Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial.

SUMMARY: This prospective study showed that the incidence of acute anterior uveitis, confirmed by ophthalmic examination, in patients receiving intravenous zoledronate infusions as part of a randomized controlled trial for fracture prevention is 1.1%. INTRODUCTION: We prospectively investigated the incidence of ocular side effects after a single intravenous zoledronate infusion. METHODS: In a secondary analysis of a double-blind, placebo-controlled trial in which early post-menopausal women (N=1054) with normal bone density or osteopenia were randomized to infusion of zoledronate 5 mg (N=703) or placebo (N=351), we analyzed significant adverse ocular events occurring within 3 months. RESULTS: Fourteen participants reported ocular symptoms after the infusion. All were examined by an ophthalmologist and eight were diagnosed with acute anterior uveitis (AAU) and one with sectoral episcleritis. The incidence of AAU and episcleritis was 1.1% (95% CI 0.5-2.1) and 0.1% (95% CI 0.0-0.7), respectively, in the zoledronate group and 0% for both conditions in the placebo group (95% CI 0.0-0.8). The mean time from infusion to symptom onset for AAU was 3 days (range 2-4). Three cases were bilateral. AAU was mild-moderate in seven participants and severe in one. All affected eyes were treated with topical cyclopentolate 1% (to break, or minimize, posterior synechiae), and intensive, potent, topical corticosteroids with a tapering regime based on treatment response. The mean duration of topical corticosteroid was 26±10 days (range 17-44). The mean, best corrected visual acuity was 20/20 (range 20/20-20/40) at presentation, which remained unchanged after AAU resolution. None of the participants lost vision, and no long-term sequelae were reported at last follow-up (range 3-13 months post-infusion). CONCLUSIONS: Prescribers should inform patients about the possibility of ocular side effects with zoledronate infusions and refer promptly to an ophthalmologist if symptoms develop.

Clinical in vivo confocal microscopy of the human cornea in health and disease.

Confocal microscopy enables microstructural analysis of the in vivo cornea, allowing fresh insight into corneal microstructure in health, and in inherited and acquired corneal disease. This method of corneal examination is evolving in an exponential fashion, with rapid advances in technology being mirrored by rapid growth in both research and clinical applications. Whilst initially the evidence base for in vivo confocal microscopy consisted largely of small case studies, in recent years there has been a trend towards collecting quantitative data in an effort to better delineate between heath and disease. Confocal microscopy has been utilised clinically to aid in the diagnosis of infectious keratitis, in particular Acanthamoeba and fungal keratitis, and has also established a role in the diagnosis and phenotyping of corneal dystrophies. This article reviews in vivo confocal microscopy of the human cornea in health and disease and examines clinical and research applications of this new technology.

Corticosteroid-induced intraocular pressure elevation in keratoconus is common following uncomplicated penetrating keratoplasty.

AIMS: To determine the incidence of postkeratoplasty intraocular pressure (IOP) elevation in the eyes of subjects with keratoconus and establish the relationship between IOP and corticosteroid administrations in this population. METHODS: Following strict inclusion/exclusion criteria, a retrospective analysis was performed on a consecutive series of penetrating keratoplasties performed for keratoconus observing a standardised surgical and postoperative regimen in Auckland, New Zealand. Patient demographics, ocular, medical, and family history, and pre- and postoperative data were recorded until 12 months postkeratoplasty. RESULTS: In all, 57 eyes of 48 patients were included-31% New Zealand Europeans, 42% Pacific people, 15% Maori, and 12% other. Eighteen eyes (32%) of 17 patients (35%) exhibited elevated IOP and 12 (21%) eyes exhibited moderate-to-severe elevation of IOP. IOP elevation occurred 3-6 months postkeratoplasty in 78% of eyes. Elevated IOP was significantly less common in Maori and Pacific peoples (P=0.02). All eyes except one required reduction/cessation of corticosteroids to normalise IOP. CONCLUSIONS: The incidence of presumed steroid-related postkeratoplasty IOP elevation, in 35% of subjects with keratoconus, is markedly higher in this New Zealand study than previously reported in the US and UK studies. Further clinical and genetic analysis of associations between keratoconus and steroid-induced IOP elevation and glaucoma might improve our current understanding of this condition.

