Ferenc B Sallo

Ehud Rechtman

Tunde Peto

Dinu Stanescu-Segall

Gabor Vogt

Alan C Bird

Frederick W Fitzke

FUNCTIONAL ASPECTS OF DRUSEN REGRESSION IN AGE-RELATED MACULAR DEGENERATION

Keywords: Macula, Degeneration, Psychophysics, Imaging, AMD, drusen, natural history, regression

Aims: To investigate the functional implications of macular soft drusen regression in AMD eyes.

Methods: Patients were selected from a large ongoing collection of clinical data at Moorfields Eye Hospital. Phenotyping based on standard colour fundus images was performed according to the system defined by the International Classification for ARM, by certified graders masked to the main aim of the study. Fundus Autofluorescence (FA) was recorded using a Heidelberg Retina Angiograph 2. Where drusen regression was confirmed by independent grading, the patient was invited for photopic and scotopic Fine Matrix Mapping (FMM). Phenotype and functional data were analyzed for correlations between fundus appearance, autofluorescence and retinal sensitivity.

Results: Fundus and FA images of 960 patients were screened, soft drusen regression was detected in 34 cases, 14 patients agreed to participate in the study, ranging in age from 52 to 84 years (median 72). The mean follow-up period was 5.9 years (range 2.8-14.4 years). FMM showed generalised threshold elevation relative to normal controls both under photopic and scotopic conditions. Scotopic sensitivity loss exceeded photopic loss in all cases. Sensitivity loss over areas with drusen or regressed drusen did not differ significantly from that over non-drusen areas.

Conclusion:

Macular soft drusen may fade or disappear without detectable ophthalmoscopic, FA or psychophysical signs of local dysfunction. This phenomenon is a potential source of misclassification. The prognosis for cases with true regression of drusen compared with those without needs to be considered in future studies on AMD.

INTRODUCTION

Age-Related Macular Degeneration (AMD) is the leading cause of severe irreversible central visual loss among the elderly in western industrialized countries. [START_REF] Klein | The epidemiology of age-related macular degeneration[END_REF][START_REF] Klein | Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study[END_REF] The aetiology and pathogenesis of AMD are poorly understood. Risk factors identified include age, certain genetic variants, smoking and the presence of macular soft drusen with high-risk characteristics. [START_REF] Klein | The epidemiology of age-related macular degeneration[END_REF][START_REF] Klein | Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study[END_REF][START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF][START_REF] Sparrow | Seven year follow-up of age-related maculopathy in an elderly British population[END_REF] Clinically, early AMD is characterized by abnormalities of the retinal pigment epithelium (RPE), soft drusen and mild visual symptoms, predominantly under dark-adapted conditions. [START_REF] Bird | An international classification and grading system for agerelated maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group[END_REF][START_REF] Steinmetz | Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change[END_REF] Late AMD is dominated by either geographic atrophy (GA) or neovascularisation (NV), typically with severe central function loss. [START_REF] Bird | An international classification and grading system for agerelated maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group[END_REF] AMD affects primarily the RPE, Bruch's Membrane (BrM) and choriocapillaris (the RPE/BrM complex). In early AMD, a thickening of BrM and an accumulation of focal and diffuse lipid-rich deposits (drusen, basal linear and laminar deposits) under the RPE and within BrM are prominent. [START_REF] Sarks | Ageing and degeneration in the macular region: a clinico-pathological study[END_REF] The consequential reduction in hydraulic conductivity may impede transport through BrM and thus contribute to the pathogenesis of lesions seen in late disease. [START_REF] Zarbin | Current concepts in the pathogenesis of age-related macular degeneration[END_REF] The origin and mechanism of debris deposition are little known. Of the sub-RPE deposits, drusen alone are detectable clinically. The natural history of soft drusen may involve an increase in size, area and confluence with subsequent NV, or fading and disappearance which is believed to be associated with atrophy of the overlying RPE and photoreceptors. [START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF] The functional and prognostic implications of true drusen regression, however, have not been demonstrated. Since the RPE/BrM complex is essential for photoreceptor survival, psychophysical assessment of photoreceptor function may yield information about the significance of clinically observable retinal changes that may not be provided by other methods until later or at all. [START_REF] Curcio | Spare the rods, save the cones in aging and age-related maculopathy[END_REF] Imaging the distribution of autofluorescence in the fundus (fundus autofluorescence, FA) represents an additional tool for evaluating RPE health. [START_REF] Von Rückmann | Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope[END_REF] Visualised by a confocal Scanning Laser Ophthalmoscope (cSLO, excitation λ=488nm) FA is mainly derived from lipofuscin (LF), [START_REF] Von Rückmann | Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope[END_REF]11] a complex material produced in RPE cells from residues of incomplete lysosomal degradation of photoreceptor outer segment (POS) discs. LF contains components toxic to the RPE (primarily A2-E isomers), its excessive accumulation is believed to precede photoreceptor degeneration in AMD. [11] The aim of this study was to investigate the functional implications of macular soft drusen regression in AMD eyes.

PATIENTS AND METHODS

Patients were selected from a large ongoing collection of clinical data at the Reading Centre of Moorfields Eye Hospital. Inclusion criteria were: a clinical diagnosis of AMD, both manifest and resolved soft macular drusen, a level of fixation and general fitness sufficient to perform the full test sequence. Patients with exudative late-stage AMD in the eye studied were excluded.

Imaging

Standard 30º stereo colour images (SCI) of the fundus, centred on the fovea (Field 2) were recorded digitally. FA imaging was performed using a cSLO (Heidelberg Retina Angiograph 2, Heidelberg Engineering GmbH, Dossenheim, Germany). The fundus was illuminated using a solid-state laser (488 nm), induced fluorescence was recorded through a long-pass filter with a short-wavelength cut-off at 500nm. The image of a 30°x30° retinal area centred on the fovea was recorded digitally at 1536x1536 pixel (5µm/pixel) and 256-level grey-scale resolution. To reduce random noise, a master image was produced by averaging 16 individually recorded images for each eye in the study. Lens opacities -where present -were in all cases diffuse and permitted adequate imaging of FA.

Phenotyping

Detailed phenotyping was performed by grading based on Field 2 colour and FA images, according to the system defined in the International Classification for ARM and AMD, [START_REF] Bird | An international classification and grading system for agerelated maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group[END_REF] independently by two certified graders masked to the identity of the patients and the main aim of the study. These gradings were compared for (both inter-and intra-observer) reliability. A final copy was created by adjudication and changes over time in the final copy were analysed. In cases where the simultaneous presence of AMD, disappearance of drusen and absence of exudative disease were confirmed, the patient was invited for functional testing.

Psychophysical testing

For psychophysical testing Fine Matrix Mapping (FMM) was selected due to its superior spatial resolution and its ability to measure wide ranges of sensitivity changes. The full test sequence included a visual acuity test, a standard visual field examination using the 30-2 program of the Humphrey Field Analyzer (HFA, Carl Zeiss Ltd., UK), a photopic FMM test, pupil dilatation (with 1.0% tropicamide and 2.5% phenylephrine), dark adaptation for 45 minutes, a scotopic 30-2 visual field test, scotopic FMM and finally the determination of the location and stability of fixation.

Fine-Matrix Mapping

FMM was performed using a modified HFA. Test flashes were positioned over the retinal area of interest, including both drusen and areas where the resolution of drusen was confirmed by grading. The coordinates of four interlaced 5x5 grids (25 locations with 2° intervals) were entered in the "Custom Grid" feature of the perimeter. Each grid was offset relative to the other grids by 1° on either the x, y, or both axes. Data thus obtained were merged into a single 9° x 9° matrix of 100 test locations with 1° intervals. A standard (Goldmann) size 3 stimulus was used. Photopic testing was done using a white stimulus with a background illuminance of 31.5 apostilbs, scotopic measurements were done using a blue stimulus with no background illumination. Fixation stability was monitored through an infrared camera. Detection threshold sensitivity was expressed in decibels and thresholds as log units. The maximum stimulus illuminance of 10,000 apostilbs was interpreted as 0dB.

Data processing FMM thresholds were processed by (3x3) Gaussian filtering to improve repeatability. [START_REF] Fitzke | Image processing of computerised visual field data[END_REF] The attenuation of the original signal and loss of detail inherent in all smoothing methods was in our case insignificant and outweighed by the benefits with respect to noise reduction (repeatability). [START_REF] Fitzke | Probing visual function with psychophysics and photochemistry[END_REF] For each patient, sensitivity data were analyzed intra-individually as well as compared with age-matched normal data (collected under identical conditions) that have been published, [START_REF] Westcott | High spatial resolution automated perimetry in glaucoma[END_REF][START_REF] Guymer | Laser treatment in subjects with high-risk clinical features of age-related macular degeneration. Posterior pole appearance and retinal function[END_REF][START_REF] Wu | Fine matrix mapping of the macular region in normal subjects[END_REF] through point-by-point subtraction of averaged normal values at corresponding coordinates within the FMM matrix. Filtered data were used to calculate the mean and the maximum threshold elevation from baseline as well as elevation relative to averaged threshold levels of the normal control group. Interpolated threshold values at 0.25° intervals were used to generate a contour plot showing luminance sensitivity gradients across the matrix. Three-dimensional threshold profiles were also generated. Composite images containing overlays of aligned sequential colour fundus and FA images and sensitivity threshold plots were analyzed for correlations between fundus appearance, FA and retinal sensitivity. Total area covered by drusen at baseline and at FMM testing was measured for each zone within the IC grading grid. [START_REF] Bird | An international classification and grading system for agerelated maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group[END_REF] Areas with disappearing drusen, persistent drusen and drusen-free areas were identified and associated levels of sensitivity loss were compared. Software used include: Adobe Photoshop v7 with the 'FoveaPro' plug-in, ImageJ v1.38x, Microsoft Excel and SPSS v11.

