Nonarteritic Anterior Ischemic Optic Neuropathy and Semaglutide: What is This All About?

Nonarteritic anterior ischemic optic neuropathy (NAION) was first documented by a French physician Jean-Pierre Saint-Yves in 1817 (19th century). The clinical description of NAION was not known until 1935 when C. Miller Fischer thoroughly described it. Briefly, NAION is a rare (2.5-11.8 per 1,00,000 cases in men above 50 years) but serious condition that causes sudden painless loss of vision due to ischemia of the optic nerve.1 It is more common in Caucasians compared with Asians and is associated with various risk factors such as hypertension, type 2 diabetes (T2D), smoking, hyperlipidemia, obesity, obstructive sleep apnea, small optic nerve cup ("disk at risk"), optic nerve drusen, and certain drugs, especially phosphodiesterase type 5 inhibitors (PDE-5I), amiodarone, and cabergoline.2 Although the clinical development programs and real-world studies of semaglutide [a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for the treatment of T2D and obesity] did not report any significant increase in the risk of NAION, a recent retrospective cohort study suggested a possible link between NAION and semaglutide.3 This editorial briefly summarizes the current knowledge about NAION and its relation to metabolic disorders, cardiovascular, and antidiabetes drugs and puts a perspective concerning semaglutide.

Bilateral sequential ischemic retinopathy and optic neuropathy in IgG1 heavy chain deposition disease.

PURPOSE: To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD). OBSERVATIONS: Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss. CONCLUSIONS AND IMPORTANCE: Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.

Immune Checkpoint Inhibitors and Optic Neuropathy: A Systematic Review.

INTRODUCTION: Immune checkpoint inhibitors are a class of monoclonal antibodies that are used as a mainstay of immunotherapy for multiple solid organ malignancies. With the recent increase in popularity of these agents, immune-related adverse events including optic neuropathy are becoming more frequently reported. This review aims to explore the association between immune checkpoint inhibitors and optic neuropathy through analysis of incidence, clinical features, investigations, treatment, and patient outcomes. METHOD: A systematic search of the databases PubMed/MEDLINE, Embase, and CENTRAL was performed from inception to September 2022. Data collection and risk of bias analysis was subsequently conducted in accordance with the PRISMA guidelines. RESULTS: Eleven articles fulfilled the inclusion criteria. The results showed an increased incidence of optic neuropathy among patients receiving immune checkpoint inhibitor therapy compared to the general population. Presentation with painless reduced visual acuity and optic disc swelling was most common. Investigation findings were poorly documented. The only two patients who achieved full resolution of symptoms were treated with oral prednisolone. CONCLUSION: There is a strong association between immune checkpoint inhibitor therapy and development of optic neuropathy. Although it remains uncommon, the incidence of optic neuropathy in this population exceeds that of the general population. Future research is needed to further characterise the risk profiles of patients who are most likely to develop ICI-associated optic neuropathy, and treatment pathways for these patients.

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair.

Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/ßcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy.

Vision loss in giant cell arteritis: case-based review.

Prompt initiation of pulse glucocorticoid treatment is recommended in case of visual symptoms and suspected or proven giant cell arteritis (GCA). Pulse treatment in most cases prevents involvement of an initially unaffected fellow eye. We present the case of a biopsy-proven GCA in a 79-year-old man, complicated by sequential bilateral blindness. Initial unilateral vision loss was treated by 1 g methylprednisolone intravenously for 3 days, followed by 1 g/kg prednisone daily. Despite treatment, the second eye went completely blind 11 days after the initial vision loss. We performed a systematic search on Medline and Scopus aiming at identifying all cases of GCA complicated with loss of vision in a previously unaffected eye under pulse treatment for initially monocular vision loss. We identified 11 articles reporting 21 patients that met our inclusion criteria. Contralateral vision loss occurred 1-12 days following treatment initiation, with a median of 2 days. Treatment initiation was delayed up to 8 days since the initial vision loss, with a median delay of 2 days. Anterior ischemic optic neuropathy was the dominant mechanism of vision loss. Sequential involvement of the fellow eye in case of unilateral vision loss in GCA is rare. With 12-day interval being the longest reported, we conclude that even though the first 2 days are the most critical for the visual outcome, blindness in the initially unaffected eye may rarely occur later. Nonetheless, immediate initiation of pulse treatment remains of vital importance to preserve vision in the contralateral eye.

The Protective Effects of n-Butylidenephthalide on Retinal Ganglion Cells during Ischemic Injury.