Laser-scanning in vivo confocal microscopy reveals two morphologically distinct populations of stromal nerves in normal human corneas.

BACKGROUND: The purpose of this study was to use laser scanning in vivo confocal microscopy to elucidate the location and morphology of stromal nerves in the normal human central cornea. METHODS: Analysis was performed via an established database of laser-scanning in vivo confocal microscopy on images of the central cornea of normal subjects. The depth and morphology of the stromal nerves were determined. RESULTS: The population of this study consisted of 99 eyes of 99 healthy subjects (38 male, 61 female). The mean age of the group was 34.7 (SD 13.3, range 13-84) years. Two morphologically different populations of stromal nerves were observed: (1) straight, dichotomous branching nerves; and (2) tortuous nerves with a beaded appearance. The mean recorded depth of straight stromal nerves (186 (SD 66) mum) was significantly deeper than the mean depth of the tortuous stromal nerves (140 (SD 87) mum) (p<0.001). CONCLUSIONS: The current study identified two morphologically distinct stromal nerve populations in the normal human cornea. We hypothesise that the two morphological nerve populations described here may represent functionally heterogeneous nerves. Further research is required to determine if these in fact represent different types of sensory nerves.

In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review.

The exponential evolution of in vivo confocal microscopy (IVCM) has led to a significant enhancement in our knowledge of the living cornea in both its physiological and pathological states. Studies using white light and coherent light-based IVCM have enabled detailed quantitative analysis of sub-basal nerve parameters, and have also resulted in the elucidation of the two-dimensional architecture of the normal corneal sub-basal nerve plexus. However, accurate and repeatable methods for quantitative analysis of stromal nerves imaged by IVCM remain to be developed. The effect of corneal surgery on central corneal nerves has been well documented in many IVCM studies, and these studies provide an indication of the regenerative capacity of corneal nerves. IVCM has also clearly demonstrated the involvement of corneal nerves in diseases such as keratoconus, although it remains unclear whether these alterations are a cause of, or occur secondary to, the disease process. IVCM has also been proposed as non-invasive method of accurately diagnosing and assessing the progression of diabetic neuropathy, highlighting the potential application of this technique as an indicator of systemic disease. This review consolidates our knowledge of how IVCM has contributed significantly to our greater understanding of corneal nerves in the living human cornea in health and disease.

Identifying relationships between tomography-derived corneal thickness, curvature, and diameter and in vivo confocal microscopic assessment of the endothelium in healthy corneas of young adults.

PURPOSE: Despite the importance of a healthy endothelial layer in anterior segment surgery, the possible influence of corneal parameters on endothelial cell density (ECD) has largely been ignored in the young adult eye. This study investigated the possible associations between corneal tomographic parameters and ECD values in young adults. METHODS: Subjects aged 21-30 years, with normal corneas were recruited. Mean ECD, mean cell area (MCA), coefficient of variation for cell area (COVA), and proportion of hexagonal cells were derived by in vivo confocal microscopy. The Orbscan II system was used to measure corneal parameters including: thickness, horizontal corneal diameter, corneal curvature, anterior and posterior elevation, and eccentricity. RESULTS: Sixty-two subjects (42 female, 20 male) were included (mean age 25+/-3 years). Overall mean ECD was 3169+/-309 cells/mm(2) with no differences between genders. Mean percentage of hexagonality was 53+/-5%, male subjects (55%) had a higher percentage of hexagonal cells than female subjects (51%) (P=0.02). Central corneal thickness (CCT) was 529+/-43 microm. Central ECD was significantly correlated with CCT (Pearson's r=0.26, P=0.04). However, horizontal corneal diameter (r=0.19, P=0.14), anterior corneal curvature (r=-0.07, P=0.6), and posterior corneal curvature (r=-0.07, P=0.6) were not correlated with ECD or percentage of hexagonality. There was no statistically significant association between anterior chamber depth (3.6+/-0.3 mm) and ECD (r=0.15, P=0.3). CONCLUSION: Corneal thickness is related to ECD in normal young adult eye, with lower ECD values identified in thinner corneas; however, corneal diameter and corneal curvature do not have a significant correlation with ECD.

Laser scanning in vivo confocal microscopy and quantitative aesthesiometry reveal decreased corneal innervation and sensation in keratoconus.