Fixation stability

A major factor influencing FMM test reliability is the stability of fixation. For the measurement of fixation stability, a customized cSLO was used in a way similar to a technique described previously. [START_REF] Culham | Assessment of fixation stability in normal subjects and patients using a scanning laser ophthalmoscope[END_REF] Values thus obtained reflect eye movements and are used to calculate the bivariate contour ellipse area (BCEA), which is the area of an ellipse on the retinal surface within which the centre of the target was imaged 68% of the time. BCEA is a standardized measure which provides a means for quantification and comparison of fixation stability. Smaller BCEA values correspond to more precise fixation.

The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Before inclusion, written, informed consent was obtained from each participating patient after explanation of the nature of the study. Maximum retinal irradiance of lasers used was well below the limits established by the American National Standards Institute (ANSI Z136.1; 1993) and other international standards.

RESULTS

Sequential colour fundus and FA images of 960 patients were screened for disappearing drusen. Soft drusen regression was detected in 34 cases (25 spontaneous, 9 following prophylactic laser treatment). 19 patients met all inclusion criteria, 14 (10 female, 4 male) agreed to participate in the study, ranging in age from 52 to 84 years (median age was 72 years). The baseline of the study was defined as the earliest date when both clinical data and fundus SCI were available, and the endpoint as the date the patient was last seen clinically. The mean follow-up period was 5.9 years (ranging from 2.8 to 14.4 years).

Phenotype

The predominant phenotype in the study eye at baseline was "soft drusen" in all cases. Disappearance of drusen was followed by NV in one, GA in 3 cases, while in 10 cases no indications of end-stage disease were seen in the colour fundus images. In most cases, parallel to fading drusen, new drusen in other locations appeared and grew in size and confluence. New drusen tended to form at increasingly peripheral locations relative to the fovea (Table 1). Repeated appearance of drusen in the same retinal location was not seen. Representative images are shown in Figure 1.

Autofluorescence

FA associated with drusen varied from decreased to increased, no good correspondence was detectable. FA corresponding to areas with disappearing drusen in the absence of pigmentary changes was normal in 7 cases. In two patients increased FA was seen, in one case in an area adjacent to the junctional zone of a GA, in the other adjacent to a large crystalline druse. One other patient showed widely varying levels of FA in connection with regressed drusen (Figure 1, row 3). GA was associated with decreased FA centrally and increased FA along the boundaries. Crystalline drusen showed decreased, granular hyperpigmentation increased FA.

Functional characteristics

Best corrected visual acuities in the study eye assessed at the time of FMM testing ranged from 6/12 to 6/5 (median=6/6). All patients had less than two lines loss in BCVA compared to the baseline value. Fixation Stability was good in all cases (Table 2). Two patients (2 and 4), both with end-stage disease, showed significant (more than 2 lines) deterioration in BCVA at the endpoint as compared to the baseline value. Fine Matrix Mapping showed generalised threshold elevation relative to normal controls both under photopic and scotopic conditions (Table 2). Scotopic sensitivity loss exceeded photopic loss in all cases (Figure 2). Scotopic loss over areas with drusen or regressed drusen did not differ significantly from that over non-drusen areas (p=0.289 and p=0.989 respectively, ANOVA, Figure 3). Elevated scotopic thresholds were seen associated with GA, crystalline drusen and coarse granular hyperpigmentation, all in connection with abnormal FA. Photopic thresholds showed little topographic variation except in areas with GA.

Table 2. Functional characteristics. FMM Global estimates of sensitivity loss are based on

Gaussian filtered data and are expressed in log units.

DISCUSSION

Regression of macular soft drusen has been described in clinical, [START_REF] Klein | Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study[END_REF][START_REF] Sparrow | Seven year follow-up of age-related maculopathy in an elderly British population[END_REF][START_REF] Bressler | Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities. Waterman study[END_REF] as well as in histopathological studies. [START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF][START_REF] Sarks | Evolution of geographic atrophy of the retinal pigment epithelium[END_REF] Gass noted that drusen may fade and disappear, leaving only an irregular mottling of the RPE, while visual acuity may not be affected. [START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF] Gass also observed that most cases GA follow the fading of drusen or the collapse of a serous detachment of the RPE. [START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF] Drusen disappearance is thus believed to be associated with subsequent degeneration and atrophy of the RPE and photoreceptors. [START_REF] Gass | Drusen and disciform macular detachment and degeneration[END_REF] It was however noted in large population-based studies that in some patients, drusen may also regress without residual signs. [START_REF] Klein | Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study[END_REF][START_REF] Sparrow | Seven year follow-up of age-related maculopathy in an elderly British population[END_REF][START_REF] Bressler | Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities. Waterman study[END_REF] The prognostic implications of true drusen regression is unknown. From the clinical aspect, it raises the possibility that arrested progression or even regression of the disease process may exist naturally. In this study, ten out of 14 patients showed no ophthalmoscopic indications of manifest or incipient end-stage disease in the fundus following drusen regression. However, in nine, parallel to regression, new drusen in other locations appeared and grew in size and confluence, signifying the continued activity of the disease, with a tendency toward the periphery. Mean retinal sensitivity relative to normal controls was reduced in all patients tested, both in the light and dark adapted states, with significantly higher loss under scotopic conditions. This observation confirms that in AMD, rods are at increased risk for degeneration and function loss occurs before progression to the late clinical stage. [START_REF] Curcio | Spare the rods, save the cones in aging and age-related maculopathy[END_REF][START_REF] Owsley | Psychophysical evidence for rod vulnerability in age-related macular degeneration[END_REF] Earlier psychophysical studies found that rod-mediated sensitivity declines faster with age than photopic sensitivity and patients with early AMD have significantly lower mean central scotopic sensitivity than age-matched controls. Also, in most AMD patients, mean scotopic sensitivity loss exceeded mean photopic sensitivity loss and the peak deficit in scotopic sensitivity was within 9° of fixation, corresponding to the parafovea. [START_REF] Owsley | Psychophysical evidence for rod vulnerability in age-related macular degeneration[END_REF] Histopathologic studies show direct correlates to these findings. In early AMD, a preferential loss of macular rod photoreceptors was demonstrated, with the greatest loss occurring in the parafovea. In late AMD this leads to a reversal of the macular (9:1) rod predominance seen in the young. [START_REF] Curcio | Spare the rods, save the cones in aging and age-related maculopathy[END_REF] The rod system also shows altered kinetics with aging and in AMD. [START_REF] Steinmetz | Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change[END_REF] One possible explanation for this preferential vulnerability of rods is provided by the retinoid deficiency hypothesis. [START_REF] Curcio | Spare the rods, save the cones in aging and age-related maculopathy[END_REF] RPE cells are responsible for the transport of nutrients from the choriocapillary circulation to the photoreceptors, as well as for the recycling of the end-products of POS disc degradation. 11-cis retinal (a derivative of Vitamin A) is essential for the regeneration of photoreceptor pigment after bleaching by light as well as for photoreceptor survival. In AMD, diffuse sub-RPE deposits may act as a diffusion barrier between the choriocapillaris and the RPE, [START_REF] Zarbin | Current concepts in the pathogenesis of age-related macular degeneration[END_REF] thereby disrupting transport across BrM and leading to a local scarcity of 11-cis-retinal. Vitamin A deprivation is a known cause of outer segment degeneration and photoreceptor death. Cones have an additional retinoid delivery pathway involving Müller cells and possibly the neurosensory retina and may thus be less vulnerable to reduced transport across Bruch's membrane. [START_REF] Curcio | Spare the rods, save the cones in aging and age-related maculopathy[END_REF][START_REF] Mata | Isomerization and oxidation of vitamin a in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight[END_REF] Although generalised sensitivity loss was measured in all our patients, topographic variation in scotopic (and photopic) sensitivity loss over drusen relative to areas with normal appearance was not significant. This confirms earlier observations that the presence of macular soft drusen seems to have little effect on the local sensitivity of affected retinal areas, [22,[START_REF] Scholl | Photopic and scotopic fine matrix mapping of retinal areas of increased fundus autofluorescence in patients with agerelated maculopathy[END_REF] with the exception of large, soft foveal drusen. These may be regarded as small RPE detachments and show mildly reduced photopic and considerably reduced scotopic sensitivity as well as increased FA. [START_REF] Scholl | Photopic and scotopic fine matrix mapping of retinal areas of increased fundus autofluorescence in patients with agerelated maculopathy[END_REF] It appears reasonable, that the impact of focal barriers such as drusen on RPE metabolism and photoreceptor function may be more limited than that of diffuse deposits. We also found that scotopic sensitivity over areas with regressed drusen was not substantially different from that over unaffected retinal areas, thus we did not find functional evidence for manifest or incipient photoreceptor atrophy. In diseases, where the RPE is primarily affected, the presence of abnormal FA may be an early sign of progression. Areas with increased FA were found to precede the development of new or the enlargement of existing atrophic patches. [START_REF] Holz | Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration[END_REF] Decreased FA over the drusen overall may also reflect incipient atrophy. [START_REF] Sunness | Issues in quantifying atrophic macular disease using retinal autofluorescence[END_REF] In eyes with soft drusen but without apparent GA, if focal decreased FA is present, patches with increased FA in areas adjacent to rather than corresponding to drusen may be markers for progression to atrophy. [START_REF] Smith | Autofluorescence characteristics of early, atrophic, and high-risk fellow eyes in age-related macular degeneration[END_REF] In this study, autofluorescence of retinal areas with normal appearance in the colour image following drusen regression was in most cases normal and none of the above FA patterns associated with impending atrophy was seen. Thus, although the generalised disease persists, retinal sensitivity and FA, two direct and sensitive measures of retinal health do not indicate that disappearance of drusen is necessarily followed by local function loss and atrophy. In summary, although the limitations of this study in terms of subject numbers and follow-up time as well as the lack of psychophysical testing before the drusen disappeared may not permit definitive conclusions, our results do indicate that macular soft drusen may fade or disappear without detectable ophthalmoscopic, FA or psychophysical signs of local dysfunction or incipient atrophy. This phenomenon suggests that some normal-appearing eyes at the present time may have had some features of AMD in the past and is thus a potential source of misclassification and needs to be remembered in epidemiologic studies investigating the natural history of the disease as well as in clinical trials that evaluate the efficacy of possible therapies. [START_REF] Bressler | Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities. Waterman study[END_REF] It is not known to what extent focal and diffuse sub-RPE deposits coincide and whether the regression of drusen is accompanied by the regression of diffuse deposits. The prognosis for cases with true regression of drusen compared with those without needs to be considered in future studies on AMD.

