Felipe A. Medeiros

The Pathophysiology and Treatment of Glaucoma: A Review

IMPORTANCE Glaucoma is a worldwide leading cause of irreversible vision loss. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmologic examination and in more actively participating in the care of patients affected by this condition. OBJECTIVE To describe current evidence regarding the pathophysiology and treatment of open-angle glaucoma and angle-closure glaucoma. EVIDENCE REVIEW A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle glaucoma and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians. FINDINGS The glaucomas are a group of progressive optic neuropathies characterized by degeneration of retinal ganglion cells and resulting changes in the optic nerve head. Loss of ganglion cells is related to the level of intraocular pressure, but other factors may also play a role. Reduction of intraocular pressure is the only proven method to treat the disease. Although treatment is usually initiated with ocular hypotensive drops, laser trabeculoplasty and surgery may also be used to slow disease progression. CONCLUSIONS AND RELEVANCE Primary care physicians can play an important role in the diagnosis of glaucoma by referring patients with positive family history or with suspicious optic nerve head findings for complete ophthalmologic examination. They can improve treatment outcomes by reinforcing the importance of medication adherence and persistence and by recognizing adverse reactions from glaucoma medications and surgeries.

Prevalence of ocular surface disease in glaucoma patients.

PurposeTo examine the prevalence of ocular surface disease (OSD) in glaucoma patients. MethodsThis was a cross-sectional study. One hundred and one patients, 18 years of age or older, with open-angle glaucoma or ocular hypertension were consecutively recruited for the study. Patients with a history of use of cyclosporine, steroids, topical ocular nonsteroidal anti-inflammatory drugs, or punctal plugs within the last 3 months were excluded. Each patient completed an Ocular Surface Disease Index questionnaire and underwent evaluation by Schirmer test, corneal and conjunctival lissamine green staining, and tear break-up time. ResultsUsing Ocular Surface Disease Index for measuring symptoms of dry eye, 60 (59%) patients reported symptoms in at least 1 eye. Severe symptoms were reported by 27 (27%) patients. Schirmer testing showed 62 (61%) patients with decrease in tear production in at least 1 eye. Severe tear deficiency was presented in 35 (35%) patients. Corneal and conjunctival lissamine green staining showed positive results in 22 (22%) patients. None had severe staining. Tear break-up time showed abnormal tear quality in 79 (78%) patients and severe decrease in tear quality was found in at least 1 eye in 66 (65%) patients. Multivariate logistic regression models were used to investigate the association between the number of benzalkonium chloride (BAK)-containing eyedrops and results on the clinical tests of OSD. After adjustment for age and sex, each additional BAK-containing eyedrop was associated with an approximately 2 times higher odds of showing abnormal results on the lissamine green staining test (odds ratio=2.03; 95% confidence interval: 1.06 to 3.89; P=0.034). ConclusionA large proportion of patients with open-angle glaucoma or ocular hypertension had signs and/or symptoms of OSD in at least 1 eye. The coexistence of OSD and the use of BAK-containing medications may impact vision-related quality of life in this patient population.

Evaluation of the Influence of Corneal Biomechanical Properties on Intraocular Pressure Measurements Using the Ocular Response Analyzer

PurposeThe Ocular Response Analyzer (ORA) proposes to measure corneal biomechanical properties in vivo by monitoring and analyzing the corneal behavior when this structure is submitted to a force induced by an air jet. The purpose of this study was to evaluate the relationship between corneal biomechanical properties and corneal-compensated intraocular pressure (IOPCC) measurements as obtained by the ORA and Goldmann applanation tonometry (GAT) measurements. DesignObservational clinical study. MethodsThe study included 153 eyes of 78 subjects. All subjects underwent IOP evaluation with the ORA and GAT, and also measurements of central corneal thickness (CCT), corneal curvature, and axial length. Univariable and multivariable regression analysis were used to evaluate the associations between IOP (as measured with GAT and ORA) and CCT, corneal curvature, axial length, and age. Bland and Altman plots were used to evaluate the agreement between IOP measurements obtained by GAT and ORA. ResultsGAT IOP measurements were significantly associated with CCT (P=0.001) and corneal curvature (P<0.001), whereas ORA IOPCC measurements were not associated with any of the ocular variables. The difference between GAT and IOPCC measurements was significantly influenced by corneal thickness. Patients with thicker corneas tended to have higher GAT IOP measurements compared with IOPCC, whereas in patients with thin corneas, GAT IOP measurements tended to be lower than IOPCC. ConclusionsORA IOPCC measurements seem to provide an estimate of IOP that is less influenced by corneal properties than those provided by GAT.

Corneal thickness as a risk factor for visual field loss in patients with preperimetric glaucomatous optic neuropathy.

