Year XVI-N.10/2000

Classification of AMD

AMD is a degenerative disease of the macula (the central part of the retina) that may cause the loss of central vision.

It is classified into two types (Fig. 1) :

- non-neovascular AMD (also called dry, non-exudative, geographic or atrophic, Haab-Dimmer form)

- neovascular AMD (also called wet, exudative, disciform or serous, Junius-Kubnt form) Non-neovascular AMD is characterised by “drusen” and geographic atrophy of the retinal pigment epithelium (RPE). It is much more common than the neovascular form and accounts for approximately 80% of all cases of AMD. Non-neovascular AMD may also lead to a marked loss of vision, but only when a central scotoma (a blind spot in the visual field) is caused by foveal retina atrophy. About 10-20% of the patients with non-neovascular AMD develop a neovascular form of the disease, which is responsible for 90% of the cases of severe irreversible central vision loss (Fig. 2).

Neovascular AMD is characterised by CNV: i.e. new abnormal coroidal blood vessels that grow from the underlying choriocapillaris and proliferate through breaks in Bruch’s membrane under the RPE and in the intraretinal space (respectively known as “occult” subretinal or “manifest” intraretinal neovascularisation). These new blood vessels are fragile and leak blood and fluid, which may lead to the detachment of the RPE and neurosensory retina, and damage the outer retinal layers to the point of the formation of a fibrovascular macular scar.

The progression of neovascular AMD may take from a few days to a number of months, depending among other on the composition of the CNV (classic, occult or mixed), and the size and location of the lesion, which may be extrafoveal, juxtafoveal or subfoveal.

Fluoroangiographic classification of CNV

Classic and occult CNV are classified on the basis of precise fluorangiographic models. Classic or manifest CNV appears as a well-demarcated area of uniform hyperfluorescence in the early phases of the angiogram, which subsequently spreads and blurs the borders of the lesion during the middle and late phases (leakage).

Occult CNV is divided into two types:

- Type I is characterised by a fibrovascular detachment of the RPE, which appears as an area of stippled hyperfluorescence that unevenly increases at the level of the RPE, usually within 1-2 minutes of the fluorescein injection. The borders of the lesion are often poorly defined or difficult to demarcate, and leakage appears during the late phases.

- Type II has poorly demarcated borders with late-phase leakage originating from an undetermined source at the level of the RPE; during the early and middle phases, it does not resemble classic CNV or fibrovascular RPE detachment.

Prevalence

The prevalence of AMD in people aged more than 50 years has been estimated in a number of recent epidemiological studies, and found to vary from <2% to >10% depending on the definition of AMD, the grading system used, and the age and geographic location of the studied population (Tab.1). However, all of the studies showed that prevalence increases with age, particularly in the case of people aged more than 65 years. According to AMD Alliance International, 25-30 million people are affected by AMD throughout the world.

The epidemiological data can be summarised as follows:

- the prevalence of late AMD in subjects aged more than 75 years is 7.8% (about 600,000 cases in the USA and about 100,000 in Italy);

- the 5-year incidence of late AMD in subjects aged more than 75 years is 5.4 (300,000 in the USA and about 50,000 in Italy);

- the annual incidence of the wet form is about 0.7% in subjects aged more than 65 years.

Etiology

The etiology of AMD is largely unknown. Studies have been made of a number of risk factors other than age (Tab. 2) that may be involved in the genesis of the disease (Fig. 3). Cigarette smoking substantially increases the risk of AMD (particularly the neovascular form) in both male and female current and ex-smokers. There is also a weak association between AMD and hyperopia.

The data concerning gender, race, socio-economic conditions, arterial hypertension, diabetes, alcohol, iris colour, solar exposure and other minor factors are much more uncertain or totally negative.

On the other hand assumption of antioxidant agents with diet or/and dietary supplements would probably exert some protective effect and large RCTs on this topic are ongoing (AREDS, Age Related Eye Disease Study, etc). Neovascular AMD in one eye predisposes to the development of bilateral AMD. Forty-two percent of the patients with unilateral CNV will develop it in the second eye within 3-5 years. However, the estimates of the 5-year incidence vary from 7% to 87% because they depend on the characteristics of the patient and the other eye.

Pathogenesis

The anatomical site in which the pathological events characterising AMD develop is the choriocapillaris/external retina complex (also known as the tunica ruyschiana after the anatomist Ruysch who first described it centuries ago). It is here that the most important events in the visual cycle occur, which involve the photoreceptor cells, cones and rods, and their interactions with the retinal pigment epithelium (RPE).

