Ophthalmology: Sub-specialty—Vitreo-retinal

Ophthalmology: Sub-specialty—Vitreo-retinal

Retinal detachment

Aims

  • Understand the significance of eye floaters.
  • Describe the types of retinal detachment.
    The retina detaches if it has a hole or tear from high myopia, an inherent retinal weakness, or trauma. If part of the peripheral retina is detached, this is perceived as a peripheral vision shadow. If the macula is detached, central vision is very blurred (Figure 42.1).

Floaters and photopsia (flashing lights)

Floaters and flashes are common and alarming. The underlying cause ranges from the trivial to sight threatening.
Refer to an ophthalmologist if: new flurry of floaters (above and beyond the background basal level) or new flashing lights.
Floaters are caused by:

  • Cells: in anterior, intermediate or posterior uveitis
  • Blood: in vitreous haemorrhage
  • Collapsed vitreous: common with age or axial myopia.
    Photopsia are caused by stimulation of retinal photoreceptors by mechanical forces, simulating light activation:
  • Retinal tears or detachments
  • Detached vitreous gel tugging on the retina when abnormal adhesions are present.

Posterior vitreous detachment (PVD)

The vitreous gel pulls away or separates from the retina and collapses.
A PVD is perceived as a floating cobweb, ring or tadpole, which moves with eye movement, worse against a white or clear background.

Aetiology

  • Eye or head trauma or spontaneously with age or myopia greater than −6D.

Symptoms

  • Photopsia; more noticeable in dim light.
  • Floaters:
    ○ from a small amount of haemorrhage (which may occur with the PVD)
    ○ collapsed vitreous casts a shadow on the retina.

Natural history of floaters

The majority of floaters are self-limiting becoming less noticeable with time. Only a small proportion develop a retinal tear. In up to 15% of patients who present with an acute symptomatic PVD, the detaching vitreous pulls a hole in the retina, which can lead to a rhegmatogenous retinal detachment.

Management

  • Indirect ophthalmoscopy with scleral indentation is used for mapping the retinal detachment.
  • Laser treatment to seal a simple retinal tear with minimum or no sub-retinal fluid (SRF) and prevent retinal detachment (laser retinopexy).
  • Reassure if no tear is found.

Retinal detachment (RD)

  • An RD occurs when the retina is separated from the retinal pigment epithelium (RPE) by SRF.
  • Once the retina has been separated from its blood supply, the photoreceptors slowly degenerate, becoming permanently non-functional.
  • A RD is surgically reattached to regain vision.
  • If the RD does not involve the macula (macula ‘on’ RD) and the vision is still good, surgery is urgent within 24 h particularly in superior detachments as gravity encourages it to track down toward the macula and threaten vision.

Aetiology

There are three types of RD, and each has a different aetiology:

  • Rhegmatogenous RD (Figure 42.3): a full-thickness tear in the retina allows liquid vitreous into the space between the retina and the RPE.
    High myopia increases the risk.
  • Exudative RD: some inflammatory or neoplastic conditions lead to serous exudation from leaky blood vessels beneath the retina (in the absence of a retinal break or hole).
  • Tractional RD (Figure 42.4): fibrous or vascular membranes growing abnormally in the vitreous (e.g. in patients with fibrosis following proliferative diabetic retinopathy) contract and pull the retina away from the RPE.
  • Solid RD: rarely, a tumour such as a malignant melanoma originating in the choroid under the retina can elevate the retina. This can metastasize and needs urgent referral to a specialist ophthalmic oncologist in a specialist centre for management.

Symptoms

Rhegmatogenous RD presents with:

  • Photopsia ± floaters.
  • This is followed by a gradual blurring or loss of vision, which may
    start off as a shadow in the peripheral visual field.
  • SRF under the macula, (macula ‘off’ RD), causes blurred vision.
  • Other types of RD present with reduced vision.

Signs

  • Visual acuity (VA) normal when the macula is on.
  • Reduced VA be due to macular SRF or from a bullous RD in front of the macula.
  • ‘Tobacco dust’ visible in the anterior vitreous represent red blood cells and/or RPE cells that have migrated into the vitreous through the tear. Tobacco dust indicates a retinal tear and the need for referral to a retinal surgery ophthalmologist for further evaluation.
  • Intraocular pressure may be reduced.

Examination

Slit lamp examination for tobacco dust and with a three-mirror contact lens to detect the retinal tear and determine whether laser or surgery required.
Indirect ophthalmoscopy with scleral indentation assists viewing the RD.

Complications

  • If the RD involves the macular area, recovery of vision is poor.
  • Recurrent RD carries the risk of subretinal membrane and secondary tractional detachment.

Surgical management

  • Rhegmatogenous RD: reattachment: laser, cryotherapy plus explant or internal surgery with vitrectomy.
  • Exudative and solid RD: establish and treat the cause.
  • Tractional RD: relieve traction.
    In all types of vitreo-retinal surgery, an oil or gas may be used and patient posturing required post-operative.

Retinal and choroidal anatomy and imaging

The ability to image the microstructure of the retina and choroid has significantly altered the way we appreciate and treat retinal disease.

Aims

  • Know the anatomy of the choroid and retina.
  • Identify the main priorities of medical retinal disease.
  • Know the methods of retinal imaging and the appropriate use of a particular imaging system.
  • Understand the need for more than one modality of imaging.

Retinal and choroidal anatomy

Knowledge of retinal anatomy and physiology is vital to accurately interpret retinal images.

  • Choroid: a fenestrated capillary-rich layer which supplies oxygen and micronutrients to the retinal pigment epithelium and the outer one-third of the neurosensory retina. The capillary layer is the choriocapillaris.
  • Retinal pigment epithelium (RPE): a monolayer of pigmented cells between the neurosensory retina and Bruch’s membrane. Tight junctions exclude large molecules and form the outer part of the blood retinal barrier.
  • Bruch’s membrane: an acellular layer between the choroid and RPE, which does not form a significant part of the blood–retinal barrier.
  • Neurosensory retina: includes photoreceptors, ganglion cells and their axons (nerve fibre layer), other neurons (e.g. bipolar cells) and glial cells (e.g. Müller cells).
  • Retinal arteries, capillaries and veins: non-fenestrated vessels forming the inner blood–retinal barrier.
  • Foveal avascular zone: an approximately 0.045 mm zone in which retinal capillaries are absent.