APPENDICES

Table 1 .

 1 Change in area covered by drusen. Columns: (A) Reduction in area of soft drusen present at baseline in respective zone of the IC grading grid. (B) Overall change in area covered by drusen, including drusen appearing after baseline. Negative numbers indicate net decrease from baseline.

Figure 1 .

 1 Figure 1.Representative images from selected cases. Columns: (A) the fundus at baseline, (B-C) colour and FA images taken at FMM testing, white rectangles mark the placement of respective FMM test grid, (D-E) surface plots of photopic and scotopic FMM thresholds. Rows 1-2 and 4 (patients 3, 6 and 11) illustrate the typical picture seen in the majority of patients. Row 3 shows a case (patient 7) where areas with regressed drusen appear normal in the colour fundus image but show a speckled variation in FA. Row 5 shows a case where progression to atrophy was noted (patient 2).

Figure 2 .

 2 Figure 2. Photopic versus scotopic sensitivity loss of the 14 patients in the study.

Figure 3 .

 3 Figure 3. Regional differences in scotopic sensitivity loss at retinal locations with (C) drusen, (B) regressed drusen and (A) areas with normal appearance.

ACKNOWLEDGEMENTS

The authors thank Mr Vy Luong for his technical support and Mr Tibor Fermon and Mr Istvan Toth for useful discussions and general support.

COMPETING INTERESTS: None declared. (All authors declare that the answer to the questions on your competing interest form are all No and therefore have nothing to declare.)

FUNDING: NONE

LICENCE FOR PUBLICATION

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Youhanna W Ibrahim
email: youhannawilliam@hotmail.co.uk

David L Boase

Ian A Cree

Mr Youhanna

William Ibrahim

Epidemiologic Characteristics, Predisposing Factors and Microbiological Profile of Infectious corneal ulcers: The Portsmouth Corneal Ulcer Study

Keywords: corneal ulcer, contact lens, infectious keratitis, predisposing factors

Aim

-To identify the incidence, predisposing factors, clinical and microbiological diagnosis of infectious corneal ulcers in a population based in southern England. Methods-A retrospective review of the medical records of patients presenting with infectious corneal ulcers at the eye casualty department of Queen Alexandra Hospital, Portsmouth between January 1997 and December 2003.

Results-A total of 1,786 patients presented with infectious corneal ulcers with a mean age of 45 years and female predominance (54.5%). Contact lens wear (CLW) was the main predisposing factor in 554 patients (31%). Corneal scrapes from 1,254 patients grew positive cultures in 800 patients. Gram-positive bacteria accounted for 696 (71.1%) of the total 979 bacterial isolates, while Gram-negative bacteria accounted for 283 (28.9%) with the predominance of Pseudomonas aeruginosa. Nine out of 11 patients with Acanthamoeba keratitis were contact lens wearers (CLWs).

The majority of patients 1,728 (96.8%) sought medical help more than once and 34 patients (1.9%) had poor visual outcome. Follow-up was completed in 1633 patients (91.4%) with an average of 11.5 days.

Conclusions-Contact lenses remain the most important risk factor for infectious corneal ulcers. Reduction of the rate and severity of infectious keratitis requires continuous education of patients, and professionals.

INTRODUCTION

Infectious corneal ulceration is an avoidable vision-threatening disease that still represents a considerable proportion of the daily new cases that creates a huge burden on the resources of health services. [START_REF] Verhelst | Clinical, epidemiological and cost aspects of contact lens related infectious keratitis in Belgium: results of a seven-year retrospective study[END_REF] The epidemiology of infectious corneal ulceration is influenced by several determinants, such as predisposing risk factors, developed versus developing country, urban versus rural location, climatic and geographic factors. [START_REF] Ibrahim | Factors affecting the epidemiology of Acanthamoeba keratitis[END_REF] The presence of a predisposing factor renders the corneal epithelium more vulnerable and more susceptible to microbial infections. CLW is frequently associated with severe forms of microbial keratitis. [START_REF] Sousa | Bilateral Acanthamoeba ulcer in a user of disposable soft contact lenses: a tragic incident or a consequence of the aggressive policy of soft contact lens trading?[END_REF] Corneal trauma, previous ocular surgery, ocular surface diseases, systemic illnesses, and the abuse of topical ophthalmic drugs are significantly associated with high rates of infectious corneal ulceration. [START_REF] Lam | Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America[END_REF][START_REF] Schaefer | Bacterial keratitis: a prospective clinical and microbiological study[END_REF][START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] Little information has been published on the frequency of predisposing factors, factors affecting clinical and visual outcome and follow-up duration in patients with infectious corneal ulceration. The aim of this study is to identify the incidence, demography, predisposing factors, clinical and microbiological profile, follow-up duration and visual acuity changes in patients with infectious corneal ulceration in southern England using a large population of patients over several years.

PATIENTS AND METHODS

The medical records of patients presenting with infectious corneal ulcers to the eye casualty department of Queen Alexandra Hospital in Portsmouth between January 1997 and December 2003 were reviewed. This retrospective study was approved by the Portsmouth and South East Hampshire Health Authority Research Ethics Committee.

A corneal ulcer was defined as a suppurative corneal infiltrate associated with an overlying epithelial defect. The widest diameter was used to determine ulcer size and accordingly grouped into; small (<2mm), medium (2-4mm) or large (>4mm).

Corneal scrapes were routinely collected from all patients with corneal ulceration for the microbiology assessment unless a clearly diagnostic clinical pattern of ulcer is present. The corneal scrapes were inoculated onto blood agar, chocolate agar, fastidious anaerobe agar, brain heart infusion broth for isolation of bacteria; Sabouraud's dextrose agar for isolation of fungi; and non-nutrient E. coli enriched agar for isolation of Acanthamoeba. Selective media, such as Lowenstein-Jensen for Nocardia and Mycobacteria were used if clinically indicated.

A positive isolate was defined as a growth along the line of inoculation on solid media or growth in the liquid media that was confirmed by microscopy. Isolates were subjected to in vitro antimicrobial sensitivity testing against the commonly used antibiotics using the disc diffusion method.

The diagnosis of viral ulcers relied in the majority of cases on the characteristic clinical pattern of viral corneal ulcers. In patients with a suspicious clinical pattern, corneal samples were assessed using immuno-fluorescence.

The follow-up duration was the number of days elapsed between patient's first and the medically recommended last visit on the completion of ulcer resolution. The bestcorrected presenting visual acuity, using Snellen chart, was compared with the bestcorrected visual acuity on the last visit. Patients with impaired visual acuity due to other reasons rather than the presenting corneal ulceration and also patients who did not complete the follow-up were excluded from the visual acuity assessment. Patients were considered to have poor outcome if they lost one or more of the Snellen lines.

Chi-square and Fisher's exact test were used for the analyses of categorical data. Coxregression was used to evaluate factors affecting follow-up duration. The 95% confidence interval limits were provided and p-value ≤0.05 was considered significant. SPSS software (V11.0) for Windows was used for statistical analysis.

RESULTS

Epidemiologic characteristics

A total of 1,786 patients (3.3%) out of total 53,341 casualty attendees presented with infectious corneal ulcer between January 1997 and December 2003 with an annual incidence of 478/100,000. The average age of patients was 45 years with predominance of females (974, 54.5%). The average number of patients seen per year was 255. A simple linear regression indicated a significant linear upward trend (p=0.04). There was a significant seasonal variation in the number of patients seen (Chi-square=26.5, p=0.005) with two seasonal peaks, in January and July. The general demographic criteria are shown in Table (1).

The predisposing factors

The majority of patients (80.9%) had at least one risk factor. The average age of patients varied according to the associated risk factor. Thirty-five, 48 and 52 years were the average age in CLW, eye trauma and ocular diseases respectively. CLW was the main risk factor in 554 patients (31% Ciprofloxacin was the frequently used topical medication in 692 (88.9%) of the total 778 patients with bacterial keratitis. Only 2% of all bacterial isolates were resistant to ciprofloxacin and no Gram-negative isolates were resistant to gentamicin.

The profile of Gram-positive organisms showed no difference between CLWs and non-CLWs (Chi-square=12.6, p=0.125), however the distribution of Gram-negative bacteria was significantly dependent on CLW (Chi-square=27.7, p<0.0001).

Visual acuity changes

The presenting visual acuity ranged from 6/4 to hand movement.

Attendance and follow-up

Fifty-eight patients (3.2%) attended once (95%CI 2.5-4.2) while the majority of patients (1,728, 96.8%) repeatedly sought medical help; 1,633 patients (91.4%) completed the follow-up till ulcer resolution (95%CI 90-94) and 95 patients (5.3%) did not complete the follow-up (95%CI 4-7).

Old age, females, presence of more than one predisposing factor, bad presenting visual acuity, large and centrally located ulcers and having P. aeruginosa or Acanthamoeba keratitis were significantly more likely to prolong the duration of follow-up (p<0.001). The lower the value of the hazard ratio the more likely the patient to be old, female or having a severe form of keratitis.

DISCUSSION

The current study included 1,786 patients with infectious corneal ulcers who attended the eye casualty department at Queen Alexandra Hospital, Portsmouth, one of the busiest hospitals in south England. This large population is likely to reflect the exact incidence of infectious corneal ulcers.

