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Keywords:

  • cataract;
  • exfoliation;
  • glaucoma;
  • pseudoexfoliation;
  • ultrasound biomicroscopy;
  • zonule

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Purpose:  To assess zonular appearance using biomicroscopy (UBM) in exfoliation syndrome (XFS).

Methods:  Normal eyes and eyes with XFS were enrolled in this prospective, consecutive, comparative cohort study. Following pupillary dilation, XFS patients were classified into three clinical stages (early, moderate or severe) by a single examiner (R.R.). Cross-sectional zonular UBM images were obtained circumferentially at eight evenly spaced locations. Five experienced observers evaluated the images using a standardized scoring system based on the zonular appearance (0, none; 1, early; 2, moderate; 3, severe). The extent of zonular involvement on UBM based on UBM score of all observers was correlated with the clinical stage of XFS using a five-stage classification.

Results:  We enrolled 44 eyes (44 patients), 11 normal and 33 with XFS (10 early, 10 moderate and 13 severe) [mean age 69.4 ± 9.9 (SD) years; range 50–87 years]. UBM scores of all observers were significantly different between the normal/early and moderate/severe groups (P < 0.001, t-test). With discriminant analysis, the predicted XFS stage showed good agreement with the clinical staging [all κ > 0.61, area under receiver operating characteristic (ROC) curve > 0.86].

Conclusion:  UBM can detect zonular involvement in XFS and may be useful in preoperative planning. This may be important in eyes with posterior synechiae in which a diagnosis and the severity of XFS cannot be determined on slit-lamp examination.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Exfoliation syndrome (XFS) is an age-related disease characterized by the production and progressive accumulation of an abnormal, fibrillar extracellular material in virtually all of the tissues of the anterior segment and in many extraocular tissues, including skin and connective tissue portions of various visceral organs (Schlötzer-Schrehardt et al. 1992; Streeten et al. 1992; Ritch & Schlötzer-Schrehardt 2001). Deposits of white material on the anterior lens surface are the most consistent and important diagnostic feature of XFS.

Damage to the zonular apparatus is an integral part of XFS, and, combined with poor pupillary dilation, leads to increased intraoperative complications, such as zonular dialysis, capsular rupture, vitreous loss and retained lens fragments. Patients with XFS have been reported to have 5–10 times the rate of complications at the time of extracapsular cataract extraction than patients without XFS (Skuta et al. 1987; Høvding 1988; Goder & Rechlin 1988; Naumann et al. 1989; Zetterström et al. 1992), although this rate may be lower during phacoemulsification. (Katsimpris et al. 2004; Nagashima 2004). Recognition of patients with XFS and determination of the extent of zonular involvement could allow measures to be taken to avoid or minimize potential intraoperative complications.

We hypothesized that ultrasound biomicroscopy (UBM) might be useful in evaluating the status of the zonules in eyes with XFS. Zonular abnormalities in XFS can be detected by UBM (Gohdo et al. 1997; Naumann et al. 1998; Pavlin et al. 1998). The aims of our study were to assess zonular appearance by UBM in patients with XFS and to correlate the UBM images with the clinical aspects, determined by slit-lamp biomicroscopy, in order to define an ultrasonographic classification.

Materials and Methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Consecutive, phakic, previously unoperated patients with a clinical diagnosis of XFS and subjects with normal eye examinations performed between August and November 2001 who agreed to participate in this study were enrolled. Monocular patients or eyes with a history of trauma, diabetes or vascular or inflammatory disease were excluded. If both eyes of the patient were eligible, the eye with the smaller pupillary diameter was enrolled. If both eyes had the same pupillary diameter, the eye with the more dense cataract was selected. Written informed consent was obtained from all subjects using a consent form approved by the Institutional Review Board of The New York Eye and Ear Infirmary and following the tenets of the Declaration of Helsinki.

All patients underwent a complete ophthalmic examination. The diagnosis of XFS was made on the basis of visible exfoliation material on the anterior lens surface on slit-lamp biomicroscopy by a single examiner (R.R.) following pupillary dilation. Based on variations of the classic pattern of three distinct zones (homogeneous central disc, intermediate clear zone and peripheral granular zone), we devised a clinical classification consisting of three stages:

  • (a)
    mild: incomplete intermediate clear zone on the lens;
  • (b)
    moderate: complete intermediate clear zone on the lens;
  • (c)
    severe: complete intermediate clear zone plus exfoliation material (XFM) on the pupillary border.

