Ocular ischemic syndrome is a rare condition, which is caused by ocular hypoperfusion due to stenosis or occlusion of the common or internal carotid arteries. Atherosclerosis is the major cause of changes in the carotid arteries. Ocular ischemic syndrome is manifested as visual loss, orbital pain and, frequently, changes of the visual field, and various anterior and posterior segment signs. Anterior segment signs include iris neovascularization and secondary neovascular glaucoma, iridocyclitis, asymmetric cataract, iris atrophy and sluggish reaction to light. Posterior eye segment changes are the most characteristic, such as narrowed retinal arteries, perifoveal telangiectasias, dilated retinal veins, mid-peripheral retinal hemorrhages, microaneurysms, neovascularization at the optic disk and in the retina, a cherry-red spot, cotton-wool spots, vitreous hemorrhage and normal-tension glaucoma. Differential diagnosis of ocular ischemic syndrome includes diabetic retinopathy and moderate central retinal vein occlusion. Carotid artery imaging and fundus fluorescein angiography help to establish the diagnosis of ocular ischemic syndrome. The treatment can be local, for example, ocular (conservative, laser and surgical) or systemic (conservative and surgical treatment of the carotid artery). Since the condition does not affect the eyes alone, patients with ocular ischemic syndrome should be referred for consultation to the neurologist, vascular surgeon and cardiologist.

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Ocular ischemic syndrome – a systematic review

Background: An altered perfusion of the optic nerve head has been proposed as a pathogenic factor in glaucoma.

Aim: To investigate potential differences in the ocular haemodynamics of patients having glaucoma with progressive versus stable disease, as well as healthy volunteers.

Methods: Peak-systolic velocity (PSV), end-diastolic velocity (EDV) and resistivity index in the short posterior ciliary artery (SPCA), central retinal artery (CRA) and ophthalmic artery were recorded in 114 consecutive patients having glaucoma with an intraocular pressure (IOP) ⩽21 mm Hg, as well as in 40 healthy volunteers, by colour Doppler imaging (CDI).

Results: Of the 114 patients with glaucoma, 12 showed glaucoma progression (follow-up period: mean 295 (standard deviation (SD) (18) days). CDI measurements in these patients showed decreased PSV and EDV in the SPCA (p<0.001 and p<0.05, respectively) and decreased PSV in the CRA compared with patients with stable glaucoma and healthy controls (p<0.05). No differences in flow velocities were found for the ophthalmic artery. IOP and systemic blood pressure was similar in all the three groups.

Conclusions: Progressive glaucoma is associated with decreased blood flow velocities in the small retrobulbar vessels supplying the optic nerve head. The detected difference could represent a risk factor for progression of glaucomatous optic neuropathy.

Glaucoma Progression Is Associated With Decreased Blood Flow Velocities in the Short Posterior Ciliary Artery

Background
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil.

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Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy

Management paradigms for diabetic macular edema.

Introduction Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow. Purpose This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years. Methods The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered. Results The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin), Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist. Conclusion The clinical value of novel compounds for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action.

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Novel ocular antihypertensive compounds in clinical trials

Glaucoma is a group of eye diseases causing irreversible optic nerve damage. This review presents 4 elements of future glaucoma treatment strategies: baroprotection, vasoprotection, neuroprotection and gene therapy. New baroprotection includes compounds that alter the actin cytoskeleton (rho-kinase inhibitors, latrunculin, cytochalasin), new drugs that enhance aqueous outflow via the trabecular meshwork (statins, steroid antagonists) and via the uveoscleral route (EP2 agonists, 5-HT2 agonists), as well as new classes of components that suppress aqueous humor formation (cannabinoids). Vasoprotection includes blocking reperfusion injury (NOS-2 inhibitors, endothelin blockers, MMP-9 inhibitors). Concerning neuroprotection antiamyloids antibodies, erythropoietin and caspase inhibitors are discussed. Gene therapy may target various effectors: the trabecular meshwork (cytoskeleton regulatory proteins, miocyllin, MMPs), the ciliary body epithelium (genes modifying aqueous humor production, neuropeptides), the ciliary body cells (MMPs, genes of local PGs biosynthesis, ciliary muscle relaxants), the retinal ganglion cells (neurotrophin genes, anti-apoptotic genes), Muller cells (neurotrophins, GLAST) and conjunctiva (gene of chloramphenicol acetyltransferase, inhibitor p21). Experimental studies on the graft mesenchymal stem cells and mature retinal cells to replace the dead retinal ganglion cells are advanced. Immunotherapy, offering a vaccination, providing protection against loss of retinal ganglion cells, has been investigated.

