Alterations in anterior chamber depth in primary open-angle glaucoma patients during latanoprost therapy
Ali Bulent Cankaya MD
215 Sokak No. 3 Daire
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Purpose: The aim of this study was to evaluate changes in the anterior chamber depth (ACD) in primary open-angle glaucoma (POAG) patients during latanoprost therapy.
Methods: We carried out a prospective study in which we enrolled 66 newly diagnosed POAG patients treated with latanoprost 0.005% (group 1) and 50 ocular hypertensive and/or glaucoma suspect cases who were given no therapy (group 2 [control]). Measurements of the ACD were performed by A-scan ultrasonography before and after cycloplegia at baseline and at 3 months of latanoprost therapy. Differences in ACD and their correlations with the ocular hypotensive effect of the agent as well as the clinical significance of changes in ACD were analysed using Student’s t-test and Pearson’s correlation coefficient. Statistical significance was set at p < 0.05.
Results: Mean baseline ACD was 3.13 ± 0.35 mm (range 2.45–3.84 mm) in group 1 and 3.14 ± 0.36 mm (range 2.54–3.80 mm) in group 2 (p = 0.89). At 1 hour after instillation of cyclopentolate 1%, mean ACD in groups 1 and 2 was 3.18 ± 0.38 mm (range 2.45–3.92 mm) and 3.19 ± 0.37 mm (range 2.56–3.91 mm), respectively (p = 0.91). After 3 months of treatment, mean ACD in group 1 both without (3.05 ± 0.36 mm, range 2.14–3.76 mm) and with (3.09 ± 0.4 mm, range 2.20–3.96 mm) cycloplegia was significantly reduced compared with baseline values (p < 0.001 for both). However, there was no significant difference between mean ACD at baseline and that at month 3 in group 2. No correlation was demonstrated between the changes in ACD and the ocular hypotensive effect of latanoprost (p = 0.96, r = − 0.006). There were no changes in refractive status or visual acuity.
Conclusions: The overall results seem to suggest that latanoprost decreases mean ACD in patients with POAG. The clinical significance of this effect is uncertain.
Prostaglandin (PG) analogues are widely used in various types of glaucoma because they are effective in reducing intraocular pressure (IOP), are associated with high rates of patient compliance and few systemic side-effects and have good additive effects with other anti-glaucoma agents (Lee et al. 2007).
This group of agents has been reported to generate some structural and functional remodelling changes in the connective tissue of the uveoscleral outflow pathways by inducing matrix metalloproteinases (MMPs) which degrade connective tissue. Activated MMPs cause reductions in extracellular matrix elements of the ciliary muscles and widen the spaces between the muscle fibres (Kashiwagi & Weinreb 1997; Ashworth et al. 1999; Sagara et al. 1999; Weinreb & Lindsey 2002). These changes lead to an increase in uveoscleral outflow and a decrease in IOP (Weinreb et al. 2002).
It is reasonable to assume that latanoprost may cause alterations in the anterior chamber depth (ACD) by various possible mechanisms. The extracellular matrix structures of the anterior segment share some characteristics of composition. For example, fibrillin-1 and type IV collagen, which are sensitive to MMP activity, are components of both the ciliary muscles and ciliary zonules (Ashworth et al. 2000; Los et al. 2004). It may be possible to observe the analogous structural and functional changes induced by MMPs in both anterior segment structures. Moreover, a previous report showed that PGF2α has the potential to induce relaxation of the monkey ciliary muscle (Poyer et al. 1995). It is also possible that increased fluid volume in the uveoscleral outflow pathways may displace the ciliary body and thus change the position of the crystalline lens.
The aim of this prospective study was to investigate the alterations in ACD during latanoprost 0.005% therapy in primary open-angle glaucoma (POAG) patients. Correlations between the extent of reduction of IOP and the degree of ACD alteration, as well as the effects of latanoprost treatment on visual acuity (VA) and refractive status, were also studied.
Materials and Methods
We initiated a cross-sectional, observer-masked, prospective study in which we enrolled 66 consecutive, newly diagnosed POAG patients who were treated with latanoprost 0.005% (Xalatan; Pfizer Inc., New York, NY, USA) from May 2007 to February 2008 (group 1). We also enrolled 50 ocular hypertensive or glaucoma suspect subjects who did not receive anti-glaucoma therapy (group 2). The study was approved by the ethics committee of the Ankara Ulucanlar Eye Research Hospital before the clinical trial commenced and patients were given clear information about the study.
