Choroidal neovascularization (CNV) is a common cause of blindness in the United States. It is characterized by new, abnormal blood vessels growing from the choroid through breaks in Bruch’s membrane or the basement membrane of the retinal pigment epithelium (RPE). These vessels can leak blood and fluid and are accompanied by fibrous tissue, which often leads to damage of the retinal tissues and vision loss. CNV can be classified according to its location in relation to the fovea: subfoveal CNV is located under the center of the retina; juxtafoveal and extrafoveal CNV are located at increasing distances away from the center. Vision loss is greatest, on average, when the CNV is subfoveal.
In people older than 50 years, the main cause of CNV is age-related macular degeneration (AMD); younger people can be affected by CNV as a result of other causes. In people under 50 years of age, the etiology of CNV is varied and can include pathologic myopia, ocular histoplasmosis syndrome (OHS), angioid streaks, or idiopathic causes. Regardless of cause, the vision loss caused by CNV may have a major impact on the daily lives of the people affected, especially if both eyes develop CNV over time. These people may no longer be able to perform activities such as reading, driving, and navigating independently. Consequently, some patients may have to give up work or are at least limited in the types of tasks they can perform effectively. Not only can this be a huge emotional strain, but it may also affect their career expectations and financial status—an important consideration for younger patients who may be supporting themselves and their families.
As primary healthcare providers, optometrists are in a position to take the important first step of starting the referral process for patients who potentially have CNV so that they can be treated by a retina specialist. Treatment was largely unavailable for many patients with subfoveal CNV as a result of these conditions until the introduction of verteporfin (Visudyne; Novartis Pharma AG, Basel, Switzerland) therapy. The aims of this article are to review CNV in younger patients and the treatment options available, and to discuss how optometrists might contribute to the management of CNV.
ETIOLOGY AND PATHOPHYSIOLOGY
CNV can develop as a consequence of several conditions, including pathologic myopia, OHS, angioid streaks, and idiopathic causes. The visual prognosis without treatment for patients with CNV can be poor; for example, in one study, approximately 18% of people with CNV resulting from pathologic myopia experienced vision loss to a level of 20/200 or worse in a 1-year period.
The pathogenesis of CNV is complex and the processes involved have not been completely characterized. Nevertheless, it is believed that at the cellular level, CNV develops as a consequence of processes related to wound healing and tissue repair. The normal wound-healing process consists of inflammatory, tissue-formation, and tissue-repair phases. Angiogenesis is an essential component of this normal wound-healing process, delivering oxygen, nutrients, and inflammatory cells to the site of injury, removing debris, and assisting in tissue formation and wound closure. It is believed that an identical process occurs during the development of CNV. Essentially, cellular damage is initiated by a stimulus or “injury” within the macula region such as metabolic imbalance or hypoxia, leading to release of proinflammatory cytokines. This leads to recruitment of macrophages followed by dedifferentiation of the RPE resulting in endothelial cells forming new capillaries that cross Bruch’s membrane. This process continues until normoxia or hyperoxia is established. Finally, vascular remodeling and maturation is initiated, and a mature arterial and venous supply is established.
The initial stimulus that activates the processes leading to development of CNV can arise from several sources, depending on the underlying condition. For example, in pathologic myopia, stretching of the retina can lead to development of lacquer cracks, which may trigger the initiation of a wound-healing response. Similarly, angioid streaks are associated with disruption of the elastic layer of Bruch’s membrane and may be related to several conditions, including pseudoxanthoma elasticum, Paget’s disease of the bone, or sickle hemoglobinopathies.
Development of CNV may also be initiated as a consequence of inflammatory conditions such as uveitis, probably as a response to inflammation or nonperfusion, as well as inherited macular dystrophies such as Best’s disease.
DIAGNOSIS
Clinical Signs and Symptoms
Regardless of the underlying cause of CNV, the symptoms are similar; patients tend to notice a sudden decrease in central vision. Patients affected by CNV in one eye will often subsequently develop CNV in the fellow eye. Patients who develop CNV in both eyes may become legally blind (visual acuity of 20/200 or worse in the better-seeing eye).
