline as the first eye to be treated for glaucoma, and only data from this eye were analysed.

    Statistical methods

    Descriptive statistics were used to characterise the demographic and clinical characteristics of the CIGTS participants at enrolment. We compared the distribution of variables within the three types of glaucoma using analysis of variance for continuous variables and χ2 or Fisher's exact tests for categorical variables. Pairwise comparisons were made with adjustment for multiple comparisons by the Tukey test. Following bivariate analyses, a multinomial logistic regression model was developed to characterise the extent to which variables were associated with specific types of OAG. Backward selection was used to identify variables of significance after adjustment for all other variables that had significant associations.

    Mixed linear regression was used to evaluate associations of perimetric mean deviation (MD, from Humphrey 24-2 full threshold tests) and IOP (from Goldmann applanation tonometry) during follow-up with OAG type. Glaucoma diagnosis was added to previously published models of baseline risk factors for MD13 and IOP14 to test whether diagnosis added predictive strength. For the MD model, variables included were: treatment (surgery vs medicine), race (white and other vs black), age, diabetes, baseline MD, cataract surgery within the previous year, time from randomisation, the range of six baseline IOP measures, as well as five interaction terms. For the IOP model, variables included were treatment (surgery vs medicine), smoking status (current smoker vs other), interaction between treatment and smoking, baseline IOP, baseline MD, education, hypertension, time since randomisation (time and time squared) and centre. A heterogeneous toeplitz structure was used to model the correlation among repeated measures (MD or IOP) of a subject. The model for IOP also used a random subject intercept and slope. Statistical analyses were performed using SAS V.9.2 software.

    Results

    The descriptive characteristics of subjects with the three types of OAG are shown in table 1. Out of 607 participants, 550 (90.6%) were newly diagnosed with POAG, 28 (4.6%) with PIGM and 29 (4.8%) with PEXG. The mean ages of the subjects in these three groups differed significantly (p<0.0001). POAG subjects (58.0 years) were nine years older on average than those with PIGM (48.9 years) and seven years younger on average than those with PEXG (65.1 years). The distribution of men and women among the three types of glaucoma did not differ significantly (p=0.335); 41.5% (228) of POAG subjects indicated their race was black, whereas only 7.1% of PIGM subjects and 3.5% of PEXG subjects reported that their race was black (p<0.0001). Educational achievement varied somewhat between the groups (p=0.055), with the POAG subjects having the highest percentage (22.6%) with less than a high school education relative to PIGM subjects (3.6%) and PEXG subjects (10.3%). Follow-up time did not significantly differ for the POAG (7.2 years), PIGM (7.2 years) and PEXG (7.7 years) subjects (p=0.447).

    View this table:
    Table 1

    Descriptive characteristics of subjects with the three types of OAG

    Those with newly diagnosed POAG tended to have more non-ocular comorbidities than the other two OAG subtypes. Diabetes was found significantly more frequently (p=0.014) among subjects with POAG (18.2%) versus subjects with PIGM (3.6%) or PEXG (3.5%); 38.6% (212) of POAG subjects had systemic hypertension, whereas 21.4% of PIGM subjects and 24.1% of PEXG subjects had hypertension (p=0.063). The percentages of subjects with other vascular or cardiac diseases did not differ significantly among the three groups (p=0.376). In terms of a family history of glaucoma, 7.7% of PIGM subjects had a history of glaucoma within the immediate family, whereas 38.8% of POAG and 27.3% of PEXG subjects reported this (p=0.002). The distribution of history of glaucoma in the distant family among subjects with the three types of glaucoma did not differ significantly (p=0.268), nor did smoking status (p=0.222).

    Ophthalmic examination findings showed some significant differences among the three OAG subtypes. The mean IOP at baseline of POAG, PIGM and PEXG participants' study eyes were 27.3, 28.1, and 31.9 mm Hg, respectively (p<0.0001). Post-hoc pairwise comparisons showed a significantly higher mean IOP in those with PEXG relative to either of the other OAG diagnoses, but no difference between POAG and PIGM. Those diagnosed with PIGM were significantly (p<0.0001) more myopic on average (spherical equivalent mean value of −3.81 dioptres (D)) than the other two groups, whose mean values were −0.87 D (POAG) and −0.15 D (PEXG). The mean visual acuities at baseline, results from Humphrey 24-2 visual field testing, vertical cup to disc ratio and the presence of disc haemorrhage among the three types of glaucoma were not significantly different. In terms of bilaterality, those with PEXG were more likely to present at diagnosis with only one eye involved (p<0.0001).

