[Nonarteritic ischemic optic neuropathy animal model and its treatment applications]

Nonarteritic ischemic optic neuropathy (NAION) is one of the most common acute unilaterally onset optic nerve diseases. One management problem in terms of NAION is the difficulty of differential diagnosis between NAION and anterior optic neuritis (ON). A second problem is that there is no established treatment for the acute stage of NAION. A third problem is that there is no preventive treatment for a subsequent attack on the fellow eye, estimated to occur in 15 to 25% of patients with NAION. For differentiation of acute NAION from anterior optic neuritis, we investigated the usefulness of laser speckle flowgraphy (LSFG). In the normal control group, the tissue blood flow did not significantly differ between the right and left eyes. In the NAION group, all 6 patients had 29.5% decreased mean blur rate (MBR), which correlates to optic disc blood flow, of the NAION eye compared with the unaffected eye. In the anterior ON group, all 6 cases had 15.9% increased MBR of the anterior ON eye compared with the unaffected eye. Thus, LSFG showed a difference of the underlying pathophysiology between NAION and anterior ON despite showing disc swelling in both groups and could be useful for differentiating both groups. For the treatment of acute stage of NAION, we tried to reproduce the rodent model of NAION (rNAION) developed by Bernstein and colleagues. To induce rNAION, after the administration of rose bengal(RB) (2.5 mM) into the tail vein of SD rats, the small vessels of the left optic nerve were photoactivated using a 514 nm argon green laser (RB-laser-induction). In the RB-laser-induction eyes, the capillaries within the optic disc were reduced markedly, the optic disc became swollen, and fluorescein angiography showed filling defect in the choroid and the optic disc at an early stage, followed by hyperfluorescence at a late stage. Electrophysiological evaluation revealed that visual evoked potential (VEP) amplitude was significantly decreased but an electroretinogram (ERG) did not show a significant difference either in the b wave or in the oscillatory potentials. The scotopic threshold response (STR) was significantly reduced 3 days after induction. These findings are similar to those of rNAION and indicate that we succeeded in reproducing the rNAION. Histopathologic examination in the acute phase of rNAION, showed acellular NFL swelling anterior to the optic disc. No accumulation of inflammatory cells was noted in several microscopic sections of the optic nerve. In addition, immunochemical staining was negative throughout the retina and optic nerve. These results suggested that the rNAION-induced NFL swelling was not a result of inflammation. In the chronic phase of rNAION, the morphologic retinal changes were apparent in only the retinal ganglion cell(RGC) layer, with a reduction in the number of cells in the RGC layer. Thus, we need to evaluate the degree of the NFL swelling in the acute phase and the following thinning of the NFL in the chronic phase for efficacy of the treatment of rNAION. Therefore, we used optical coherence tomography (OCT) for the objective and quantitative evaluation of the retinal nerve fiber layer (RNFL) thickness around the optic disc changes in rNAION. The second method was to use the STR for the evaluation of the RGC function. The third method was to count the number of surviving RGCs observed and photographed through the fluorescence microscope with the Fluorogold staining. A possible rationale for treatment of NAION is that dilation of the posterior ciliary artery (PCA) increases the blood flow to the optic nerve and could improve the optic nerve function. To clarify the vasodilatory effects of medications, we used in vitro isometric tension recording methods and examined the vasodilatory effects of bevacizumab as an anti-vascular endothelial growth factor (VEGF) antibody, methylprednisolone as a corticosteroid and sodium nitroprusside (SNP, a nitric oxide donor) as a vasodilator on high-K (potassium) solution-induced contraction in isolated rabbit PCA. Bevacizumab did not relax rabbit PCA. Methylprednisolone relaxed rabbit PCA nitric oxide (NO) independently. SNP relaxed rabbit PCA by exogenous NO. On the basis of these results, we selected the following candidates for rNAION treatment: methylprednisolone as the corticosteroid and L-arginine as the NO related agent. Intravenous infusion of methylprednisolone significantly decreased the degree of acute disc edema but did not reduce inner retinal thinning, decrease STR amplitude, or decrease RGC numbers in rNAION. Intravenous infusion of L-arginine after rNAION induction significantly decreased the disc edema at the acute stage and the thinning of the inner retina, reduced the decrease in STR amplitude, and reduced the decrease in RGC numbers during rNAION. These results indicated that L-arginine treatment is effective for reducing the anatomical changes and improving visual function in the acute stage of rNAION. To strengthen the neuroprotective effect for rNAION, we tried treatment using transcorneal electric stimulation (TES). We evaluated the effect using STR and survival RGCs. Decreased amplitude in the STR of the TES group was significantly better preserved than in the control group on the 28th day after treatment. RGC survival in the TES group was significantly larger than in the control group on the 14th and 28th days. The neuroprotective effect of TES was better than that of L-arginine. For preventive treatment of subsequent attack in the fellow eye, we investigated whether pretreatment with L-arginine might reduce the severity of the anatomical changes associated with NAION and preserve the visual function when NAION occurs in the other eye. In the L-arginine pretreated eyes, the disc edema at the acute stage and the thinning of inner retina were significantly decreased, and the decrease of STR amplitude and the decrease in RGC numbers during rNAION were reserved. These results indicate that pretreatment with L-arginine is effective for the reduction of the severity during recurrence in the other eye. We will perform clinical trials in a small series of cases, and if the treatment is effective, we will proceed to multicenter randomized treatment trials. In addition to that, more work needs to be done to discover better treatment options for NAION.