• Treatment
• Visudyne ®
• Therapy at a glance
• CNV
• Therapy - a selective approach
• Clinical Development
• Efficacy
• Safety
• Pharmacokinetics
• Pharmacodynamics
• Administration
• Patient Information
• References

Choroidal neovascularization

Detection and diagnosis
Symptoms of CNV
Classification of CNV using fluorescein angiography
Age-related macular degeneration
Prevalence
Etiology
Current proven treatments
Pathologic myopia
Prevalence
Etiology
Current proven treatments
Other causes of CNV

CNV is a degenerative condition that, unidentified and untreated, can cause severe, irreversible central vision loss. It develops secondary to several disorders of the eye including AMD, pathologic myopia, and OHS. Although patients’ peripheral vision is maintained, severe central vision loss as a result of CNV significantly reduces their ability to undertake basic everyday activities – reading, telling the time, recognizing faces, and driving become increasingly difficult.¹ The resulting loss of independence, productivity, and self-esteem can, in some cases, lead to psychological problems including anxiety, depression, anger, reduced drive, tiredness, and confusion.²

Despite the significant effect that CNV can have in terms of vision loss and impact on patient lifestyle, its precise etiology has yet to be elucidated. While the pathogenesis of the associated eye disorders varies, a distinct sequence of events leads to central vision loss once CNV has developed (Figure 2.1). Central vision loss may occur when the macula is damaged by CNV which develops when new abnormal choroidal blood vessels grow from the underlying choriocapillaris and proliferate through breaks in Bruch’s membrane into the subretinal and pigment epithelial space(Figure 2.2).³ These new blood vessels are fragile and leak blood and fluid, which can lead to detachment of the retinal pigment epithelium (RPE) or neurosensory retina, formation of a fibrovascular scar, and loss of the outer retinal tissue.³

Deterioration of vision is regarded as a natural part of the aging process and is therefore not voluntarily reported by many people.4 Indeed, signs and symptoms of vision loss may go unnoticed when only one eye is affected by CNV, and patients often do not seek medical help until the disease is at an advanced stage or until it has also affected the fellow eye. Early detection, diagnosis, and treatment of CNV are, however, essential to maximize the preservation of central vision and to prevent blindness.

Progression of CNV

(a) Normal retina – the RPE separates the choroidal layer from the photoreceptors.

(b) Bruch’s membrane thickens and drusen (arrows) develop forming a barrier between the RPE and the choroid.

(c) New abnormal blood vessels (CNV – arrows) from the choriocapillaris proliferate and penetrate Bruch’s membrane into the subretinal or subpigment epithelial space.

(d) New blood vessels leak blood and fluid causing a build-up of fibrocytes between and within the RPE and photoreceptors leading to detachment of the RPE, formation of fibrovascular scars, and loss of outer retinal tissue.

Figure 2.1 Schematic examples and fundus photographs showing progression of CNV.

Figure 2.2 Anatomy of the eye (a) and the macula (b), with cross-section showing damage resulting from CNV (c).

The use of an Amsler grid and regular medical eye examinations are the best methods for detecting CNV before severe vision loss occurs.⁵ Patients known to be at high risk of CNV and associated conditions should be encouraged to use an Amsler grid regularly to monitor their own vision. This is easy to use; signs suggestive of CNV include distortion, blurring, darkening or discoloration of the grid lines, or an inability to fix on the dot in the center of the grid (Figure 2.3).⁶

Regular medical eye examinations are recommended every 2 to 4 years for people aged 40 to 64 years, and every 1 to 2 years for people aged 65 years or over.⁷ A full ophthalmic examination, including visual acuity testing, fluorescein angiography, contrast sensitivity testing, and ophthalmoscopy, is necessary to accurately diagnose the cause of vision loss.⁸ Fluorescein angiography can be used to confirm the presence and location of CNV.⁸

Figure 2.3 When fixating on the center of an Amsler grid (a), a patient with CNV perceives the grid as distorted (b).