CNV may not be symptomatic until the late stages of the condition, and therefore it may first be detected only during a comprehensive eye and vision examination. The biomicroscopic features of CNV may vary depending on its underlying cause and the age of the patient. The hemorrhage at the site of the membrane or in the subretinal space may extend into the vitreous. In the case of subretinal hemorrhage at the level of the pigment epithelium, direct examination of the macula reveals a discrete, round-to-oval, elevated lesion. Often surrounded by a subretinal hemorrhage, the lesion appears greenish-gray or dirty brown. A halo of pigment may also surround the lesion. Other evidence of CNV includes subretinal lipid or blood (associated with an overlying thickened, detached neurosensory retina) and serous retinal pigment epithelial detachment (characterized ophthalmoscopically as a well-demarcated, dome-shaped, elevated, yellowish-orange lesion). The overlying neurosensory retina may be detached, and the separation often exceeds the boundaries of the pigment epithelial detachment, providing further evidence of CNV.
In younger patients, clinical characteristics of CNV can include all of these findings, but some of the characteristics are more typical in the younger patient. The biomicroscopic findings of CNV in younger patients are generally better defined compared with CNV in older patients with AMD. The CNV is usually visible as a grayish-green subretinal membrane, surrounded by a halo of pigmentation, sometimes with clearly visible subretinal blood, fluid, or lipid, and small in area (<1>
Other diseases can present with similar symptoms and signs of CNV. The differential diagnosis of CNV in younger patients includes exudative maculopathies such as central serous chorioretinopathy, Best’s disease, various inflammatory lesions of the choroid or retina, and branch retinal vein occlusion. Other nonexudative diseases that can simulate CNV include macular dystrophies, macular hole, lacquer cracks, and drusen. Central serous chorioretinopathy, being exudative with fluid, is the most common misdiagnosis of CNV in younger patients, but the clinical course in central serous chorioretinopathy is usually benign and self-limited. Fluorescein angiography is an extremely important tool for the accurate diagnosis of CNV.
Early Detection and Referral
The visual prognosis for patients with CNV is often poor, regardless of the underlying cause. In a retrospective study of 100 patients with CNV secondary to pathologic myopia, it was found that after 5 years, all CNV involved the center of the fovea and mean visual acuity was 20/160 in the 50 patients in the natural history group. In another retrospective study of 148 patients with subfoveal or juxtafoveal CNV secondary to ocular histoplasmosis, it was found that, after an average follow-up of 39 months, 103 eyes (70%) had visual acuity equal to or worse than 20/200. Therefore, it is paramount that the symptoms of CNV are recognized so that patients with clinical signs of the condition or unexplained symptoms can be referred promptly to a retina specialist for further evaluation and possible treatment. In general, patients should not be referred if the symptoms are consistent with and explained by another examination finding such as cataract or mild epiretinal membrane.
There is usually only a narrow window of time before the patient’s vision and quality of life will deteriorate to a level at which there is unlikely to be treatment benefit. Furthermore, there is a high risk that CNV will eventually develop in the fellow eye, and prompt treatment may avoid legal blindness.
Optometrists can facilitate the referral process by being aware of the signs, symptoms, and risk factors for CNV in younger patients. Any patient presenting with signs and symptoms indicative of CNV should be referred promptly to a retina specialist for confirmation of CNV by fluorescein angiography. Patients who are at risk of CNV should be encouraged to self-monitor for early signs and symptoms of neovascular AMD; many eye care providers recommend an Amsler grid. Detailed instructions on the use of the grid should be given to the patient. Also, the patient should be urged to pay attention to any significant change in visual acuity, even in the absence of Amsler grid changes. It is our experience that patients often present months after dramatic vision loss has occurred and, when they are asked why they did not return sooner, they say that they saw no changes on the Amsler grid. The visual acuity of an individual suspected of having CNV can also be assessed using a standard eye chart; however, this will indicate only an overall deterioration in vision, a finding that is not specific to a particular underlying condition such as CNV. If the patient has already experienced vision loss at the time of examination, it may be beneficial to also consult with an optometrist who has advanced training in, or clinical experience with, low-vision rehabilitation.