After clinical examination, one of the authors (H.T.) performed UBM examination (Model P-40; Paradigm Medical Industries, Inc., Salt Lake City, Utah, USA) on the selected eye of each patient. Scanning was performed in the supine position under standardized room illumination using topical anaesthesia. A 17-mm-diameter eye cup was placed gently on the globe and filled with saline solution as a coupling medium. Fixation and accommodation were held constant by having the patient fixate with the fellow eye on a ceiling target.

Visualization of zonules by UBM was obtained with a 50 MHz transducer, providing lateral and axial physical resolution of approximately 50 µm and 25 µm, respectively, and a frame rate of 8 Hz. Tissue penetration is approximately 4–5 mm. Ultrasonographic images were visualized in real time, captured and saved digitally on diskette. With the oscillations of the transducer head oriented radially toward the limbus, images were obtained from lens, zonular bundles and angle region at 12:00, 1:30, 3:00, 4:30, 6:00, 7:30, 9:00 and 10:30. To obtain clear images of zonules, we used a technique placing the focal zone of the transducer at the anterior zonular region, orienting the scanning plane perpendicular to the zonular path, and moving the probe slightly to optimize sound reflection from this structure (Pavlin et al. 1998). Images of each sector were then evaluated by five experienced UBM observers masked to the clinical status of the patients. For the analysis, we devised a scoring system based on the zonular appearance (Fig. 1):

image

Figure 1.  XFM grading. (A) Clear, well-defined zonule(s) without any patchy deposit. (B) Uneven and/or disrupted zonule(s) without any patchy deposit (arrow). (C) Uneven and/or disrupted zonule(s) with any patchy deposit (arrow). (D) Diffuse granulation of zonule(s) and/or abnormal thick zonules (white arrow) and/or net- or web-like structure between zonules. (E) Extensive loss of zonules (S, sclera; CB, ciliary body; L, lens).

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  • 0
    clear, well-defined zonule(s) without patchy XFS deposits;
  • 1
    uneven and/or disrupted zonule(s) without patchy deposits;
  • 2
    uneven and/or disrupted zonule(s) with patchy deposits;
  • 3
    diffuse granulation of zonules(s) and/or abnormal thick zonule(s) and/or net- or web-like structure between zonules;
  • 4
    extensive loss of zonules.

For the purposes of analysis, patients were divided into two groups: normal/early XFS (grades 0, 1, 2; 20 patients) and moderate/severe XFS (grades 3, 4; 21 patients).

A mean score for all sectors was calculated for each patient. Statistical analysis was performed using JMP version 4 for Windows (SAS Institute Inc., Cary, North Carolina, USA). The relationship between the extent of zonular involvement as determined by UBM and the clinical stage of XFS as seen at the slit-lamp was evaluated by Student's t-test. Discriminant analysis was performed and reported with area under the receiver operating characteristic (ROC) curve to assess the relationship between clinical staging and UBM appearance. The agreements between the clinical staging and the predicted staging based on UBM assessment were reported with κ value, which measures the degree of agreement on a scale from zero (no agreement) to one (full agreement). Mean UBM scores of XFS patients with narrow angles were compared to those with wide open angles.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We enrolled 44 eyes of 11 normal and 33 XFS patients (10 early, 10 moderate and 13 severe XFS). There were 25 women and 19 men. The mean age was 69.4 ± 9.9 (SD) years (range 50–87). The mean refractive error was −0.2 ± 1.86 dioptres. There were no statistically significant differences in mean refractive error, age, race and gender between groups (P > 0.05) (Table 1).

Table 1.   Demographic information.
 Normal/ early XFSModerate/ advanced XFS P
  • XFS, exfoliation syndrome; RE, refractive error.

  • *

    Student t-test.

  • Chi-Square.

Gender:
 Male/female6/1410/110.24*
Race:
 White16200.12
 Black10 
 Hispanic20 
 Asian10 
 Indian01 
Age (years):
 Mean (± SD)66.8 (± 10.7)72.5 (± 7.9)0.07*
 Range50–8554–87 
RE (dioptres):
 Mean (± SD)+ 0.38 (± 1.80) −  0.71 (± 1.76)0.08*
 Range −3.50 to +3.50 −4.50 to +2.00 

The mean of the five UBM scores was significantly higher in the moderate/severe group [19.0 ± 7.7 (SD) (range 4.0–31.6)] than in the normal/early group [8.5 ± 3.0 (SD) (range 3.8–18.6)] (P < 0.0001). The UBM scores were not significantly different between normal eyes (7.9 ± 2.1) and eyes with early XFS (10.0 ± 3.8), nor between eyes with moderate (15.6 ± 6.9) and severe (21.0 ± 8.0) involvement.