All patients underwent a complete ophthalmic examination, which included autorefractometric measurement (RM 8800-Autorefractometer; Topcon Corp., Tokyo, Japan), uncorrected and best corrected Snellen VA, anterior and posterior segment examinations, gonioscopy with the Goldmann three-mirror lens, IOP measurements with the Goldmann applanation tonometer, central corneal thickness measurements by ultrasonic pachymetry, visual field examinations with Humphrey automated perimetry and confocal scanning laser ophthalmoscopy with the Heidelberg Retinal Tomograph (HRT III).
Subjects with a previous history of any ocular surgery, trauma or uveitis were excluded from the study. Eyes with high spherical (myopia > 7.0 D or hyperopia > 3.0 D) or cylindrical (> 1.0 D) refractive errors, pseudoexfoliative material in the anterior segment, any signs of zonular weakness (phacodonesis, iridodonesis), narrow anterior chamber angle (grade 0–2 according to the Shaffer grading system), peripheral anterior synechiae or excessive pigment deposition in the anterior chamber angle were also excluded. In patients with bilateral treatment, only the right eye was included for analysis.
ACD can be defined as the distance between the posterior vertex of the cornea and the anterior face of the crystalline lens at the optical axis of the eye. All ACD measurements were recorded using an 11-MHz probe for an A-mode ultrasound device (Cine Scan; Quantel Medical SA, Clermont-Ferrand, France) by the same masked, experienced observer (PT). Measurements were performed 5 mins after the instillation of one drop of proparacaine hydrochloride 0.5% (Alcaine; Alcon Laboratories UK Ltd, Hemel Hempstead, UK). After occlusion of the fellow eye, patients were asked to fixate at the level of the 2/10 line on the Snellen chart, at a distance of 4 m. Measurements were conducted in the same room with uniform luminance (dim). The examiner tried to touch the probe perpendicularly to the centre apex of the cornea without applying pressure. The ultrasound device was set to take the mean of 10 consecutive measurements automatically. Results were noted and the procedure was repeated in the same manner. The mean of the two sets of measurements (totalling 20 measurements) was accepted as ‘baseline ACD’. The same measurement protocol was employed 1 hour after the instillation of one drop of cyclopentolate 1% and the results were noted as ‘baseline cycloplegic ACD’. Crystalline lens thickness measurements were recorded at the same time.
The POAG patients were asked to instil latanoprost 0.005% once daily at 22.00 hours. In month 3 of the study protocol, patients were asked about compliance. Any patients whose compliance was doubtful were excluded. Measurements of refractive status, uncorrected VA, IOP and ACD were taken with and without cycloplegia at the end of month 3 of treatment.
Results are expressed as the mean ± standard deviation (SD). Version 13.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis, using the Student’s t-test and Pearson’s correlation coefficient. Statistical significance was accepted as p < 0.05.
Group 1 consisted of 66 eyes in 66 patients (32 men, 34 women) with a mean age of 58.0 ± 9.5 years (range 40–79 years) and group 2 consisted of 50 eyes in 50 subjects (23 men, 27 women) with a mean age of 59.8 ± 8.9 years (range 45–75 years) (p = 0.29). Mean baseline ACD was 3.13 ± 0.35 mm (range 2.45–3.84 mm) in group 1 and 3.14 ± 0.36 mm (range 2.54–3.80 mm) in group 2 (p = 0.89). Other demographic and clinical features of both groups are summarized in Table 1.
Table 1. Clinical and demographic features of the latanoprost therapy (group 1) and control (group 2) subjects.
|Age, years||58.0 ± 9.5||59.84 ± 8.9||0.29|
|Visual acuity, Snellen||0.73 ± 0.29||0.72 ± 0.24||0.7|
|IOP, mmHg||22.8 ± 4.3||20.6 ± 2.59||0.002|
|C/D||0.49 ± 0.18||0.35 ± 0.07||0.00|
|Refractive error, spherical equivalent, D||− 0.14 ± 1.68||0.17 ± 1.07||0.09|
|CCT, μm||551.12 ± 38.09||553.32 ± 23.71||0.72|
|ACD, mm||3.13 ± 0.35||3.14 ± 0.36||0.9|
|Lens thickness, mm||4.74 ± 0.4||4.69 ± 0.47||0.39|
Mean ACD after cycloplegia was significantly increased to 3.18 ± 0.38 mm (range 2.45–3.92 mm) in group 1 and 3.19 ± 0.37 mm (range 2.56–3.91 mm) in group 2 (p = 0.91, difference between groups) at baseline (p < 0.01, difference between baseline and cycloplegia for both groups). The mean increase in ACD after cycloplegia in group 1 was calculated to be 0.043 ± 0.053 mm (range − 0.06 to 0.17 mm).