PURPOSE: The purpose of this study was to quantitatively analyse laser scanning in vivo confocal microscopy images of the corneal epithelium and sub-basal nerve plexus in patients with keratoconus and to correlate these microstructural observations with corneal sensitivity. METHODS: A total of 31 eyes of 31 normal human subjects, and 27 eyes of 27 subjects with an established diagnosis of keratoconus were recruited. Twelve subjects with keratoconus had never worn contact lenses (K-NCL). Fifteen subjects with keratoconus wore contact lenses routinely (K-CL). All eyes were examined using slit-lamp biomicroscopy, Orbscan topography, non-contact corneal aesthesiometry, and laser scanning in vivo confocal microscopy. RESULTS: Central corneal sensation was significantly lower in K-CL compared to normal (P=0.028). However, there was no significant difference in corneal sensation between the normal and K-NCL groups (P=0.059). Both sub-basal nerve density (P<0.001) and basal epithelial density (P<0.001) were significantly lower than normal in all keratoconic subjects. Central corneal sensation was only significantly correlated with sub-basal nerve density (P=0.001) and was not significantly correlated with any of the basal epithelial parameters. Sub-basal nerve density showed significant positive correlation with basal epithelial density (P<0.001). CONCLUSION: This quantitative study reveals decreased corneal innervation, sensation, and basal epithelial density in keratoconus. The results of this study provide strong evidence that both the sub-basal nerves and the basal epithelium may be involved in the pathogenesis of keratoconus, although it is uncertain whether these are primary or secondary changes.

The Dundee University Scottish Keratoconus study: demographics, corneal signs, associated diseases, and eye rubbing.

AIM: To investigate and correlate the corneal, refractive, topographic and familial characteristics of a large cohort with keratoconus. METHODS: Prospective observational study of 200 consecutive patients presenting with keratoconus during the 4 year-period 1997-2000. Subjects were examined at enrolment and at a final review. Data were collected on demographic characteristics, referral route, symptoms, refractive correction, eye rubbing, family history, medical history, slit-lamp biomicroscopic corneal signs, and computerized corneal topography. RESULTS: Mean age at enrolment was 30.9+/-10.4 (range, 12.2-72) years (N=200, 62.5% male, 93% white Caucasian) with a 5% family history of keratoconus. Atopic diseases included asthma (23%), eczema (14%), and hay fever (30%). Only 9% wore contact lenses before referral. Mean follow-up was 1004 days +/-282 (range, 390-1335) and 9.7+/-8.9 (range, 1.1-60) years from diagnosis. The mean simulated K1 corneal power at enrolment was 51.74+/-5.36 (range, 42.59-67.32) D and 88.5% exhibited bilateral keratoconus. Fifty-three (15%) topographically confirmed cones exhibited no clinical corneal signs at presentation. At enrollment, 56% had a pachymetry <0.480 mm increasing to 77% at final review. Forty-eight percent of subjects reported significant eye rubbing and there was a highly statistically significant difference (two sample t-test P=0.018) between keratoconus and control groups. TMS-2 axial corneal power was strongly associated with corneal scarring and age at diagnosis. The size of the scarring effect was 2.2 D (95% confidence interval (CI) 1.34, 3.06). CONCLUSIONS: This study provides an overview of a large population with keratoconus highlighting presenting features and clinical and topographic progression over a 4 year-period.

The Dundee University Scottish Keratoconus Study II: a prospective study of optical and surgical correction.

AIM: To investigate and correlate optical correction, and progression to penetrating keratoplasty (PKP), with the corneal, refractive, topographic and familial characteristics of subjects with keratoconus, within the Tayside region of Scotland. METHOD: Prospective, observational, longitudinal study design. Two hundred subjects with keratoconus were enrolled into the Dundee University Scottish Keratoconus Study (DUSKS) and were assessed during a 4-year period using standardised clinical assessment, computerised corneal topography and questionnaires. RESULTS: Keratoconic subjects in this study wore rigid contact lenses (90.6%) for longer than 12 hours per day (81%), 7 days a week (91%) and achieved a very good level of Snellen visual acuity (97%, > or =6/9). Corneal staining was observed in the majority of corneas (71%), although only a small percentage of subjects reported major problems of: discomfort (18%), hyperaemia (16%), or the lens falling out (4%). Poor visual acuity was the main reason (79%) for undergoing PKP usually in the latter part of the third decade of life, approximately a decade after diagnosis. During the study period 4% of eyes progressed to PKP. Only a small percentage of eyes (9.5%) required no visual correction postoperatively. CONCLUSION: The main mode of visual rehabilitation for keratoconus was rigid contact lenses, which were mostly worn successfully with good visual acuity. During the study period a small minority of keratoconics progressed to corneal graft surgery. It is advisable to emphasise that postoperatively refractive correction will be required in the majority of these cases.

