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Editors Selection IGR 17-3

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Comment by Louis Pasquale on:

53854 Longitudinal hemodynamic changes within the optic nerve head in experimental glaucoma, Cull G; Burgoyne CF; Fortune B et al., Investigative Ophthalmology and Visual Science, 2013; 54: 4271-4277

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Cull and coworkers assess longitudinal changes in optic nerve head (ONH) blood flow using a nonhuman primate model of experimental glaucoma. The investigators used argon laser irradiation to induce trabecular meshwork damage in one eye of 15 animals with the fellow eye serving as a control. The authors carefully document the intraocular pressure (IOP) history with rebound tonometry, retinal nerve fiber layer thickness (RNFLT) changes with ocular coherence tomography (OCT) and ONH blood flow with laser speckle flowgraphy in both eyes at baseline and in follow-up after glaucoma induction.While most animals had peak IOPs higher than most primary openangle glaucoma (POAG) patients (mean peak IOP = 42.2 mmHg), the overall mean IOP in experimental glaucoma eyes (20.2 mmHg) was closer to typical levels for untreated POAG patients. Nine eyes progressed to moderate disease and six eyes progressed to mild disease in one year or less. The study protocol was rigorous and uniformly applied to all animals and overall the methodology was sound. After careful data analysis the authors concluded that in early stage glaucoma there is an increase in ONH blood flow but as the disease progressed to moderate and advanced stages there was a decline in ONH blood flow.

The authors make excellent use of an animal model of glaucoma to chronicle longitudinal blood flow changes that occur as IOPinduced optic nerve changes occur. The real questions are: (a) Do the blood flow changes documented by Cull and coworkers correspond to changes documented in the human disease? (b) Do these results provide any new insights into the pathogenesis of POAG?

With respect to the first question, the answer is yes. In 1995, Feke and coworkers showed that among untreated patients with ocular hypertension, those with the thinnest RNFLT on OCT had the highest ONH capillary blood speed.¹ Subsequently, Berisha and co-workers found the same association between RNFLT and retinal blood flow as measured with the Cannon laser Doppler blood flow instrument among patients with early stage normal tension glaucoma.² In contrast, Plange et al. found that in later stage glaucoma, retrobulbar central retinal artery speed measured with a color Doppler instrument decreased considerably.³ These cross-sectional data are entirely consistent with the longitudinal data provided by Cull et al. Berisha et al.³ postulated that the initial optic nerve insult produced by either vascular or mechanical factors stimulate inducible nitric oxide synthase. Glial activation of this enzyme generates elevated nitric oxide levels that might be responsible for increased ocular blood flow seen in early stage glaucoma. In any event, Cull and coworkers have an incredible opportunity to find biomarkers that produce this increase in ocular blood flow in early glaucoma. Therefore the answer to the second question is potentially yes.

In the discussion, the authors suggest that elevated IOP might lead to altered retinal vascular dysregulation. It is certainly possible that a very high IOP can overcome the normal autoregulatory capacity of the retinal vasculature. The authors certainly understand the limitations of their animal model but they should also entertain the possibility that genetic predisposition to systemic vascular dysregulation is upstream to elevated IOP and retinal vasculopathy in triggering POAG. In this regard, Buyset al. developed a model of open-angle glaucoma whereby mice lacking the alpha-1 subunit of the nitric oxide receptor soluble guanylate cyclase (sGC), develop modestly elevated IOP, nerve fiber layer thinning, and impaired retinal vascular response to nitric oxide donators.⁴ More importantly a candidate gene locus in the gene region coding for the alpha-1 and beta-1 subunit of sGC was associated with paracentral visual loss among women with POAG.⁴

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