Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.

Neuroprotective effects of low-dose G-CSF plus meloxicam in a rat model of anterior ischemic optic neuropathy.

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.

Associations between thrombophilic risk factors and determinants of atherosclerosis and inflammation in patients with non-arteritic anterior ischaemic optic neuropathy.

UNLABELLED: Non-arteritic anterior ischaemic optic neuropathy (NAION) is caused by ischaemia of the optic nerve head. The pathophysiology of NAION is unclear, and no proven effective treatment exists. PATIENTS, METHODS: We analyzed thrombophilic risk factors and determinants of atherosclerosis and inflammation in 109 consecutive patients and 109 age- and sex-matched volunteers using a case-control design. RESULTS: High levels of fibrinogen (>384 mg/dl; OR 3.2, p = 0.003), factors VIII:C (>183%; OR 2.6, p = 0.02), IX (>153%; OR 2.6, p = 0.026), XI (>142%; OR 3.4, p = 0.006), von Willebrand factor (activity >205%; OR 3.1, p = 0.005; antigen >194%; OR 3.5, p = 0.002), and triglycerides (>228 mg/dl; OR 2.8, p = 0.026), higher platelet counts (>294,000/µl; OR 2.5, p = 0.04), low levels of HDL cholesterol (<40 mg/dl; OR 2.7, p = 0.032), and an accelerated erythrocyte sedimentation rate (>20 mm/h; OR 4.4, p = 0.003) were associated with NAION. CONCLUSION: Our findings support the contention of a complex pathogenesis of NAION resulting from the coincidence of proatherogenic, prothrombotic and proinflammatory processes. The alterations described could be causative, side effects, or just coincidental findings.

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

OBJECTIVE: To correlate potential inflammatory responses in nonarteritic anterior ischemic optic neuropathy (NAION) with a lesion possessing many physiologic and histologic similarities from a model of nonhuman primate NAION (pNAION). METHODS: Using immunohistochemistry and confocal microscopic analysis, we evaluated the relative numbers of inflammatory cell types in the single available clinical specimen of early NAION (21 days after event). We correlated this with the temporal inflammatory response occurring in optic nerve tissue at different times following pNAION induction. RESULTS: In pNAION, there is a previously unsuspected infiltration of polymorphonuclear leukocytes occurring almost immediately after infarct induction, followed by invasion of ED1+ extrinsic macrophages, which peaks 5 weeks after infarct. Intrinsic microglia accumulate up to 70 days after induction in the area of primary axonal loss. The analyzed human NAION specimen was similar to 21-day pNAION tissue, with extrinsic macrophages and intrinsic microglial cells in the region of focal axon loss. CONCLUSIONS: Cellular inflammation plays a major early role following white-matter (optic nerve) infarct, with both polymorphonuclear leukocyte and macrophage function involved in debris elimination and tissue remodeling. The optic nerve in NAION and its primate model are associated with early cellular inflammation, previously unsuspected, that may contribute to postinfarct optic nerve damage.

Arteritic anterior ischemic optic neuropathy with positive myeloperoxidase antineutrophil cytoplasmic antibody.

BACKGROUND: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is related to smallvessel vasculitis. There have been some reports of optic nerve involvements with increased values of MPO-ANCA. We report two cases of anterior ischemic optic neuropathy (AION) in which ANCA-associated vasculitis was suspected to be responsible for the pathogenesis. CASES: A 66-year-old man and a 72-year-old man had ocular symptoms of AION in both eyes with positive MPO-ANCA. OBSERVATIONS: Both patients showed high erythrocyte sedimentation rate, C-reactive protein, and MPOANCA values at first. Temporal artery biopsies were negative for temporal arteritis, whereas small-vessel vasculitis was found only in the latter patient. Visual dysfunctions remained unchanged after steroid pulse therapy, although laboratory data returned to normal levels after the treatment. Fluorescein angiography revealed selective occlusion of capillaries, arterioles, and precapillaries in the retina and choroid as well as in the optic disc. CONCLUSIONS: The identical characteristics of the angiographic findings of both eyes in the two cases indicated that the obliteration of small vessels in the intraocular arterial system was closely related to MPO-ANCA-associated vasculitis.

Pegylated interferon alpha-associated optic neuropathy.