CNV rarely affects both eyes simultaneously and the symptoms from one affected eye may go unrecognized until the fellow eye becomes affected. Patients with unilateral CNV are at significant risk of developing CNV in the fellow eye within 3 to 5 years.⁹

The major symptoms of visual disturbance experienced by patients developing CNV are (Figure 2.4):

• reduced central visual acuity
• central scotoma (a blind spot in the visual field)
• metamorphopsia (image distortion)

Figure 2.4 Reproduction of central vision loss in CNV when a patient fixates on the center of a photograph.

Other symptoms may include:

• increased glare sensitivity
• decreased contrast sensitivity
• decreased color vision
• photopsia (flickering or flashing lights)
• formed or unformed hallucinations (usually in late stage of the disease if significant scarring has occurred)

Classification of CNV using fluorescein angiography

Fluorescein angiography has been used extensively to confirm the presence and location of CNV and to determine the size and type of lesion.⁸ Classification of the two types of CNV, classic and occult, is based on the distinct patterns captured using fluorescein angiography (Figure 2.5).¹⁰

Fluorescein angiograms of CNV types

(a) Classic CNV – early- and mid-phase frames of an angiogram of classic CNV.

b) Occult CNV – early- and mid-phase frames of an angiogram of occult CNV.

(c) Classic and occult CNV – early- and mid-phase frames of an angiogram of classic CNV (straight arrow) and occult CNV (curved arrow).

Figure 2.5 Fluorescein angiograms showing classic CNV, occult CNV, and mixed classic and occult CNV.

Classic CNV appears as a well-demarcated area of uniform hyperfluorescence surrounded by a hypofluorescent margin in the early-phase frames of the angiogram, with fluorescein leakage that obscures the boundaries of the lesion through the mid- and late-phase frames.

Occult CNV is divided into two types.

• Type I is characterized by a fibrovascular RPE detachment that appears as stippled hyperfluorescence with irregular elevation of this fluorescence at the level of the RPE, usually within 1–2 minutes of fluorescein injection. The boundaries are often poorly defined or difficult to demarcate and there is fluorescein leakage in the late-phase frames of the angiogram.
• Type II has poorly demarcated boundaries with fluorescein leakage from an undetermined source at the level of the RPE in the late-phase frames of the angiogram, which do not correspond to classic CNV or fibrovascular pigment epithelial detachment in the early- or mid-phase frames.

The proportion of the lesion that is classic or occult CNV can, in some patient populations, be an important factor for selecting patients who are likely to benefit from therapy. Lesion composition is assessed using fluorescein angiography and the classification is defined by the proportion of the lesion that is classic CNV (Figure 2.6) Predominantly classic lesions are defined as those in which the classic component comprises 50% or more of the area of the entire lesion (including occult CNV, blood, and other components that block fluorescence). Lesions in which the classic component comprises less than 50% of the entire lesion area are defined as minimally classic, and those with no evidence of classic CNV are defined as no classic.

Figure 2.6 Schematic and early- to mid-phase angiographic examples of baseline lesion composition.

Left untreated, predominantly classic lesions have been associated with poorer vision outcomes than minimally classic lesions or lesions with no evidence of classic CNV.¹¹ In a retrospective analysis of untreated eyes by the Macular Photocoagulation Study (MPS) Group, visual acuity remained stable for 3 years in 25% of eyes with occult CNV and no classic CNV.11 Classic CNV developed within 3 months in 23% of eyes with no classic CNV at baseline and within 12 months in a further 23%.¹¹

CNV is responsible for 80–90% of cases of severe, irreversible central vision loss in patients with AMD (Figure 2.7).^12,13 The neovascular form of AMD (also termed wet, exudative, disciform, or serous AMD), which is characterized by CNV, occurs in only approximately 20% of AMD patients, but it is the leading cause of blindness among people over 50 years of age in the western world.^12,13

Most vision loss in AMD is due to CNV

Figure 2.7 Causes of vision loss in AMD.

Severe vision loss can also result from the non-neovascular form of AMD, but only in rare cases when a central scotoma develops as a result of geographic atrophy in the fovea.¹³ Nonneovascular AMD (also termed dry, non-exudative, geographic, or atrophic AMD) is characterized by drusen and geographic atrophy of the RPE and is clearly distinguished from the neovascular form of the disease when visualized on fluorescein angiography (Figure 2.8).