Clinically, acute ischemic symptoms in the eyes are one of the main causes of vision loss, with the associated inflammatory response and oxidative stress being the key factors that cause injury. Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common type of ischemic optic neuropathy (ION); however, there are still no effective or safe treatment options to date. In this study, we investigated the neuroprotective effects of n-butylidenephthalide (BP) treatment in an experimental NAION rodent model (rAION). BP (10 mg/kg) or PBS (control group) were administered on seven consecutive days in the rAION model. Rats were evaluated for visual function by flash visual evoked potentials (FVEPs) at 4 weeks after NAION induction. The retina and optic nerve were removed for histological examination after the rats were euthanized. The molecular machinery of BP treatment in the rAION model was analyzed using Western blotting. We discovered that BP effectively improves retinal ganglion cell survival rates by preventing apoptotic processes after AION induction and reducing the inflammatory response through which blood-borne macrophages infiltrate the optic nerve. In addition, BP significantly preserved the integrity of the myelin sheath in the rAION model, demonstrating that BP can prevent the development of demyelination. Our immunoblotting results revealed the molecular mechanism through which BP mitigates the neuroinflammatory response through inhibition of the NF-κB signaling pathway. Taken together, these results demonstrate that BP can be used as an exceptional neuroprotective agent for ischemic injury.

Simultaneous Bilateral Primary Occlusion of the Ophthalmic Artery due to Florid Giant Cell Arteritis.

PURPOSE: To report a case of simultaneous bilateral ophthalmic artery occlusion in diagnosed giant cell arteritis (GCA). OBSERVATIONS: A 77-year-old male patient presented to the emergency department with simultaneous vision loss in both eyes for 3 hours. Headache at both temples and jaw claudication had been present for 3 weeks. Laboratory values demonstrated an initially increased C-reactive protein (CRP) of 202.0 mg/L and an erythrocyte sedimentation rate (ESR) of 100 mm within the first 20 minutes. Duplex sonography of the right and left temporal arteries revealed a "halo sign." A case of GCA was suspected, and intravenous high-dose methylprednisolone therapy was immediately administered. The clinical examination revealed a bilateral central retinal artery occlusion and fluorescein angiography showed a hot optic disc in the right eye and patchy choroidal hypoperfusion in both eyes. Biopsy of the left temporal artery was performed, which confirmed a florid temporal arteritis with complete thrombotic occlusion of the vascular lumen. Despite a good response to the administered therapy (CRP 17.0 mg/L 1 week after initiation), the visual prognosis was significantly limited through retinal and optic nerve involvement. By the follow-up examination 8 weeks later, the near visual acuity was 20/400 in the right and left eye at a distance of 16 inches. CONCLUSION AND IMPORTANCE: We hereby present a simultaneous bilateral ophthalmic artery occlusion as a rare complication of GCA. The combination of central retinal artery occlusion, arteritic anterior ischemic optic neuropathy, and choroidal hypoperfusion suggests an acute inflammatory involvement of the ophthalmic artery. In cases of the slightest suspicion of giant cell arteritis, an immediate high-dose steroid therapy initiation is of utmost importance.

Visual Recovery with Iloprost Added to Corticosteroids in a Case of Giant Cell Arteritis.

INTRODUCTION: To date, corticosteroids remain the cornerstone treatment of ocular involvement of GCA, and no other treatment has proven to be effective in this setting. We herein report on a unique case of GCA with ocular involvement worsening despite high dose corticosteroids and recovering with intravenous iloprost. CASE REPORT: A 70-year-old man presented with acute vision loss in his left eye related to anterior ischemic optic neuropathy. The diagnosis of giant-cell arteritis was confirmed by a temporal artery biopsy. Despite intravenous pulse methylprednisolone for 3 days then oral prednisone at 60 mg/day, the patient developed from day 5 fluctuating vision loss in the right eye, related to ocular ischemia by occlusion of the ophthalmic artery, and responsive to hyperhydration. Iloprost, an analog of prostacyclin PGI2, was then administered intravenously for 5 days and resulted in a stable improvement in visual acuity in the right eye. CONCLUSION: This case highlights the potential role of vasodilatator agents in giant cell arteritis with ocular involvement.

[Ischemic optic neuropathy despite pulse methylprednisolone therapy in a giant cell arteritis patient with perineural optic nerve enhancement].

A 76-year-old woman with a 1-month history of headache, jaw claudication, scalp tenderness, and blurred vision was admitted to our hospital. Erythrocyte sedimentation rate was highly elevated. Brain MRI showed marked perineural optic nerve enhancement and superficial temporal artery enhancement bilaterally. Neuro-ophthalmic examination detected left dominant decline in critical fusion frequency whereas visual acuity, visual fields, and ophthalmoscopy were normal. Intravenous pulse methylprednisolone was administered for 3 days to treat suspected giant cell arteritis (GCA); however, visual acuity in the left eye declined and horizontal hemianopia developed. Ophthalmoscopy revealed pallid optic disc edema on the left. Histopathologic examination of a right temporal artery biopsy specimen showed intimal thickening, mild mural inflammation consisting predominantly of lymphocytes with occasional giant cells, and focal disruption of the internal elastic lamina, consistent with GCA. Perineural optic nerve enhancement on contrast-enhanced MRI may be a valuable clue for diagnosing ischemic optic neuropathy and may indicate the need for urgent treatment.