With discriminant analysis, the predicted XFS stage by UBM showed good agreement with the clinical staging by slit-lamp for each of the five examiners, with all κ values > 0.61 and all areas under ROC curves > 0.86 (Table 2, Fig. 2). The nine patients with XFS and narrow angles had higher UBM scores (15.3 ± 9.58) than the patients with wide open angles (13.2 ± 7.0) (P < 0.05).

Table 2.   Determination of clinical stage by ultrasound biomicroscopy assessment and agreement between two methods with discriminant analysis.
 Examiner 1Examiner 2Examiner 3Examiner 4Examiner 5
  1. ROC, receiver operating characteristic.

Area under ROC0.860.900.860.870.89
κ value0.610.710.610.610.70
image

Figure 2.  Determination of clinical stage by ultrasound biomicroscopy assessment: receiver operating characteristic curves of five examiners.

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Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The zonular apparatus is involved extensively in XFS. Whether the zonules are just coated with XFM or actually replaced by it, they are often frayed and broken (Dark et al. 1977; Takei & Mizuno 1978; Mizuno & Muroi 1979; Chijiiwa et al. 1989; Futa & Furuyoshi 1989; Ritch & Schlötzer-Schrehardt 2001). At the ciliary body, zonular tendons are infiltrated with XFM, while the lenticular attachments are elevated from the lens surface by XFM produced locally at the pre-equatorial lens epithelium (Schlötzer-Schrehardt & Naumann 1994).

Zonular fragility and inadequate pupillary dilation have been suggested as the most important risk factors for capsular rupture and vitreous loss. Exfoliation syndrome may involve the zonules prior to the development of the peripheral granular zone and may appear as subtle striations of exfoliation material and/or pigment on the surface of the lens (Bartholomew 1973). Cycloscopy in patients with clinically unilateral involvement revealed exfoliation material on the ciliary processes in all affected eyes and on the zonule or ciliary processes or both in 77% of fellow eyes in which it was not clinically visible on the lens surface or pupillary border (Mizuno & Muroi 1979).

Detection of XFS and the extent of zonular disruption prior to cataract extraction would allow the surgeon to anticipate potential difficulties and to take appropriate precautions. A transmission electron microscopic study revealed XFS in 64% of eyes with circular posterior synechiae receiving antiglaucoma therapy (Mardin et al. 2001). Zonular involvement can be detected by ultrasound biomicroscopy. Gohdo et al. (1997) showed a single image of thick, well-defined zonules coated with XFM. Pavlin et al. (1998) observed prominent zonular remnants attached to a lens capsule. Naumann et al. (1998) demonstrated XFM deposits on the anterior zonular insertion to the lens surface hidden behind dense posterior synechiae.

The direct approach by UBM can confirm clinical impressions of zonular fragility based on indirect signs such as phacodonesis or reveal alterations not seen at slit-lamp examination. Only two of our patients had phacodonesis during clinical examination; one was classified as moderate XFS and the other as severe XFS. They were among the three highest UBM scores obtained from a mean of five examiners (31.6 and 23.4).

Nine of 33 XFS patients presented initially with narrow or closed angles. These eyes had a greater mean UBM score than eyes with wide open angles. In a study of consecutive patients with uncomplicated primary angle-closure glaucoma (ACG) or occludable angles, 28.3% of patients had XFS either clinically or detected on conjunctival biopsy (Ritch 1994). Anterior chamber depth decreases significantly in eyes with XFS when going from the supine to the prone position (Esaki et al. 2001). The decrease in anterior chamber depth between the supine and prone position is greater in eyes with XFS than in fellow eyes (Lanzl et al. 2000). The greater UBM score in our patients with XFS and angle closure reflects the more severe zonular involvement that facilitates forward lens movement and pupillary block.

Examination of zonules by UBM could prove of greatest value in eyes that do not dilate, precluding a definitive diagnosis of XFS in the absence of exfoliation material on the pupillary border. Future refinement of diagnostic criteria for XFS should prove of benefit in the management of the numerous sequelae of this disorder.

Acknowledgements

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported in part by an unrestricted grant from the Pharmacia Corporation, the New York Eye and Ear Infirmary Department of Ophthalmology Research Fund, (H.V.T.); and by the Joseph Cohen Research Fund of the New York Glaucoma Research Institute.

Drs Vessani and Tran contributed equally to this article.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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