Future possibilities in glaucoma therapy.

Aims To assess the additive effect of dorzolamide hydrochloride 2% on the diurnal intraocular pressure (IOP) curve and retrobulbar haemodynamics in patients with primary open-angle glaucoma (POAG) treated with morning-dosed bimatoprost 0.03%. Methods Twenty-five patients with POAG were evaluated in a prospective, single-masked study. After a 1 week run-in period with bimatoprost all patients were treated with bimatoprost dosed once in the morning for 1 month, after which dorzolamide was added twice daily for 2 months. Goldmann applanation IOP, arterial blood pressure (ABP) and heart rate were measured every 2 h for 24 h and diurnal ocular perfusion pressure (OPP) was calculated. Colour Doppler imaging (CDI) of the ophthalmic artery (OA) and the central retinal artery (CRA) was recorded five times daily. All measurements were taken after the two phases of treatment and were compared. Results The mean baseline IOP was 14.8±3.5 mm Hg. Mean IOP following bimatoprost monotherapy (12.8±2.9 mm Hg) and after 2 months of dorzolamide adjunctive therapy (12.2±2.6 mm Hg) were not statistically significantly different (p=0.544). Only at the 4:00 h time point was IOP significantly reduced using the bimatoprost/dorzolamide combined treatment (p=0.013). The 24 h IOP fluctuations were lower when dorzolamide was added (6.0±2.3 mm Hg vs 4.6±1.5 mm Hg, p=0.0016). Repeated analysis of variance detected a significant decrease of vascular resistance in the OA (p=0.0167) with adjunctive dorzolamide treatment. Conclusions The addition of dorzolamide to morning-dosed bimatoprost had an additive hypotensive effect only on the night-time IOP curve at 4:00 h and resulted in a lower IOP fluctuation. Dorzolamide added to bimatoprost may reduce vascular resistance in the OA.

https://bjo.bmj.com/content/bjophthalmol/94/10/1307.full.pdf

The additive effect of dorzolamide hydrochloride (Trusopt) and a morning dose of bimatoprost (Lumigan) on intraocular pressure and retrobulbar blood flow in patients with primary open-angle glaucoma

Background Photodynamic therapy (PDT) is considered a selective method of treatment which works in areas of choroidal neovascularization (CNV); however, there are reports of choroidal hypoperfusion after PDT. This paper presents a clinical case of choroidal circulation disturbances caused by PDT, accompanied by CNV progression. Case report The patient, a 75-year-old woman, was qualified for PDT in the right eye--first treatment due to progression of occult CNV. Best corrected visual acuity (BCVA) in the right eye at baseline was +0.3 logMAR. After PDT, a rapid decrease in visual acuity to +0.7 logMAR in the right eye was observed, central choroidal hypoperfusion in fluorescein angiography (FA) with subretinal fluid appeared and, as a consequence, progression of neovascular age-related macular degeneration (AMD). After stabilizing the local state through conservative therapy, a decision was made to treat the right eye with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitor. During a 12-month period of observation, 7 doses of ranibizumab were administered. A regression in activity of wet AMD was observed, with visual acuity of +0.6 logMAR. Conclusions Choroidal circulation disturbance after PDT is possible and has to be taken into account. Sporadically, it can lead to an acute decrease in visual acuity and local state. After stabilization of AF and optical coherence tomography imaging, further treatment of neovascular AMD with intravitreal injections of anti-VEGF agents should be considered.

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Severe decrease in visual acuity with choroidal hypoperfusion after photodynamic therapy.