One of the most important events in this interaction – first suggested by me as long ago as 1963 in what has since become a classic paper written in collaboration with A. Bairati and confirmed by Young a few years later – is the continuous elimination of apical fragments of the external segments, which are phagocyted by the RPE (phagosomes), where they undergo enzymatic degradation (Fig. 4).

The process of renewal of the external segments lasts throughout life and, as people become older, residues of their enzymatic degradation begin to engulf the cytoplasm of RPE cells, thus causing what is probably one of the initial event of the alteration of the external retinal layers leading to AMD. In particular, the lipofuscin granules whose number considerably increase in the senile pigmented epithelium are thought to be an undigestable derivate of this process.

The altered RPE and the underlying choriocapillaris could therefore undergo atrophy (dry AMD) or promote a vasoproliferative stimulus leading to the formation of new sub-retinal vessels (wet AMD). In either case, the initial alteration of the ocular fundus is very often represented by the “drusen”, small polimorphous sub-epithelial deposits, commonly found in senile maculae.

Principal symptoms

Drusen phase: - No reduction in vision, or - Slight image distortion, particularly straight lines (metamorphopsia) Wet (neovascular) form: - Metamorphopsia - Reduced visual acuity - Central scotoma (a central blind spot in the visual field making it difficult to read and recognise faces) Dry (non-neovascular) form: -The same as the wet form, but less accentuated, more slowly evolving and with a less severe functional outcome.

Other symptoms

- Increased sensitivity to bright light

- Decreased contrast sensitivity

- Decreased colour vision

- Photopsia (flickering or flashing lights)

- Complete or incomplete hallucinations (usually in the late stage of the disease if significant scarring has occurred) If present in only one eye, the symptoms may pass unnoticed; however, they are easily perceived once the second is affected. An example of central vision loss in AMD is shown in Fig. 6.

Detection and diagnosis

Early detection of neovascular AMD is possible by making a regular eye examination and using an Amsler grid (Fig.7). The signs suggestive of neovascular AMD include distortion, blurring, darkening or discoloration of the grid lines, or an inability to fix on the dot in the centre. A complete eye examination is necessary to exclude other causes of vision loss and fluoroangiography and ICGA, whenever possible, is used to confirm the presence and location of the CNV.

The characteristics of the angiographic examination, which is essential in this disease, are described in a later chapter by my colleague Prof. G. Staurenghi. Before confirming the diagnosis of CNV secondary to AMD, it is necessary to exclude other CNV-inducing conditions, such as pathological myopia, presumed ocular histoplasmosis syndrome, etc.

An early detection and treatment of AMD is essential in order to maximise the preservation of useful vision and prevent legal blindness in patients who already have one affected eye. Neovascularisation can evolve in just a few days or weeks. Amsler grids are easy to use and high-risk patients should be encouraged to use them to monitor their own vision.

Regular eye examinations are recommended every 1-2 years in people aged more than 65 years, even in the absence of symptoms (American Academy of Ophthalmology Policy Statement, 1990).

Current AMD treatments

Before the introduction of photodynamic therapy, CNV laser photocoagulation was the only treatment for neovascular AMD, but its efficacy was uncertain even in selected patients. Only 13-26% of such patients (i.e. those with extrafoveal, juxtafoveal, or small and well-demarcated subfoveal lesions) are suitable for this therapy, and 50% of those actually treated experience persistent or recurrent CNV usually within two years of treatment.

Furthermore, laser photocoagulation may be associated with severe and immediate vision loss as a result of unavoidable damage to the retina overlying the treated area.

Laser photocoagulation of subfoveal CNV typically causes an immediate loss of an average of three lines of visual acuity.

Photodynamic therapy, which has been available also in Italy for about six months, allows ophthalmologists to treat previously untreatable patients and in any case with a better chance of success.

It is possible to reduce the risk of vision loss in subjects with prevalently classic subfoveal CNV (i.e. covering >=50% of the total area of the lesion) without permanently damaging the overlying neurosensory retina. In another chapter, my colleagues Dr. F. Bottoni and Dr. C. O. Pierrottet will describe in detail the therapeutic and rehabilitation issues of AMD in the light of the latest results.

(traduzione dell’autore)

Nicola Orzalesi

Fig.1: Angiograms of AMD: left, the dry non-neovascular form; right, the wet neovascular form.

Fig.4: TEM of the cytoplasm of a human RPE cell (62 years) containing a phagolisosome (FL), a secondary lisosome (LS) and granules of lipofuscin (L). Fixation: gluteraldehyde-osmium; staining: lead-uranyl acetate. x 30000

Fig.6

Fig.7 Amsler grid