The annual number of patients with infectious corneal ulcers averaged 255 cases, representing 3.3% of the total ophthalmic attendees. In New Zealand 7 infectious keratitis accounted for 2% of total attendees. In the Hong Kong study, [START_REF] Lam | Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America[END_REF] 223 patients were recruited in 17 months and in France 6 291 patients were examined in 20 months.

The relatively high rate of infectious keratitis reported in our series could be due to the long period of our study. Furthermore, unlike the French study [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] that involved only patients with pure bacterial keratitis, our study included all types of infectious ulcers.

The average age of patients was 45 years, exactly the same age reported in the New Zealand study, [START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF] but was higher than age averages; 39, 40.7 and 44.3 years reported in France, [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] Taiwan 8 and Switzerland 5 respectively. The average age varied according to risk factor type. CL-related keratitis occurred in young patients at average age 35 years compared with 48 and 52 years in patients with corneal trauma and ocular disease respectively. Different studies reported comparable young mean of age in CLrelated keratitis. [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF][START_REF] Neumaier-Ammerer | Corneal infiltrates and ulcers. A retrospective study of 239 eyes[END_REF][START_REF] Mcnally | Risk factors for corneal infiltrative events with 30-night continuous wear of silicone hydrogel lenses[END_REF] The average age also varied significantly according to infection type. In bacterial and viral keratitis, the average age was 47 years compared with 32 years for Acanthamoeba keratitis. This low average age could be due to the tendency of Acanthamoeba to occur in CLW, who tended to be young. Our results showed that 81.8% of Acanthamoeba patients were CLW.

Female preponderance in our study may be because the majority of CLW were females. Females accounted for 63.7% and 50.4% of CLW and non-CLW respectively. McNally et al. [START_REF] Mcnally | Risk factors for corneal infiltrative events with 30-night continuous wear of silicone hydrogel lenses[END_REF] reported that 70% of lens-related infiltrative events occurred in women.

Our results showed seasonal variation in infectious keratitis in patients among whom CLW was the main risk factor. Despite the fact that there is no clear, obvious or direct correlation has been found between CLW and seasonal variation in the literature, it has been suggested that lens wear has an at least additive effect that increases the possibility of infectious keratitis. [START_REF] Reddy | Relationship of contact lenses, pregnancy, and herpes simplex virus[END_REF] At least one predisposing factor was detected in 80.9% of patients. This is lower than the results of other keratitis studies; 88%, 7 90.6% 6 and 97% 12 respectively. Lens wear, associated ocular disease and corneal trauma were the main risk factors that matched the findings of other studies. [START_REF] Schaefer | Bacterial keratitis: a prospective clinical and microbiological study[END_REF][START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF][START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF][START_REF] Gudmundsson | Factors influencing predilection and outcome in bacterial keratitis[END_REF][START_REF] Miedziak | Risk factors in microbial keratitis leading to penetrating keratoplasty[END_REF][START_REF] Morlet | Risk factors for treatment outcome of suspected microbial keratitis[END_REF] CLW accounted for 31% of our patients. However, CLW can account for up to 56% 9 compared with 0.6% in places where CLW was unpopular. [START_REF] Sharma | Trends in contact lens-associated microbial keratitis in Southern India[END_REF] A declining trend in the rate of lens-related keratitis was noticed since the late 90s following the introduction of fluoroquinolones. [START_REF] Prajna | Bacteriologic and clinical efficacy of ofloxacin 0.3% versus ciprofloxacin 0.3% ophthalmic solutions in the treatment of patients with culture-positive bacterial keratitis[END_REF] The relatively low rate of lens-related keratitis in our study could be because only patients with true ulceration were included, but not cases with stromal infiltrations covered with intact epithelium, which frequently associate the CLW and resolve upon CLW discontinuation. The inclusion of frank ulcers avoided giving false overestimation of the actual figures of lens-related keratitis. [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] Soft lenses were used by 96.3% of patients compared with the reported 92.5%, [START_REF] Verhelst | Contact lens-related corneal ulcers requiring hospitalization: a 7-year retrospective study in Belgium[END_REF] 89.4% 6 and 53%. [START_REF] Neumaier-Ammerer | Corneal infiltrates and ulcers. A retrospective study of 239 eyes[END_REF] Hard and rigid gas-permeable lenses were used by 3.6% of patients compared with the reported 10.6% 6 and 28.4% [START_REF] Inoue | Contact lens-induced infectious keratitis in Japan[END_REF] It is agreed among different authors that ocular surface diseases predispose to infectious keratitis. [START_REF] Lam | Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America[END_REF][START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] History of ocular diseases accounted for 23.7% of the total population that was comparable to the reported 21%. [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] Gram-positive organisms accounted for 71.1% of the proved bacterial growth. The predominance of Gram-positive bacteria in our study is comparable with other results. [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF][START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF][START_REF] Reddy | Relationship of contact lenses, pregnancy, and herpes simplex virus[END_REF][START_REF] Tuft | In vitro antibiotic resistance in bacterial keratitis in London[END_REF][START_REF] Toshida | Trends in microbial keratitis in Japan[END_REF] Gram-negative bacteria accounted for 28.9% of the total positive isolates, higher than the 17% reported in France 6 and 18.2% in Japan 20 but less than the 40% reported in the USA. 12 P. aeruginosa was the main Gram-negative bacterium isolated from 12% of all isolates. This predominance of P. aeruginosa was comparable to 14% 12 and 21.1% 21 reported in other keratitis studies.

Our results showed that Gram-positive bacteria were the main bacteria isolated from 61.9% of CLWs. The predominance of Gram-positive bacteria accounted for 67% [START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF] and 82.9% [START_REF] Inoue | Contact lens-induced infectious keratitis in Japan[END_REF] of CL-related keratitis. However, these results are at variance with the results of other investigators [START_REF] Lam | Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America[END_REF][START_REF] Neumaier-Ammerer | Corneal infiltrates and ulcers. A retrospective study of 239 eyes[END_REF] that showed predominance of Gram-negative bacteria in CLW that could account for up to 70%. [START_REF] Verhelst | Contact lens-related corneal ulcers requiring hospitalization: a 7-year retrospective study in Belgium[END_REF] Our results showed that S. epidermids was the main isolated bacteria from patients with infectious keratitis. The S. epidermidis is the most frequently isolated bacterium from ocular flora. [START_REF] Pfaller | Laboratory, clinical, and epidemiological aspects of coagulase-negative staphylococci[END_REF] The predominance of coagulase negative staphylococci isolated from keratitis patients has been reported. [START_REF] Schaefer | Bacterial keratitis: a prospective clinical and microbiological study[END_REF][START_REF] Bourcier | Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases[END_REF][START_REF] Miedziak | Risk factors in microbial keratitis leading to penetrating keratoplasty[END_REF] In addition, S. epidermidis strains from endophthalmitis, corneal ulcers and conjunctivitis represented 34.1%, 33.9% and 46% of the reported oxacilin resistance respectively. [START_REF] Juárez-Verdayes | Isolation, vancomycin resistance and biofilm production of Staphylococcus epidermidis from patients with conjunctivitis, corneal ulcers, and endophthalmitis[END_REF] Genetic differences between pathogenic strains of S. epidermidis isolated from keratitis and endophthalmitis and those constituting the normal commensal conjunctival flora have been reported [START_REF] Frebourg | PCR-based assay for discrimination between invasive and contaminating Staphylococcus epidermidis strains[END_REF] with the suggestion that commensal strains can evolve into pathogenic ones. [START_REF] Melles | Natural population dynamics and expansion of pathogenic clones of Staphylococcus aureus[END_REF] Anterior uveitis was a common feature in 48.4% of patients and 16% of them had hypopion either at presentation or during the course of the infection. Wong et al. [START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF] reported anterior uveitis in 59% of cases with 20% exhibited a hypopyon at presentation.

Acanthamoeba keratitis was diagnosed in 1.6% of lens-related infectious keratitis.

The spectrum of lens related Acanthamoeba keratitis ranged from 0.49% 21 to 4.7%. [START_REF] Butler | Six-year review of Acanthamoeba keratitis in New South Wales, Australia: 1997-2002[END_REF] Acanthamoeba and P. aeruginosa infections were associated with severe keratitis particularly in CLWs that eventually led to poor visual outcome. In our series 1.9% of patients had poor visual outcome compared with 5% 6 and 5.8% 5 reported in other studies.

As expected, centrally located and large sized-corneal ulcers were associated with high rate of poor presenting visual acuity, poor vision outcome that matched the findings of others. [START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF][START_REF] Miedziak | Risk factors in microbial keratitis leading to penetrating keratoplasty[END_REF] Large and central ulcers are commonly complicated with endophthalmitis 34 and needed surgical treatment with penetrating keratoplasty. [START_REF] Miedziak | Risk factors in microbial keratitis leading to penetrating keratoplasty[END_REF] The mean time of follow-up period, which reflects the duration of corneal ulcer resolution, was 11.5 days. Suchecki et al. [START_REF] Suchecki | Peripheral corneal infiltrates associated with contact lens wear[END_REF] reported that 1.74 weeks (12.2 days) was the mean time needed to complete resolution for all corneal infiltrates. Two weeks [START_REF] Morlet | Risk factors for treatment outcome of suspected microbial keratitis[END_REF] and 14.7 days [START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF] were the reported average time needed for complete healing of corneal ulcers. Unsurprisingly, the follow-up time of patients was significantly prolonged in elderly, multiple risk factors, compromised corneas, poor presenting visual acuity, resistant infections, large-sized and centrally located ulcers. [START_REF] Wong | Severe infective keratitis leading to hospital admission in New Zealand[END_REF]

Table ( 1): General characteristics of 1786 patients with infectious keratitis Variable Particulars No. of patients %

 (

	Age group	11-20	153	8.6
		21-30	322	18
		31-40	365	20.4
		41-50	268	15
		51-60	254	14.2
		61-70	192	10.8
		71-80	143	8
		81-90	73	4.1
		91-97	16	0.9
	Gender	Female	974	54.5
		Male	812	45.5
	Annual distribution	1997	208	11.6
		1998	257	14.4
		1999	264	14.8
		2000	236	13.2
		2001	268	15
		2002	272	15.2
		2003	281	15.7
	Seasonal variation	January	167	9.3
		February	122	6.8
		March	128	7.2
		April	128	7.2
		May	157	8.8
		June	166	9.3
		July	176	9.9
		August	170	9.5
		September	148	8.3
		October	141	7.9
		November	129	7.2
		December	154	8.6

Table ( 2): Predisposing factors in 1786 patients with infectious keratitis

 ( Soft contact lenses (CL) were used by 534 patients (96.4%) while rigid gas permeable and hard (CL) were used by 13 (2.3%) and 7 (1.3%) patients respectively.The wearing modality of 51 soft lens wearers (9.6%) was not documented. Other risk factors including; ocular diseases (424, 23.7%), ocular trauma (115, 6.4%), regular use of medications (87, 4.9%) and systemic diseases (84, 4.7%) are presented in Table(2).