Medical retinal disease priorities

The management of medical retinal disease has been revolutionized as a result of developments in retinal imaging, the advent of molecular genetics and new treatment modalities.
Retinal imaging modalities, together with psychophysical and electrophysiological evaluation, are very valuable in diagnosing disorders of the retina, RPE and choroid.

Imaging

Fundus camera

  • A high-resolution digital fundus camera can be used to document baseline retinal findings and track disease progression, and for screening (e.g. for diabetic retinopathy) and clinical studies. Colour fundus photography and fluorescein and indocyanine green angiography are used to image the retina and surrounding structures. Digital images allow rapid diagnosis and review, and are electronically transferred; they are useful for telemedicine.

Optical coherence tomography (OCT)

This is non-invasive diagnostic imaging analogous to an ultrasound B scan except that light and not sound is used; a higher resolution is therefore obtainable. A highly coherent light source is used to scan the retina and produces high-resolution, cross-sectional, threedimensional (3D) images. Used for assessing retinal thickness, retinal oedema and optic nerve head imaging in glaucoma, and for assessing macula pathology. OCT is becoming the most commonly performed retinal imaging. Fluorescein angiography can be done using an OCT machine. Also see Appendix 4 for full OCT reports.

Dyes used in imaging

  • Fluorescein: sodium fluorescein is an orange dye excited by a blue light to emit a yellow-green light. It is a small molecule, only 80% bound to blood proteins, which diffuses freely through the choriocapillaris, Bruch’s membrane, optic nerve and sclera.
  • Indocyanine green (ICG): this is a green dye, which when excited by a near-infrared light emits a near-infrared light. It is almost 100% protein bound, so it only leaks slowly through the fenestrated capillaries of the choriocapillaris.

Fundus fluorescein angiogram (FFA)

This is a sequence of fundus images taken immediately after sodium fluorescein dye is injected into a peripheral vein. The fundus is illuminated by a blue light, causing the fluorescein molecules to fluoresce in the yellow-green spectrum. Barrier filters block reflected blue light so that only yellow-green (i.e. fluorescent) light is transmitted to the film or digital camera. A detailed 3D view of the retina and of the level of fluorescence can be achieved by using a stereoscopic viewing device or computer software. FFA is good for viewing retinal detail.

Indocyanine green angiography (ICGA)

Near-infrared fluorescence is recorded with infrared film or, more commonly, with a digital camera, after the injection of ICG into a peripheral vein. Light of this wavelength has better penetration of red or brown pigments (e.g. melanin in RPE cells or sub-retinal blood).
ICGA is useful in investigating choroidal disease (e.g. choroidal neovascularization and choroidal tumours).

Confocal scanning laser ophthalmoscope (SLO)

This is a fundus camera using a low-power scanning laser for illumination at different focal planes in the retina to produce tomographic images.

Terms used when describing fluorescein angiograms

  • Hyperfluorescence: increased fluorescence relative to other structures; seen as black on white if negative film is used and white on black with digital photography
  • Hypofluorescence: reduced fluorescence relative to other structures (e.g. due to blocked fluorescence or decreased vascular perfusion)
  • Window defect: increased choroidal fluorescence seen through a window of attenuated RPE (e.g. geographic atrophy or laser scars)
  • Blocked fluorescence: masking of fluorescence by opacity anterior to it (e.g. sub-retinal haemorrhage)
  • Fluorescein leakage: characteristic of conditions in which the outer (RPE) or inner (retinal vasculature) blood–retinal barrier is disrupted
  • Autofluorescence: fluorescence occurring without the injection of fluorescein dye.

Inherited retinal disorders and age-related macular degeneration

Improved imaging techniques including high-resolution optical coherence tomography (OCT) and the availability of multiple intravitreal treatments and novel interventions such as gene and stem cell therapies has revolutionized the management of inherited retinal disorders and age-related macular degeneration (AMD). Inherited retinal disorders most commonly present in childhood or early adulthood whereas AMD is most common in older adults. AMD is the most common cause of visual loss in the western world. In the UK, inherited retinal disease is the second commonest cause of visual loss in childhood and the commonest cause in the working-age population.

Aims

  • Appreciate the types of inherited retinal degeneration.
  • Know the significance of early central visual symptoms of neovascular age-related macular degeneration (nAMD) and refer promptly for early treatment.
  • Be aware of the range of treatment options and increasing clinical trials for patients with inherited retinal degeneration and AMD.

Children and young adults

Inherited retinal disorders

  • Divided into predominantly stationary conditions (cone or rod dysfunction syndromes e.g. achromatopsia and congenital stationary night blindness, respectively)—or progressive disorders (retinal dystrophies—rod-cone dystrophies, cone-rod dystrophies, and chorioretinal dystrophies).
  • Stationary disorders tend to present at birth or early infancy whereas Progressive disorders often present in the first or second decades.
  • Clinical and genetic variability in inherited retinal disease within and between families severity, age of onset, and rate of progression.
  • Retinal dystrophies Stargardt disease, Best’s disease (Figure 44.1), North Carolina macular dystrophy cone–rod dystrophy (Figure 44.2).
  • Retinitis pigmentosa (RP) (Figure 44.3) is a rod-cone dystrophy incidence of approximately 1 in 3000. Early features due to loss of rod function are night blindness and progressive peripheral visual field loss, with later loss of cone function resulting in central visual loss.
    Full-field electroretinograms in the early stages show a greater reduction in the responses of the rod system than the cone system, with often unrecordable ERGs at later stages. Characteristic retinal findings: optic disc pallor, retinal vessel attenuation and widespread bone-spicule retinal pigmentation. RP is most commonly isolated (non-syndromic) but can be associated with systemic disease (syndromic RP), including Usher syndrome (RP with deafness) and Kearns–Sayre syndrome (RP with ophthalmoplegia, ataxia and cardiac conduction defects).
  • Genetic counselling, advice on prognosis and increasingly molecular genetic testing are important in the management of these disorders.
  • There are no proven cures for inherited retinal disorders—we are in an era of increasing clinical trials of gene therapy, stem cell therapy, artificial vision, and neuroprotective and pharmacological approaches.
    Further information from www.clinicaltrials.gov and the research section on the website of Retinitis Pigmentosa Fighting Blindness.
  • Management: ensuring appropriate spectacle correction, low visual aids, providing educational and social support, and visual impairment certification. The use of vitamin A in RP is controversial with most authorities no longer recommending its use. Patients with Stargardt disease should not take Vitamin A as it is likely to be harmful. Patients are advised to not smoke, have a healthy balanced diet rich in green vegetables (lutein containing), and to avoid excessive exposure to bright sunlight including wearing sunglasses with good ultra-violet light blocking properties.

