Arun Kapil's research while affiliated with Biomedical Informatics Centre and other places

This case report describes a diagnosis of central retinal artery occlusion in a patient in their early 30s who presented with decreased vision in the left eye for 1 week.

Nearly 1.2 million retinal ganglion cell axons converge at the optic disc to exit the eye and form the optic nerve. The morphology of the optic disc is a fair reflection of axonal health. The axons are carried in the neural rim of the optic disc, leaving a physiological cup in the centre. The size of the optic disc is critical as the axons get crowded in a small optic disc. Loss of axons in open-angle glaucoma (OAG) manifests as notching of the neural rim and enlargement of the cup. Optical coherence tomography (OCT) can objectively measure the thickness of the axons in the circumpapillary (cRNFL) area, the macula, and the thickness of the neural rim even before perimetric changes appear. Characteristics patterns of the loss of the ganglion cell-inner plexiform layer (GCIPL) thickness on OCT can provide the earliest clues to diagnosing OAG. Binasal thinning of the GCIPL is the earliest sign of pituitary adenomas. Non-mydriatic camera images and OCT are replacing direct ophthalmoscopy in emergency rooms. Accurate assessment of the optic disc signs can avoid unnecessary neuroimaging. A significant challenge is differentiating psudopapilledema from true papilledema. The increased thickness of the cRNFL indicates raised intracranial pressure. OCT changes, MRI, and positive Aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies are diagnostic of optic neuritis. Thinning of the GCIPL layer at 1 month accurately assesses the neuronal damage and progression of optic neuritis. A nocturnal dip in perfusion pressure is a major risk factor for the most common optic neuropathy (non-arteritic). On the other hand, anterior ischaemic optic neuropathy due to giant cell arteritis is a blinding disorder and constitutes an ophthalmic emergency.

Retinal vascular occlusions, especially arterial occlusions, strongly correlate with underlying cardiovascular and cerebrovascular disorders. The most common cause of non-arteritic branch or central retinal arterial occlusion is emboli that arise from either the carotid atherosclerotic plaques or heart valves. A stroke may precede or follow within days to weeks of retinal emboli. A stroke unit should evaluate patients with embolic retinal artery occlusion within 4.5 h of the onset for possible treatment with an intravenous injection of tissue plasminogen activator that can restore blood flow by dissolving a fibrin-platelet embolus. However, irrespective of the visibility of an embolus, a doppler scan to rule out haemodynamically unstable carotid atherosclerosis and echocardiography must be done. Giant cell arteritis affecting the small arteries or poly arteritis nodosa that affects medium to small arteries may present with the central retinal artery or the posterior ciliary artery occlusion. Although uncommon, they need to be recognized urgently to save the occlusion of the contralateral eye. Arteriosclerotic changes due to long-standing hypertension are a major risk factor for branch retinal vein occlusion (BRVO). Many patients may show spontaneous resolution, but others have persistent macula oedema in the perfused BRVO or, if ischaemic, develop retinal neovascularization. Central retinal vein occlusions may be perfused or non-perfused. The latter runs the risk of developing anterior segment neovascularization. The standard of care for venous occlusions is intravitreal injections of anti-VEGF agents given every month.

Sighting of haemorrhages in the eye is an ominous sign as it indicates the breakdown of normal homeostasis that keeps the macromolecules and cellular elements away from the normally transparent tissues and spaces of the eye. Without any obvious trauma, haemorrhages in the eye, specifically the retina should prompt a thorough review of systems. Haemorrhages may occur at any age or occupy any compartment of the eye. Those in the retinal periphery may remain asymptomatic and, if present in the anterior chamber or vitreous cavity, may completely obscure vision. Foveal haemorrhages during childbirth are no longer believed to cause amblyopia or nystagmus. Multilayered haemorrhages extending into the far retinal periphery below 5 years should arouse the suspicion of abusive head trauma. Several hematological disorders in children, including thrombophilia, thrombocytopenia and anaemia, leukaemia, paroxysmal nocturnal hematuria, hypertension, sepsis, and meningitis, may manifest in the retina as haemorrhages. White-centred retinal haemorrhages signify elevated leucocytes, and leukaemia must be ruled out in such children. Megaloblastic anaemia caused by a combined deficiency of vitamin B12 and folic acid leads to severe retinal haemorrhages contrasting with iron-deficiency anaemia that seldom causes retinal haemorrhages. In older individuals, hypertension, diabetes, and retinal vein occlusions cause retinal haemorrhages. Linear haemorrhage at the disc margin should prompt investigations for open-angle glaucoma. Neurological disorders like cortical venous thrombosis and idiopathic intracranial hypertension often cause papilloedema and retinal haemorrhages.