	Clinical characteristics
	Infectious corneal ulcers involved the left, right and both eyes simultaneously in 855
	(47.9%), 799 (44.7%) and 132 (7.4%) patients respectively. The majority of ulcers
	were single (1,591, 89%) and small (1,645, 92.1%). Medium and large-sized ulcers
	occurred in 100 (5.6%) and 41 (2.3%) patients respectively. There was a
	predominance of midperipheral localisations (37.7%) followed by marginal (24.3%),
	central (23.6%) and paracentral (14.3%) zones. Ulcer location varied significantly
	Predisposing between (CLW) and non-(CLW) (Chi-square=38.2, p<0.0001). One or more of ocular Particulars No. (%) Total (%) (95% CI) factor inflammatory signs and complications occurred in 287 patients (16.1%) including;
	Contact lens wear anterior uveitis 139 (48.4%), hypopion 46 (16%), corneal neovascularisation 36 Soft 534 (29.9) 554 (31) (29 -33) Rigid gas permeable 13 (0.7)
	Hard Previous keratitis (12.5%), corneal scar 35 (12.2%), corneal abscess 18 (6.3%), endophthalmitis 9 7 (0.4) Ocular diseases 173 (9.7) 424 (23.7) (22 -26)
	Blepharitis (3.1%), severe corneal thinning or perforation 8 (2.8%) and sclerokeratitis 5 (1.7%). 41 (2.3)
		Dacryocystitis	40 (2.3)
		Dry eye	27 (1.5)
		Chronic conjunctivitis	26 (1.5)
		Chronic marginal keratitis	25 (1.4)
		Exposure keratitis	15 (0.8)
		Lid margin position disorders	13 (0.7)
		Recurrent erosion syndrome	11 (0.6)
		Allergic conjunctivitis	11 (0.6)
		Previous ocular surgery	10 (0.6)
		Glaucoma	9 (0.5)
		Orbital cellulitis	6 (0.3)
		Scleritis	5 (0.3)
		Endophthalmitis	4 (0.2)
		Lid cancer	3 (0.2)
		Ocular radiation	3 (0.2)
		Corneal melt	2 (0.1)
	Corneal trauma	Mechanical trauma	69 (3.9)	115 (6.4)	(5-8)
		Corneal foreign body	26 (1.5)
		Chemical burn	9 (0.5)
		Thermal burns	6 (0.3)
		Phototoxicity (Ultraviolet rays)	5 (0.3)
	Medications	Topical steroids	42 (2.4)	87 (4.9)	(4 -6)
		Topical antibiotics	33 (1.8)
		Topical anaesthetics	7 (0.4)
		Immunosuppressants	5 (0.3)
	Systemic illness	Rheumatoid arthritis	20 (1.1)	84 (4.7)	(4 -6)
		Flu	13 (0.7)
		Diabetes mellitus	10 (0.6)
		Malignancy	10 (0.6)
		Systemic lupus	9 (0.5)
		Eczema	8 (0.5)
		Organ failure	6 (0.3)
		Asthma	5 (0.3)
		GIT inflammatory diseases	3 (0.2)
	Mixed factors			181 (10.1)	(9 -12)
	Unknown cause			341 (19.1)	(17 -21)

). The majority (353, 63.7%) of CLWs were females.

Microbiological characteristics

In 532 patients (29.7%) corneal ulcers were diagnosed and treated according to the presenting clinical features, 442 (83.1%) of them were treated with antiviral medications while the remaining 90 (16.9%) ulcers were treated with topical antibiotics. Corneal scrapes from 1,254 patients grew positive cultures in 800 patients (63.8%) as shown in Table

(

3).

Table ( 3): Microbial growth pattern in 1254 cultures Variable Particulars No. (%)

 ( Pure bacterial growth was detected in 683 (54.5%) cultures with the predominance of single bacterial species (522, 41.6%). The majority of the isolated bacterial organisms were Gram-positive (696, 71.1%) with a predominance of Staphylococcus epidermidis (310, 31.7%). Gram-negative bacterial isolates accounted for 283 (28.9%) of the total 979 bacterial isolates with the predominance of P. aeruginosa

	(117, 12%) as presented in Table (4).
	Pure bacterial growth	Single species	522 (41.6)
		Two species	130 (10.4)
		≥Three species	31 (2.5)
	Mixed microbial growth	Bacteria and viruses	64 (5.1)
		Bacteria and Chlamydia	12 (1.0)
		Bacteria and Acanthamoeba	11 (0.9)
		Bacteria and fungus	8 (0.6)
	Pure viral growth		22 (1.8)
	Positive cultures		800 (63.8)
	Negative cultures		454 (36.2)
	Total		1254 (100)

Table ( 4): Distribution of 979 bacterial isolates in 800 positive cultures

 (

	Isolated organisms	Single species	Mixed bacteria with other	Mixed microbes with other	Total (%)
	Gram positive organisms
	Staphylococcus epidermidis	171	97	42	310 (31.7)
	Staphylococcus aureus	71	22	20	113 (11.5)
	viridans streptococcus	31	40	2	73 (7.5)
	Diphtheroids	20	38	11	69 (7)
	Streptococcus pneumoniae	31	14	1	46 (4.7)
	Methicillin resistant S. aureus	9	10	5	24 (2.5)
	Haemolytic Streptococci	7	10	4	21 (2.1)
	Bacillus species	12	6	1	19 (1.9)
	Enterococcus species	2	10	---	12 (1.2)
	Propionibacterium acnes	---	4	---	4 (0.4)
	Micrococcus species	3	---	---	3 (0.3)
	Streptococcus mitis	1	---	---	1 (0.1)
	Lactococcus lactis	---	1	---	1 (0.1)
	Subtotal	358	252	86	696 (71.1)
	Gram negative organisms
	Pseudomonas aeruginosa	63	47	7	117 (12)
	Coliforms	59	37	8	104 (10.6)
	Proteus species	10	7	1	18 (1.8)
	Haemophilus influenzae	12	2	2	16 (1.6)
	Moraxella catarrhalis	11	2	1	14 (1.4)
	Neisseria species	4	3	1	8 (0.8)
	Serratia marcescens	4	---	---	4 (0.4)
	Acinetobacter Iwoffii	1	1	---	2 (0.2)
	Subtotal	164	99	20	283 (28.9)
	Total	522	351	106	979 (100)

Competing Interest

Competing Interest: None declared A highly significant relationship was found between follow-up completion and the presence of risk factors, presenting visual acuity, type of infection, ulcer location (p=<0.0001), ulcer size (p=0.006), age (p=0.012), occurrence of complications (p=0.056). The follow-up duration ranged from 7 to 42 days with an average of 11.5 days. Cox-regression analysis for factors affecting the follow-up duration in 1,633 patients who completed follow-up is presented in Table (5).


Vikas Chadha

Mark Wright

Small Margin Excision of Periocular Basal Cell Carcinomas

Keywords:

Aims: To analyse the outcome of small margin (up to 2mm) excision of primary clinically well-defined peri-ocular basal cell carcinomas (BCCs).

Methods:

Retrospective evaluation of 90 well-demarcated primary basal cell carcinomas having a minimum follow-up of 36 months. All patients underwent excision of the tumour with maximum margins of 2mm. Resulting defects were, if possible, closed directly.

Reconstruction of defects requiring flaps or grafts was delayed until receipt of the histological report which was obtained in all cases.

Results: One-stage excision and direct closure was performed in 67 patients (74.4%). In 23 patients (25.6%) excision was performed on one day and reconstruction was done four days later, after receipt of the histopathology report. Histological assessment confirmed complete excision after the first excision in 78 (86.7%) rising to 83 (92.2%) after 2 excisions. The mean follow-up was 47.5 + 9.1 months. Of the 12 cases with incompletely excised lesions, seven of the patients chose not to have any more surgery and only one of these recurred.

There were two other recurrences, and in both of them the lesion had initially been reported as completely excised. Overall the recurrence rate in our study was 3.3% (n=3).

Conclusions:

Our recurrence rate compares well with published results following conventional excision of BCCs. In the absence of availability of Mohs surgery, well demarcated nodular basal cell carcinomas can be safely excised using smaller margins than conventionally practised.