Older adults

Age-related macular degeneration

AMD is the commonest cause of blindness in the Western world. See Table 44.1 for the associated risk factors; two main forms of AMD occur: dry and wet; tobacco smoking is the main modifiable risk factor; genetic risk factors—consistent with an inflammatory basis to AMD, with complement factor H (CFH) and C3 genes implicated in the pathogenesis of AMD. Non-complement factor associated genes include ARMS2/HTRA1; other significant risk factors: family history of AMD (OR = 3.95: CI 1.35–11.54), race. AMD is more common in whites.

Pathology
  • Dry AMD accounts for 90% of cases. Oxidative stress and inflammation play an important role in pathogenesis. Retinal waste products including lipofuscin and A2-E accumulate in the RPE, impairing its function and resulting in photoreceptor and choriocapillaris damage.
    A2-E activates the complement system leading to localized chronic inflammation and further impairment of RPE function. Specific retinal changes include: localized collection of extracellular material (drusen) at Bruch’s membrane (Figure 44.4), loss of RPE/photoreceptors, thickening of Bruch’s membrane and choriocapillary atrophy.
  • In 10% of patients, under the control of vascular endothelial growth factor (VEGF), blood vessels grow from the choroid, through Bruch’s membrane and into the retina: wet AMD. These choroidal neovascular membranes (CNVMs; Figure 44.5) leak and cause scarring in the macula, hence causing irreversible loss of central vision.
Investigations
  • Dry AMD—OCT and fundus autofluorescence imaging (FAF) can help document baseline disease severity and monitor progression.
  • Wet AMD—Fundus fluorescein angiogram (FFA): important for diagnosis and assessment for treatment, identifying type of CNVM, and monitoring progress. OCT: detects macular oedema, subretinal fluid, pigment epithelial detachment (Figure 44.6 and 44.7). OCT measures disease progression and guide treatment. ICG: primarily used in diagnosis of idiopathic polypoidal choroidal vasculopathy with a role in diagnosis of retinal angiomatous proliferation.
  • The two main types of wet AMD can be clearly diagnosed using FFA: early leakage of dye (classic neovascular membranes, Figure 44.8) and slower later leakage (occult CNVM; Figure 44.9).
Managing AMD
  • Dry AMD: Lifestyle changes; cessation of smoking, protect eyes from excessive bright sunlight, healthy life style with weight reduction, well balanced diet high in natural antioxidants, green-leafy vegetables.
    Nutritional supplementation based upon AREDS / AREDS2 such as Ocuvite Lutein. Low visual assessment and aids. Amsler grid to monitor any new distortion (suggestive of conversion to the wet form of the disease). Future therapies include Complement system inhibitors: phase 2 trials underway.
  • Wet AMD: The mainstay is intravitreal anti-VEGF which stop the stimulus for blood vessel growth and leakiness by injecting regular anti-VEGF drugs directly into the vitreous (through the pars plana and not damaging the neurosensory retina).
  • We are guided for further repeat injections by serial assessments of visual function, retinal examination and OCT.
  • Two principal NICE approved agents which are administered at differing intervals following the loading phase, ranibizumab and aflibercept. This provides disease stability is achieved in approximately 90% of patients, 3 line improvement in 30–40%.
Rehabilitation

Consider patients with wet or dry AMD for a Certificate of Visual Impairment.

  • Entitlements: financial allowance, disabled person’s parking badge, talking books and clocks etc; a home visit by a low-vision therapist to assess disability; initiate community care, social and/or voluntary services and contact with self-help groups.
Low-vision aids
  • optical aids: magnifiers and telescopes
  • non-optical aids: lighting, large-print books and bank statements.

Diabetic retinopathy classification and typical lesions

Aims

  • Understand the pathogenesis and classification of diabetic retinopathy (DR) with relevance to visual loss.
  • Understand the role of DR screening and the two-way communication between the community and the hospital.

Introduction

  • DR is an important microvascular complication of diabetes mellitus.
  • It is the leading cause of blindness in the working population in the developed world.
  • The annual incidence of blindness from DR varies between 0.02% and 1%.
  • An international standard classification of DR is essential for guidelines in screening, treatment protocols and research.

Pathology

One must think of DR as a continuum of disease, with a stepwise progression that leads to the various clinical manifestations (Figure 45.1). At the epicentre of this universe is ischaemia:

  • Thickening of basement membranes, damage to and proliferation of endothelial cells, and increased platelet aggregation all lead to narrowed vessels.
  • This causes ischaemia and leads to weakening of capillary walls, resulting in out-pouching of vessels.
  • Further phosphorylation, glycosylation and disorganization of tight junctions, with a loss of pericytes, leads to breakdown of the inner blood–retinal barrier. Once enough damage to the vessel walls occur, they become leaky (large enough for extravasation of protein, lipids, red blood cells and fluid).
  • Continual ischaemia leads to cotton wool spots and intra-retinal microvascular abnormalities (IRMAs).
  • The retinal response to ischaemia is the release of vasogenic agents, including vascular endothelial growth factor (VEGF), which ultimately lead to neovascularization. Unfortunately, these new vessels are weak, friable and prone to haemorrhage. The endpoint is blindness from tractional retinal detachment or rubeotic glaucoma.