Haemorrhage under the neurosensory retina or the retinal pigment epithelium in the macula is a sight-threatening condition. It is a significant public health concern in the ageing population the world over. The varying severity of haemorrhage from the rupture of the new vessels of choroidal origin compromises central vision that may go unnoticed in the first eye. Two distinct variants are seen. Stigmata of age-related macular degeneration (AMD) in the form of drusen and pigmentary changes accompany bilateral disease in the Caucasian population. In contrast, the one in the Asian population often presents with unilateral features and can become bilateral lateris characterized by a network of vessels and the formation of polyps under the RPE that cause massive haemorrhagic pigment epithelial detachments (polypoidal choroidal vasculopathy, PCV). Moreover, AMD is characterized by age-related thinning of choroid and ischemia, while PCV has a thick and hyperpermeable choroid. There is evidence that polymorphisms in the alternate complement pathways lead to low-grade inflammation and interfere with the debris removal pathways. Smoking, a strong epigenetic factor, increasesthe risk of age-related macular degeneration several folds in genetically predisposed individuals. Imaging techniques such as OCT, OCT angiography, FA, and ICG can detect the earliest asymptomatic stages of the new vessels and minimize vision loss by appropriate use of anti-VEGF injections.

Being the most common cause of severe vision loss in the working age group in the Western world, physicians should be familiar with new vessels that develop on the optic disc and elsewhere in the retina in patients with diabetes mellitus. Ophthalmologists and physicians caring for people with diabetes are critical in preventing unnecessary blindness from diabetic retinopathy. Other less common causes of retinal neovascularization include ischaemic branch retinal vein occlusion, a complication for which the major risk factor is hypertension and its resultant arteriosclerotic changes. In preterm babies, likewise, ophthalmologists and neonatologists play the most critical role in preventing the development of retinopathy of prematurity, which has a very narrow window of opportunity to prevent life-long blindness in these hapless babies. This chapter reviews the current understanding of the pathophysiology of these blinding disorders. Hypoxia-induced vascular endothelial growth factor (VEGF) overexpression is at the root of pathological retinal neovascularization. Many anti-VEGF agents dramatically regress the pathological retinal new vessels, albeit temporarily. Monthly intravitreal injections of anti-VEGF agents have been stressful for patients and care providers. Notably, to date, underlying retinal ischaemic areas cannot be reperfused. Moreover, as the effect of blocking VEGF on neurodevelopment in preterm babies is unknown, the use of these agents in ROP is restricted to the type 1, zone 1, and posterior zone 2 diseases with a meticulous follow-up until complete normal vascularization of the retina.

Maintenance of the transparency of the neurosensory retina is critical to obtaining sharp and high-resolution images. The tight endothelial barrier does not allow fluid movement into the retina. A neurovascular unit comprising Muller cell processes and the capillary endothelial cells and pericytes ensures a balanced hydrous state of the retina. It gets disturbed in metabolic, inflammatory, degenerative, and dystrophic disorders besides the retinal vascular occlusions and drug toxicities resulting in the intraretinal and subretinal fluid collection. The outer plexiform layer in the blood supply watershed zone becomes the prime site for fluid collection in the extracellular space and swelling of the cellular elements. Macular oedema in diabetes is the most common cause of moderated visual loss. In the last 20 years, optical coherence tomography has supplanted documentation of macular oedema on stereoscopic fundus photographs and fundus fluorescein angiography. The central subfield thickness in a diameter of 1 mm on the foveal centre is the most crucial metric to diagnose and monitor the outcome of various therapeutic interventions. The standard of care intervention for macular oedema due to diabetic retinopathy and retinal vein occlusions is monthly anti-vascular endothelial growth factor injections. Intravitreal corticosteroids remain the treatment of choice for inflammatory macular oedema.