TEXT

Introduction

Basal cell carcinoma (BCC) is the most common of all malignant eyelid tumours accounting for 90-95% of cases. They occur most commonly at the lower lid (50-60%) and then at the medial canthus, upper eyelid and lateral canthus in decreasing frequency. [START_REF] Bernardini | Management of malignant and benign eyelid lesions[END_REF] Surgical excision is regarded as the definitive mode of treatment though many other modalities including cryotherapy, radiotherapy, photodynamic therapy and topical treatment have been described. Moh's micrographic surgery is widely regarded as the gold standard for the complete excision of any dermatological tumour because it preserves the maximum amount of healthy tissue while providing the best assurance of the completeness of removal. [START_REF] Malhotra | The Australian Mohs database, part II. Periocular basal cell carcinoma at 5-year follow-up[END_REF] However it is time consuming, expensive and requires local expertise, and is, therefore currently impractical for all tumours due to it's patchy availability in the UK.

Conventionally, basal cell carcinomas are excised with 3-4mm margins, combined with primary repair. [START_REF] Wolf | Surgical margins for basal cell carcinoma[END_REF] In the peri-ocular region, especially when the lid margin is involved, such wide excision results in large defects requiring complex reconstruction. Hsuan et al have reported excellent results following the use of 2mm margins in peri-ocular BCCs excised in a staged manner. [START_REF] Hsuan | Small margin excision of periocular basal cell carcinoma: 5 year results[END_REF] For the past 8 years, we have used similar margins for all clinically welldefined primary lesions in order to preserve more healthy tissue enabling more straightforward closure resulting in reduced patient morbidity. We undertook this retrospective study to ascertain the histological clearance rate and the recurrence rate of our practise of small-margin (2mm) excision of BCCs.

Materials and Methods

Patient details were obtained from a diary record dating back to 1999 in which the details of all patients undergoing a lid lesion biopsy were recorded. The case notes for all histopathologically proven basal cell carcinoma excised between January 1999 to December 2003 were examined. The following cases were then excluded from the study:

1. Clinically poorly demarcated BCC's (irrespective of histopathology) 2. Follow up of less than 36 months from date of excision

Recurrent BCCs

Procedure of excision

The margins of excision were marked 2mm outside the clinical margins of the tumour. This was often done with magnification of the slit lamp to facilitate identification of the margins of the tumour. [START_REF] Macrae | Non-micrographic excision of eyelid tumours-ten practical tips[END_REF] All tumours were excised under local anaesthetic (2% lignocaine with 1:200,000 adrenaline.) All resulting defects were, if possible, closed directly. Others ie those needing a flap or a graft were scheduled for reconstruction four days later with a request to the department of pathology for an urgent report to be provided before the day of reconstruction.

No arrangements for Moh's surgery existed locally. Therefore, all samples were sent for conventional pathological examination by paraffin section.

Results

A total of 113 cases were identified of which case notes were available for 102 patients.

Ninety cases (n=90) fulfilled the inclusion criteria. The age ranged between 35-97 years with a mean of 73.9 + 11.8 years. Forty-nine (54%) of these patients were female. The distribution of the basal cell carcinomas was as follows: lower lid = 45 (50%), medial canthus = 23 (26%), upper lid = 14 (16%) and lateral canthus = 8 (9%).

Type of Excision

One-stage clinical margin-controlled excision and reconstruction was performed in 67 (74.4%) of the patients. In 23 patients (25.6%) excision was performed on one day and reconstruction was done four days later after receipt of the histopathology report. If histopathology indicated inadequate excision, the patient underwent further excision before reconstruction. However reconstruction was not delayed a second time and was performed without awaiting the second histopathological report.

All defects that could be closed directly without the use of flaps or grafts were reconstructed in the same setting. It was felt that if after one-stop direct closure the histology subsequently deemed the tumour to be incompletely excised, further excision and closure is not been compromised by the initial surgery. The majority of the lesions in the group undergoing delayed reconstruction can be assumed to be larger as they were obviously not amenable to direct closure. However data on the exact sizes was not available.

Pathology results

Overall, 78 (86.7%) tumours were reported as completely excised after the first surgery. Of the 12 inadequately excised tumours, 8 were in the clinical margin controlled group (i.e. the group which underwent primary direct closure). After considering various risk factors including size, location and pathology, and discussing the pros and cons of the options of further excision or close follow-up, a joint decision was made to observe 7 of these 8 inadequately excised tumours. One of these 7 patients had a recurrence and underwent further surgery two years after the first excision. One patient decided to undergo further excision which was done three weeks after the first excision. Histopathology reported this sample as having no evidence of residual BCC.

Four of the inadequately excised tumours belonged to the group which underwent two-stage surgery. All of these underwent further excision of 2mm from the involved margin before reconstruction. However reconstruction was not delayed to await the report from the second sample. Of these, one was reported as having no evidence of residual BCC and three were reported completely excised.

The BCC was reported as nodular in 87 patients and morpheic in 3 (3.3%) patients. All morpheic tumors were reported as completely excised.

Recurrence

The follow-up ranged between 37-59 months with a mean of 47.5 + 9.1 months. Over this period there were 3 (3.3%) clinical recurrences noted. Two of these were in the lower lid tumors (presenting 14 and 18 months after the first excision) and one in a medial canthal lesion (presenting at 17 months after surgery) All of these recurrences occurred in the clinical margin controlled group. Thus the recurrence rate for the patients who underwent a two-staged procedure was 0%.

Figure 1 shows the results including distribution of the recurrences according to adequacy of excision. Two cases of recurrence occurred in whom the tumour was reported as having been completely excised.

Discussion

No clear standards have been laid down for histological clearance and recurrence rates after periocular BCC excision. Ideally a 100% histological clearance should be obtained before reconstruction and this should equate to 0% recurrence. This may be possible with a method of histological examination being available at the time of surgery as in Moh's technique or with frozen section examination. Both these techniques are dependent on the existence of appropriate equipment and skills in the unit and are more labour intensive. A second way of attempting to achieve complete histological clearance is by performing the surgery in at least two stages-excision and then awaiting the conventional paraffin section to be reported before proceeding with reconstruction. This second alternative requires at least two visits of the patient to the operating room and therefore increases the load on the service.

Table 1 shows that our histological clearance and recurrence rates are comparable to some of the large studies reporting results following conventional excision using 2-8mm margins. [START_REF] Hsuan | Small margin excision of periocular basal cell carcinoma: 5 year results[END_REF][START_REF] Hamada | Eyelid basal cell carcinoma: non-Mohs excision, repair and outcome[END_REF][START_REF] Conway | Surgery for primary basal cell carcinoma including the eyelid margins with intraoperative frozen section control: comparitive interventional study with a minimum clinical follow-up of 5 years[END_REF][START_REF] Wong | management of periocular basal cell carcinoma with modified en face frozen section controlled excision[END_REF] Frozen section control appears to give lower recurrence rates than conventional excision. [START_REF] Conway | Surgery for primary basal cell carcinoma including the eyelid margins with intraoperative frozen section control: comparitive interventional study with a minimum clinical follow-up of 5 years[END_REF][START_REF] Wong | management of periocular basal cell carcinoma with modified en face frozen section controlled excision[END_REF][START_REF] Pieh | Long term results after basal cell carcinoma excision in the eyelid region[END_REF] Moh's technique, however, has been reported to have recurrence rates as low as 0.6% making it the technique of choice if available and practical. and used 2mm margins in 13% of their 162 cases. [START_REF] Hamada | Eyelid basal cell carcinoma: non-Mohs excision, repair and outcome[END_REF] These were all small nodular BCCs. Their overall recurrence rate was 4.3% but data on the recurrence rate in the 2mm-margin subgroup has not been reported. Hsuan et al reported on five-year follow up for 55 patients who had a clinically well-demarcated nodular BCCs excised with 2mm margins and delayed repair. [START_REF] Hsuan | Small margin excision of periocular basal cell carcinoma: 5 year results[END_REF] They awaited the result of formal paraffin sections before proceeding for reconstruction (i.e.

two-stage surgery). Ten of their excisions were reported to have incomplete margins and underwent a further 2mm excision. Using this method they achieved a 0% recurrence rate in their cohort. One big advantage of our approach over Hsuan et al's approach is that majority (75 %) of our patients had their treatment completed at one visit saving a large amount of theatre time. Further, 2 of our 3 recurrences occurred in patients in whom the subsequent histology report had indicated that the tumour was completely removed, and 2 patients were in the one-stage surgery group. If we had chosen to delay closure until receipt of the pathology report then these patients would have had had two visits rather than one and would still have had recurrence of their tumours.

A two-stage procedure (primary excision with delayed repair) provides the opportunity to excise more tissue before reconstruction if the first sample has been noted as incompletely excised. Our recurrence rate of 0% in all the patients who underwent a two-staged procedure is the same as in Hsuan et al's study. Of the patients undergoing two-stage surgery, we did not wait for receipt of the (second) histology report before reconstruction. Thus, none of our patients returned for a third visit. In all of these four patients, the second pathology report subsequently showed complete tumour clearance and none of these tumours recurred. We believe that this approach, as in the one-stage surgery, is a reasonable compromise and is justified on the basis of our results. This helps prevent a significant increase in the caseload and a consequent increase in waiting times.

If positive margins are reported and no re-excision performed, the risk of recurrence is high.

Our recurrence rate in this group was 14.3% (1 of 12). Other studies have reported recurrence rates of up to 67%. [START_REF] Macrae | Non-micrographic excision of eyelid tumours-ten practical tips[END_REF] Two (2.6%) of our 'completely excised' BCCs recurred within the study period. It has been suggested that conventional paraffin sections examine only about 1% of the specimen, and therefore follow-up is essential even in 'complete excisions'.

If complete excision is reported, we see our patients at 1 month, 6 months and then annually for a total of five years. In cases of incomplete excision, the follow-up is more frequent for the first two years-at 1 month, 4 months and then 6-monthly for the next three visits before reverting to the annual visits. All patients are made fully aware of the risk of recurrence irrespective of the reported completeness of excision and are advised to contact us if they suspect any sign of recurrence. In case the patients travelling from long distances, we are equally happy to rely on local follow-up arrangements. In this situation we ensure that preoperative and post-operative photographs are sent to the department where follow-up is being organised. Some authors recommend life-long follow-up for all patients with periocular BCC. [START_REF] Wong | management of periocular basal cell carcinoma with modified en face frozen section controlled excision[END_REF] This may be ideal, but is impractical in the NHS setting.