National screening committee classification of DR

  • R0 = no DR
  • R1 = mild non-proliferative or pre-proliferative DR disease (Figure 45.2)
    ○ Microaneurysms (MAs): out-pouching of retinal capillaries; may bleed, leak or become occluded.
    ○ Haemorrhages: bleeding from these leaky vessels, at various layers of the retina.
  • R2 = moderate and severe non-proliferative or pre-proliferative DR disease (Figure 45.3)
    ○ Hard exudates: lipid components that are not easily removed by macrophages accumulate, often at the edge of the oedema, as characteristic yellowish lesions.
    ○ All of the following are indicative of established retinal ischaemia:
    ■ cotton wool spots (CWSs): micro-infarct of the retinal nerve fibre layer (NFL) causing a localized swelling of the NFL axon
    ■ venous beading: venous irregularities, ‘sausaging’ and engorgement
    ■ IRMAs: new vessels growing from the venous side of the bed of vessels, to compensate for an area of arterial non-perfusion.
  • R3 = proliferative retinopathy, pre-retinal fibrosis and tractional retinal detachment (Figures 45.4)
    ○ Retinal neovascularization and new vessels: fragile new vessels grow outside the retina along the posterior surface of the vitreous.
    Changes in blood flow or traction on the new vessels, including posterior vitreous detachment, may cause them to haemorrhage into the vitreous cavity (vitreous haemorrhage; Figure 45.5). These vessels can grow as neovascularization of the optic disc (NVD) or as neovascularization elsewhere (NVE).
  • M0 = no maculopathy
  • M1 = diabetic maculopathy (Figure 45.6)
    ○ The macula is a circle centred around the fovea. The radius of the circle is the fovea to the disc margin. Clinically significant macular oedema (CSMO) involves or is near the fovea, and this is defined as the following:
    ■ thickening of the retina within 500 μm from the fovea
    ■ hard exudates and adjacent thickening of the retina within 500 μm from the fovea
    ■ area of retinal thickening one disc size (or larger), part of which is one disc diameter from the fovea.
    ○ To put these distances into perspective, the diameter of the disc is 1500 μm: so to assess CSMO, use one-third of this distance.
    ○ There are two main types of CSMO (ischaemic versus non-ischaemic): distinguishing is via fundus fluoroscein angiogram (FFA) and dictates management (Figure 45.6b).

Screening

  • The screening service in the United Kingdom is a robust method of detecting early changes.
  • Annual digital photographic screening in the community is mandatory for diabetic patients.
  • Patients with at least R2 or M1 disease must be seen by an ophthalmologist (within 10 and 2 weeks, respectively).

Diabetic retinopathy treatment

Aims

  • Understand that systemic control is key in treatment.
  • Appreciate the various management options in treating diabetic retinopathy.

Blood pressure (BP), lipid and glycaemic control

Control of these will:

  • Reduce the progression and severity of diabetic retinopathy (DR): aim to bring down HbA1C slowly to 6.5–7.0%. If it comes down too quickly, there will be a transient worsening of the retinopathy.
  • Reduce the need for laser treatment.
  • Patients should also be advised not to smoke as this contributes to vascular damage.
  • The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study suggests that DR progression in type 2 diabetics is reduced by intensive glycaemic and lipid control, and only regular BP control.
  • Patients benefit from the pleiotropic effects of statins and should be started on them even if lipid levels are in the normal range. It was shown in 2005 that these wider effects of statins include improving endothelial cell function, decreasing oxidative stress and inflammation and inhibiting the thrombogenic response.
  • The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed less progression to macular oedema and proliferative disease if patients were administered fenofibrate (the mechanism is more than just lipid lowering).

Treatment options

Prior to any laser, one must have a fundus flourescein angiography (FFA). This will give conclusive diagnosis of new vessels (which can be clinically difficult to distinguish from an intra-retinal microvascular abnormality). More importantly, it can differentiate ischaemic maculopathy (do not laser) from non-ischaemic (treat with laser).

Panretinal photocoagulation (PRP)

  • Indicated for proliferative DR (Figure 46.1), rubeosis and vitreous haemorrhage (with adequate view).
  • Laser photocoagulation is used to produce 1500–3000 burns of between 200 and 400 μm diameter in the peripheral retina, sparing the macula, papillomacular bundle and optic nerve head. This causes regression of neovascularization of the optic disc (NVD) and neovascularization elsewhere (NVE). The patient will have reduced peripheral and night vision post PRP. Transient worsening of central vision may be noted.
  • PRP is performed in the outpatient clinic using a laser attached to a slit lamp. The treatment requires topical anaesthesia as a special contact lens is used to apply the laser burns. Once adequate laser has been applied, the abnormal vessels will regress in about 8 weeks.
  • When counselling patients prior to the procedure, one should quote figures from the Early Treatment Diabetic Retinopathy Study (ETDRS) study. The risk of severe visual loss within 2 years in patients with high-risk proliferative DR reduces from 38% to 19% with PRP.

Macular laser

  • This can be focal or grid, depending on whether a local or diffuse leakage pattern is seen.
  • Patients must be warned that macular laser treatment is used to prevent vision from getting worse, but it does not always improve visual acuity. Some patients notice a scotoma after macular laser treatment.
  • Again, patients can be informed of the data from the ETDRS study, which showed that the risk of moderate visual loss of three lines over 3 years was reduced from 24% to 12%.

Vitrectomy

This is a specialized procedure performed by a vitreo-retinal surgeon, whereby the vitreous is removed via a three-port pars plana incision (TPPV). The indications are:

  • To clear vitreous haemorrhage—allowing the surgeon to visualize the retina and apply further PRP laser.
  • To relieve retinal traction and repair retinal detachment.
  • To treat diffuse macula oedema due to vitreous traction.

Clinical evidence for treatment

  • The initial evidence for the use of macular laser was shown in the ETDRS study in 1985. However, only 3% of treated eyes actually have visual improvement, seen as letters gained on the LogMar chart.
  • Rather, it is a measure to reduce the risk of visual loss in patients with clinically significant macular oedema (CSMO).
  • Whilst laser will remain the gold standard treatment, recent advances include the administration of pharmacological agents into the vitreous cavity, such as steroidal and anti-VEGF (vascular endothelial growth factor) agents.
  • These are now being used increasingly in clinical practice. A plethora of evidence supports the use of anti-VEGF agents, including four studies comparing intravenous (IV) ranibizumab with the gold standard (laser):
    ○ DRCR.net:
    ■ It was shown that ranibizumab with laser is more effective than laser alone after 1 year (gain of 9 letters versus 3, respectively).
    ○ READ-2:
    ■ At 6 months, patients gained more letters with ranibizumab alone, compared to in combination with laser or laser alone (7.2, 3.8 and 0.4, respectively).
    ○ RESTORE:
    ■ The same results as the READ-2 study were seen in the RESTORE study.
    ■ And the benefit was still evident after 12 months (a 6.1-letter gain in the ranibizumab monotherapy group, 5.9-letter gain in the ranibizumab and laser group and 0.8-letter gain in the laser-only group).
    ○ RESOLVE:
    ■ Ranibizumab was superior to sham injections, with patients gaining 10.3 letters at 12 months (compared to −1.4 letters with sham and rescue laser).
  • Hence, over the next few years we will see the use of IV agents and combination therapy used readily to treat CSMO.
  • The upcoming RIDE and RISE studies will give more indication as to whether injections should be given in a monthly fashion, regardless of clinical response, or on a pro re nata basis.