BACKGROUND The aim of this study was to evaluate the visual acuity and structural outcomes of combined phacovitrectomy with ILM peeling, retinal endophotocoagulation and use of bevacizumab in patients with diffuse diabetic macular edema (DDME). MATERIAL/METHODS In this prospective, nonrandomized, interventional study we included 29 eyes of 26 patients with DDME. The best-corrected visual acuity (BCVA) and central retinal thickness and volume (CRT and CRV) were recorded at 4, 8, 12, and 16 months after surgery. RESULTS The mean preoperative BCVA was 0.74±0.36 logMAR (0.3-1.5) and improved finally to 0.4±0.24 logMAR (-0.1-1.0) p=0.000006. The mean preoperative CRT in the 1mm zone was 516±184 microm (256-950) and decreased postoperatively at the last control to 237±75 microm (117-489) p=0.000003. The mean preoperative CRV in the 1mm zone was 0.39±0.14 microL (0.19-0.74) and decreased postoperatively at the last control to 0.17±0.06 microL (0.09-0.36) p=0.000003. The mean preoperative CRT in the 6 mm zone was 407±105 microm (279-640) and decreased postoperatively at the last control to 282±40 µm (212-380) p=0.000004. The mean preoperative CRV in the 6 mm zone was 11.4±2.9 microL (7.85-17.93) and decreased postoperatively at the last control to 7.92±1.0 microL (5.62-10.97) p=0.000003. The 23 (79.3%) eyes showed improvement in BCVA ≥0.2 logMAR, 5 (17.2%) eyes improvement or stabilization of BCVA and 1(3.5%) eye deterioration. Preoperative BCVA was a positive factor for prognosis of BCVA at 12th month follow-up (b=0.42; p=0.006), while the negative factors were: previous panretinal photocoagulation (b=-0.24; p=0.04), presence of vitreomacular traction (b=-0.29; p=0.02) and preoperative CRT in the 1000 microm zone (b=-0.24; p=0.07). A greater visual acuity improvement occurred in eyes with worse baseline visual acuity (b=-1.01; p=0.00001). The presentation of vitreomacular traction (b=-0.38; p=0.02), previous panretinal photocoagulation (b=-0.31, p=0.04) and greater preoperative CRT in the 1000 µm zone (b=-0.31; p=0.07) were negative factors for visual improvement. CONCLUSIONS This combined treatment resulted in improvement or stabilization of BCVA and decrease of CRT and CRV. Larger comparative studies are necessary to establish the real impact of this therapeutic approach.

Triple therapy: Phaco-vitrectomy with ILM peeling, retinal endophotocoagulation, and intraoperative use of Bevacizumab for diffuse diabetic macular edema

There are at least three avenues of investigation that support the theoretical value of vitrectomy for the treatment of DME, based on (1) vitrectomy with ILM peeling for the relief of traction on the macula, (2) vitrectomy to improve oxygenation of the macula leading to decreased vascular permeability with subsequent resolution or decrease in DME, and (3) ILM peeling to remove a part of the Muller cell endfeet and the horizontal gliosis. Visual improvement could be due to the induction of a higher overexpression of GFAP at the Muller cells level. It is likely that the proliferation of GFAP-stained gliofibrils, observed in these cells, preserves the blood-retinal barrier, reinforces architectural cohesion, and opposes the installation of the edema. In addition, the search for a specific pharmacological treatment is ongoing on the basis of new findings regarding the involvement of cytokines and growth factors in the formation of macular edema. Vascular endothelial growth factor (VEGF), inhibitors are currently being investigated in clinical studies. However, endogenous VEGF is required for visual function. Growing body evidence indicates that VEGF acts also on nonvascular cells, it plays survival role on Muller cells and photoreceptors. Therefore anti-VEGF therapies should be administered with caution.

Jacek Robaszkiewicz

Papers

Future possibilities in glaucoma therapy.

The additive effect of dorzolamide hydrochloride (Trusopt) and a morning dose of bimatoprost (Lumigan) on intraocular pressure and retrobulbar blood flow in patients with primary open-angle glaucoma

Severe decrease in visual acuity with choroidal hypoperfusion after photodynamic therapy.

Triple therapy: Phaco-vitrectomy with ILM peeling, retinal endophotocoagulation, and intraoperative use of Bevacizumab for diffuse diabetic macular edema

Combined surgical and pharmacological treatment of diabetic maculopathy