The conclusion of a comprehensive adult eye examination and vision examination should include review and discussion of the examination outcomes. Patients should be provided with information about their potential diagnosis, the prognosis of their condition, and the treatment options to aid in the management of their expectations. They should be aware of the next steps in their disease management process, which include referral to a retina specialist who will perform specialized evaluation tests. The patient should also be informed about the possible symptoms associated with CNV and be asked to return promptly in the event of any new symptoms. Otherwise, regular optometric follow-up examinations should be scheduled with their frequency related to the risk of the underlying condition as assessed by the optometrist. For example, a patient with OHS and an active lesion or a history of CNV in one eye and quiet chorioretinal scars in the fellow eye has a high risk of developing CNV and should be followed closely (e.g., initially every 3 months and then every 6 months if no activity is found).
Specialist Ophthalmic Evaluations
Retina specialists have several tools at their disposal to evaluate CNV, including biomicroscopy, ophthalmoscopy, fundus photography, fluorescein angiography, and optical coherence tomography. Fluorescein angiography is particularly useful because the fluorescent dye leaks from abnormal blood vessels of the retina or choroid and enables visualization of some pathologic vascular conditions such as fibrovascular CNV. Indocyanine green angiography (ICGA) has been shown to provide useful additional information on the composition of CNV in patients with AMD but has not been used extensively in other conditions associated with CNV. It has, however, been suggested that ICGA may be useful for detecting and describing lacquer cracks in pathologic myopia but has yet to be shown to have proven benefits in the management of any specific ocular disease.
AVAILABLE TREATMENTS
Of the many treatment modalities potentially available for younger patients with CNV, only laser photocoagulation and verteporfin therapy have been proven to be beneficial in large-scale, randomized clinical trials at this time, although other therapies may be added to these regimens over the next few years. Although the antiangiogenic agent pegaptanib sodium (Macugen®; [OSI] Eyetech and Pfizer Inc.) has recently been approved in the United States for the treatment of subfoveal CNV resulting from AMD based on the results from two phase II/III trials, there are currently no trials investigating its use for other causes of CNV, although it is likely that some retina specialists will use it for CNV in other conditions.
The treatment indicated for CNV in younger patients largely depends on its location. If the CNV is located away from the fovea (extrafoveal or juxtafoveal), laser photocoagulation may be recommended, whereas for subfoveal lesions, verteporfin therapy is the treatment of choice. Submacular surgery might be considered for some patients with CNV, although the results of randomized clinical trials evaluating this have been disappointing. Current guidelines state that there should be no lower age limit for the use of verteporfin therapy, based on clinical data from the Treatment of AMD with Photodynamic therapy (TAP) Investigation and the Verteporfin In Photodynamic therapy (VIP) Trial, although it should be noted that no data are available on the treatment of CNV in the pediatric setting. Similarly, the key studies of laser photocoagulation enrolled patients as young as 20 years of age, but there are no data from large-scale studies of children.
Laser Photocoagulation
Laser photocoagulation is administered on an outpatient basis and normally takes around 15 minutes. CNV is damaged by the heat radiating from the RPE after absorbing light from a laser beam directed at the region of CNV identified by fluorescein angiography. The MPS, in which our group participated for 15 years, proved the benefit of laser photocoagulation for extrafoveal and juxtafoveal CNV resulting from AMD, OHS, and idiopathic causes. Laser photocoagulation is usually performed with only topical anesthesia and is well tolerated. Patients typically resume their usual routines within a day.
Because the thermal effects of laser photocoagulation also damage the healthy part of the retina, it will cause the formation of a scar in the macula. This is usually well tolerated in extrafoveal locations but may be problematic for juxtafoveal lesions and very destructive for subfoveal treatment. Laser scar enlargement has sometimes been observed when treating CNV resulting from pathologic myopia. The effects of laser on retinal tissue can expand in the direction of the fovea, making juxtafoveal treatment risky. A risk of vision loss resulting from laser injury accompanies treatment of all CNV; this risk should be weighed against the potential benefit of treatment.
Verteporfin Therapy
Verteporfin therapy is a treatment, based on a photodynamic principle, for subfoveal CNV secondary to a number of diseases.