Retinal artery obstruction

You should recognize sudden painless loss of vision from a central retinal artery occlusion (CRAO). It is an ocular emergency.

Aims

  • Understand the vascular anatomy of the retina and optic nerve head.
  • Identify the clinical features of a CRAO.
  • Be able to manage a patient with CRAO.

Anatomy

The eye has a rich blood supply from the ophthalmic artery via the central retinal artery (CRA) and the posterior ciliary arteries (PCAs). The CRA supplies the superficial nerve fibre layer and inner two-thirds of the retina. The PCAs supply the rest of the anterior optic nerve and uvea (iris, ciliary body and choroid), and hence the deep retinal layers. The anatomy is known from vascular casts (in vitro) and from live fluorescein angiographic studies. In vascular casts of the eye, the
cadaver ophthalmic artery has been injected with a plastic and the tissue has dissolved away, leaving only the vessel lumen—the cast.

The CRA is an end artery of the ophthalmic artery, which supplies the inner two-thirds of the retina. The choriocapillaris, supplied by the posterior ciliary arteries, supplies the outer retina.

Pathology

Cilioretinal artery

Note that 15–20% of individuals have a supplementary arterial supply to the macula via a cilioretinal artery derived from the posterior ciliary circulation at the disc. In the event of a CRAO, the macula would remain perfused in these patients with some preservation of vision.

Diagnosis and management

Symptoms

  • Painless loss of vision (note that non-ocular pain may occur such as temporal or scalp tenderness in giant cell arteritis (GCA)).
  • Profound drop in visual acuity (unless cilioretinal artery sparing).
  • Afferent papillary defect.

Signs

Perform a dilated fundal examination to detect:

  • cherry red spot at the macula (Figure 47.4a)
  • embolus occasionally visible at the optic disc
  • attenuation of arterioles
  • retinal pallor
  • mild disc swelling.

Treatment

The aim is to re-establish circulation within the CRA. This is attempted by:

  • Lowering the intraocular pressure (IOP) using:
    ○ acetazolamide 500 mg IV
    ○ ocular massage
    ○ anterior chamber paracentesis (1 ml aqueous withdrawn).
  • Vasodilation: rebreathe into a paper bag (carbon dioxide increases).
  • Start cholesterol-lowering statins (e.g. Simvastatin and Atorvastatin).
  • Start antiplatelets (e.g. aspirin 300 mg stat, then 75 mg daily or
    clopidogrel 75 mg daily) within 48 hr.

Outcome

Visual recovery is dependent on the interval between onset and presentation. There has not been a clinical trial comparing treatment versus no treatment—but it is believed that 66% of patients have vision <6/60 following CRAO.

Other investigations

Examine for carotid bruits, heart murmurs and irregular pulse (atrial fibrillation is a cause—needs anticoagulation). Arrange carotid Doppler studies, 24 h Holter monitor and echocardiogram. Follow-up is by a physician.

Retinal vein occlusion

Aims

  • Identify the clinical features of central and branch retinal vein occlusion.
  • Updates on managing vein occlusions.

Retinal vein occlusion

This is a common cause of painless loss of vision. It can occur at any age, with 85% of patients aged >50 years. It’s classified into central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) and hemispheric retinal vein occlusion (HRVO), depending on the site of the obstruction.

Pathology of visual loss in vein occlusion

  • Macular oedema:
    ○ caused predominantly by increased venous pressure (intraluminal), vasoactive / inflammatory mediators (such as vascular endothelial growth factor [VEGF]) and dysregulation of tight junctions
  • Ischaemia:
    ○ this can be isolated (macular ischaemia) or generalized retinal ischaemia.
    ○ Significant generalised retinal ischaemia can lead to ocular neovascularization via hypoxia induced production of vasoactive mediators, with VEGF being the primary mediator (neovascularization in the anterior segment (iris new vessels) results in rubeotic glaucoma; neovascularization in the posterior segment (new vessels on the disc and new vessels elsewhere) can result in vitreous haemorrhage and tractional retinal detachment.

Visual prognosis and management depend on the type of occlusion, the severity of the occlusion and the ocular sequelae. Visual loss is worse in CRVO than BRVO/HRVO. Some small BRVOs are asymptomatic, especially if they are located in only one quadrant nasal to the disc (i.e. away from the macula).

Central retinal vein occlusion

The central retinal vein (CRV) deep in the optic cup is occluded, affecting drainage from all four retinal quadrants,
resulting in usually unilateral painless visual loss. The pathogenesis of CRVO is believed to be due to in situ thrombosis
in the CRV.

Ischaemic CRVO

25 to 33% of cases are ischaemic, associated with new vessel formation on the iris (rubeosis iridis), disc or elsewhere. Ultimately these vessels can result in visual loss, either by occluding and contracting the irido-corneal angle (rubeotic glaucoma) or by bleeding (vitreous haemorrhage) and exerting traction on the retina. Ischaemic CRVO requires panretinal photocoagulation (PRP) laser treatment to reduce the aforementioned risk of visual loss.

Signs include:

  • relative afferent pupillary defect (RAPD) and markedly reduced vision (often 6/60 or less)
  • extensive widespread deep retinal haemorrhages
  • multiple widespread cotton wool spots
  • large areas of capillary non-perfusion (detected with FFA).

Non-ischaemic CRVO

  • Variable number of haemorrhages in 4 quadrants
  • Tortuous dilated retinal veins
  • No RAPD and visual loss not as profound as in ischaemic CRVO (usually better than 6/60)
  • Neovascularization of anterior or posterior segment is rare in true non-ischaemic CRVO (<2% incidence)
  • 30% of cases convert to the ischaemic form, and usually associated with further visual deterioration
  • Recovery to normal vision is seen in fewer than 10% of cases.