    The multinomial logistic regression model results (figure 1) identified four factors that were significantly associated with a diagnosis of PIGM versus a diagnosis of POAG: age, race, history of glaucoma in the immediate family and spherical equivalent. Relative to POAG, those with PIGM were younger (OR 0.44 for a 10-year increment in age), more likely to be white (OR 13.70), less likely to have an immediate family history of glaucoma (OR 0.12), and more likely to have a more negative (myopic) spherical equivalent value (OR 0.77 for a 1 D increment).

    Figure 1
    Figure 1

    Odds ratios for associations of variables that differ between subtypes of open-angle glaucoma (relative to POAG). OR estimates with upper CI greater than 15 were truncated. PEXG, pseudoexfoliative open-angle glaucoma; PIGM, pigmentary open-angle glaucoma; POAG, primary open-angle glaucoma.

    Six factors were significantly associated with having a diagnosis of PEXG relative to POAG: age, sex, race, visual acuity, IOP and bilaterality. Relative to POAG, CIGTS enrollees with newly diagnosed PEXG were significantly older (OR 3.61 for a 10-year increment), more likely to be women (OR 7.57) and more likely to be white (OR 8.01). PEXG subjects had higher IOP than POAG subjects (OR 2.69 for a 5 mm Hg increment), and their visual acuity at baseline was somewhat better (OR 2.16 for a five-letter increment). PEXG subjects were less likely to have bilateral disease relative to those with POAG (OR 0.20).

    In two binary logistic regression models (PIGM vs POAG and PEXG vs POAG) in which non-significant effects were stepped out, multivariable results showed similar effects to those of the multinomial logistic regression results. Univariable results were also similar for all but the gender effect. This effect was weakened due to its collinearity with baseline IOP (r=−0.19)—men had significantly higher baseline IOP than women. See supplementary table 1 (available online only) for a comparison of effects between the multinomial logistic regression, multivariable binary logistic regression and univariable binary logistic regression results.

    The relationship of glaucoma diagnosis with two treatment outcomes (MD and IOP) was evaluated over 7 years of follow-up. Boxplots of these two outcomes over time by diagnosis are shown in figures 2 and 3. The association of glaucoma diagnosis with these outcomes was investigated using repeated measures linear regression. Glaucoma diagnosis was added to previously published models of baseline risk factors13 ,14 to determine if diagnosis added predictive strength. Glaucoma diagnosis was not associated with MD over time (p=0.627). There were no significant interactions between diagnosis and either treatment or time. Glaucoma diagnosis was also not associated with IOP measures during follow-up (p=0.310), with no significant interactions between diagnosis and treatment or time. As baseline IOP was significantly higher in those with PEXG than in POAG or PIGM, we evaluated and found a significant interaction (p=0.030) between baseline IOP and glaucoma diagnosis on follow-up IOP. The interaction resulted from differing trends in IOP reduction over time relative to baseline IOP in patients with PEXG, in whom the higher the baseline IOP, the lower the follow-up IOP, whereas in patients with POAG and PIGM, baseline IOP and follow-up IOP were directly related.

    Figure 2
    Figure 2

    Relationship of open-angle glaucoma diagnosis with mean deviation during follow-up after treatment initiation. PEXG, pseudoexfoliative open-angle glaucoma; PIGM, pigmentary open-angle glaucoma; POAG, primary open-angle glaucoma.

    Figure 3
    Figure 3

    Relationship of open-angle glaucoma diagnosis with IOP during follow-up after treatment initiation. IOP, intraocular pressure; PEXG, pseudoexfoliative open-angle glaucoma; PIGM, pigmentary open-angle glaucoma; POAG, primary open-angle glaucoma.

    Discussion

    Of the three types of OAG eligible for enrolment in the CIGTS, POAG is the most frequent and thereby has an extensive literature on characteristics found in people with this condition. Among numerous reviews of OAG epidemiology, the review of Tielsch15 focuses on POAG and identifies demographic factors (older age and black race), ocular factors (elevated IOP and myopia), and a positive family history as consistently associated with POAG, whereas gender and systemic comorbidities (diabetes and hypertension) were less consistently reported associations with POAG across studies. Within the CIGTS enrollees, who do not constitute a representative population of newly diagnosed subjects, we identified four unique characteristics of our POAG enrollees relative to those with the other two types of OAG. Enrollees diagnosed with POAG were more likely to report their race as black, presented more frequently with two systemic comorbidities (diabetes and hypertension), and were more likely to report a history of glaucoma in their immediate family.

