Common Causes Visual Impairment Older People Pathophysiology Treatment Biology Essay

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Progressive aging results in visual decline, common causes of visual impairment in elderly include Glaucoma, cataract, and age related macular degeneration. Glaucoma is a multi-factorial, degenerative optic neuropathy characterised by slow loss of retinal ganglian cells, causing expansion of the optic disc cup, eventually leading to loss of vision. Glaucoma is a major cause of irreversible blindness worldwide, predominantly in elderly.

In order for the eye to maintain its spherical shape, the intraocular pressure (IOP) must be above that of the atmosphere. The lens is avascular, it lacks vascular transport mechanism which would provide these two structures with nutrients and oxygen, and remove their metabolites. Nevertheless, the lens is immersed in aqueous humour, which provides necessary nutrients and allows the removal of metabolites. Ciliary body is responsible for production of the aqueous humour (AH). AH flows around the lens, through the pupil into the anterior chamber then is filtered through the trabecular meshwork (TM), AH is eventually emptied into blood stream via the schelmm's canal. With increased age, modulations of the TM and ciliary muscle occur. Additionally, there is loss of trabecular meshwork cells. The sheath of the elastic fibres belonging to TM and ciliary muscle thicken, a plaque builds up due to the adhesion of fine fibrilis and components of the matrix. These modulations play a pivotal role in reducing outflow of AH, resulting in increased IOP. Prolonged IOP induces structural anatomical changes, to retinal ganglion cell axons (RGC), causes stretching of lamina cribrosa giving rise to cupping. Compression of retinal ganglion cell axon supresses trophic factor axonal transport, leading to death of the cells by trophic insufficiency. Moreover, suppression of axonal transport starves RGC's from brain-derived neurotrophin factors, which are essential for cell survival, deprivation leads to RGC apoptosis.

Retina relies on its constant blood supply to meet its high metabolic requirement. A dysfunction in blood flow autoregulatory mechanism, is thought contributes to local ischemia. In elderly this mechanism is debilitated, it can't cope with fluctuations in ocular perfusion pressure, leading to ischemia and eventually loss of retinal ganglion cells.

Glutamate mediated toxicity is another proposed theory thought to contribute to development of Glaucoma. Excitotoxicity occurs due to over activation of N-methyl-Daspartate aspartate subtypes in the glutamatergic system causing retinal ganglian cell death.

With increased age, there is accumulation of free radicals and reduced antioxidant levels, making the elderly susceptible to oxidative damage. Recent studies have reported presence of different isoforms of nitric oxide synthase (NOS) in astrocytes, in the prelaminar, and lamina cribrosa regions of optic nerve head, in glaucomatous eye. Increased intraocular pressure causes reactive astrocytes to produce nitric oxide (NO) free radical, induced by NOS. NO is able to diffuse into the cell and cause destruction of cellular component, leading cell death. Furthermore, hydrogen peroxidise is able cause DNA damage trabecular meshwork cells, resulting cytoskeleton rearrangements, which in turn causes increased IOP and decreased outflow. Tumour necrosis factor-alpha (TNF-alpha) it is also thought to mediate neurodegeneration in glaucoma via oxidative stress.

The aim of therapy in glaucoma is to lower and maintain the intraocular pressure to a level which prevents further damage to individual's optic nerve. Intraocular pressure is the only target, which has shown desirable effects, and has progressively proven to be a treatable risk factor. According to the European Glaucoma Society, pharmacotherapy should be applied primarily, if deterioration of the optic nerve continues laser surgery should be performed. Currently there isn't an established threshold to which the IOP is reduced to. The severity of the damage caused by glaucoma, determines by how much the pressure needs to be reduced by. Generally the IOP is reduced by 30-50%. In my opinion, the target IOP of a patient should be regularly examined to decide its suitability, by comparing current optic nerve status with previous examinations and baseline readings. Nevertheless, in some patients lowering the IOP alone is inadequate to halt disease progression.

IOP can be lowered by using agents such as β-blockers, α2 adrenergic agonists and parasympathomimetic agents. These compounds work by primarily down regulating the secretion of aqueous humour and increasing uveoscleral outflow. β-blockers reduce the IOP by 20-25%, in contrast they can induce cardiovascular and respiratory adverse effects, especially in elderly individuals. Alpha-2 agonists can reduce the IOP by as much as 27%, however they can cause systematic and local side effects. Carbonic anhydrase inhibitors can reduce IOP by 20-25%. They work by lowering aqueous humour secretion, by suppressing the activity of carbonic anhydrase enzyme in the ciliary body. Prostaglandin analogues (PA) activate metalloproteinases, causing structural modulations to extracellular matrix, which in turn results in increased uveoscleral outflow of AH. PA's can lower the IOP by as much as 33% and have limited systemic side-effects. I believe that the decision to prescribe any of these agents should be based on the IOP level and optic nerve status in an individual.