Branch retinal vein occlusion

BRVOs are three times more common than CRVOs and occur at arteriovenous crossings where the artery and vein share a common adventitial sheath. It is postulated that the rigid artery compresses the retinal vein, which results in turbulent flow and endothelial damage, followed by thrombosis and obstruction of the retinal vein. Patients present with painless loss of central vision, or as an incidental finding if the macula is not involved. Retinal haemorrhages and cotton wool spots are confined to one area. BRVO is superotemporal in more than 60% of cases, suggested to be due to the increased number of arteriovenous crossings in that quadrant. BRVO can be ischaemic or non-ischaemic. Hypertension is the most common association of BRVO. Macular oedema and retinal/disc neovascularization are the major complications requiring intervention, with rubeosis much less common compared with CRVO.

Usually, the central retinal vein is formed ahead of the opening in the sclera and leaves the eye with the artery, to drain directly into the cavernous sinus or superior ophthalmic vein. However, in 20% of the population, two branch retinal veins, draining the superior and inferior halves of the retina respectively, leave the eye. Hence, the central retinal vein forms posterior to the scleral opening (i.e. the lamina cribrosa). A hemispheric vein occlusion is an occlusion of one of these trunks (Figure 48.6). They can also be either ischaemic or non-ischaemic. They are often managed as per a BRVO.

Management

Medical management

  • Check blood pressure, full blood count (FBC), erythrocyte sedimentation rate (ESR), urea and electrolytes (U&E), lipid profile, blood sugar, and plasma proteins.
  • In a young patient, a thrombophilia screen must be done, including:
    ○ protein C
    ○ protein S
    ○ anti-cardiolipin Ab
    ○ anti-nuclear Ab
    ○ factor V Leiden’s mutation.
    ○ plasma homocysteine
  • Medical treatment of cardiovascular risk factors
  • Aspirin
  • Treat raised intraocular pressure (IOP).

Current treatment (Detailed guidelines can be found on the Royal College website)

Ischaemic CRVO
  • Monthly follow-up.
  • PRP is required with onset of new vessels (anterior or posterior segment).
  • Consider adjunctive intravitreal anti-VEGF agents, including bevacizumab, to help manage iris new vessels in the acute phase.
Rubeotic glaucoma (typically occurs at 3 months, hence ‘100-day glaucoma’)
  • If no visual potential = atropine and steroids.
  • If visual potential = Following complete PRP—IOP control, cycloablation and/or surgery to lower IOP.
Macular oedema secondary to non-ischaemic BRVO and non-ischaemic CRVO
  • Intravitreal therapies are being increasingly employed for macular oedema without significantly compromised macular perfusion— including a biodegradable dexamethasone implant (Ozurdex), and intravitreal ranibizumab / bevacizumab / aflibercept.
  • Macular photocoagulation can still be considered in patients with BRVO and vision 6/12 or worse, and more than 3 month duration of macular oedema.

Important studies

Branch vein occlusion study (BVOS)

  • Landmark study as it was the first to advocate treatment of macular oedema based on a randomized controlled trial.
  • Twice as many patients treated with laser, compared to the control group, gained two lines at 3 years.
  • Evidence from this trial established macular laser as the gold standard treatment for 25 years.
  • It also demonstrated that scatter laser photocoagulation could significantly prevent the development of both neovascularization and vitreous haemorrhage. The data suggested that peripheral scatter laser be applied after, rather than before, the development of neovascularization.

Central retinal vein occlusion study (CVOS)

  • Showed that macular laser did not improve vision for patients with oedema secondary to CRVO.
  • Prophylactic PRP did not prevent the development of rubeosis. This suggested that with careful follow-up it is safe to wait for the development of early iris neovascularization and then apply PRP.

Standard care vs. corticosteroid for retinal vein occlusion (SCORE)—BRVO

  • Twenty-five years on from BVOS, the first trial to compare a treatment against the gold standard of macular laser.
  • Intravitreal triamcinolone (Trivaris) has no benefit over laser in patients with BRVO.
  • The effect is transient and repeat injections may be necessary. Also, the risk of glaucoma and cataract development is significant.

Standard care vs. corticosteroid for retinal vein occlusion (SCORE)—CRVO

  • Intravitreal triamcinolone was found to be superior to observation for treating vision loss associated with macular edema secondary to non-ischaemic CRVO.
  • The 1 mg dose has a safety profile superior to that of the 4 mg dose.
  • As with SCORE BRVO repeat injections are likely to be necessary, with significant risk of glaucoma and cataract development.

GENEVA

  • Patients with macular oedema from either CRVO or BRVO were given either a dexamethasone implant or sham.
  • The implant is approved by NICE for non-ischaemic CRVO and indicated in BRVO if laser treatment has not been beneficial, or is not possible due to the extent of macular haemorrhage.
  • Regular monitoring of IOP required. Moderate IOP rise in 15%, peaking at 2 months following implant. Cataract formation often accelerated.

BRAVO

  • Patients with macular oedema secondary to BRVO were randomized to sham, 0.5 mg or 0.3 mg ranibizumab.
  • At 12 months, the mean letter gains were 12.1, 18.3 and 16.6, respectively.
  • Treatment has now been approved by NICE.

CRUISE

  • Patients with macular oedema secondary to non-ischaemic CRVO were randomized to sham, 0.5 mg or 0.3 mg ranibizumab.
  • At 12 months, the mean letter gains were 7.3, 14.9 and 12.7, respectively.
  • Treatment has now been approved by NICE.

HIV infection and AIDS

With current antiretrovirals, there is less advanced HIV ocular involvement. Be alert to a diagnosis of HIV in adults with unexplained eyelid, orbital and retinal disease.

Aims

Know how:

  • HIV-related disease affects the eye and can lead to permanent visual loss.
  • Treatment of specific ophthalmic opportunistic infections.