PURPOSE To determine whether central corneal thickness (CCT) is a risk factor for visual field loss development among patients diagnosed with preperimetric glaucomatous optic neuropathy (GON). DESIGN Observational cohort study. METHODS The study included 98 eyes of 98 patients with GON, with a mean follow-up time of 4.3 +/- 2.7 years. Diagnosis of GON was based on masked assessment of optic disk stereophotographs. All patients had normal standard automated perimetry visual fields at baseline. Criteria for visual field abnormality were derived from a prior study. Several clinical factors (CCT, intraocular pressure, vertical cup-to-disk ratio, refraction, age, gender, family history of glaucoma, high blood pressure, cardiovascular disease, and migraine) were investigated to ascertain whether there is an association with development of repeatable visual field loss. Cox proportional hazards models were used to obtain hazard ratios (HR) and identify factors that predicted which individuals developed glaucomatous visual field loss during the follow-up period. RESULTS Thirty-four patients (35%) developed repeatable visual field abnormality during follow-up. In multivariate analysis, risk factors that predicted the development of visual field loss were a thinner CCT (adjusted HR = 1.62/40 microm thinner; P =.023; 95% confidence interval [CI]: 1.07-2.45), higher baseline intraocular pressure (adjusted HR = 1.07/mm Hg; P =.022; 95% CI: 1.01-1.14), and larger baseline vertical cup-to-disk ratio (adjusted HR = 1.63/0.1 larger; P =.009; 95% CI: 1.13-2.35). The mean +/- standard deviation CCT of GON patients who developed visual field loss was 543 +/- 36 microm compared with 565 +/- 35 microm of those who did not develop visual field abnormalities (P =.005, Student t test). CONCLUSIONS Central corneal thickness is a risk factor for development of visual field loss among patients diagnosed with preperimetric GON. It is important to consider CCT when establishing target intraocular pressure of patients with GON.

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Reproducibility of RTVue retinal nerve fiber layer thickness and optic disc measurements and agreement with Stratus optical coherence tomography measurements.

PURPOSE To evaluate RTVue spectral-domain optical coherence tomography (OCT) (Optovue Inc, Fremont, California, USA) reproducibility and to assess agreement with Stratus time-domain OCT (Carl Zeiss Meditec, Dublin, California, USA) measurements. DESIGN Observational clinical study. METHODS Scans were obtained from both eyes of all participants 3 times using the RTVue nerve head map 4-mm diameter protocol and once using Stratus OCT within the same session. RTVue reproducibility and agreement with Stratus OCT were evaluated for retinal nerve fiber layer (RNFL) and optic disc measurements. RESULTS Thirty healthy participants (60 eyes) and 38 glaucoma patients (76 eyes) were included in the study. RTVue reproducibility was good in both healthy participants and patients. For average RNFL thickness, the intraclass correlation coefficients in healthy eyes and patient eyes were 0.97 whereas for rim area they were 0.97 and 0.96, respectively. The correlation between RTVue and Stratus measurements generally was good, especially for average RNFL thickness (healthy eyes and patient eyes, r(2) = 0.82 and 0.86, respectively) and rim volume (healthy eyes and patient eyes, r(2) = 0.78 and 0.76, respectively). Bland-Altman plots showed good agreement between the instruments, with better agreement for average RNFL thickness (95% limits of agreement in healthy eyes and patient eyes, -8.6 to 12 microm and -5.6 to -14.8 microm, respectively) than optic disc parameters. Cup-to-disc ratio 95% limits of agreement in healthy eyes and patient eyes were -0.3 to 0.4 and -0.2 to 0.3, respectively. Optic disc measurements with RTVue were smaller than those with Stratus OCT (eg, disc area was on average 0.4 mm(2) smaller and rim area was 0.3 mm(2) smaller with RTVue). CONCLUSIONS Reproducibility of RTVue RNFL and optic disc measurements was excellent in both groups. The level of agreement between RTVue and Stratus measurements suggests that RTVue has the potential to detect glaucomatous structural changes.

Agreement between Spectral-Domain and Time-Domain OCT for measuring RNFL thickness.

Background/aims: To evaluate spectral-domain (SD) optical coherence tomography (OCT) reproducibility and assess the agreement between SD-OCT and Time-Domain (TD) OCT retinal nerve fibre layer (RNFL) measurements. Methods: Three Cirrus-SD-OCT scans and one Stratus-TD-OCT scan were obtained from Diagnostic Innovations in Glaucoma Study (DIGS) healthy participants and glaucoma patients on the same day. Repeatability was evaluated using Sw (within-subject standard deviation), CV (coefficient of variation) and ICC (intraclass correlation coefficient). Agreement was assessed using correlation and Bland–Altman plots. Results: 16 healthy participants (32 eyes) and 39 patients (78 eyes) were included. SD-OCT reproducibility was excellent in both groups. The CV and ICC for Average RNFL thickness were 1.5% and 0.96, respectively, in healthy eyes and 1.6% and 0.98, respectively, in patient eyes. Correlations between RNFL parameters were strong, particularly for average RNFL thickness (R2 = 0.92 in patient eyes). Bland–Altman plots showed good agreement between instruments, with better agreement for average RNFL thickness than for sectoral RNFL parameters (for example, at 90 µm average RNFL thickness, 95% limits of agreement were −13.1 to 0.9 for healthy eyes and −16.2 to −0.3 µm for patient eyes). Conclusions: SD-OCT measurements were highly repeatable in healthy and patient eyes. Although the agreement between instruments was good, TD-OCT provided thicker RNFL measurements than SD-OCT. Measurements with these instruments should not be considered interchangeable.

