Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

67.Weve H (1923) Varix aneurysmaticus vicariens retinae (Pseudoaneurysma arteriovenosum racemosum retinae) Arch Augenheilkd 93:1 – 13

68.Wiedersheim O (1942) Über zwei seltene angiomatöse Veränderungen des Augenhintergrundes und über Erweiterung des Begriffs Angiomatosis retinae. Klin Monatsbl Augenheilkd 108:205 – 213

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69.Wyburn-Mason R (1943) Arteriovenous aneurysm of midbrain and retina, facial naevi, and mental changes. Brain 66:163 – 203

70.Yanoff M, Fine BS (1975) Ocular pathology. Arteriovenous communication. Harper and Row, New York, p 528

Core Messages

Retinal arterial macroaneurysms (RAMs) are acquired vascular dilatations of the large arterioles of the retina

RAMs occur most often in women aged between 60 and 80 years

Frequently associated systemic findings in patients with RAMs are hypertension, generalized arteriosclerosis and lipid anomalies

After RAM formation, a period of active exudation or hemorrhage from the malformed vessel wall occurs which is followed by spontaneous involution of the vessel anomaly

The majority of RAMs remain asymptomatic. However, depending on the location and activity, exudative or hemorrhagic complications involving the macula may cause significant visual deterioration and structural damage to the retinal tissue

The broad spectrum of clinical presentations and similarity to other retinal disorders often lead to initial misdiagnosis (RAM as a “masquerade syndrome”)

Although the overall prognosis (closure of RAM and visual restoration) is described as favorable, patients considered at a high risk of permanent structural damage of the macula should be considered for treatment

The main goal of therapy is to prevent or limit permanent visual loss due to exudative or hemorrhagic maculopathy

Various surgical options including laser and vitrectomy with a variety of additional measures have been suggested. However, up to now, no conclusive data exists that any therapy is of benefit/value. Thus, symptomatic, individual and logic-based decision-making should be considered in such cases

Keys to success in surgery for hemorrhagic RAMs are early diagnosis of subretinal blood components and atraumatic surgical techniques [e.g., recombinant tissue plasminogen activator (rt-PA)-assisted blood lysis and removal]

22.3.1 Clinical Presentation

22.3.1.1 Typical Clinical Findings

Retinal arterial macroaneurysms (RAMs) are characterized by unilateral, solitary round or fusiform dilatations of major retinal arteries within the first three orders of arteriolar bifurcation. Commonly, they are located at the site of an arteriolar bifurcation or an arteriovenous crossing at the posterior pole. The supratemporal artery is most commonly the site of RAMs; however, nasal arteries may be affected as well. Moosavi et al. [38] have analyzed the distribution of 34 RAMs and found 50 % on superotemporal, 44.7 % on inferotemporal and the remaining 5.2 % on nasal vessels. Similar observations were reported by Tezel et al. [64], who investigated 21 symptomatic RAMs and found them to be located in 52.4 % supe-

rotemporally, in 38 % inferotemporally and in 9.6 % nasally.

Simple RAMs consist of the vessel anomaly only. Narrowing of the distal artery may be observed, rarely branch arterial occlusion. In complex RAMs, exudation and bleeding into the adjacent retina occurs. These complications lead to macular edema or extrafoveal retinal edema, serous retinal detachment, circinate figure and intraretinal hemorrhages surrounding the aneurysm. Subtle microvascular changes may be present, in particular when using fluorescein angiography (FAG) for imaging (Fig. 22.3.4). Some RAMs show visible pulsations. The clinical significance is not clear, in particular, if this indicates a high risk of hemorrhagic complications [3]. Some eyes show focal yellow plaques (atheroma) in close proximity to the aneurysm. They are observed for retinal emboli, but according to the his-

544 III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

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Fig. 22.3.1. Clinical spectrum of RAMs. a–c Primary exudative retinopathy and a characteristic lesion are surrounded by a circinate figure. A fleshy-appearing nodule bordered by small hemorrhages indicates an active lesion (a, b) whereas a whitish lesion reflects an inactive RAM that has undergone sclerosis (c). d–f Hemorrhagic complications due to RAM. Hemorrhages may be located primarily subretinally (d), preretinally (e) or may involve various layers (“mixed type,” f)

topathologic findings they more likely represent arteriosclerotic vessel wall alterations. Moreover, the clinical spectrum of complex RAMs includes massive hemorrhage into the preand subretinal space and even into the vitreous cavity (Fig. 22.3.7). A “mixedtype” hemorrhage is highly suggestive of RAMs and usually does not involve retinal or choroidal vascular diseases of other origins (Fig. 22.3.13).

The spectrum of typical symptomatic clinical presentations is depicted in Fig. 22.3.1.