Age-related differences in the normal human cornea: a laser scanning in vivo confocal microscopy study.

AIMS: To quantify and establish baseline normative data for age-related differences in cellular and innervation density in the normal, healthy, human cornea using laser scanning in vivo confocal microscopy. METHODS: Cross-sectional study of 85 normal subjects assessed via corneal topography and laser scanning in vivo confocal microscopy. RESULTS: Mean age was 38+/-16 years (range 18-87 years) and 60% of subjects were female. Anterior keratocyte density declined by 0.9% per year (r = -0.423, p<0.001), posterior keratocyte density declined by 0.3% per year (r = -0.250, p = 0.021) and endothelial cell density declined by 0.5% per year (r = -0.615, p<0.001). Sub-basal nerve fibre density declined by 0.9% per year (r = -0.423, p<0.001). No association was observed between age and basal epithelial cell density, or between age and central corneal thickness, corneal astigmatism or horizontal corneal diameter (p>0.05). No association was observed between subject gender and corneal cell or innervation density. CONCLUSIONS: Using laser scanning in vivo confocal microscopy this study highlights a significant, and relatively linear, reduction in keratocyte and endothelial cell density with increasing subject age. Interestingly, corneal sub-basal nerve fibre density also significantly decreases with increasing age. In vivo laser scanning confocal microscopy provides a safe, non-invasive method for the establishment of normative data and assessment of alterations in human corneal microstructure following surgery or disease processes.

Quantitative analysis of corneal microstructure in keratoconus utilising in vivo confocal microscopy.

PURPOSE: To establish and quantify the in vivo confocal microscopic features of moderate to advanced keratoconus. METHODS: Nineteen keratoconus subjects were catergorised using Orbscan-derived corneal apex power and pachymetry as exhibiting moderate (n=7) and advanced (n=12) keratoconus. Control subjects included 23 noncontact lens wearers (Group A) and 15 contact lens wearers (Group B). All subjects underwent Confoscan slit scanning in vivo confocal microscopy. RESULTS: Compared with Group A (4912+/-434 cells/mm(2)), basal epithelial density was significantly lower in both moderate (4592+/-414 cells/mm(2), P<0.05) and advanced keratoconus (4530+/-596 cells/mm(2), P=0.01). In comparison to Group A (761+/-118 cells/mm(2)), anterior stroma keratocyte density was significantly greater in both moderate keratoconus (883+/-111 cells/mm(2), P=0.001) and advanced keratoconus (952+/-122 cells/mm(2), P<0.001). Compared to Group A (504+/-80 cells/mm(2)) posterior stroma keratocyte density was also significantly greater in advanced keratoconus (599+/-97 cells/mm(2), P<0.001) and posterior stromal keratocyte density appeared to increase with increasing severity of keratoconus (P<0.05). However, comparing control Groups A and B, contact lens wear per se, was associated with significantly reduced (P=0.000) keratocyte density in the anterior stroma (609+/-66 cells/mm(2)) and demonstrated a trend (P=0.056) in the posterior stroma (470+/-63 cells/mm(2)). Keratoconic corneas (429+/-72 microm) were significantly thinner than control Groups A (508+/-77 mm) and B (495+/-80 microm). The presence of keratoconus did not affect the endothelial cell density (P=0.54). CONCLUSION: In vivo confocal microscopy can provide insight into the microstructural changes that occur in keratoconus.

The variable expression of keratoconus within monozygotic twins: dundee University Scottish Keratoconus Study (DUSKS).

