Functional and Structural Imaging for Glaucoma

Glaucoma is the second leading cause of blindness in the US. The diagnosis and monitoring of glaucoma are important problems, not only because of its prevalence, but also because of its silent and irreversible nature. However all of the current diagnostic tests have serious limitations. Although elevated intraocular pressure (IOP) is a risk factor, most glaucoma patients actually have IOP within normal range. Visual field (VF) tests are poorly reproducible, and a series of 3 tests are needed to establish diagnosis or confirm progression. Although ophthalmoscopic examination can detect optic nerve head (ONH) and nerve fiber layer (NFL) defects, reliability in diagnosis and tracking is hampered by its subjective and semi-quantitative nature. Although quantitative imaging with optical coherence tomography (OCT), scanning laser polarimetry (SLP), and confocal scanning laser ophthalmoscopy (cSLO) can more objectively detect ONH and NFL defects, their diagnostic accuracies are still not sufficient to be relied on alone for diagnostic screening. It has been estimated that about half of glaucoma patients in the US do not know that they have the disease. Thus, there is a need for improvements in glaucoma diagnostic technologies. One approach that deserves further exploration is blood flow imaging.

There is much circumstantial evidence that vascular factors play important roles in the pathophysiology of glaucoma:

• Systemic vasculopathy increases the risk of developing glaucoma. Hypertension, diabetes, and vasospastic conditions are all known risk factors. Normal tension glaucoma has also been linked to peripheral endothelial dysfunction and erectile dysfunction. This suggests that poor circulation may be a causative factor or a facilitative factor that predisposes the ONH to damage by elevated IOP.
• Decrease or fluctuation in ocular perfusion pressure was identified as an independent risk factor for progression in the Collaborative Normal-Tension Glaucoma Study and other studies. Nocturnal hypotension is also a risk factor for glaucoma progression.
• Medications that improve ocular perfusion appear to have protective effects that are not explained by the lowering of IOP.
• Optic disc hemorrhage and peripapillary atrophy are both associated with accelerated glaucoma progression. These finding may support a role for focal ischemia.
• Animal experiments show that increased IOP causes decreased ONH blood flow in the presence of low systemic blood pressure.

Despite the evidence, the management of glaucoma remains focused on the lowering of IOP, the one causative factor that responds to treatment and can be easily measured. Blood flow measurement is a research topic, but currently has no clinical role in the diagnosis, prognostic evaluation, or treatment of glaucoma. Therapies aimed at improving ocular circulation cannot be effectively developed without a practical method for quantitative and reproducible evaluation of ONH and retinal perfusion. Thus there is a great need to develop better technology for the evaluation of ocular circulation.

Using high-speed OCT systems, we have developed new methods to image and measure optic nerve head (ONH) and retinal blood flow. Preliminary results showed that VF loss was more highly correlated with retinal blood flow as measured by OCT than any neural structure measured by OCT or other imaging modality. Accordingly, the goal of the proposed project is to improve the diagnostic and prognostic evaluation of glaucoma by further developing novel functional OCT measurements using ultrahigh-speed (70-100 kHz) OCT technology.

Retinal blood flow, ONH circulation, optic disc rim volume, peripapillary nerve fiber layer volume, and macular ganglion cell complex volume are all pieces of the same glaucoma puzzle. This project will develop novel imaging methods that allow us to look at the whole picture using one tool - ultrahigh-speed OCT.

Inclusion criteria

Normal Subjects (both eyes must meet all criteria)

• No history or evidence of retinal pathology or glaucoma
• Normal Humphrey 24-2 VF: A mean defect (MD), corrected pattern standard deviation (CPSD) within 95% limits of normal reference, and glaucoma hemifield test (GHT) within normal limits (97%).
• Intraocular pressure < 21 mm Hg
• Central corneal pachymetry > 500 microns
• No chronic ocular or systemic corticosteroid use
• Open angle (gonioscopy must show 75% or more of the angle to be Grade 2 or more by Shaffer's grading system)
• Normal appearing ONH and NFL: vertical and horizontal cup/disc ratio (CDR) ≤ 0.5 and intact neuroretinal rim without peripapillary hemorrhages, notches, localized pallor, or NFL defect
• Symmetric ONH between left and right eyes: CDR difference < 0.2 in both vertical and horizontal dimensions

Inclusion criteria

Glaucoma Group

• ONH or NFL defect visible on slit-lamp biomicroscopy defined as one of following:

• diffuse or localized thinning of the rim
• disc (splinter) hemorrhage
• notch in the rim
• vertical cup/disc ratio greater than the fellow eye by > 0.2
• Presence or absence of VF defects as measured by Humphrey SITA 24-2 VF.

Exclusion criteria

All Groups

• Best-corrected visual acuity less than 20/40
• Age < 40 or >85 years
• Refractive error of > +3.00 D or < -7.00 D
• Previous intraocular surgery except for uncomplicated keratorefractive surgery and cataract extraction with posterior chamber intraocular lens implantation
• Diabetic retinopathy
• Other diseases that may cause VF loss or optic disc abnormalities
• Inability to clinically view or photograph the optic discs due to media opacity or poorly dilating pupil
• Inability to perform reliably on automated VF testing
• Life-threatening or debilitating illness making it unlikely patient could successfully complete the study.
• Refusal of informed consent or of commitment to the full length of the study