A 52-year-old man with chronic hepatitis C presented with painless, bilateral, simultaneous nonarteritic anterior ischemic optic neuropathy (NAION) and peripheral neuropathy. Symptoms began 19 weeks after starting peginterferon alpha-2a. The peripheral neuropathy and vision of the right eye improved, but the vision of the left eye worsened after stopping interferon. We identified 23 additional cases of NAION during interferon alpha therapy. At least 12 of these patients suffered bilateral NAION. Patients lost vision 1-40 weeks after initiating therapy. Of 21 eyes that had documented initial and follow-up acuities, 8 improved, 1 worsened, and the rest remained stable. One patient had a painful peripheral neuropathy. Treatment with interferon alpha may result in NAION. Discontinuation of therapy deserves consideration after weighing individual risks and benefits.

[Retinal vein occlusion followed by ischemic optic neuropathy with anticardiolipin IgG antibody: a case report].

BACKGROUND: Anticardiolipin antibodies in the autoimmune mechanism can cause vasculitis, leading to hypercoagulability-related thrombosis. We report a case of retinal vein occlusion followed by ischemic optic neuropathy in a young woman with anticardiolipin IgG antibody. CASE: A 17-year-old woman with dilatation and tortuosity of the retinal veins and retinal hemorrhage in the superior quadrant of the retina OS. Fluorescein retinal angiography showed a delay of filling time in the upper quadrant of the retina and a 3mm-continuous stain along the superior retinal vein. Laboratory tests were repeatedly positive for anticardiolipin IgG antibodies. Although the retinal hemorrhage disappeared 2 months after subtennon injection of 20 mg triamcinolone acetonide (TA), ischemic optic neuropathy occurred 9 months later. CONCLUSIONS: The staining of the vessel wall and the effectiveness of TA suggest that vasculitis may be associated with the pathology of this condition. The presence of anticardiolipin IgG antibodies suggests that autoimmune mechanism is involved in the vasculitis.

Optic nerve infarction and post-ischemic inflammation in the rodent model of anterior ischemic optic neuropathy (rAION).

Nonarteritic anterior ischemic optic neuropathy (NAION) results from isolated anterior optic nerve (ON)-axonal ischemia near the retina-optic nerve junction. We utilized a rodent model of NAION (rAION) to study the in vivo inflammatory response after pure axonal ischemic infarct. ON ischemia was generated using laser-coupled rose Bengal dye photoactivation, and the infarct localized using tetrazolium red and histology. ON inflammation was evaluated following infarct using extrinsic macrophage (ED1) and microglial (isolated Iba1) cell markers. In naive ONs, some ED1(+)/Iba1(+) cells, representing extrinsic macrophages, were present in intraretinal ON region, but not in the retroscleral (isolated ON) region. Numerous ED1(-)/Iba1(+) cells, likely representing intrinsic microglia, were present throughout the entire ON. One day post-stroke, slight increases in both ED1(+) and Iba1(+) cells were apparent in the eye region immediately surrounding the anterior ON. Three days post-stroke, there was marked infiltration and aggregates of ED1(+)/Iba1(+) cells, with axon structural disruption in the region of the ischemic infarct. ED1(+) and Iba1(+) cells were present in the portion of the ON surrounding the infarct, possibly representing a penumbral region similar to that seen in ischemic brain infarcts. Although ED1(+) cells decreased by 7-14 days post-stroke, large numbers of Iba1(+) cells persisted in the anterior ON. Similar to other CNS ischemic strokes, pure axonal ischemia results in the early recruitment of extrinsic macrophages to the ischemic region. Manipulation of the inflammatory response may be an important variable that could potentially improve visual outcome.

Antiphospholipid antibodies in ocular arterial and venous occlusive disease.

PURPOSE: It was the aim of this study to evaluate antiphospholipid antibodies (APA), i.e. lupus anticoagulants (LA) and anticardiolipin (ACA) IgG and IgM, in ophthalmic occlusive disease. METHODS: Over a 3.5-year period, APA were evaluated in 368 patients. RESULTS: Eighty-six patients (23.4%), compared to 5% in the general population, tested positive for APA. APA did not differ significantly between patients with venous (20.6%) or arterial (25.5%) occlusive disease. This included 93 patients with central retinal vein occlusion (18% APA positive), 67 with retinal branch vein occlusion (24% APA positive), 41 with central retinal artery occlusion (22% APA positive), 53 with retinal branch artery occlusion (32% APA positive), 71 with anterior ischemic optic neuropathy (23% APA positive), 12 with posterior ischemic optic neuropathy (33% APA positive) and 31 patients with amaurosis fugax (23% APA positive). Excluding patients with accepted main risk factors, APA were positive in 15.3% of 85 patients. CONCLUSION: The high APA prevalence confirms its relevance in ocular occlusive disorders.