The retrospective nature of the study has certain drawbacks. There was no data on the size of the tumours excised. This is an important prognostic factor. Periocular BCCs larger than 10mm have been reported to have nearly four times the recurrence rates of smaller BCCs in the same location. [START_REF] Thissen | A systematic review of treatment modalities for primary basal cell carcinomas[END_REF] Further all the patients were not operated by the same surgeon. Finally, this study is somewhat limited by its minimum three year follow-up although the mean follow-up was nearly four years. It is said that only 66% of all recurrences appear within three years of the primary excision. [START_REF] Rowe | Long term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up[END_REF] Our study suggests that the histological clearance rates and recurrence rates at our department are not significantly compromised by using smaller (2mm) than conventional margins for clinically well-demarcated nodular basal cell carcinomas. Mohs surgery remains the technique which results in minimum tissue excision. However, in the absence of its availability, healthy periocular tissue can be preserved by using 2mm margins for clinically well-defined lesions simplifying subsequent reconstructive procedures.

Licence for Publication

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BJO and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://bjo.bmj.com/ifora/licence.pdf).

Competing Interest: None declared.

TOTAL NUMBER OF BCCS N = 90

Completely

  FIGURE 1

Table 1 : Comparison of our results with some large published studies

 1 [START_REF] Malhotra | The Australian Mohs database, part II. Periocular basal cell carcinoma at 5-year follow-up[END_REF][START_REF] Mohs | Micrographic surgery for the microscopically controlled excision of eyelid cancers[END_REF]

	Study	Technique	Number Mean	Histological	Recurrence
				Follow-up	clearance	rate
	Our	Clinical margin	90	4 yrs	86.7%	3.3%
	Study	(2mm) controlled		(min 3yrs)
		and two-stage
	Hsuan 4	2 mm margins;	55	5.8 yrs	81.8%	0%
	et al 2004	Two-stage		(min 5yrs)
	Hamada 6	Clinical margin (2-	69	Min 5 yrs 84%	4.3%
	et al 2005	4 mm) controlled
	Conway 7	Clinical margin (4-	31	6.4 yrs	90.3%	9.7%
	et al 2004	8mm) controlled		(min 5yrs)
		Frozen section	114	6.9 yrs	0%	0%
		controlled (3-4mm)		(min 5yrs)
	Wong 8	Clinical margin	113	2.6 yrs	92.9%	1.8%
	et al 2002	(3mm) controlled	20	5 yrs		5%
		Frozen section	423	2.6 yrs	--	0.7%
		controlled (2-4mm)	90	5 yrs		2.2%
	Pieh 9	Frozen section	298	5.7 yrs	--	5.36%
	et al 1999	controlled
	Only two published studies have reported on 2mm margins for clinically well-demarcated
	peri-ocular BCCs. Hamada et al analysed the outcome of non-Moh's excision in their unit


Mark Richard Wilkins

Bruce Allan

Moorfields Gary Rubin

Spectacle use after routine cataract surgery

Keywords:

published or not. The documents may come

Spectacle use after routine cataract surgery

INTRODUCTION

The standard treatment for patients undergoing routine cataract surgery is to insert a monofocal or fixed focus intraocular lens (IOL). When inserting such an IOL we frequently select an IOL power that will leave the patient with an emmetropic or low myopic prescription. Following bilateral phacoemulsification surgery where emmetropia has been targeted spectacle dependence for distance is at least 40%. 1 2 What is not clear is what factors in the post-operative refraction predict whether a patient will be spectacle dependant for near or distance. Knowledge of such factors would allow the surgeon, by changing the IOL power selected, or by managing preoperative astigmatism, to reduce spectacle dependence.

METHODS

This study is an analysis of data collected from a study to examine vision related quality of life after routine bilateral sequential phacoemulsification. Three hundred cataract patients were entered into a prospective study of visual outcomes after bilateral cataract surgery. Patients were randomised to sequential implantation with either the Tecnis Z9000 or the Acrysof MA60AC monofocal intraocular lenses.

Computer-generated randomization using a nonblocked coin-toss protocol was used to allocate patients to sequential bilateral implantation of the Z9000 IOL or MA60AC IOL. A spherical equivalent from 0 to -0.5 D was targeted in each eye. This study has been reported in detail elsewhere. [START_REF] Moorfields | Binocular implantation of the Tecnis Z9000 or AcrySof MA60AC intraocular lens in routine cataract surgery: prospective randomized controlled trial comparing VF-14 scores[END_REF] Inclusion criteria were : age 30 years and above, presence of bilateral visually significant cataracts. Exclusion criteria were: ocular co-pathology which might influence postoperative vision, congenital cataracts or a history indicative of amblyopia, pre-operative astigmatism greater than 1.5 D as measured by the IOLMaster keratometer. Wherever cataract density permitted biometry was performed using the IOLMaster, otherwise A-scan biometry was performed. Manufacturers' ultrasound A constants were used throughout. Information on the biometry technique used was retrospectively collected by examining the notes.

Four months after the second eye was operated on patients were interviewed about whether they wore spectacles for near and distance visual tasks and underwent a subjective refraction. Patients were asked whether they wore distance spectacles "always", "for driving/ TV only", or "never". They were also asked if they wore reading glasses "always", "for fine print only", or "never". Binocular uncorrected visual acuity (UCVA) and binocular best spectacle corrected visual acuity (BSCVA) were tested using Early Treatment of Diabetic Retinopathy Study (ETDRS) log minimum angle of resolution (logMAR) letter charts projected on a high resolution liquid crystal display at 4 metres from the subject. Refractions were performed by 2 trained ophthalmic technicians, using a precise protocol. The duochrome technique was not used. All refractions were recorded in minus cylinder format. Near acuities were not recorded as the original primary aim of the study was to assess the effect of 2 IOL designs on distance vision related quality of life. Spherocylindrical powers were converted to a 3 dimensional vector notation that included astigmatism and sphere powers (M, J 0 and J 45 ). [START_REF] Raasch | Clinical refraction in three-dimensional dioptric space revisited[END_REF] The spherical error (M) refers to the spherical equivalent, J0 and J45 refer to Jackson crossed cylinders with orientations of 0 and 45 degrees respectively. The values for M, J 0 and J 45 specify a point in space and the distance of this point from the origin represents overall refractive error (D). The astigmatic error (J) is half the cylindrical power. Visual acuity has been shown to decline systematically as D increases, regardless of the proportions of sphere and cylinder contributing to the blur. [START_REF] Raasch | Spherocylindrical refractive errors and visual acuity[END_REF] Logistic regression was used to evaluate whether the questionnaire responses to spectacle dependence for near and distance were related to D, M, and J. Normally M, J and D are unsigned. For the logistic regression we also used a signed version of M hypothesizing that sign would be important for reading spectacle dependence. For each pair of eyes one was labelled as "better" and the other as "worse". For analysis of distance spectacle use the "better" eye was the one with the lower value of M.

Where the M values were the same then the eye with the lower cylinder magnitude was labelled as better. For analysis of reading spectacle use the "better" eye was the one with the more myopic MRSE. A p value <0.01 was taken to be significant.

RESULTS

Between May 2003 and October 2006 300 patients underwent bilateral sequential cataract surgery. 179 patients attended for a refraction and assessment 4 months after their second eye was operated on. The low return rate was due to the trial population being recruited from a mobile, multiethnic population and a large number of cases were unavailable or could not be contacted. Refractive and questionnaire outcomes were available on 169 patients. The mean age of the patients was 70.7 years, 63 were male and 106 female. Average mean post-operative refractive spherical equivalent in the right eye was -0.03 D (range +2.0 to -1.5 D, SD 0.55 D) and the mean right cylinder was -0.64D (range 0 to -3.25 D, SD 0.63 D). In the left eye similar results were achieved mean refractive spherical equivalent= 0.00 D (range +1.75 to -1.85D, SD 0.57 D) and mean left cylinder = -0.70 D (range 0 to -3.0 D, SD 0.65 D). The best spheres were normally distributed (Shapiro Wilk test N.S.). Figures 1 and2 show the distribution of best sphere and manifest cylinder respectively for right and left eyes. Ninety six patients received Acrysof, 73 received TECNIS. Biometry in the right eye had been performed using the IOLMaster in 145, A-scan in 17. Information on the biometry technique used was not retrospectively available for 7 patients. The figures for the left eye were similar. The mean absolute difference in spherical equivalent between eyes was 0.34D (SD 0.34 D).

Since the surgery, 103 patients had obtained new spectacles. Ten (5.9 %) wore glasses with a distance prescription all the time, 28 (16.6 %) wore them some of the time. A total of 38 (22.5 %) wore glasses either some or all of the time. 131 (73.1%) never used distance glasses. 113 (66.7%) patients always wore glasses for reading, 47 (27.8%) for fine print only and nine (5.3 %) never wore glasses for reading. Table 1 shows the mean cylinder and spherical equivalents, unaided and aided logMAR binocular acuities for the 3 categories of distance spectacle use. Table 2 shows the mean cylinder and spherical equivalents, for the 3 categories of near spectacle use. There was no significant difference in the percentage of patients reporting near or distance spectacle use between Acrysof an TECNIS IOL recipients (Chi square test P>0.05).

The odds ratios for wearing spectacles "all of the time vs never" and "some of the time vs never" per dioptre of overall refractive error, spherical error and astigmatic error are shown in Table 3-distance spectacles, and Table 4-near spectacles.