Figure 2.8 (a) Late-phase frame of fluorescein angiogram of geographic atrophy in non-neovascular AMD (b) Early-phase frame of fluorescein angiogram of neovascular AMD.

Approximately 10–20% of patients with non-neovascular AMD develop CNV and progress to the neovascular form.¹² The time scale for this progression may vary from a few months to several years and depends on the composition of the CNV and the size and location of the lesion.

Epidemiologic prevalence estimates of AMD range from less than 2% to over 10% of people over 50 years of age; the variation in estimates depends on the definition of AMD, the grading system used, and the age and geographical location of the study population (Table 2.1). Irrespective of these factors, however, the prevalence of neovascular AMD was found to increase with age, particularly in people aged over 65 years. In countries where the average age of the population is increasing (Figure 2.9),²⁴ the prevalence of neovascular AMD is also expected to rise. This increase in people at risk of developing AMD will represent a major public health consideration.

The proportion of people aged ≥ 60 years in the western world is increasing

Figure 2.9 Actual (solid line) and projected (dashed line) growth of the population aged ≥ 60 years in established market economies and the former socialist economies of Europe, 1980–2020.²⁴

Table 2.1: Summary of selected epidemiologic studies of AMD

General public awareness of AMD remains low despite its increasing prevalence and the high risk of severe vision loss. One international survey found that only 2% of adults surveyed considered AMD as the leading cause of blindness in people over 50 years of age; 82% of the survey group were ‘not familiar’ with AMD as a condition.²⁵

The etiology of AMD is largely unknown, but several risk factors have been identified.^12,26 Age is the only known definite risk factor for AMD – the older the patient, the higher their risk of developing AMD (Figure 2.10).^20,26

The risk of developing AMD increases with age

Figure 2.10 Age and AMD – data are derived from an epidemiologic study of 1000 individuals in Copenhagen, Denmark.²⁰

The presence of AMD in one eye also predisposes people to developing the condition bilaterally. Five-year incidence estimates for bilateral disease range from 7% to 87% and are known to depend on patient characteristics and on the fellow eye; on average, however, 42% of patients with neovascular AMD in one eye will develop it in the other eye within 5 years.²⁷

Other factors that are possibly associated with AMD include:⁹

• gender – the Beaver Dam Eye Study found that women were twice as likely to develop neovascular AMD as men²²
• race – white populations are more likely to suffer vision loss from neovascular AMD than black or Hispanic populations
• hypertension and/or cardiovascular disease
• family history – although no specific gene for AMD is known, some candidate genes have been suggested recently
• ocular conditions such as light iris color, lens opacities, aphakia, and hyperopia
• cigarette smoking
• exposure to blue light or sunlight
• nutrition, such as low levels of carotenoids

Current proven treatments

Visudyne^® therapy and laser photocoagulation represent two therapeutic options for the management of neovascular AMD that have been proven effective in large-scale randomized clinical studies.^28,29 Early detection and diagnosis of patients eligible for therapy is critical so that treatment can be initiated as quickly as possible to maximize the p otential for reducing the risk of vision loss.

Laser photocoagulation has been used for several years and provides visual benefits in a small number of patients – only 13 to 26% of neovascular AMD patients presenting with extrafoveal, juxtafoveal, or small and well-demarcated subfoveal lesions meet treatment eligibility criteria.28 Persistent or recurrent CNV, usually within 2 years of treatment, has been reported in approximately 50% of patients treated.³⁰ In addition, significant and immediate vision loss has been found to occur after laser photocoagulation as a result of indiscriminate damage to the retina overlying the treated area;²⁸ typically, an immediate 3-line loss of vision has been reported.30 The limited usefulness of laser photocoagulation coupled with visionrelated adverse events highlight the need for new therapies.

Visudyne^® therapy represents a major advance in the treatment of neovascular AMD. Ophthalmologists now have available a treatment option for patients with subfoveal lesions. Results from clinical investigations demonstrate that Visudyne^® therapy can effectively and safely reduce the risk of vision loss in AMD patients with predominantly classic subfoveal lesions and many patients with occult CNV but no classic CNV, without causing permanent damage to the overlying neurosensory retina.