At month 3 of treatment, mean ACD was 3.05 ± 0.36 mm (range 2.14–3.76 mm) without cycloplegia and 3.09 ± 0.4 mm (range 2.20–3.96 mm) with cycloplegia in group 1. Both values were significantly lower than their baseline counterparts (p < 0.001). The mean differences in ACD before and after treatment were found to be − 0.085 ± 0.16 mm (range − 0.73 to 0.21 mm) without cycloplegia and − 0.082 ± 0.17 mm (range − 0.71 to 0.31 mm) with cycloplegia (Table 2). By contrast, mean ACD in group 2 was 3.14 ± 0.36 mm (range 2.51–3.90 mm) without cycloplegia and 3.19 ± 0.38 mm (range 2.55–3.93 mm) with cycloplegia at month 3. These values were not statistically significant compared with those measured at baseline (p = 0.95 and p = 0.66, respectively).
Table 2. Anterior chamber depth (ACD) measurements at baseline and at 3 months in eyes undergoing latanoprost therapy (group 1) and control eyes (group 2).
| No cycloplegia||3.13 ± 0.35||0.00||3.14 ± 0.36||0.00|
| Cycloplegia||3.18 ± 0.38||3.19 ± 0.37|
| Difference||0.043 ± 0.053|| ||0.053 ± 0.046|| |
| No cycloplegia||3.05 ± 0.36||0.00||3.14 ± 0.36||0.00|
| Cycloplegia||3.09 ± 0.4||3.19 ± 0.38|
| Difference||0.047 ± 0.089|| ||0.054 ± 0.15|| |
|Differences between baseline and month 3 measurements|
| No cycloplegia||− 0.085 ± 0.16||0.58||0.0 ± 0.044||0.95|
| Cycloplegia||− 0.082 ± 0.17||0.0 ± 0.074|
In the treatment group (group 1), the difference between ACD measurements with or without cycloplegia (0.047 ± 0.089 mm, range − 0.17 to 0.28 mm) at month 3 was similar to that between baseline measurements (0.043 ± 0.053 mm, range − 0.06 to 0.17 mm) (p = 0.58).
In group 1, the mean crystalline lens thickness at baseline was 4.74 ± 0.4 mm (range 3.96–5.62 mm) without cycloplegia and 4.72 ± 0.33 mm (range 3.98–5.57 mm) with cycloplegia (p = 0.89). Neither value was significantly changed at 3 months of latanoprost therapy. At month 3, equivalent measurements were 4.75 ± 0.48 mm (range 3.90–5.68 mm) and 4.71 ± 0.42 mm (range 3.90–5.60 mm), respectively (p = 0.90).
Mean IOP was determined to be 22.8 ± 4.3 mmHg (range 17–32 mmHg) before latanoprost therapy and 17.6 ± 3.6 mmHg (range 15–26 mmHg) at month 3 of therapy (p < 0.001). The mean IOP reduction was 5.1 ± 3.5 mmHg (range 0–12 mmHg). No correlation was detected between the degree of IOP reduction and alterations in ACD (p = 0.96, r = − 0.006). The mean percentage of IOP reduction was calculated as 21.05 ± 13.19% (range 0–45.8%); there was no correlation with ACD measurements (p = 0.84, r = 0.025).
The mean uncorrected VA of eyes in group 1 was 0.73 ± 0.29 (range 0.05–1.0) at baseline and 0.73 ± 0.27 (range 0.1–1.0) at month 3 of latanoprost therapy (p = 0.94). The mean spherical equivalent was − 0.14 ± 1.68 D (range 3.0 to − 7.0 D) before latanoprost therapy and − 0.13 ± 1.67 D (range 2.75 to − 6.5 D) at month 3 of treatment (p = 0.86).
In this prospective, observer-masked study, latanoprost was found to have a decreasing effect on ACD in eyes both with and without cycloplegia during the 3-month study period. Although the decrease was statistically significant, no effect on the clinical status of patients and no correlation with the degree of IOP reduction were found.