22.3.1.2 Special Clinical Findings

Multiple RAMs occur in approximately 15 – 20 % of affected eyes. They can be observed in one eye along the same artery or elsewhere [18 % in our series of hemorrhagic RAMs, up to 20 % reported in the literature (Figs. 22.3.4, 22.3.11b, 22.3.13b)] [48]. Bilateral

disease is found in approximately 10 % [31, 48] (Fig. 22.3.12).

Exceptional locations of a RAM are the cilioretinal artery [14] and the optic disk [5, 17, 30].

Some rare complications due to RAMs include macular hole formation [8, 36, 61], retinal detachment [62] and CNV [51]. To complete the clinical spectrum of unusual aneurysmal conditions, retinal venous macroaneurysms, RAMs associated with venous occlusive disease, have sporadically been reported [27, 29, 55].

22.3.1.3 Clinical Symptoms

Many RAMs remain asymptomatic and are being found by routine ophthalmoscopy. RAMs may become symptomatic for two major reasons: first, progressive and chronic exudative processes involv-

ing the macula, and, second, rupture of the aneurysm as a result of high intravasal arterial pressure leading to intra-, sub-internal limiting membrane (ILM) and vitreous hemorrhages (Figs. 22.3.1, 22.3.8). Typically, patients experience a slow or sudden visual loss with/without floaters. Complex RAMs indicate an active vision-threatening process, and therapy should be considered.

Asymptomatic active or asymptomatic non-leak- ing RAMs should be monitored regularly to allow early diagnosis in case the disease should progress and threaten the macula (Fig. 22.3.4).

22.3.2 Epidemiologic Data and Risk Factors

Large clinical series have shown that woman between 60 and 80 years of age are predominantly affected (approximately 70 %) and mean age is 68 – 74 years [38, 41]. Sixty-four to 75 % of patients have a history of systemic hypertension and clinical or ophthalmoscopic evidence of arteriosclerosis [32, 38, 42, 48]. Furthermore, an association with elevated serum lipid abnormalities was found [9]. As many diabetic patients suffer from hypertension as well, not diabetes mellitus, but hypertension is thought to be a major etiologic factor for RAMs. The association of hypertensive retinopathy and RAMs suggests a common pathophysiologic process [51].

The true incidence of RAMs is not known, as most often only symptomatic ones are diagnosed. Valsalva maneuvers are thought to increase the risk of bleeding.

22.3.3Pathogenesis and Pathomorphology

Hypertensive and arteriosclerotic changes of arterial vessels (ageing symptoms) may explain the formation of RAMs, including medial muscle fiber replacement by collagen, hyaline degeneration of the vessel wall, endothelial cell damage with atheromas lining the inner wall leading to narrowing of the lumen, increased vessel rigidity, elevated intravasal pressure and transmural stress. Loss of autoregulation and blood flow turbulence are further circulatory disturbances. On the basis of these alterations, focal vessel dilatation and formation of RAMs occur. The pathogenetic process of aneurysm formation and rupture is not fully understood. There is histologic evidence suggesting focal thrombosis and localized embolic events to be inciting factors, until dissection of the inner vessel wall and full thickness rupture take place.

Histopathologic studies have shown a distended thickened vessel wall (hyalosis) that is more or less obstructed by a fibrinous substance (fresh or

organized thrombus). Proteinaceous, lipid-rich material and hemosiderin deposits or blood can be found in the adjacent retina and subretinal space. Dilatated capillaries surround the lesion [11, 44].

So far, no standardized classification for the variety of clinical presentations of RAMs has been recommended. As suggested before, RAMs can be described as simple (without associated retinal changes) and complex (associated with exudation and bleeding), which also correlates with an active or inactive process. Exudative complications with lipid deposits indicate a chronic stage, but significant hemorrhages are considered an acute stage of the disease. In terms of the predominant clinical finding, RAMs can also be classified into quiescent, exudative and hemorrhagic [31].

Palestine et al. [41] suggested categorizing RAMs on the basis of their anatomic location and vision affecting complications:

RAMs within the vascular arcade and macular involvement due to complicating factors (e.g., edema, exudates, hemorrhages)

RAMs within the vascular arcade ± complicating factors without macular involvement

RAMs peripheral to the vascular arcade ± complicating factors without macular involvement

Visual prognosis was found to be strongly associated with macular complications. Asymptomatic RAMs (Groups 2, 3) were found to have a favorable prognosis, but visual prognosis in symptomatic disease (Group 1) was uncertain.

Furthermore, the shape of RAMs may influence the complication rate. Round or saccular RAMs were found to have fewer hemorrhagic complications compared to fusiform aneurysms [38].

