Colm O'Brien

Patients' perception of visual impairment in glaucoma: a pilot study.

BACKGROUND/AIMS There is a paucity of useful information on the level of visual disability suffered by glaucoma patients. The aims of this study were to determine and rank the frequency of self reported visual disability in daily tasks performed by glaucoma patients; to examine the interrelation between disabilities using factor analysis; to study the relation between perceived visual difficulty and a measure of the severity of visual field loss; to develop a glaucoma specific subgroup of questions; and examine the validity and reliability of this subgroup of questions. METHODS 63 glaucoma patients completed a questionnaire containing 62 questions covering 10 broad aspects of daily life activities using a five point answer scale. Patients were classified into three groups as having mild, moderate, and severe field loss on the basis of the perimetric results. The relation between a measure of the severity of visual field loss and subjective visual disability in the three groups was examined. RESULTS Using factor analysis, the most frequently reported problems were grouped into the following four categories: outdoor mobility, glare and lighting conditions and activities demanding functional peripheral vision, household tasks, and personal care. These four factors accounted for 72% of the variability in the patients’ questionnaire responses. With increasing severity of binocular visual field loss there was an increase in the number of self reported visual problems. A loss of confidence in performing some routine daily tasks tended to precede self reported specific visual disabilities. The factor “glare and lighting and activities demanding functional peripheral vision” was found to have a significant relation with a measure of visual field loss and was used to create a glaucoma specific subset of questions. Cronbach’s α showed a high degree of reliability and internal consistency (α =0.96) in this glaucoma specific subset of questions. Furthermore, the validity of this new subset of questions was shown to be significant (r=0.037, p<0.05) for the correlation between a measure of the severity of binocular visual field loss and the mean score of the variables used in the glaucoma specific subgroup of questions. CONCLUSIONS Outcome measures and quality of life issues need to be addressed in glaucoma. This pilot study identified common problems encountered by patients which at the present time are not assessed in routine glaucoma care. It also identified a subgroup of questions that seems to be specific for glaucoma. Further research is required if a significant impact on the quality of life of glaucoma patients is to be achieved.

Pulsatile ocular blood flow investigation in asymmetric normal tension glaucoma and normal subjects

AIMS This study was designed to investigate pulsatile ocular blood flow (POBF) in normal tension glaucoma (NTG) patients and in normal controls. NTG patients with unilateral field loss were evaluated to compare POBF values between eyes with and without field loss. METHODS POBF measurements from more than 1500 subjects were collected during a period of 6 months from six optometric centres. Subjects with systemic vascular diseases (such as systemic hypertension and diabetes), ophthalmic diseases, a positive family history of glaucoma, and those individuals receiving treatment with systemic β blockers were excluded on the basis of a questionnaire. For comparison, 95 NTG patients with unilateral field loss, selected from 403 consecutive patients with NTG, underwent POBF testing. For each individual age, sex, intraocular pressure, refraction, and pulse rate were entered into a database. RESULTS Data from 777 subjects were included in the analysis. POBF measurements of patients and subjects were compared allowing for differences in age, sex, intraocular pressure, refraction, and pulse rate. POBF was significantly lower in eyes of NTG patients with and without field loss (p <0.001 and p = 0.01 respectively). Eyes of NTG patients with field loss showed significantly lower POBF than the contralateral eyes with normal field (p < 0.001). CONCLUSIONS POBF was significantly lower in eyes of NTG patients with and without field loss than in normal subjects, suggesting that differences in ocular blood perfusion are relevant to the development of NTG and are detectable from the early stage of the disease. Furthermore, the finding of lower POBF in NTG eyes with field loss than in the contralateral eyes with normal field suggests that haemodynamic differences between fellow eyes contribute to determine the side of onset of the disease.