Patients with greater overall refractive error (D) and greater astigmatic error (J) were much more likely to use glasses for distance. Within the range of refractions studied, astigmatic error had a much greater effect on the likelihood of spectacle use than overall error. In the better eye a patient was 33.96 times more likely to always use glasses per dioptre of astigmatic error compared to only 9.53 times more likely per dioptre of overall refractive error. Spherical error (M) was not predictive of distance spectacle use, and the sign of M (myopic vs. hypermetropic) was not relevant. These effects were seen for both the better and worse eyes, although the effect was less for the worse eye. Although refractive error in the "better" and "worse" eyes predicted distance spectacle use when separate models were fit for the two eyes, the "worse" eye no longer predicted distance spectacle use when both eyes were put into a single model.

For near spectacle use, unlike for distance, spectacle use was not dependent on overall refractive error (D) nor on astigmatic error (J). It was only related to the sign of the spherical error (M) in the "worse" eye. A patient was 6.74 times more likely to use near spectacles all of the time per dioptre of positive residual sphere. This effect is shown in mosaic plots of the regression analysis (Figure 3 and Figure 4). The plots show the percentage of patients who use spectacles for either distance or near vision as a function of astigmatic error (J) or spherical error (M). The mean difference in spherical error between eyes was low at 0.34 D. The difference in spherical error (M) between eyes was not a significant predictor of near or distance spectacle use (p > 0.5). Unplanned monovision thus had no significant effect on near spectacle use.

DISCUSSION

Reducing spectacle dependence is a common aim for cataract surgeons. Very little evidence exists about how spectacle independent patients are for distance tasks when emmetropia is targeted. There are 2 studies where spectacle dependence after bilateral monofocal IOLs has been described. 1 6 Javitt et al reported that 40% of patients targeted to receive emmetropia/ very low myopia were dependant on spectacles for distant use. [START_REF] Javitt | Cataract extraction with multifocal intraocular lens implantation: a multinational clinical trial evaluating clinical, functional, and quality-of-life outcomes[END_REF] In a second study comparing bilateral multifocal with monofocal IOL implantation Nijkamp showed that between 42 and 60% of monofocal patients reported always using distance glasses; the figure varied depending on the time point after the surgery. [START_REF] Nijkamp | Effectiveness of multifocal intraocular lenses to correct presbyopia after cataract surgery: a randomized controlled trial[END_REF] If emmetropia is targeted then most surgeons would assume that their patient would be dependant on reading glasses for near tasks. The same two studies found that 4-11% of patients were not dependant on reading glasses when emmetropia was targeted with monofocal IOLs. [START_REF] Javitt | Cataract extraction with multifocal intraocular lens implantation: a multinational clinical trial evaluating clinical, functional, and quality-of-life outcomes[END_REF] In this study we have shown that distance spectacle dependence after bilateral cataract surgery with a mean achieved spherical equivalent of 0 D is 22.5%, while near spectacle dependence is 95.7%. Furthermore the components of the refraction did not equally predict spectacle use. The odds of using distance glasses were 9.53 times greater for every dioptre of overall refractive error in the "better" eye, and 33.96 greater for each dioptre of astigmatic error in the "better" eye. Post-operative spherical error (M) had no predictive effect on the use of distance spectacles. Overall refractive error in the "worse" eye did not predict distance spectacle use when "better" and "worse" eyes were put into a single model.

For near spectacles overall refractive error, spherical error, and astigmatic error did not predict near spectacle use while only signed spherical error in the worse eye did. The more hypermetropic the spherical error in the "worse" eye the more likely the patient was to report wearing reading glasses. We were unable to demonstrate a monovision effect. Signed spherical error in the "better" (more myopic) eye did not predict near spectacle use, nor did the difference in spherical equivalent between eyes predict their use. However the mean absolute difference in spherical equivalent was small, 0.34 D it may well be that the amount of monovision achieved was too small for an effect to be seen. Some work has suggested that patients who end up with low myopia combined with some astigmatism after cataract surgery achieve "good" unaided near and distance acuity. 7 8 Both studies looked at eyes rather than patients and neither assessed the spectacle dependence of patients. 7 8 Although targeting low myopia with some myopic astigmatism does confer some unaided distance and unaided near acuity it may well be that static reading tasks such as the near test type don't really reflect real world situations. [START_REF] Elliott | Comparing clinical tests of visual function in cataract with the patient's perceived visual disability[END_REF] Phakic presbyopes fitted with contact lenses to give them either low spherical myopia (-0.5 D) or myopic astigmatism (plano/-1.0 D) have better intermediate distance acuity and refractive quality of life with spherical myopia rather than with myopic astigmatism, and there is no difference in distance and near acuities. [START_REF] Savage | Myopic astigmatism and presbyopia trial[END_REF] Studies analysing the effect of post cataract surgery low myopia and astigmatism have used an acuity ≥ 6/12 to select patients with relatively good unaided acuity. 7 8 Patients close to 6/12 unaided in each eye might have trouble meeting the minimal legal requirement to drive in the UK which approximates to 6/10. 11 Equally for near tasks variables such as maximum reading speed and critical print size may be more relevant. We have no information from the same studies about such variables.

Our use of the manufacturers A constants rather than ones optimised for the IOLmaster meant that our mean spherical equivalent was 0 D rather than between 0 and -0.5 D as targeted. The trial was started before this issue was widely known about. The standard deviation was 0.55D in the right eye and 0.57D in the left. Thus 95% of eyes had a spherical equivalent ± 1.0 D of emmetropia. This has allowed us to assess the effect of spherical equivalent for low hypermetropic and myopic outcomes. Previous studies have found a near spectacle independence rate of 0-11%. 1 2 6 Our figure of 5.3% falls in the middle of this range. We found that near spectacle use was significantly associated with signed spherical error. The association between spherical equivalent and near spectacle independence in this and the other 3 studies is shown in Table 5. The current interest in multifocal IOLs has heightened interest in achieving spectacle independence for near and distance tasks. Studies have highlighted the impact of astigmatism on the visual acuity in patients receiving multifocals. 12 13 Distance and intermediate acuities suffer greater impairment from astigmatism than monofocal IOLs. [START_REF] Hayashi | Influence of astigmatism on multifocal and monofocal intraocular lenses[END_REF] It is thus likely that distance spectacle dependence would be more sensitive to astigmatism in patients implanted with multifocals.

This study suggests that astigmatism needs to be corrected if distance spectacle dependence with monofocal IOLs is to be as low as possible. Even where multifocals are not being inserted accurately counselling and consenting patients prior to surgery is essential. Where a patient has astigmatism pre-operatively either they should be made aware of the chances of wearing glasses for distance tasks postoperatively or advised on available measures to reduce the astigmatism. Making one eye slightly myopic could also reduce near spectacle dependence.

The Blue Mountains study shows that 13% of patients have astigmatism over 1.5 D. [START_REF] Attebo | Refractive errors in an older population: the Blue Mountains Eye Study[END_REF] Furthermore the prevalence of astigmatism increases with age. [START_REF] Attebo | Refractive errors in an older population: the Blue Mountains Eye Study[END_REF] The mean cylinder was -0.6 D in persons aged 49-59 years while it rose to -1.2 D in those age 80-97 years. Knowledge of the impact of astigmatism on distance spectacle dependence is therefore crucial for ophthalmologists performing cataract surgery since the prevalence of cataracts and astigmatism both increase with age. [START_REF] Mitchell | Prevalence of cataract in Australia: the Blue Mountains eye study[END_REF]

See attached file

See attached file

See attached file

Figure 1

 1 Figure 1 Distribution of best sphere (D) for right and left eyes.

Figure 2

 2 Figure 2 Distribution of manifest cylinder (D) for right and left eyes.

Figure 3 Figure 4

 34 Figure 3 Percentage of patients who use spectacles for distance vision as a function of astigmatic error (J) in better eyes (top panel) and worse eyes (bottom panel) See attached file Figure 4 Percentage of patients who use spectacles for near vision as a function of spherical error (M) in better eyes (top panel) and worse eyes (bottom panel)

Table 1

 1 Numbers of patient reporting that they wore glasses for distance tasks against mean spherical equivalent and cylinder, binocular logMAR uncorrected (UCVA) and best spectacle visual acuities (BSCVA)

			R sph	R	L sph	L	Binocular	Binocular
		n	equiv	cylinder	equiv	cylinder	UCVA	BSCVA
	Always	10	-0.25	-1.17	-0.23	-1.28	0.1	-0.0086
	Driving/TV 28	-0.10	-0.66	-0.04	-0.75	0.069	-0.029
	Never	131	-0.01	-0.45	-0.00	-0.52	-0.032	-0.067

Table 2

 2 Numbers of patient reporting that they wore glasses for near tasks against mean spherical equivalent and cylinder

			R spherical	R	L spherical	L
		n	equivalent	cylinder	equivalent	cylinder
	Always	113	0.02	-0.61	0.03	-0.66
	Fine Print Only	47	-0.04	-0.62	-0.03	-0.77
	Never	9	-0.64	-1	-0.31	-0.83

Nijkamps's figure varied between 4 and 6.2% depending on the time post-op.[START_REF] Nijkamp | Effectiveness of multifocal intraocular lenses to correct presbyopia after cataract surgery: a randomized controlled trial[END_REF] A third study reported no patients receiving monofocal lenses were independent of glasses for all reading tasks.[START_REF] Harman | Comparing the 1CU accommodative, multifocal, and monofocal intraocular lenses: a randomized trial[END_REF]

The Moorfields IOL Study Group Study design: Bruce Allan, Catey Bunce, Fred Fitzke, Gary Rubin Recruiting surgeons: Wajda Abdullah, Bruce Allan, David Gartry, Alexander Ionides, Vincenzo Maurino, Stephen Tuft, Mark Wilkins, Richard Wormald Trial coordinator: Norman Dudley Visual assessment technicians: Kanom Bibi, Edward White Data entry: Wen Xing, Nicola Harris, Samantha Mann Data analysis: Catey Bunce, Gary Rubin, Samantha Mann, Wenn Xing, Mark Wilkins