Ophthalmoscopy reveals a focal fleshy saccular or fusiform thickening of the artery affected (Figs. 22.3.1, 22.3.3, 22.3.6, 22.3.9, 22.3.10, 22.3.13). Clear diagnosis may be difficult if secondary exudative changes dominate the picture or hemorrhages obscure the vessel anomaly. In those cases, angiography is indicated.

Fluorescein angiography shows a uniform filling in the early phase. Partial or incomplete filling (Figs. 22.3.4, 22.3.6b) is a sign of inner vessel wall thrombosis at the site of vessel dilatation. Blood flow may be restored completely and the vessel returns to normal. Residual findings can be subtle: a focal narrowing of the blood stream and irregular track or visible focal sclerosis of the artery (Figs. 22.3.2d, 22.3.6d, 22.3.12b).

Late phase angiography varies from little or no staining of the vessel wall to marked leakage into the adjacent retina. Unlike in age-related macular degeneration (ARMD), leakage only occurs at the site of the vessel anomaly, but does not affect the whole area showing exudative changes (Fig. 22.3.2b).

Microvascular anomalies surrounding RAMs can be found: a widening of the capillary-free zone around the vessel anomaly, adjacent capillary dilatation and non-perfusion, microaneurysms and small collateral vessels. They contribute to late phase leakage (Figs. 22.3.2b, 22.3.4).

In the case of RAMs with significant hemorrhages, FAG is useful for diagnosis. If the retinal vasculature is not completely obscured by blood, the presence of a characteristic hyperfluorescent nodule that is not visible on direct examination allows dif-

ferential diagnosis from other diseases with macular hemorrhage (Fig. 22.3.5).

Indocyanine angiography (ICG-A) allows better visualization of deeper retinal and choroidal structures, and near infrared light penetrates blood to a certain degree. Furthermore, the higher proteinbinding capacity of ICG (98 % to serum albumin) compared to fluorescein (60 %) results in less dye leakage and more defined images. In case FAG shows no characteristic findings, ill-defined hyperfluorescence or dense hemorrhages, ICG-A may delineate the underlying pathology [16, 57, 66].

In about 50 % of hemorrhagic RAMs, FAG leads to the correct diagnosis and ICG-A in about 75 %. Thus, angiography contributes to the actual diagnosis at first examination and allows appropriate treatment or follow-up.

22.3.7 Differential Diagnosis

The broad spectrum of clinical presentations in RAMs and the similarity to other well-defined disorders often lead to misdiagnosis. Spalter has termed RAMs a “new masquerade syndrome” [60]. Depending on the leading symptom, RAMs mimic a variety of retinal disorders (Table 22.3.1).

Most often, complex RAMs with exudation and/or hemorrhage are misdiagnosed for wet ARMD, in particular when exudative maculopathy and subretinal hemorrhage dominate the clinical picture (Figs. 22.3.1a, d, 22.3.2d, 22.3.6). FAG then allows easy differentiation. Thick blood clots are sometimes misdiagnosed for malignant melanoma [44, 59].

Evaluation of our series with RAMs associated with severe hemorrhage showed that almost half of the cases were referred for treatment of hemorrhagic ARMD. Eccentric hemorrhage location surrounding an artery is highly suggestive of RAMs, even if the vessel anomaly itself is hidden by blood (Figs. 22.3.12c, 22.3.14a). Another important hint of RAMs is the fact that blood often involves various retinal layers. High pressure within the lumen of the artery

Table 22.3.1. Differential diagnosis of RAM

Leading symptom: atypical vessel structure

Angiomatosis retinae Cavernous hemangioma

Vessel malformation in venous occlusive disease, diabetic retinopathy

Leading symptom: exudative retinopathy

Exudative ARMD

Disciform ARMD Diabetic macular edema

Idiopathic parafoveal teleganiectasia

Leber’s miliary aneurysm retinopathy/Coats’ disease Radiation retinopathy

Leading symptom: macular hemorrhage/dark mass in the macula

ARMD (subretinal/sub-RPE hemorrhage) and other conditions associated with SNVMs/hemorrhages

Proliferative diabetic retinopathy (subhyaloidal hemorrhage) Chorioidal melanoma

Leading symptom: vitreous hemorrhage

Acute PVD, retinal tear

Ischemic retinal diseases (branch vein occlusion, central vein occlusion, PDRP, etc.)

Mass hemorrhage in ARMD

causes severe bleeding that does not respect the natural horizontal barriers of the retina, but extends into adjacent tissue sheets. Thus, a “mixed type” of hemorrhage is highly suggestive of RAMs (Figs. 22.3.1f, 22.3.8a, 22.3.13a). Similar findings may be present in Terson’s syndrome, which is easy to exclude by the medical history.