Measurement of ocular blood flow velocity using colour doppler imaging in low tension glaucoma

The purpose of this study was to compare the velocity of blood flow and vascular resistance measured by colour Doppler imaging in the ophthalmic and central retinal arteries in 34 eyes of 34 patients (mean age 68.1 years) with low tension glaucoma (LTG) and 17 eyes of 17 agematched normal controls (mean age 65.2 years). The Acuson 128 machine (using a 7.5 MHz probe) was used to measure peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI). The EDV of the ophthalmic artery (OA) in the LTG was significantly (p = 0.04) less than in the normal control group. There was a significant (p = 0.02) increase in the vascular RI of both the OA and central retinal artery in the LTG group compared with the normal controls. The OA RI increased with age (r = 0.61, p = 0.0001), and the OA EDV decreased with age (r = −0.50, p = 0.003), in the LTG group but not in the normal control group. The results suggest an increased resistance to blood flow in the ophthalmic and central retinal arteries of LTG patients.

The Role of Glia, Mitochondria, and the Immune System in Glaucoma

Author(s): Tezel, Gulgun; Fourth ARVO/Pfizer Ophthalmics Research Institute Conference Working Group

Systemic vascular endothelial cell dysfunction in normal pressure glaucoma

Aim: Vascular risk factors, and particularly vasospasm, are thought to play a part in the pathogenesis of normal pressure glaucoma (NPG). This study aimed to determine whether the function of systemic resistance arteries was altered in patients with NPG. Methods: Contractile and relaxant function was assessed in arteries dissected from gluteal fat biopsies (11 NPG, 12 control) using small vessel myography. Results: Responses to K+ and noradrenaline were similar in patients and controls and were unaffected by endothelial removal. In contrast, responses to 5-hydroxytryptamine (5-HT; pD2; 7.29 (SD 0.16) v 6.66 (0.19); p=0.03) and endothelin-1 (ET-1; pD2, 9.12 (0.10) v 8.72 (0.13); p=0.03) were enhanced in arteries from patients with NPG. Removal of the endothelium enhanced responses to 5-HT (pD2, 6.66 (0.19) v 7.66 (0.08); p=0.003) and ET-1 (pD2, 8.72 (0.13) v 9.66 (0.39); p=0.02) in control arteries but not in those from patients. ET-1 mediated contraction in control and patient arteries was reduced in the presence of (10−5 M) nifedipine. Endothelium dependent and independent relaxation was not impaired in arteries from patients. Conclusions: This study has identified dysfunction of the systemic vascular endothelial cell in patients with normal pressure glaucoma. The vascular endothelium modulates contractile responses to 5-HT and ET-1 in human subcutaneous resistance arteries but this effect is lost in patients with NPG, indicating a selective defect in agonist mediated release of endothelium derived vasodilators. Selective antagonists of 5-HT and ET-1 may, therefore, help to prevent vasospasm in patients with NPG.

Elevated aqueous humour tissue inhibitor of matrix metalloproteinase-1 and connective tissue growth factor in pseudoexfoliation syndrome

Background/aims: Pseudoexfoliation syndrome (PXF) was recently found to be associated with increased expression of transforming growth factor β1 (TGFβ1) in the aqueous humour. As concern has been raised regarding anti-TGFβ therapy, which can potentially disrupt the maintenance of anterior chamber asso-ciated immune deviation, the authors explored the levels of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), and connective tissue growth factor (CTGF) in aqueous humour to determine if these may represent alternative therapeutic targets. Methods: Aqueous humour samples were collected from patients who underwent routine cataract surgery. All patients were categorised into three main groups—PXF, uveitis, and control. The PXF group was further subcategorised into three grades based on the density of the exfoliative material observed on biomicroscopy, as well as the presence or absence of glaucoma. TIMP-1, MMP-9, and CTGF levels were measured using specific enzyme immunoassays (ELISA). Results: Eyes with PXF had significantly higher aqueous humour TIMP-1 concentration (n = 56, mean (SE), 9.76 (1.10) ng/ml) compared with controls (n = 112, 5.73 (0.43) ng/ml, p<0.01). Similarly, the CTGF level in PXF eyes (n = 36, 4.38 (0.65) ng/ml) was higher than controls (n = 29, 2.35 (0.46) ng/ml, p<0.05). Further, the CTGF concentration in the PXF glaucoma group is significantly higher compared with PXF eyes without glaucoma (6.03 (1.09) ng/ml v 2.73 (0.45) ng/ml, p<0.01). The MMP-9 levels were low and below detection limit in all PXF and control samples with no statistical difference between groups. Conclusion: A raised TIMP-1 level and a low MMP-9 level in aqueous humour of PXF eyes may imply a downregulation in proteolytic activity. The increased CTGF concentration supports the proposed fibrotic pathology of PXF. Regulation of MMP/TIMP expression and anti-CTGF therapy may offer potential therapeutic avenues for controlling PXF associated ocular morbidity.