    PIGM has been reported primarily to affect young myopic male patients, and is usually bilateral. The average age of the onset of PIGM is between the third or fourth decades.8 These associations are also found in the results we report, as the mean age of the onset of PIGM was 48.9 years, 64% were men, and the mean spherical equivalent at baseline was −3.8 D. While a study eye was identified at baseline for comprehensive follow-up in the CIGTS, the fellow eye of those with PIGM in the study eye shared this diagnosis in 75% (21/28) of enrollees. PIGM is said to be prevalent in white individuals, with a lower prevalence in black, Latino and Asian individuals.8 While our finding of PIGM in two black and 26 white individuals is of interest, enrolment of study participants at clinical trial centres does not yield prevalence estimates, and so population-based findings are best used to evaluate this.

    The proportion of OAG accounted for by PEXG varies considerably across the world, and is affected by the prevalence of exfoliation syndrome in the particular area. In the USA, most estimates range from 2% to 12% for the proportion of OAG accounted for by PEXG,16–18 whereas in the eastern region of the Arabian peninsula, 77% of all OAG was reported to be associated with exfoliation syndrome.19 A recent evaluation of two large cohorts of health professionals in the USA identified increasing latitude as a risk factor for PEXG (as well as exfoliation syndrome).20 Very few PEXG cases have been reported among black individuals.10 Only one CIGTS enrollee was black among the 29 CIGTS participants who had PEXG. Teus and colleagues11 reported that IOP at diagnosis is usually higher in patients with PEXG than POAG, which we also found. PEXG study participants had a mean IOP at baseline (31.9 mm Hg) that was higher than those with POAG (27.3 mm Hg) or PIGM (28.1 mm Hg). Our finding that those newly diagnosed with PEXG were significantly older than either of the other OAG groups fits well with the strong association reported between older age and the risk of exfoliation glaucoma by Kang et al.20 In contrast to the people with POAG and PIGM included in the CIGTS, less than 50% of those with PEXG presented with bilateral disease.

    Budde and Jonas21 evaluated the frequency of a positive family history (in a first or second degree relative) among subjects with POAG, PIGM and PEXG. They found that the frequency of a positive family history of glaucoma among subjects with PIGM and PEXG was not different compared with that among subjects with POAG when adjusted for age. Our unadjusted and adjusted findings indicate that POAG has a much stronger association with a history of glaucoma in the immediate (first degree) family relative to those with PIGM, but not relative to those with PEXG.

    One of the strengths of this study is that the CIGTS included carefully standardised examinations by glaucoma subspecialists at 14 centres around the USA. Even so, some caveats should be noted in considering these findings. The diagnostic criteria used to identify those with POAG, PIGM and PEXG were left to the discretion of the examining ophthalmologist, which may have led to some variation in diagnoses of glaucoma subtypes. CIGTS was not designed to enrol a representative sample of newly diagnosed OAG, and so our 607 enrollees may be quite different from such a sample. Finally, given the relatively few enrollees identified with PIGM and PEXG, small sample sizes limit our ability to be definitive about factors that were associated with these two conditions.

    Conclusions

    Characteristics of newly diagnosed enrollees into a clinical trial of OAG treatment differed by the type of OAG. While some of these differences relate to the underlying pathogenesis of the specific type of OAG, such as higher IOP among those with PEXG, the associations we found with the type of OAG should be evaluated within population-based samples of subjects with newly diagnosed OAG.