Giant cell arteritis with ocular involvement successfully treated with tocilizumab and very short-course glucocorticoids: A case report.

PURPOSE: To report the case of a patient with arteritic anterior ischemic optic neuropathy (AAION) with a history of glucocorticoids (GC) hypersensitivity treated with monthly intravenous tocilizumab (IV TCZ) and short course of GC. CASE REPORT: A 71-year-old Caucasian patient presented with AAION related to giant cell arteritis (GCA) confirmed by temporal artery biopsy. Past medical history was significant for GC hypersensitivity proven by allergy evaluation and the patient was managed with IV TCZ and very short-course GC. CONCLUSION: TCZ therapy with very short-course GC could be effective in GCA with ophthalmic involvement as a first-line strategy. Clinical trials are needed for thorough evaluation of the efficiency of TCZ as a first-line treatment to induce and maintain remission in patients with GCA and ocular involvement.

Intravitreal Injection Of The Granulocyte-Colony Stimulating Factor For The Treatment Of Non-Arteritic Anterior Ischemic Optic Neuropathy: A Pilot Study.

Purpose To investigate the efficacy of intravitreal injection of granulocyte colony-stimulating factor (G-CSF) for the treatment of non-arteritic anterior ischemic optic neuropathy (NAION).Methods: Patients with acute NAION were enrolled in this prospective interventional case series. They received an intravitreal injection of 60 micrograms in 0.1 ml of G-CSF within 2 weeks of the onset of the disease. Visual acuity, visual field, intraocular pressure (IOP), corneal endothelial cell density, and peripapillary retinal nerve fiber layer (RNFL) thickness were recorded before injections and 1 week, 1 month, 3 months, 6 months, and one year after the injections. Full-field electroretinography (ERG) was obtained at the baseline, 1 month, and 12 months post- injections.Results: Fourteen eyes of 14 patients entered the study. Best-corrected visual acuity (BCVA) significantly improved in the first month following injections (p = .007), decreased subsequently, and the final BCVA showed no significant improvement (p = .278) compared to the baseline measurements. A significant decrease in RNFL thickness was observed in all quadrants compared to the baseline measurements. Also, no improvement in the visual field parameters was observed. From the toxicity aspect, no significant changes in the corneal endothelial cell density, IOP, and ERG recordings were observed.Conclusion: Intravitreal injection of G-CSF seems to be safe. The effect may last for one month and then decline.

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.

Therapeutic Effects of Puerarin Against Anterior Ischemic Optic Neuropathy Through Antiapoptotic and Anti-Inflammatory Actions.

Purpose: This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods: The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results: In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1ß, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPß in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions: PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.

Visual loss due to optic nerve infarction and central retinal artery occlusion after spine surgery in the prone position: A case report.

RATIONALE: Visual loss after spine surgery in the prone position is a serious complication. Several cases of central retinal artery occlusion with ophthalmoplegia after spine surgery have been reported in patients with ophthalmic arteries fed by the internal carotid artery (ICA) in a normal manner. PATIENT CONCERNS: A 74-year-old man developed visual loss after undergoing a spinal decompression and fusion operation in the prone position that lasted approximately 5 hours. DIAGNOSES: We detected an extremely rare case of visual loss due to optic nerve infarction and central retinal artery occlusion through fundoscopic examination, fluorescein angiogram, brain magnetic resonance imaging, and magnetic resonance angiography. The patient's visual loss may have been caused by compromised retrograde collateral circulation of the ophthalmic artery from branches of the external carotid artery in the presence of proximal ICA occlusion after a spinal operation in the prone position. INTERVENTIONS: To recover movement of the left extraocular muscles, the patient received intravenous injections of methylprednisolone for 3 days and then oral prednisolone for 6 days. OUTCOMES: Twenty days after the treatment, the motion of the left extraocular muscles was significantly improved. However, recovery from the left visual loss did not occur until 4 months after the operation. LESSONS: In high-risk patients with retrograde collateral circulation of the ophthalmic artery from the external carotid artery due to proximal ICA occlusion, various measures, including the use of a head fixator to provide a position completely free of direct compression of the head and face, should be considered to decrease the risk of postoperative visual loss.

Bilateral ocular ischemia-induced blindness as a presenting manifestation of Takayasu arteritis: a case report.