Comparison of Different Spectral Domain Optical Coherence Tomography Scanning Areas for Glaucoma Diagnosis

PURPOSE To evaluate retinal nerve fiber layer (RNFL), optic nerve head (ONH), and macular thickness measurements for glaucoma detection using the RTVue spectral domain optical coherence tomograph. DESIGN Diagnostic, case-control study. PARTICIPANTS One hundred forty eyes of 106 glaucoma patients and 74 eyes of 40 healthy subjects from the Diagnostic Innovations in Glaucoma Study (DIGS). METHODS All patients underwent ocular imaging with the commercially available RTVue. Optic nerve head, RNFL thickness, and macular thickness scans were obtained during the same visit. Receiver operating characteristic (ROC) curves and sensitivities at fixed specificities (80% and 95%) were calculated for each parameter. MAIN OUTCOME MEASURES Areas under the ROC curves (AUC) and sensitivities at fixed specificities of 80% and 95%. RESULTS The AUC for the RNFL parameter with best performance, inferior quadrant thickness, was significantly higher than that of the best-performing ONH parameter, inferior rim area (0.884 vs 0.812, respectively; P = 0.04). There was no difference between ROC curve areas of the best RNFL thickness parameters and the best inner macular thickness measurement, ganglion cell complex root mean square (ROC curve area = 0.870). CONCLUSIONS The RTVue RNFL and inner retinal macular thickness measurements had good ability to detect eyes with glaucomatous visual field loss and performed significantly better than ONH parameters.

Detection of glaucoma progression with stratus OCT retinal nerve fiber layer, optic nerve head, and macular thickness measurements.

PURPOSE To evaluate and compare the ability of optical coherence tomography (OCT) retinal nerve fiber layer (RNFL), optic nerve head, and macular thickness parameters to detect progressive structural damage in glaucoma. METHODS This observational cohort study included 253 eyes of 253 patients. Images were obtained annually with the Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) along with optic disc stereophotographs and standard automated perimetry (SAP) visual fields. The median follow-up time was 4.01 years. Progression was determined by the Guided Progression Analysis software for SAP (Carl Zeiss Meditec, Inc.) and by masked assessment of optic disc stereophotographs performed by expert graders. Random coefficient models and receiver operating characteristic (ROC) curves were used to evaluate the relationship between change in Stratus OCT parameters over time and progression as determined by SAP and/or stereophotographs. RESULTS From the 253 eyes, 31 (13%) showed progression over time by stereophotographs and/or SAP. Mean rates of change in average RNFL thickness were significantly higher for progressors compared with nonprogressors (-0.72 mum/y vs. 0.14 mum/y; P = 0.004), with sensitivity of 77% for specificity of 80%. RNFL parameters performed significantly better than ONH and macular thickness measurements in discriminating progressors from nonprogressors. The parameters with the largest ROC curve areas for each scanning area were inferior RNFL thickness (0.84), cup area (0.66), and inferior inner macula thickness (0.64). CONCLUSIONS Stratus OCT RNFL parameters discriminated between eyes progressing by visual fields or optic disc photographs and eyes that remained stable by these methods and performed significantly better than ONH and macular thickness parameters in detecting change over time.

The African descent and glaucoma evaluation study (ADAGES): Design and baseline data

OBJECTIVE To identify factors accounting for differences in glaucoma onset and rate of progression between individuals of African descent and European descent. DESIGN A prospective, multicenter observational cohort study of 1221 participants of African descent and European descent with no glaucoma (normal), suspected glaucoma, and glaucoma. Six hundred eighty-six patient participants in the African Descent and Glaucoma Evaluation Study will be followed up longitudinally. Four hundred thirty-six participants of European descent from the Diagnostic Innovations in Glaucoma Study (DIGS) were also included. Baseline demographics, visual function (standard automated perimetry, short-wavelength automated perimetry, frequency doubling technology perimetry), optic nerve structure (retina tomography, optical coherence tomography), clinical status, and risk factors were measured. RESULTS Individuals of African descent had (1) thinner corneas (P < .001) across all diagnostic groups, (2) a higher percentage of reported diabetes mellitus (P < .001) and high blood pressure (P < .001) and a lower percentage of reported heart disease (P = .001), and (3) worse pattern standard deviation for standard automated perimetry fields overall (P = .001) and within normal limits (P = .01) than individuals of European descent. No differences were present for mean intraocular pressure (P = .79). CONCLUSIONS Significant baseline differences were found in a number of clinical findings between persons of African descent compared with European descent. Longitudinal data from the African Descent and Glaucoma Evaluation Study will be important for determining which baseline features are important and predictive for accurate diagnosis and follow-up in this high-risk group. Trial Registration clinicaltrials.gov Identifier: NCT00221923.