INTRODUCTION: As part of a longitudinal observational prospective study (Dundee University Scottish Keratoconus Study, DUSKS) a caucasian female subject was identified with keratoconus affecting both corneas. Of interest was that the subject's mother was a monozygotic twin, however, the mother was reportedly unaffected by keratoconus, although her sister (the subject's aunt) had been diagnosed with keratoconus. METHOD: Computer video-keratoscopy (CVK) was undertaken was on this family to clarify this apparent discordance. RESULTS: CVK demonstrated the variable expression of the keratoconic phenotype, by identifying evidence of subclinical keratoconus in the 'unaffected' twin. CONCLUSION: So far only one set of monozygotic twins with keratoconus have been reported within the UK, this paper reports a second. Since CVK has been available the majority agree on concordance of keratoconus expression but not all, including this study. If monozygotic twin studies demonstrate heterogeneity of keratoconus this may at least explain the contradictory data that exists within the literature and why the inheritance pattern of keratoconus is still unclear in 2005.

Comparison of intraocular pressure measured by Pascal dynamic contour tonometry and Goldmann applanation tonometry.

AIMS: To compare the intraocular pressure (IOP) measurements obtained using the Pascal dynamic contour tonometer (PDCT) with the standard Goldmann applanation tonometer (GAT) and to correlate these with central corneal thickness (CCT) in patients with normal corneas. METHODS: A prospective, masked, comparative case series of 116 eyes from patients attending a glaucoma clinic. IOP was measured with PDCT by one examiner and with GAT by a masked, independent examiner. A mean of six CCT readings was used for analysis. RESULTS: IOP measured by the two instruments correlated significantly (r=0.77; P<0.0001). IOP measured by GAT correlated strongly with CCT (r=0.37, P=0.0001) whereas the relationship between IOP measured by PDCT and CCT approached significance (r=0.17, P=0.073). The differences between GAT and PDCT measured IOP also correlated strongly with CCT (r=0.37, P<0.0001). The 95% limits of agreement between GAT and PDCT were +/-4.2 mmHg. Dividing the eyes into three groups on the basis of CCT, demonstrated those in the thickest tertile showed a poorer agreement between instruments and the GAT measured significantly higher IOP in this group (P=0.003) while the PDCT showed no significant differences with different CCTs (P=0.37). CONCLUSION: Demonstration of the relative independence of PDCT IOP measurements from CCT supports a potential clinical role for this instrument, particularly for subjects with CCT outside the normal range.

Atypical unilateral superior keratoconus in young males.

Generally in keratoconus the corneal apex displacement is inferior in position and bilateral in expression. Two young male keratoconic subjects enrolled in the Dundee University Scottish Keratoconus Study (DUSKS) demonstrated with corneal topography the presence of unilateral superior keratoconus. Successful visual rehabilitation of a superior cone with contact lens fitting represents a particular challenge to the contact lens practitioner. This report discusses the management of two such cases.

The indications and outcome of paediatric corneal transplantation in New Zealand: 1991-2003.

AIM: To evaluate patient characteristics, indications, surgical details, and outcome of paediatric keratoplasty in New Zealand. METHODS: As part of a prospective longitudinal study, paediatric keratoplasty data collected by the New Zealand National Eye Bank (NZNEB) was analysed for the 13 year period 1991-2003. RESULTS: During the study period the NZNEB supplied 2547 corneas for keratoplasty, of which 65 (3%) were used for paediatric patients (14 years or younger). The 65 keratoplasties were performed in 58 eyes of 52 patients (66% male, 34% female, mean age 10.6 years, SD 4.3 years). Indications were classified into three groups: congenital (16%, n = 9), acquired non-traumatic (74%, n = 43), and acquired traumatic (10%, n = 6). Peters' anomaly (7% of total), keratoconus (67%), and penetrating trauma (8%) were the most common indications in each group, respectively. 82% of keratoplasties with known outcome survived (clear graft) 1 year postoperatively, 16% failed, and one patient died. Keratoplasty for congenital indications had a lower 1 year survival rate (78%) compared to acquired non-traumatic (85%) and traumatic (100%) indications, although the difference was not statistically significant (p = 0.65). 38% of patients with known outcome had a 1 year postoperative best corrected Snellen visual acuity (BCSVA) of 6/9 or better, and 60% had a BCSVA of 6/18 or better. Visual outcome was significantly better for acquired compared to congenital indications (p = 0.03). CONCLUSION: Analysis of the NZNEB database provided valuable information in relation to paediatric keratoplasty in New Zealand. In particular, this study highlighted an unusually high prevalence of keratoconus as an indication for keratoplasty. In addition, a high 1 year survival rate and good visual outcome were identified, especially in cases of keratoplasty for acquired conditions.

