Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model

Autor: Steven L. Bernstein, Neil R. Miller, Cristian M. Salgado, Fernandino L. Vilson
Rok vydání: 2011
Předmět:
Zdroj: Archives of ophthalmology (Chicago, Ill. : 1960). 129(12)
ISSN: 1538-3601
Popis: THE OPTIC NERVE (ON) IS A central nervous system (CNS) white-matter tract composed of retinal ganglion cell axons and supporting glia. The retinal ganglion cell axons synapse in the lateral geniculate nuclei. Nonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of sudden ON-related vision loss in the developed world,1 with an incidence in the United States from 3 to 10 cases per 100 000 population per year.1,2 There currently is no effective treatment for this condition, largely because little is known about its pathophysiology and early cellular changes following onset. The reason for this lack of knowledge is that few histopathologically studied cases of acute NAION exist and partially because until recently no relevant NAION animal models existed. In 2003, our laboratory developed the first reproducible murine model of human NAION (rAION).3 This model is generated by laser activation of the photosensitive dye rose bengal. Following induction in this model, pathologic assessment including immunohistochemical analysis reveals not only ischemia but also an early significant inflammatory response in the infarct region4 that may contribute to subsequent ON damage. Using a technique similar to that used to induce rAION, our laboratory recently developed a nonhuman primate (NHP) model of NAION (pNAION). This model is clinically, electrophysiologically, and angiographically identical to human NAION and has the added advantage of identifying primate-specific responses to ON ischemia.5 Although no early histologic findings have been reported in this model, late histologic findings (5-9 weeks after induction of pNAION) show changes consistent with an isolated optic neuropathy.5 Immunohistochemical evaluation of affected ONs in this model reveals a consistent late inflammatory response in the region of the infarct similar to that observed in rAION.5 Currently, NAION-associated ON damage is theorized to result from thrombotic or hypoperfusion ischemia, which produces tissue edema in the confined space of the ON sheath. This process results in a compartment syndrome, with additional vascular compromise, similar to that which occurs in other CNS white-matter strokes.6 Thus, NAION may be considered a stroke of the ON, similar to white-matter strokes elsewhere in the brain.3 A complex temporal and sequential cellular inflammatory response has been identified in cortical lesions following middle cerebral artery occlusion.7 Nonarteritic anterior ischemic optic neuropathy should therefore result in inflammatory responses similar to those of other CNS regions. Although histologic examination of recently infarcted CNS white matter reveals both ischemic changes and postischemic inflammation that may have an important role in the evolving brain ischemic final injury,8 early human NAION pathology has been described in very few reports. One study digitally analyzed the region of the ischemic lesion in a patient who died 20 days after developing NAION and found an infarct confined to the region of the lamina cribrosa (the junctional region between the retina and the ON).9 Although these investigators did not detect pathologic evidence of an inflammatory response in this region, they did not use any specialized stains to identify inflammatory cells. A large retrospective histopathologic review of 193 eyes with presumed ischemic optic neuropathy of different etiologies was performed by Knox et al.8 In none of these cases had an ophthalmic examination been performed just before the patient’s death, although in 23 of 193 cases (11.9%), there was a history of acute vision loss, and in a small number of these cases, death occurred shortly after the occurrence of an acute systemic vascular event. In these acute cases, focal ischemic edema was associated with foamy macrophages (ie, gitter cells), but similar to the single human study,9 no immunohistochemical stains were used to assess inflammation in the areas of ON damage.8 The question of human NAION-associated inflammation is relevant to potential treatment. An early post-NAION inflammatory response could cause persistent or even progressive nerve dysfunction. If this latter effect occurs, early treatments aimed at selectively reducing the inflammatory response could theoretically result in improved visual outcome in patients with NAION. The aims of this study were 3-fold: (1) to determine, using the ON of the patient who died shortly after developing well-documented NAION9 and whose ON tissue was provided to us, whether inflammation is a prominent feature of early human NAION as opposed to a generalized epiphenomenon that occurs only in the later stages of CNS ischemia; (2) to determine whether the pNAION model shows early inflammatory changes similar to those observed in our rAION model; and (3) to compare the relative timing and type of observed inflammatory response in the pNAION model with any inflammation identified in the human specimen, using tissue from pNAION-affected animals at different times following induction of pNAION, thus enabling us to capture the timing and potential range of different immune responses that may occur during the development and progression of isolated ON infarction in humans and other Old World primates.
Databáze: OpenAIRE
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