Transforming growth factor‐β‐regulated gene transcription and protein expression in human GFAP‐negative lamina cribrosa cells

Primary open‐angle glaucoma (POAG) is a progressive optic neuropathy, which is a major cause of worldwide visual impairment and blindness. Pathological hallmarks of the glaucomatous optic nerve head (ONH) include retinal ganglion cell axon loss and extracellular matrix (ECM) remodeling of the lamina cribrosa layer. Transforming growth factor‐β (TGF‐β) is an important pro‐fibrotic modulator of ECM metabolism, whose levels are elevated in human POAG lamina cribrosa tissue compared with non‐glaucomatous controls. We hypothesize that in POAG, lamina cribrosa (LC) glial cells respond to elevated TGF‐β, producing a remodeled ONH ECM. Using Affymetrix microarrays, we report the first study examining the effect of TGF‐β1 on global gene expression profiles in glial fibrillary acidic acid (GFAP)‐negative LC glial cells in vitro. Prominent among the differentially expressed genes were those with established fibrogenic potential, including CTGF, collagen I, elastin, thrombospondin, decorin, biglycan, and fibromodulin. Independent TaqMan and Sybr Green quantitative PCR analysis significantly validated genes involved in regulation of cell proliferation (platelet‐derived growth factor [PDGF‐α]), angiogenesis (vascular endothelial growth factor [VEGF]), ECM accumulation and degradation (CTGF, IL‐11, and ADAMT‐S5), and growth factor binding (ESM‐1). Bioinformatic analysis of the ESM‐1 promoter identified putative Smad and Runx transcription factor binding sites, and luciferase assays confirmed that TGF‐β1 drives transcription of the ESM‐1 gene. TGF‐β1 induces expression and release of ECM components in LC cells, which may be important in regulating matrix remodeling in the lamina cribrosa. In disease states such as POAG, the LC cell may represent an important pro‐fibrotic cell type and an attractive target for novel therapeutic strategies.

Trends in blind registration in the adult population of the Republic of Ireland 1996–2003

Background/aim: The Republic of Ireland has a centralised database of all registered, blind people in the country. The last study of the national blind register was undertaken in 1996. The current study sought, firstly, to investigate and identify any recent changes in the register composition. Secondly, there is concern that many eligible people are not appropriately registered. To examine this further, registration levels among patients attending an Irish outpatient ophthalmology clinic were determined. Methods: Criteria for blind registration in Ireland are (1) a best corrected visual acuity of 6/60 or less in the better eye, or (2) a visual field subtending an angle of 20 degrees or less. The National Council for the Blind in Ireland (NCBI) is the sole custodian of a national registration database recording all eligible, registered people. This computerised database was analysed to provide information on the demographics and blind registration condition of those on the register in 2003. This information was compared with the results of the 1996 study. To assess the accuracy of the current register, the registration status of eligible patients attending the outpatient clinic of a busy, tertiary referral ophthalmology department, over a 9 week period, was studied. Results: 6862 adults were registered as blind on the NCBI register in Ireland in 2003, representing an increase of 37% since 1996. The leading causes of registration were age related macular degeneration (ARMD) (25%), glaucoma (12%), and retinitis pigmentosa (7%). Comparing the 1996 and 2003 data, dramatic increases in the numbers registered caused by ARMD (from 812 to 1729 people, a 113% increase) and diabetic retinopathy (DR) (from 147 people to 323 people, a 120% increase) were found. The numbers registered as a result of glaucoma were relatively stable (795 in 1996 and 811 in 2003). A substantial drop, of 53%, was noted in the number of people registered as a result of cataracts, from 561 people to 261. Of the 672 new cases registered in 2003, ARMD accounted for 44%, glaucoma 13%, and DR 7%. Over the 9 week study period 75 patients, out of a total 2320 patients who attended the outpatient department, fulfilled the blind registration criteria. It was found that 21% (16 of 75) of the eligible clinic outpatients had not been appropriately registered. Conclusion: An overall increase in adult blind registration of 37% in the Republic of Ireland was found between 1996 and 2003. There were large increases in registered blindness as a result of ARMD (113%) and DR (120%). A notable decrease in registration as a result of cataracts was discovered. Vigilance by clinicians is necessary to ensure that eligible patients are registered.