Laser trabeculoplasty works by opening small channels in the trabecular meshwork, increasing outflow, thus lowering IOP by 5-6 mm Hg. This procedure is ideal for the elderly as they may be intolerant to medication, and surgery puts them at great risk. Laser cyclophotocoagulation damages non-pigmented epithelial cells of the ciliary body to reduce the production of AH. Trabeculotomy, involves cutting a small section from trabecular meshwork in order to increase outflow. Trabeculotomy is combined with mitomycin C, which prevent scar formation, this is the most widely and successful procedure. Glaucoma implants can be used if everything else has failed, it works by placing a silicon tube to allow free passage of aqueous humour, hence increasing outflow.

Lens is composed of epithelium cells, these differentiate into fibre cells during this process crystallins are produced, all together they maintain the shape, clarity, refractive index and provide a defensive mechanism for the lens. With increased age the protective mechanism of the lens deteriorates, the lens becomes thicker and compact due to aggregation of modified proteins causing opacification of the lens, cataract.

Epithelium cells have an important role in the transport, detoxification and metabolism of the lens. The density of lens epithelium cells and the process of differentiation diminishes due to cell death by apoptosis. These age induced modifications are detrimental to normal development and protection of underlying fiber cells against oxidative injury. Taken altogether these factor contribute to the development of cataract.

The crystallins produced in the lens are α, β, and γ. The aged human crystallin are mainly insoluble in water, predominantly concentrated in the nuclear region of the lens. It is proposed that the insolubilization of the lens crystallins is the end result of denaturation and aggregation that has taken place over time . Crystallins, essentially focus the light on the retina by maintaining the clarity of the lens. Alpha crystallin it consists of αA and αB subunits, the subunits are capable of dissociating and associating giving α-crystallin a chaperone like activity. Moreover, chaperone activity inhibits aggregation of proteins which have modified during their lifetime. With increasing age proteolysis and fragmentation of crystallins are up regulated, leading to loss of chaperone activity, hence development of cataract. Interaction of denatured β, and γ crystallin with alpha subunits results in decreased subunit exchange, enhancing development light scattering crystallin aggregates causing lens opacification.

With increased ageing, the deamintaion process and concentration of advanced glycation enproducts (AGE) increase. Recent studies have found that AGE and deamination cause extensive structural modulation to the α-crystallin subunits at several sites, these modifications are over-expressed in the cataractous lens. Moreover, structural alteration leads to reduced chaperone activity, increased crystalline aggregation and lens opacification.

Other mechanism which cause structural and functional change to crystallins include, UV filter modification, acetylation , carbamylation, truncation, and methylation, all together they inhibit the chaperone activity of α-crystallin.

Opacification of the lens is thought to be as a direct result of oxidative stress. With increasing age there is a reduction in the lenticular antioxidant glutathione in the nuclear region of the lens. The ability of glutathione reductase to synthesise glutathione disulfide, to glutathione is suppressed, this characteristic is strongly associated with age related cataract. In advanced cataract protein sulfhydryl (protein-SH) groups are lost and methione residues become oxidized to methionine sulfoxide. Oxidative stress also affects the α-crystallin subunit structure and function inhibiting their ability to prevent protein aggregation.

The ATP-dependent proteolytic activity and ubiquitin-conjugating ability of lens proteases deteriorates with age, furthermore this leads to aggregation of modified proteins in the nuclear region and also immature development of fiber cells, causing cataract.

Age related cataract is divided into 3 types. Lens consist of epithelium cells which give rise to lens fibres, continuous build up fibre layers causes nuclear sclerosis cataract, characterised by myopic shift, loss of colour discrimination and vision. Modifications of the homeostasis of the lens cortex, and protein insolubilisation results in cortical cataract. With aging cortical spoke like opacities form in the lens cortex, and the anteroposterior diameter of the lens increases. Posterior subcapsular cataract, occurs due to granular opacities p at the subcapsular cortex, hence the name.

Currently surgical interventions are applied in the treatment of cataract. Extracapsular cataract extraction (ECCE) requires an incision of 11mm where the cornea and the sclera meet, through which the anterior lens capsule along with softer cortex of the lens is extracted, an intraocular lens is then implanted. However, phacoemulsification is more advanced in the sense that the incision is much smaller only 3mm. In contrast, this represented a problem, the intraocular lens as it is 6mm in diameter, whereas the incision is 3mm. However, the folding of the lens allowed successful delivery. Nevertheless, a small incision is associated with limited complications such as prolapse of the iris, maintaining the integrity of the anterior chamber, and suppressing spillage of vitreous humour in the wound. Furthermore, small incisions are characteristic of a speedy recovery. During surgery there are several complications that can occur such as the rupture of posterior capsule, which then causes the prolapse of vitreous body. Postoperative complications include posterior capsular opacification and prolonged corneal oedema which can delay visual recovery. However, the therapeutic effect phacoemulsification, outnumber the side effects and risk factors, making it method of choice. Viscoelastics are applied in cataract surgery, in order to maintain the structures of anterior segments and prevent corneal endothelial cell loss. Nevertheless, their long term effects from physiological changes such IOP are unknown. Furthermore, incomplete removal of Viscoelastics leads to inflammation. Surgical treatment of cataract has proven to be very successful. Nevertheless, this procedure is very expensive and not widely available in developing countries where the number of incidence is very high. This raises the question for the need of medical treatment. Carnosine is currently undergoing clinical trials (Morton et al 2007) and is exhibiting good results.