BACKGROUND: Takayasu arteritis is a granulomatous panarteritis that predominantly affects the aorta and its major branches. The initial manifestations of this large-vessel vasculitis are usually nonspecific; however, as the disease progresses, typical symptoms of arterial occlusion, aneurysmal formation, and vascular pain become evident. Ischemic ocular complications of Takayasu arteritis which could lead to complete loss of vision are not uncommon and depend on the obliterated portion(s) of carotid(s), the intensity and rate of progression of ocular vascular insufficiency, and sufficiency of the collateral blood supply to the eye. CASE PRESENTATION: A 24-year-old woman of African descent with prior normal vision was referred to us with a 3-year history of gradual decline in visual acuity in both eyes and unintentional weight loss (17 kg) within the past 1 year. A physical examination revealed feeble brachial and radial arterial pulses on her left side. She had sinus tachycardia (136 beats/minute) and her blood pressure was 85/59 mmHg on her left and 134/82 mmHg on her right side. Bilateral microaneurysms, dot and blot hemorrhages, and multiple ischemic areas of retina together with neovascularization in her right eye were noted during a funduscopic examination. Computed tomography angiography of her thoracic and abdominal aorta revealed irregular narrowing with variable degrees of stenosis, tapering, and corrugated appearance. CONCLUSIONS: Despite its rarity, Takayasu arteritis significantly impairs a patient's quality of life and has a life-threatening potential. Early initiation of appropriate therapy could delay disease progression and reduce the associated complications.

Tocilizumab for giant cell arteritis with corticosteroid-resistant progressive anterior ischemic optic neuropathy.

BACKGROUND: Giant cell arteritis is an inflammatory disorder of the medium- and large-size arteries. Permanent visual loss related to arteritic anterior ischemic optic neuropathy is among the most serious complications of this disease and initial treatment usually consists of high dose corticosteroids. There is no consensus in the literature concerning the optimal therapeutic approach in giant cell arteritis patients with corticosteroid-resistant arteritic anterior ischemic optic neuropathy. CASE REPORT: A 73-year-old Caucasian female with biopsy-proven giant cell arteritis developed an acute visual loss of the right eye due to arteritic anterior ischemic optic neuropathy. Despite 5 daily methylprednisolone pulses, systemic symptoms persisted and rapid involvement of the controlateral eye was documented. Therefore, tocilizumab (humanised monoclonal antibody binding the human interleukin-6 receptor) was introduced as a potential salvage therapy with a swift consecutive resolution of the systemic symptoms and stabilization of the ophthalmic lesions. CONCLUSIONS: Although a late effect of steroids pulses cannot be formally ruled out in this dramatic situation, tocilizumab likely offered a decisive effect in preventing bilateral blindness and may have contributed to steroid tapering. Tocilizumab may represent a new early effective second-line treatment option in corticosteroid-resistant anterior ischemic optic neuropathy. More data are needed to confirm this observation and to evaluate the safety profile of this treatment.

Neuroprotective Effects of Omega-3 Polyunsaturated Fatty Acids in a Rat Model of Anterior Ischemic Optic Neuropathy.

Purpose: The purpose of this study was to investigate the therapeutic effect of omega-3 polyunsaturated fatty acid (ω-3 PUFA) administration in a rat model of anterior ischemic optic neuropathy (rAION). Methods: The level of blood arachidonic acid/eicosapentaenoic acid (AA/EPA) was measured to determine the suggested dosage. The rAION-induced rats were administered fish oil (1 g/day EPA) or phosphate-buffered saline (PBS) by daily gavage for 10 consecutive days to evaluate the neuroprotective effects. Results: Blood fatty acid analysis showed that the AA/EPA ratio was reduced from 17.6 to ≤1.5 after 10 days of fish oil treatment. The retinal ganglion cell (RGC) densities and the P1-N2 amplitude of flash visual-evoked potentials (FVEP) were significantly higher in the ω-3 PUFA-treated group, compared with the PBS-treated group (P < 0.05). The number of apoptotic cells in the RGC layer of the ω-3 PUFA-treated rats was significantly decreased (P < 0.05) compared with that of the PBS-treated rats. Treatment with ω-3 PUFAs reduced the macrophage recruitment at the optic nerve (ON) by 3.17-fold in the rAION model. The M2 macrophage markers, which decrease inflammation, were induced in the ω-3 PUFA-treated group in contrast to the PBS-treated group. In addition, the mRNA levels of tumor necrosis factor-alpha, interleukin-1 beta, and inducible nitric oxide synthase were significantly reduced in the ω-3 PUFA-treated group. Conclusions: The administration of ω-3 PUFAs has neuroprotective effects in rAION, possibly through dual actions of the antiapoptosis of RGCs and anti-inflammation via decreasing inflammatory cell infiltration, as well as the regulation of macrophage polarization to decrease the cytokine-induced injury of the ON.