Verteporfin therapy is administered in two steps: 1) the photosensitizer verteporfin is infused intravenously in the patient’s arm; and 2) the drug is activated using a nonthermal laser applied only to the area of the eye affected by CNV. The drug accumulates preferentially in the areas of neovascularization. When the drug is activated by the laser, the CNV is occluded as a result of endothelial cell damage and thrombus formation, whereas the rest of the eye is usually unaffected by the laser or the drug. Therefore, there is less risk of damage to any viable retina overlying the CNV than with laser photocoagulation, and immediate vision loss with verteporfin therapy is less likely.
Verteporfin therapy increases the chance of stable or improved vision in patients with subfoveal CNV secondary to pathologic myopia compared with no treatment. A multinational, randomized clinical trial showed that a small percentage of patients treated with verteporfin therapy can have an improvement in vision. However, the main aim of treatment is to reduce the risk of vision loss. Smaller studies of verteporfin therapy in OHS have also shown benefit.
Furthermore, verteporfin therapy has shown some promise in treating CNV as a result of other, less common causes. These include angioid streaks, juxtafoveolar telangiectasis, and inflammatory and idiopathic causes. In small studies and case reports, verteporfin therapy has been shown to be beneficial in patients with these rare causes of CNV. Like in CNV resulting from AMD, several treatments over time were usually required, but most of the patients in these reports ultimately had complete or partial closure of the CNV and stabilization or improvement in visual acuity.
Verteporfin therapy can also have beneficial effects on contrast sensitivity, which is an important measure of a patient’s functional ability and directly related to tasks such as reading, navigating, and recognizing faces. Rehabilitation may also be facilitated by verteporfin therapy. The size of the scotoma is very significant to low vision rehabilitation for reading and other activities of daily living independent of visual acuity. A small, uncontrolled case series that aimed to determine if macular scotomas in 64 patients with neovascular AMD were affected by verteporfin therapy showed that, at 3 months, the majority (77%) of patients had stabilization or improvement in their scotomas. This finding may also extend to patients with non-AMD causes of CNV.
Patients should be advised that verteporfin therapy may involve multiple treatments; regular follow-up visits and additional courses of therapy may be required as often as every 3 months until a point of stability is reached. At follow-up visits, the presence or absence of fluorescein leakage from CNV will be determined using fluorescein angiography. If there is any leakage, presumed to be a sign of further risk of vision loss if left untreated, treatment with verteporfin is recommended in many cases. It is important for the patient to understand that verteporfin therapy is a disease-modifying therapy that attempts to slow or halt the progression of the disease. Therefore, the patient’s expectations need to be set appropriately; they are likely to experience some continued erosion of vision until their lesion stabilizes.
The most important treatment-related adverse event is acute severe visual acuity decrease (loss of more than or =20 letters or more than or =4 lines on a standard eye chart within 7 days after treatment). This was reported in three patients (0.7%) in the TAP Investigation and 10 patients (4.4%) in the AMD arm of the VIP Trial. More than half of these patients recovered their vision to within 20 letters of baseline within 3 months of treatment. It must be stressed that acute severe visual acuity decrease as an adverse event is distinct from the vision loss associated with the natural history of CNV. The risk of long-term severe vision loss without treatment is greater than the risk of acute severe visual acuity decrease with treatment in patients with AMD with predominantly classic CNV or occult with no classic CNV and presumed recent disease progression.
No cases of acute severe visual acuity decrease were reported in clinical studies involving patients with pathologic myopia or OHS; however, it is likely that there is at least some risk of severe visual acuity decrease associated with treatment in these patients. Other adverse events most commonly reported in verteporfin-treated patients in the pathologic myopia arm of the VIP Trial through 2 years included visual disturbance (19 [23%] verteporfin-treated patients; 8 [21%] patients in the placebo group) and injection site reactions (8 [10%] verteporfin-treated patients; 2 [5%] patients in the placebo group).