Effect of cyclical mechanical stretch and exogenous transforming growth factor-beta1 on matrix metalloproteinase-2 activity in lamina cribrosa cells from the human optic nerve head.

Purpose:Extensive remodeling of the lamina cribrosa extracellular matrix occurs in primary open angle glaucoma. The transforming growth factor-β (TGF-β) and matrix metalloproteinase (MMP) protein families are implicated in this process. The authors investigated (a) the effect of cyclical mechanical stretch on TGF-β1 mRNA synthesis, TGF-β1 protein secretion, MMP-2 protein activity and (b) the effect of exogenous TGF-β1 on MMP-2 protein activity in human lamina cribrosa cells in vitro. Methods:Primary human lamina cribrosa cells grown on flexible and rigid plates were exposed to cyclical stretch (1Hz, 15%) or static conditions for 12 and 24 hours. Cells grown on 100-mm plates were exposed to human TGF-β1 (10 ng/ml) or vehicle (4 mM HCl/1% BSA) for 24 hours. TGF-β1 mRNA synthesis in stretched and static cells was measured using real-time polymerase chain reaction. TGF-β1 protein secretion in stretched and static cell media was measured using enzyme linked immunosorbent assay. Gelatin zymography measured MMP-2 activity in stretched, static, TGF-β1- treated and vehicle-treated cell media. Results:Cyclical stretch induced significant increases in TGF-β1 mRNA synthesis after 12 hours (**P < 0.01) and TGF-β1 protein secretion after 24 hours (*P < 0.05). Cyclical stretch significantly (*P < 0.05) increased MMP-2 activity in cell media after 24 hours. Exogenous TGF-β1 induced a significant (**P < 0.01) increase in cell media MMP-2 activity after 24 hours. Conclusions:These results suggest that cyclical stretch and TGF-β1 modulate MMP-2 activity in human lamina cribrosa cells. TGF-β1 and MMP-2 release from lamina cribrosa cells may facilitate matrix remodeling of the optic nerve head in primary open angle glaucoma.

Psychophysical evidence for a selective loss of M ganglion cells in glaucoma

We measured resolution acuity at 12 different retinal locations using sinusoidal gratings in a group of normals, ocular hypertensives and glaucoma patients. Resolution was measured using both stationary gratings, which selectively stimulate parvocellular ganglion cells (P cells), and gratings which phase reversed at 30 Hz, which selectively stimulate a higher proportion of magnocellular ganglion cells (M cells). With stationary gratings, peripheral resolution was found to be significantly reduced in glaucoma patients and, to a lesser extent, in ocular hypertensives. When the stimuli phase reversed at 30 Hz these differences between groups were larger. The ratio of resolution with and without phase reversal also showed a significant difference between the three groups. These results provide strong psychophysical evidence for a selective loss of M ganglion cell density over P ganglion cell density in glaucoma.