Pathologic myopia

Pathologic myopia is the most frequent cause of CNV in patients under 50 years of age – approximately 60% of CNV is secondary to pathologic myopia in this age group.³¹

Estimates of the prevalence of pathologic myopia vary. A population-based Australian study reported a prevalence rate of approximately 2% in people over 40 years of age.³² Ethnicity may predispose people to an increased risk of pathologic myopia with a 9% prevalence rate reported in Chinese people aged between 40 and 79 years.³³

Pathologic myopia is characterized by progressive increases in the axial length of the eye and highly negative spherical equivalents (typically -6.00 diopters or more negative) (Figure 2.11); approximately 5–10% of patients with an axial length greater than 26.5 mm develop CNV.³⁴ Most patients with pathologic myopia present with classic CNV.³⁵

As in AMD, the underlying cause of CNV in pathologic myopia involves degeneration of Bruch's membrane followed by the growth of new vessels. The elongation of the eyeball in patients with pathologic myopia is thought to cause the choroid to stretch. As the condition progresses, continued stretching and degeneration of the choroid lead to the development of breaks in Bruch's membrane, known as lacquer cracks,³⁴ which have been identified in approximately 80% of patients with CNV secondary to pathologic myopia.³⁶ The presence of these cracks allows vessels from the choriocapillaris to proliferate into the subretinal pigment epithelium.

Angiographic examples of CNV in pathologic myopia

Figure 2.11 (a) Early-phase and (b) late-phase frames of fluorescein angiograms of subfoveal CNV in pathologic myopia.

Current proven treatments

Uncontrolled studies show that, although laser photocoagulation may stabilize visual acuity in eyes with extrafoveal CNV secondary to pathologic myopia, there is no evidence to suggest benefits in patients with subfoveal CNV.^37,38 These studies of laser photocoagulation in extrafoveal lesions also show a high rate of recurrence and a risk of spontaneous progressive enlargement of the atrophic photocoagulation scar leading to worsening of visual acuity.^39,40 In addition, laser photocoagulation has recently been linked to the development of new or expanded lacquer cracks in the region of the laser scar.⁴¹

In patients with subfoveal CNV secondary to pathologic myopia, Visudyne^® therapy has been shown to stabilize and even improve vision,³⁵ thus providing the means to treat a condition for which no other treatment has been proven effective.

Other causes of CNV

A large number of patients develop CNV secondary to conditions other than AMD and pathologic myopia, even though these are the most frequent causes of CNV in patients aged over 50 and under 50 years, respectively. CNV can also develop as a consequence of OHS (Figure 2.12) which may cause approximately 12% of CNV occurring in patients under 50 years of age.³¹ This disease is thought to be associated with the fungus Histoplasma capsulatum. The prevalence of CNV secondary to OHS shows geographic variation, with most cases occurring in areas where the fungus is endemic, such as the central and eastern United States.⁴² Vision loss associated with CNV secondary to OHS usually affects a population in their thirties or forties.⁴² Patients with subfoveal CNV secondary to OHS generally have a poor prognosis.⁴³

Examples of CNV in OHS

Figure 2.12 (a) Fundus photograph and (b) early-phase frame of fluorescein angiogram of CNV in OHS.

No evidence to date supports the use of laser photocoagulation in eyes with subfoveal CNV secondary to OHS. In patients with extrafoveal CNV, laser photocoagulation reduced the risk of a loss of 6 or more lines of visual acuity after 5 years of follow-up, but was associated with a recurrence rate of 26%.⁴⁴ Similar benefits have been observed in eyes with juxtafoveal CNV.⁴⁵ The potential use of Visudyne^® therapy in patients with subfoveal CNV secondary to OHS is currently being investigated.

Angioid streaks may also be responsible for the development of CNV in some patients. Laser photocoagulation may be beneficial in patients with CNV due to angioid streaks,^46,47 although there have been some reports of poor outcomes and subretinal neovascular proliferation near to the treatment site.^48,49

Further research will determine if Visudyne^® therapy reduces the risk of visual acuity loss in patients with CNV due to angioid streaks or other ocular conditions.

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