Ophthalmologic disorders in HIV

Patients with HIV/AIDS who have CD4 counts less than 50 per μl are at high risk of developing opportunistic infections in the eye.
Ophthalmic problems in AIDS can involve any ocular or orbital tissue, but the sight-threatening disease affects the posterior segment. The incidence of posterior infections is much less frequent since the advent of highly active antiretroviral therapy (HAART). Note that there is no evidence that HIV can be transmitted via tears, and no extra
precaution need be taken when examining patients in clinic.
The following occur in various parts of the eye in those with low CD4 counts:

Adnexa and anterior segment

  • Molluscum contagiosum on eyelids (Figure 49.1a)
  • HIV-related conjunctivitis
  • Kaposi’s sarcoma—flat or raised (if present >4/12) violaceous vascular conjunctival lesion, surrounded by tortuous and dilated vessels (Figure 49.1b). Treated by excision, chemotherapy or radiotherapy.
  • Conjunctival granulomas due to cryptococcal infection, tuberculosis and other mycotic infections
  • Aggressive conjunctival or cutaneous eyelid squamous cell carcinoma. Associated with human papillomavirus
    infection.
  • Herpes zoster ophthalmicus (HZO): also often affects the seventh cranial nerve (Figure 49.1c).
  • Herpes simplex keratitis
  • Microsporidia: a protozoal infection causing coarse, superficial,
    punctate keratitis with minimal conjunctival reaction.

Orbit

  • Periorbital B cell lymphoma
  • Burkitt’s lymphoma
  • Kaposi’s sarcoma.

Posterior segment

HIV retinopathy (microvascular disease)
  • Comprises cotton wool spots, retinal haemorrhages, microaneurysms and ischaemic maculopathy.
Immune recovery uveitis (IRU)

Occurs in eye with quiescent cytomegalovirus retinitis (CMVR) in patients responding to HAART, defined as vitritis of ≥1+ or trace of cells plus epiretinal membrane or cystoid macular oedema.

Retinal opportunistic infections
  • CMVR (Figure 49.3)
    ○ ‘Pizza pie fundus’: haemorrhagic or non-haemorrhagic, frosted-branch angiitis or mimics central retinal vein occlusion.
  • Toxoplasmosis retinochoroiditis (Toxoplasma gondii) (Figure 49.4)
    ○ White or yellow patch of focal retinal necrosis
    ○ In the immunocompromised, lesions tend to be larger; bilateral
    disease in 18–38%; unusual forms occur (solitary, multifocal or
    miliary), minimal vitritis; prolonged therapy is required.
  • Syphilitic retinitis (Figure 49.5)
    ○ Syphilis is the great mimic and can present as vitritis, multifocal choroiditis, retinal vasculitis, neuroretinitis, optic atrophy or oedema, exudative retinal detachment, choroidal effusion, pigmentary retinopathy and venous and arterial occlusions.
  • Cryptococcal choroiditis (Cryptococcus neoformans)
    ○ Variably sized deep choroidal infiltrates; may be asymptomatic.
  • Mycobacterium tuberculosis choroiditis
    ○ Single large granuloma or multifocal; plus or minus retinal vasculitis; frequently bilateral; choroidal neovascularization may develop at sites of healed spots.
  • Candida endophthalmitis (Candida albicans)
    ○ Small, whitish, multifocal, circumscribed chorioretinal infiltrates; retinal haemorrhages; dense vitritis and ‘fluff balls’ (vitreous abscesses) progress to endophthalmitis
  • Progressive outer retinal necrosis (PORN)
    ○ Herpes simplex virus or varicella zoster virus (Figure 49.6)
    ○ Multifocal deep retinal patches, predominantly at the posterior pole.
    ○ PORN affects the choroid, leading to round yellow-white flat lesions in the posterior pole (Figure 49.7). Visual symptoms are rarely seen.
  • Pneumocystis jirovecii, formerly known as P. carinii
    ○ Pneumocystis pneumonia (PCP) is caused by a yeast-like fungus. Predominantly affects the lungs.
Primary intraocular B cell lymphoma

Typically high grade; significant vitritis with or without iritis; peripapillary infiltrates; disc swelling; yellow-white sub-RPE lesions; vascular sheathing and vein or artery occlusion.

Neuro-ophthalmic disorders in HIV

  • You must always assess for a relative afferent pupillary defect in HIV patients as quite often the optic disc is involved:
    ○ Optic disc swelling secondary to cryptococcal meningitis.
    ○ Optic atrophy secondary to retinal disease.
  • Look carefully for bilateral swollen optic discs, as papilloedema can be evident secondary to:
    ○ Progressive multifocal leucoencephalopathy (PML)
    ○ Cerebral infarction
    ○ Intracranial toxoplasmosis
    ○ Lymphoma.
  • Cranial nerve palsies can be secondary to intracranial space-occupying
    lesions or infection.

Treatment

Ophthalmologists liaise with HIV physicians to ensure that patients are controlled on triple or quadruple HAART treatments.

  • CMVR
    ○ Various regimes include:
    ■ Oral valganciclovir
    ■ Intravenous gancyclovir
    ■ Sustained-release gancyclovir implanted directly into the vitreous. A trial in 1997 showed that an implant reduces the risk of progressive retinitis by one-third in comparison with intravenous gancyclovir. Each implant lasts for 5–8 months; it needs to be replaced surgically.
  • Toxoplasmosis
    ○ Treatment with clindamycin, pyrimethamine, azithromycin and atovoquone.
    ○ No place for steroids in toxoplasma infection in the immunocompromised.

Tropical ophthalmology: tropical eye disease

Aims

  • Epidemiology of tropical eye disease.
  • Understand how the causes of blindness and low vision vary globally.

These conditions are not commonly seen in the United Kingdom. You may come across them if you undertake a medical elective in a tropical country, or if a patient comes from a country where the disease is endemic. They are important causes of global blindness.

Trachoma

  • Caused by Chlamydia trachomatis—a microorganism that spreads through contact with eye discharge from the infected person (on towels, handkerchiefs, fingers etc.) and through transmission by eye-seeking flies.
  • After years of repeated infection, the inside of the eyelid may be scarred so severely that the eyelid turns inwards (trichiasis) and the lashes rub on the eyeball, scarring the cornea. If untreated, this leads to the formation of irreversible corneal opacities and blindness (Figure 50.1).
  • Affects about 84 million people, of whom about 8 million are visually impaired.
  • Seen in many of the poorest and poor rural areas of Africa, Asia, Central and South America, Australia and the Middle East.
  • Environmental risk factors are water shortage, flies, poor hygiene conditions and crowded households.
  • Management is via the SAFE strategy. This consists of lid surgery (S), antibiotics to treat the community pool of infection (A), facial cleanliness (F) and environmental changes (E).