The presence of even a single retinal capillary microaneurysm (MA) portends an underlying serious systemic disorder, most importantly diabetes mellitus (DM). Development of retinal MAs remains asymptomatic for several years till leakage from these starts affecting the transparency of the macula. Retinal MAs arise because of a hypoxic state in the inner neurosensory retina. Moreover, there is indirect evidence that DM has been present for at least 5 years and calls for a systematic search of the diabetes-associated comorbidities such as hypertension, coronary artery disease, nephropathy, peripheral neuropathy, and peripheral arterial disease. Other significant causes of retinal MAs include hypertension, carotid atherosclerosis, ocular ischaemic syndrome, Takayasu’s arteritis, and retinal venous occlusions. See Box 1.1. Clinically, the MAs are best appreciated on direct ophthalmoscopy by physicians or stereoscopic biomicroscopy by ophthalmologists. Ancillary investigations like fundus fluorescein angiography (FFA) reveal many more MAs than are clinically evident. The MAs lack tight junction proteins, a hallmark of the retinal vessels. Fluid and macromolecular leakage from the MAs results in the swelling of the neurosensory retina and the deposition of lipoproteins, causing moderate visual loss. In the past, focal laser photocoagulation of individual leaky MAs was the standard of care. Presently, it has been supplanted by pharmacotherapy.

Inflammation of the outermost layer of the white coat of the eye, the episclera, is fairly common. It may cause discomfort and although benign may be recurrent. Autoimmune inflammations of the sclera although less common than episcleritis cause painful, diffusely red eye. Scleral inflammations may be nodular and necrotizing with or without inflammation. Posterior scleritis can be diffuse or nodular and is mostly non-necrotizing. A painless necrotizing variant, scleromalacia perforans and necrotizing scleritis with inflammation are associated with systemic inflammatory diseases such as rheumatoid arthritis and granulomatosis with polyangiitis and are a harbinger of systemic vasculitic complications. These carry a high risk of fatal outcomes. Necrotizing scleritis is often accompanied by peripheral ulcerative keratitis (PUK) which carries a risk of globe perforation. While mild to moderate inflammations of the sclera can be treated with non-steroidal anti-inflammatory drugs (NSAIDs), necrotizing scleritis requires urgent treatment with intravenous corticosteroids and NSAIDs. Non-responders in the past were treated with intravenous cyclophosphamide for quick remission. Presently, it is reserved for patients who do not respond to biological agents; the most preferred are TNF-α inhibitors, rituximab, and IL-6 inhibitor tocilizumab.

The neurosensory retina and the RPE are normally glued to each other by an interphotoreceptor-binding protein matrix without forming any adhesions. An active pump located at the apical aspect of the RPE microvilli keeps the potential subretinal space dry. However, several disorders, including central serous chorioretinopathy, pachychoroid spectrum disorders, diabetic macular oedema, retinal vein occlusions, neovascular membrane in the macula, hypertensive choroidopathy, posterior uveitis, and metastatic lesions in the choroid, may lead to accumulation of fluid in the subretinal space termed the exudative retinal detachment. The subretinal fluid accumulates most often due to increased hydrostatic pressure in the choroid. Central serous choroidopathy is part of a pachychoroid spectrum. The increased hydrostatic pressure in the choroid is likely due to venous overload choroidopathy. Disruptions in the ellipsoid zone ELM and hyperreflective foci, inflammatory cytokines, and high blood pressure are risk factors for subretinal fluid in diabetic macular oedema. In retinal vein occlusion, excessive fluid leakage through the Muller cells may lead to subretinal fluid. The attachment of the neurosensory retina to the RPE may be overwhelmed by tractional forces on the neurosensory retina in proliferative diabetic retinopathy, branch retinal vein occlusion, retinopathy of prematurity, and high myopia. Traction can be relieved only by surgery with subsequent absorption of the subretinal fluid. Tears or holes in the neurosensory retina allow ocular fluids to flow into the subretinal space and cause a rhegmatogenous retinal detachment (RRD). A fresh RRD appears as a semitransparent, undulating membrane with folds in its outer layers. Depending on the location of the retinal breaks in the upper or lower half, the retinal detachment is bullous and fast progressing or shallow and slow progressing, respectively. Locating and sealing all the breaks during surgery is vital to successfully reattach the retina.