    References

    1. ↵
      1. Friedman DS,
      2. Wolfs RC,
      3. O'Colmain BJ,
      4. et al
      ; Eye Diseases Prevalence Research Group. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 2004;122:532–8.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Weinreb RN,
      2. Khaw PT
      . Primary open-angle glaucoma. Lancet 2004;363:1711–20.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Tielsch JM,
      2. Sommer A,
      3. Katz J,
      4. et al
      . Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Study. JAMA 1991;266:369–74.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Tielsch JM,
      2. Katz J,
      3. Sommer A,
      4. et al
      . Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey. Arch Ophthalmol 1994;112:69–73.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Quigley HA,
      2. Enger C,
      3. Katz J,
      4. et al
      . Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol 1994;112:644–9.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Leske MC,
      2. Connell AMS,
      3. Wu S-Y,
      4. et al
      . Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 1995;113:918–24.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Le A,
      2. Mukesh BN,
      3. McCarty CA,
      4. et al
      . Risk factors associated with the incidence of open-angle glaucoma: the visual impairment project. Invest Ophthalmol Vis Sci 2003;44:3783–9.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Sugar HS
      . Pigmentary glaucoma. A 25-year review. Am J Ophthalmol 1966;62:499–507.
      OpenUrlPubMedWeb of Science
    9. ↵
      1. Lichter PR,
      2. Shaffer RN
      . Diagnosis and prognostic signs in pigmentary glaucoma. Trans Am Acad Ophthalmol Otolaryngol 1970;74:984–98.
      OpenUrlPubMed
    10. ↵
      1. Schlötzer-Schrehardt U,
      2. Naumann GO
      . Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol 2006;141:921–37.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Teus MA,
      2. Castejón MA,
      3. Calvo MA,
      4. et al
      . Intraocular pressure as a risk factor for visual field loss in pseudoexfoliative and in primary open-angle glaucoma. Ophthalmology 1998;105:2225–9; discussion: 2229–30.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Musch DC,
      2. Lichter PR,
      3. Guire KE,
      4. et al
      . The Collaborative Initial Glaucoma Treatment Study: study design, methods, and baseline characteristics of enrolled patients. Ophthalmology 1999;106:653–62.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Musch DC,
      2. Gillespie BW,
      3. Lichter PR,
      4. et al
      . Visual field progression in the Collaborative Initial Glaucoma Treatment Study. The impact of treatment and other baseline factors. Ophthalmology 2009;116:200–7.
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Musch DC,
      2. Gillespie BW,
      3. Niziol LM,
      4. et al
      . Factors associated with intraocular pressure before and during 9 years of treatment in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology 2008;115:927–33.
      OpenUrlCrossRefPubMed
    15. ↵
      1. Tielsch JM
      . The epidemiology and control of open angle glaucoma: a population-based perspective. Annu Rev Public Health 1996;17:121–36.
      OpenUrlPubMedWeb of Science
    16. ↵
      1. Layden WE,
      2. Shaffer RN
      . The exfoliation syndrome. Am J Ophthalmol 1974;78:835–41.
      OpenUrlPubMedWeb of Science
    17. ↵
      1. Roth M,
      2. Epstein DL
      . Exfoliation syndrome. Am J Ophthalmol 1980;89:477–81.
      OpenUrlPubMedWeb of Science
    18. ↵
      1. Cashwell LF Jr,
      2. Shields MB
      . Exfoliation syndrome in the southeastern United States. I. Prevalence in open-angle glaucoma and non-glaucoma populations. Acta Ophthalmol Suppl 1988;184:99–102.
      OpenUrlPubMed
    19. ↵
      1. Bialasiewicz AA,
      2. Wali U,
      3. Shenoy R,
      4. et al
      . [Patients with secondary open-angle glaucoma in pseudoexfoliation (PEX) syndrome among a population with high prevalence of PEX. Clinical findings and morphological and surgical characteristics] (In German). Ophthalmologe 2005;102:1064–8.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Kang JH,
      2. Loomis S,
      3. Wiggs JL,
      4. et al
      . Demographic and geographic features of exfoliation glaucoma in 2 United States-based prospective cohorts. Ophthalmology 2012;119:27–35.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Budde WM,
      2. Jonas JB
      . Family history of glaucoma in the primary and secondary open-angle glaucomas. Graefes Arch Clin Exp Ophthalmol 1999;237:554–7.
      OpenUrlCrossRefPubMedWeb of Science

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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    Footnotes

    • An additional table is published online only. To view this file please visit the journal online (http://dx.doi.org/10.1136/bjophthalmol-2012-301820)

    • This research was presented in part at the annual meeting of ARVO, Ft. Lauderdale, FL, May 2010.

    • Funding This research was supported by NIH/NEI grant EY020912 and a departmental grant from Research to Prevent Blindness (RPB), New York, NY, USA. DCM is a recipient of the RPB Lew R. Wasserman Merit Award.

    • Competing interests None.

    • Ethics approval Ethics approval was provided by UM Medical School Institutional Review Board (IRBMED), HUM00037985.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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