Chlamydia in anterior ischemic optic neuropathy.

There is an increasing body of evidence linking the common respiratory human pathogen Chlamydia pneumoniae with atherosclerosis and other vascular disorders. Our research was designed to investigate the association of this organism with anterior ischemic optic neuropathy (AION), representing an acute ischemic disorder of the optic nerve head. Sera were examined of 14 consecutive patients with AION and of 14 age- and sex-matched control subjects with noncardiovascular, nonpulmonary disorders. Antibodies against chlamydial lipopolysaccharide (LPS) and outer membrane proteins of C. pneumoniae were determined by ELISA. Further, nucleic acid amplification tests were done in order to detect C. pneumoniae-specific nucleotide sequences. Four patients (29%) were IgA positive, 11 (79%) were IgG positive and 1 (7%) was IgM positive for chlamydial LPS antibodies. In the control group, 36, 79 and 7% were IgA, IgG and IgM positive and showed no significant difference. IgA, IgG and IgM antibodies to C. pneumoniae were found in 43, 79 and 0% and did not differ from matched controls. By the nucleic acid amplification test, specific C. pneumo niae sequences were neither detected in the AION patients nor in the control group. These data do not support the association of AION with previous C. pneumoniae infection. However, it remains unclear whether Chlamydia actually initiates atherosclerotic injury, facilitates its progression or plays another role in other vascular disorders.

Anticardiolipin antibodies and occlusive vascular disease of the eye: prospective study.

There is a recognized association between the presence of anticardiolipin antibodies and vascular occlusive disease. The purpose of our study is to detect the presence of high titers of anticardiolipin antibodies (ACA) in the serum and to correlate the titers with the severity of the vascular disease in patients with occlusive ocular vascular disease. 82 patients were included in a prospective study; 25 patients with anterior ischaemic optic neuropathy, 36 with retinal vein occlusion and 21 with retinal artery occlusion. ACA (IgG and IgM isotypes) were measured by ELISA in the sera of all patients. The group of the patients (group A) was compared to an age-matched control group of 79 healthy individuals (group B). IgG isotype (but not IgM) titers of ACA were found significantly higher in group A (P < 0.001). In patients with titers of ACA (IgG isotype) > 100 units we noted a higher incidence of a more severe disease (recurrency, involvement of both eyes or extraocular manifestations) especially among those with anterior ischaemic optic neuropathy and secondarily in those with retinal artery occlusion. Our results suggest that the association between high titers of ACA and occlusive vascular disease of the eye concerns only the IgG isotype. In addition, the detection of high titers of IgG/AGA in patients could be a useful marker for disease severity and prognosis and this observation seems to be more explicit in cases with arterial occlusive disease than in cases with venous occlusive disease.

A case of bilateral optic neuropathy and recurrent transverse myelopathy associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA).

A case involving a 52-year-old man having bilateral optic neuropathy and recurrent transverse myelopathy is reported. His clinical features resembled multiple sclerosis, but neuroimaging failed to show evidence of demyelination or inflammation in the brain or the optic nerves. The patient experienced sudden visual loss despite massive steroid therapy. Positive perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) is suggestive that optic neuropathy and recurrent transverse myelopathy may have been caused by some common inflammatory processes associated with p-ANCA, however, having a different etiology from multiple sclerosis.

Anterior ischemic optic neuropathy in a patient with positive antinuclear antibody and lupus anticoagulant findings.

A 64-year-old woman complained of blurred vision in her right eye. A pale optic disc with a blurred nasal margin was found in the right fundus. An inferior altitudinal defect in the right eye was observed on Goldmann perimetry. Her right visual acuity deteriorated to 0.1. Her antinuclear antibody and lupus anticoagulant test results were positive. Intravenous methylprednisolone (1,000 mg/day) improved her right visual acuity to 1.0. We believe that the anterior ischemic optic neuropathy in our patient may be associated with the presence of positive antinuclear antibody and lupus anticoagulant findings.