Onchocerciasis

  • An insect-borne disease caused by a parasite, Onchocerca volvulus, and transmitted by blackflies of the species Simulium damnosum. Often called ‘river blindness’ because the blackfly that transmits the
    disease resides in fertile riverside areas.
  • Adult worms of O. volvulus live in nodules in a human body, where the female worms produce high numbers of first-stage larvae known as microfilariae. They migrate from the nodules to the sub-epidermal layer of the skin, where they can be ingested by blackflies. They further develop in the body of the insect, from which more people can be infected (Figures 50.2, 50.3 and 50.4).
  • Eye lesions in humans are caused by microfilariae. They can be found in all internal tissues of the eye where they cause inflammation, bleeding and other complications that can ultimately lead to blindness.
  • This is a major cause of blindness in many African countries. It is also prevalent in Yemen and in Latin America. It is estimated that there are about half a million blind people due to river blindness.
  • The disease can now also be treated with an annual dose of the drug ivermectin (Mectizan®), which also relieves the severe skin itching caused by the disease.

Leprosy

  • Leprosy is caused by Mycobacterium leprae—predominantly seen in South America, South-east Asia and Africa.
  • Leprosy is still endemic in many developing countries. It is estimated that 200 000–300 000 patients suffer from blindness.
  • With modern anti-leprosy treatment, patients are made non-infectious almost immediately. Patients are generally treated as outpatients. Most people have a natural immunity against leprosy. Health workers
    who work with leprosy patients are unlikely to contract leprosy.
  • Causes of blindness include iritis, exposure keratitis, corneal opacity, interstitial keratitis, chronic uveitis, cataract, glaucoma and trichiasis with corneal scarring.

Vitamin A deficiency (VAD) and measles

  • Vitamin A in small amounts is necessary for the normal functioning of the visual system, erythropoiesis and immunity and to maintain cell growth and functioning.
  • If a person eats an inadequate diet during critical stages of development, Vitamin A liver stores deplete and serum retinol concentrations become deficient, raising the risk of xerophthalmia.
  • Xerophthalmia, which is caused by vitamin A deficiency and sometimes precipitated by measles, accounts for more than half of the new cases of childhood blindness each year. The conjunctiva becomes dry, thick and wrinkled. If untreated, it can lead to corneal ulceration and ultimately in blindness as a result of corneal damage (Figure 50.5).
  • In addition to blindness, these young children are at increased risk of death. Prevention plays an important role: vitamin A supplementation, measles vaccination and nutritional advice have led to a marked reduction in this condition.

Tropical ophthalmology: global eye health

Aims

  • Epidemiology of tropical eye disease.
  • Understand how the causes of blindness and low vision vary globally.

Introduction

Global estimates suggest that 285 million people are visually impaired worldwide, of which 39 million are blind and 246 have low vision (Figures 51.1 and 51.2). The number of people affected by infectious causes (e.g. trachoma, onchocerciasis and leprosy) has decreased over the last 20 years as access to improved diet, sanitation and antibiotics
has increased. Almost 90% of blind people live in low-income countries.

Cataract

Cataract is the leading cause of blindness worldwide. Seventeen million people globally are estimated to be blind from cataract. In well-resourced countries, cataract extraction by phacoemulsification is readily available. The introduction of a technique called small incision cataract surgery (SICS) has reduced the cost of surgery in low- income settings and has a faster recovery time. The availability of low-cost, good-quality intraocular lenses (IOLs) has increased the number of cataract surgeries and improved the visual outcome for patients. In some countries (e.g. Nigeria) couching is still practised, a procedure where a curved needle is used to dislocate the lens to the back of the eye. This leads to chronic ocular inflammation and poor vision.

Refractive error

The World Health Organization definitions of blindness prior to 2008 failed to include correctable refractive error; it has only recently been recognized as a cause of avoidable blindness. It is estimated that 43% of global visual impairment is due to uncorrected refractive errors. Spectacles that are low cost and good quality are becoming more available, but in many countries there is still a need for good refraction services and optometrists.

Glaucoma

Due to the lack of a proper definition or to the constant revision of the definition and classification of glaucoma, the estimated number of individuals blinded by this condition might be falsely low. It has been suggested that 60 million people are likely to have some form of glaucoma, and 8 million are likely to be blind. In many low- and middle-income countries, effective treatment for glaucoma is inaccessible. Medical treatment requires the availability of affordable drugs and long-term follow-up. Surgical treatment requires skilled surgical expertise and experience; patient acceptance is also a factor—in some African countries, the word for ‘surgery’ is the same word used for butchery of animals.

Age-related Macular Degeneration (AMD)

AMD is responsible for 7% of all blindness worldwide, ranging from close to 0% in sub-Saharan Africa to 50% in industrialized countries. With an aging population, the number of AMD cases is likely to increase globally. The number affected is expected to double by the year 2020. The main risk factors are age, race, smoking, a family history of the condition, hypertension, high cholesterol, high fat intake and high Body Mass Index. The complement factor H gene has also been implicated. Current available treatments are expensive, and low-vision aids can also be difficult to access in resource-limited settings.

Corneal blindness

Corneal blindness encompasses a wide range of infectious and inflammatory eye diseases; in the developing world, it tends to be related to infectious causes.
The main causes include:

  • trachoma
  • onchocerciasis
  • xerophthalmia
  • traumatic corneal abrasion—a major risk factor for microbial keratitis in low- and middle-income countries.

Diabetic retinopathy (DR)

Diabetes is a global leading cause of death, disability and economic loss. In South Asia and the Middle East, the prevalence of type 2 diabetes (or diabetes mellitus) is increasing rapidly. This is likely to lead to a high prevalence of DR in this region and subsequent visual impairment unless screening and treatment of retinopathy are undertaken.

Childhood blindness

The number of blind children in the world is approximately 1.4 million. Approximately three-quarters of the world’s blind children live in the poorest regions of Africa and Asia. Half a million new cases of childhood corneal blindness are seen each year, and 70% of them are due to vitamin A deficiency, leading to xerophthalmia. Approximately 500 million doses of vitamin A are given annually worldwide, which has greatly reduced childhood mortality and blindness. Paediatric cataract is an important cause of avoidable blindness. Surgical techniques for paediatric cataract have improved, as well as the availability of high-power IOLs that are suitable for children. Retinopathy of prematurity is also emerging as a cause of blindness in urban centres in India, China and other countries in Asia.