Patients should also be advised that they will be photosensitive after verteporfin therapy. Regulatory authorities in the United States recommend that precautions against photosensitivity be taken for 5 days after therapy; however, clinical expert opinion is that precautions are necessary for only 2 days after verteporfin therapy. Patients should wear long sleeves and pants, a wide-brimmed hat, and sunglasses and should avoid long exposure to bright lights or sunlight during this time. Exposure to ambient household light can be encouraged, because this may reduce the period of photosensitivity through a process known as photobleaching. Very few cases of photosensitivity occurred in clinical trials; provided patients follow these guidelines, the risk of a reaction is low.
Submacular Surgery
Submacular surgery is another treatment option for subfoveal CNV, although like with laser photocoagulation, the effectiveness of surgery in patients with pathologic myopia is unclear. The Submacular Surgery Trials (SST), a set of National Eye Institute-sponsored multicenter, randomized clinical trials in which we participated and that recently concluded, were designed to compare surgical removal vs. observation in patients with subfoveal CNV secondary to AMD, OHS, or idiopathic causes. In the group of patients with OHS or idiopathic causes, only a slight benefit was found in the treatment group. At the 24-month visit, 55% of 112 eyes assigned to the surgery arm had a successful outcome (defined as 24-month visual acuity better or no more than one line [seven letters] worse than at baseline) compared with 46% of 113 eyes assigned to the observation arm. Subgroup analysis showed that eyes with poorer visual acuity at baseline were more likely to benefit from surgery. In the subgroup of eyes with initial visual acuity worse than 20/100, 76% of 41 eyes in the surgery arm had a successful outcome compared with 50% of 40 eyes in the observation arm. Also, among the 42% of eyes in the surgery arm that did not develop recurrent CNV by 24 months, 74% had a successful outcome.
Submacular surgery can result in retinal damage caused by the removal of some retinal tissue with the CNV. Additional complications of submacular surgery include macular hole, retinal detachment, visual field restriction from optic nerve damage, cataract, and recurrent CNV, which can lead to poor visual outcomes. Therefore, the precise benefits and risks to the patient remain unknown and make it difficult to determine in whom surgical excision for CNV should be recommended. Further investigation may be needed to refine methods and characterize patients who might benefit from this treatment option.
VISION REHABILITATION AND LONG-TERM SUPPORT
For patients with vision loss from CNV, irrespective of whether they have received treatment, vision rehabilitation may enable them to continue performing their usual activities of daily living such as reading. In addition to referring such patients to a low-vision specialist, it may also be useful to determine the potential benefits of comprehensive low-vision rehabilitation using task-oriented evaluations. Low-vision devices may help people to continue to read when otherwise they could not. Other nonoptical measures such as orientation and mobility instruction can be used to allow visually impaired people to develop the necessary skills to navigate in a familiar environment. Such tools might enable them to maintain an independent life and may reduce the emotional burden of losing their sight. In addition, support groups for the visually impaired can provide other resources such as books on tape. When patients reach the visual acuity level defined as legal blindness, they should be encouraged to obtain assistance from government and social service agencies.
Optometrists can offer continuing, long-term care in addition to offering a portal of entry to specialists for those conditions that warrant referral. This may be particularly important for people who are bilaterally affected by subfoveal CNV resulting from pathologic myopia, OHS, angioid streaks, or idiopathic causes, because they are often affected when under the age of 50 years and may need support for over 30 years of their lives.
CONCLUSIONS
CNV is an important cause of vision loss in younger patients. CNV in this population is usually the result of pathologic myopia, OHS, angioid streaks, or idiopathic causes. Until recently, many patients with subfoveal CNV could not be treated because of the risk of central vision loss associated with laser photocoagulation. Verteporfin therapy has been proven to reduce the risk of vision loss in some patients with subfoveal CNV and is recommended for consideration in patients with pathologic myopia, ocular histoplasmosis, or those in whom the outcome with treatment is judged to be better than the natural history of the disease. Optometrists can be instrumental in the early detection and referral of patients they suspect may have CNV, thereby potentially improving long-term vision prognosis. They also have the opportunity to provide essential long-term care for these patients, including educating patients about the symptoms of CNV. They can provide low-vision aids and practical instruction on optimizing visual performance for patients who have permanent vision damage from the complications of CNV.
No comments:
Post a Comment