Age-related macular degeneration (AMD) is a multifactorial disease with a poorly understood pathosphysiology, which commonly causes irreversible loss of vision in the elderly. AMD is classified into two types: the dry form, characterised by atrophy in the retinal pigment epithelium (RPE) and in photoreceptors. However, the wet form is associated with choroidal neovascularisation, which swell and cause leakage into the macular, leading to macular damage and eventually visual loss.

Variants in the complement factor H (CFH) gene are strongly linked with enhanced risk for AMD. Nevertheless, retina is susceptible to oxidative injury, due to its lifelong exposure to light and its high metabolic need for oxygen, these factors attribute to up regulation of reactive oxygen species (ROS). Furthermore, polyunsaturated fatty acids undergo peroxidation due to oxidative stress, leading to production and aggregation of undegradble lipofuscin (LF), in the lysosomal compartments of retinal pigment epithelium (RPE). With age RPE lose their lysosomal function, they are unable to phagacytosise and degrade constantly shed photoreceptor segments, leading to aggregation of oxidatavely modified lipofuscin. LF constituent's 4-hydroxynonenal and malondialdehyde have toxic poperties, which promote lysosomal dysfunction of postmiotic RPE cells. Deterioration of RPE due to accumulation of LF leads to degeneration of photoreceptors, causing irreversible visual loss.

Drusen, are accumulation of lipids in the Bruchs membrane, located between the RPE and the choroid, they are visible hallmark of AMD. Progressive build up of Drusen suppresses the diffusion of oxygen and nutrients between RPE and choroid, resulting in RPE detachment, leading to atrophic Macular Degeneration. Enlarged Drusen are susceptible to an immune attack, which in turn causes inflammation. Localised inflammation, activation of complement cascade and up regulation of membrane attack complexes enhances formation of Drusen, bruch's membrane disruption and RPE/photoreceptor degeneration.

Choroidal neovascularisation in macular, occurs due to imbalance between pro-angiogenics such as vascular endothelial growth factors (VEGF) and anti-angiogenics such as pigment epithelium derived factors (PEDF). With age there is a reduction in PEDF, however VEGF is up regulated. VEGF elevate vascular leakage, enhances the inflammatory response and induces angiogenesis (Ferrara et al. 2003). VEGF up regulation is promoted by hypoxia, which is a direct result of Drusen build up in the Bruch's membrane causing reduced diffusion, hence limited oxygen supply. Immune response also contributes to increased VEGF, localised inflammation results in the recruitment of monocytes and macrophages which release VEGF. The newly formed blood vessels are highly permeable and form scares in the macular leading to stomata, these are characteristics of wet AMD.

With ageing, apoptosis of the RPE cells gets more prevalent, there is loss of choriocapillaries and, and also los of outer neurosensory retina, this degeneration are referred to as geographic atrophy, characteristic of dry form of AMD.

Treatment of AMD, aims to halt disease progression. Current therapies mainly target wet form of AMD, as there isn't an established effective treatment for the dry form.

Photodynamic therapy (PDT) utilises a laser light to activate an intravenously administrated photosensitiser verteporfin agent. Oxidation of endothelial cells results in inhibition of blood vessel haemorrhage. Thermal laser coagulation (TLP) is applied to obliterate extrafoveal CNV. TLP damages retinal function, and has 80 % rate of recurrence over a 5 years. In comparison PDT, it doesn't damage retina, and scotoma are not visible. However PDT is thought to induce production of VEGF's. Nevertheless, VEGF's can be counterattacked by anti-angiogenic agents. For a more efficient therapy, verteporfin can be combined with intravitreal triamcinolone, limiting the number of courses patient may require and long-term maintenance.

Pegaptanib (Macugen), is intravitreally administrated, it specifically inhibits the activity of VEGF-165 isoform, suppressing permeability and angiogenesis. Trails have demonstrated that 0.3mg showed to be an effective does over a period of two years. However, intravitreal injection is associated with damage to eye structures and it induces endophthalmitis. Ranibizumab and Bevacizumab bind to all VEGF isoforms. Nevertheless, Ranibizumab has higher efficacy and binds with high affinity to VEGF, 0.5 mg of ranibizumab is an affective dose. Furthermore, Ranibizumab is a fragment of humanised monoclonal antibody (Mab), thus it diffuses through retina easily and reach the subretinal space. In contrast, Bevacizumab is a full-length recombinant Mab, therefore it has slow diffusion rate. Combination of PDT and Macugen has shown to decrease the number of treatment required, thus this form of treatment is time and cost effective.

I believe that education of people is pivotal in preventing AMD, cataract and glaucoma. Diet, high in antioxidants such as vitamins A and C, glutathione are essential in preventing oxidative damage, also wearing sunglasses protects people from exposure to UV light.