Collagen type IV and fibrillin are the main structural elements of the ciliary zonules (Ashworth et al. 2000; Los et al. 2004). MMPs, are neutral proteinases which degrade extracellular matrix molecules including collagen (Nagase & Woessner 1999). It has been observed that PG increases MMP activity by enhancing the transcription of the MMP-1, 3 and 9 genes and decreases the amount of collagen and widens the interstitial space between the ciliary muscle fibres in the uveoscleral outflow pathway (Sagara et al. 1999; Weinreb & Lindsey 2002; Weinreb et al. 2004; Lee et al. 2007). The remodelling effect of MMPs on the fibrillin-rich zonular microfibres is already known (Ashworth et al. 1999).
It has been demonstrated that the PG-induced decrease in the amount of collagen can also be detected in the sclera and iris root near the ciliary body (Sagara et al. 1999). It has also been suggested that, as well as local biosynthesis, MMPs may easily diffuse in the aqueous humour and reach and affect neighbouring tissues (Huang et al. 1996). There are conflicting reports of the effects of latanoprost on the ciliary muscle. Poyer et al. (1995) reported that PGF2α has the potential to induce relaxation of carbachol precontracted ciliary muscle in rhesus monkeys. However, in another study PGF2α and latanoprost were found to have no significant effect on ciliary muscle contraction (Yamaji et al. 2005).
Gutierrez-Ortiz et al. (2006) reported that a 1-month period of latanoprost therapy might lead to a decrease in ACD; however, it had no impact on the ACD reductive effect of pilocarpine. Moreover, the authors did not notice any change in the crystalline lens thickness and concluded that latanoprost had no contractile effect on the ciliary muscle. Hence, they postulated that activated MMPs degrade and loosen the ciliary zonulae, leading to a decrease in ACD. According to Marchini et al. (2003), latanoprost causes a marked increase in ciliary body thickness but does not alter the conformation of the anterior segment, including the ACD, after 1 week of treatment.
In our study the same degree of decrease in ACD was found in eyes with and without cycloplegia during latanoprost therapy at month 3. If the ACD reduction was caused by increased zonular fibre laxity, as reported by Gutierrez-Ortiz et al. (2006), it should have been greater in the cycloplegic than in the non-cycloplegic state. Moreover, if both the ocular hypotensive effect and the reduction in ACD are the results of changes in the connective tissue induced by latanoprost-activated MMPs, we would expect to find a positive correlation between the reduction in IOP and the decrease in ACD. However, we were unable to identify such a correlation.
The effect we observed may be based on increased fluid volume in the uveoscleral outflow pathways. In this way, the ciliary body is displaced under traction by the zonular fibres, mimicking the effect of a slight ciliary muscle contraction. This may displace the crystalline lens somewhat in an anterior direction. However, if this hypothetical mechanism were correct, we would expect to see some correlation between the reduction in IOP and the decrease in ACD, but we did not.
Some changes can be expected in the refractive power and VA of an eye in which ACD is decreased as the result of a change in the position of the crystalline lens. We used uncorrected VA to follow the changes in VA so that it would be possible to detect a change in refractive power secondary to a change in ACD. However, we did not identify any changes in refractive status or VA. We interpret this as indicating that the degree of change in the position of the crystalline lens is too small to impact on VA. Moreover, the Reykjavik Eye Study confirmed that ocular refraction is not correlated with ACD (Olsen et al. 2007).
In clinical practice, ACD is most commonly measured using an ultrasonic technique. Although this technique is accepted as the reference standard, A-scan measurements of ACD are known to be less reproducible than measurements obtained using advanced technological devices such as the Orbscan, IOLMaster and Pentacam, a fact that may represent a limitation of our study (Vogel et al. 2001; Findl et al. 2003; Hashemi et al. 2005). However, the 20 consecutive measurements were conducted by a single experienced observer using the same device under the same physical conditions and no difference was detected between the baseline and 3-month measurements obtained in the control group, which indicates a good reproducibility. Moreover, Sohajda et al. (2008) found a positive significant correlation between measurements obtained with different A-scan instruments.
In conclusion, latanoprost causes a statistically significant decrease in ACD. The clinical significance of this finding remains uncertain. Further studies are needed to investigate the possible mechanisms underlying the decrease in ACD and to determine whether the changes in ACD are progressive or not. In order to resolve these issues, it may be necessary to take measurements over a longer period of time and to measure the ACD after the termination of latanoprost treatment.