The Auckland Cataract Study: 2 year postoperative assessment of aspects of clinical, visual, corneal topographic and satisfaction outcomes.

AIM: To assess clinical, visual, computerised corneal topographic, and subjective satisfaction with visual acuity, in a cohort of subjects 2 years after phacoemulsification surgery in a public hospital in New Zealand. METHODS: Prospective study of a representative sample of 97 subjects (20%) randomly selected from 480 subjects in the original Auckland Cataract Study (ACS) cohort. The clinical assessment protocol was identical to the ACS and included an extensive questionnaire to enable direct comparisons to be made between the two groups. RESULTS: The study population was predominantly female (66%) with a mean age of 76.3 (SD 9.9) years. New systemic and ocular disease affected 18.4% and 10.3% of subjects respectively, and 10.3% required referral to either a general practitioner (2.1%) or ophthalmologist (8.2%). Mean best spectacle corrected visual acuity (BSCVA) was 0.2 (0.2) logMAR units (6/9 Snellen equivalent), with mean spherical equivalent -0.37 (1.01) dioptres (D) and astigmatism -1.07 (0.70) D 2 years postoperatively, compared to mean BSCVA 0.1 (0.2) logMAR units (6/7.5 Snellen equivalent), spherical equivalent -0.59 (1.07) D, and astigmatism -1.14 (0.77) D 4 weeks after surgery. 94.9% of subjects retained a BSCVA of 6/12 or better, irrespective of pre-existing ocular disease. The overall posterior capsule opacification (PCO) rate was 20.4% and this was visually insignificant in all but 3.1% of eyes that had already undergone Nd:YAG posterior capsulotomy. Orbscan II elevation technology demonstrated corneal stability 2 years after uncomplicated phacoemulsification. Although corneal astigmatism was eliminated in approximately half of the subjects 1 month postoperatively, astigmatism showed a tendency to regress towards the preoperative level with local corneal thickening at the site of incision 2 years after cataract surgery. Of fellow eyes, 61.2% had undergone cataract surgery. Overall, 75.3% of subjects were moderately to very satisfied with their current level of visual acuity. CONCLUSION: Two years after cataract surgery subjects are generally satisfied with their current level of vision and distance BSCVA is 6/12 or better in the majority of eyes. Although only a minority of eyes develop sufficient PCO to require capsulotomy 10.3% of eyes develop new vision threatening ocular pathology.

The effects of corneal parameters on the assessment of endothelial cell density in the elderly eye.

BACKGROUND: The possible impact of corneal thickness, curvature, and size on the measurement of endothelial cell density (ECD) has largely been ignored in the normal eye. The aim of this study was to investigate the possible impact of the main corneal parameters on the analysis of ECD values at the central, superior, and temporal parts of the corneal surface. METHODS: All 75 participants (52 females, 23 males) were assessed as part of a pre-cataract surgery investigation. The mean age was 75.7 (SD 10.9) years. Confocal microscopy was used to measure ECD and the percentage of six sided cells at the central, superior, and temporal parts of the cornea. The Orbscan II topography system was used to measure corneal thickness, topography, and horizontal corneal diameter. RESULTS: The mean central ECD measured was 2488 (SD 301) cells/mm(2), compared with 2525 (SD 505) cells/mm(2) in the temporal cornea and 2639 (SD 398) cells/mm(2) in the superior cornea. The regional differences in ECD were not significant (p>0.14). The central ECD was significantly correlated to the central (mean 0.593 (SD 0.039) mm, p = 0.021) as well as the temporal (0.628 (SD 0.039) mm, p<0.001) and the superior corneal thickness (SD 0.644 (SD 0.048) mm, p = 0.018). The mean corneal curvature at the centre (7.7 (SD 0.34) mm, p = 0.002) as well as 3 and 5 mm from the apex was significantly related to ECD (p = 0.008 and p = 0.009, respectively). CONCLUSIONS: The study suggests that in an older population, lower ECD values would be expected in thinner and/or steeper corneas.