Suspected underlying conditions in eyes that present with vitreous hemorrhage are venous occlusive disease, acute posterior vitreous detachment and diabetic retinopathy [34, 35].

Table 22.3.1 summarizes retinal disorders to be considered in the differential diagnosis of RAMs [13].

Fig. 22.3.6. Symptomatic RAM before (a, b) and

6 weeks after indirect laser treatment (c, d). Exudative maculopathy caused visual deterioration to 0.4. Careful laser was applied to the vessel wall. Fundus examination 6 weeks later revealed involution of the vessel anomaly. Temporarily hard exudates increase as a sign of increased phagocytotic processes in the retina (c). FAG shows minor irregularities in the area of RAM regression, normal perfusion, and no leakage (d). Final visual outcome was 0.7 after 6 months

a

c

22.3 Retinal Arterial Macroaneurysms 549

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b

d

22.3.8 Therapy

Treatment for RAMs is a controversial issue. In the face of the overall benign spontaneous prognosis, therapy is considered in symptomatic and active RAMs only. Indications may include [52]:

Macular edema Macular exudates

Macular hemorrhage (preand subretinal) Vitreous hemorrhage

A variety of therapeutic options for symptomatic RAMs have been suggested. Depending on the presenting symptoms, they range from laser therapy to subretinal surgery. An overview of current options will be given taking into account the leading symptom.

22.3.8.1 Exudative Complications

22.3.8.1.1 Laser for Exudative Retinopathy

Accumulation of fluid and lipids surrounding RAMs may originate from the leaking macroaneurysm itself and from microvascular anomalies surrounding the aneurysm. The main rationale for laser treatment is to induce thrombosis and sclerosis at the site of vessel dilatation, in other words, to enhance spontaneous involution and prevent retinal damage due to chronic edema and exudates, macular pigment

changes and scarring. Although indications for laser treatment are poorly defined [4], most experts agree that laser should be performed, if edema and exudates involve or threaten the fovea [1, 12, 15, 17, 26, 31, 41, 46, 69].

Different laser techniques have been suggested:

Direct laser of the RAMs (center)

Indirect laser of the RAM (treating the vessel wall and bordering retina)

Perianeurysmal laser (scatter laser in the adjacent area of microvascular changes)

Laser settings consist of low-power, medium-sized spots (200 – 500 μm) of longer duration (0.2 – 0.5 s) in order to avoid vessel rupture or complete vessel obstruction resulting in branch retinal artery occlusion. Both argon green and yellow krypton laser have been used, both with similar results.

Therapeutic efficacy is difficult to evaluate. There is clinical evidence that laser therapy actually induces rapid closure of the RAMs and this is followed by subsequent resolution of retinal edema and exudates (Figs. 22.3.4, 22.3.6, 22.3.9c, 22.3.14c). Which laser technique is more effective remains unclear. The risk of laser-induced complications, e.g., arteriolar occlusion, is considered a lower risk after indirect laser application [52]. Furthermore, final scientific verification of functional outcomes in laser-treated eyes compared to non-treated eyes (= natural course) is still lacking.

22.3.8.2.1 Laser for Preretinal Hemorrhage

Bleeding toward the inner retina and vitreous can split/separate the ILM or the posterior vitreous cortex and become encapsulated. Blood resorption is then often delayed. Since the central retina is obscured as well, evaluation and treatment of possibly associated exudative maculopathy or subfoveal hemorrhage is not possible. Drainage of blood into the vitreous cavity [43] will allow more rapid clearance.

For these reasons, photodisruption of the bordering/separating membranous tissue (“laser hyaloidotomy”) was suggested [7, 10, 25, 28, 37, 47, 49, 50, 63, 67]. Neodymium-YAG, argon and krypton laser were applied in eyes presenting with encapsulated premacular hemorrhage with similar effect (Fig. 22.3.8). Most eyes treated showed marked clearing of hemorrhages and rapid improvement of function. Complications, in particular laser-induced retinal damage, were rarely reported. Park demonstrated that in case laser hyaloidotomy could not be achieved, pneumatic displacement is an option to induce posterior vit-

reous detachment (PVD) and allow blood to disperse into the vitreous cavity [43].

22.3.8.2.2 Surgery for Premacular Hemorrhage

If laser fails to induce blood evacuation into the vitreous cavity or the blood pocket is too close to the macula, vitreous surgery may be considered. Vitrectomy with surgical PVD and incision of the ILM allows safe removal of encapsulated hemorrhages (Figs. 22.3.9, 22.3.13). Immediate visualization of RAM-related findings allows the decision of possible further measures in order to treat additional complications. In case of exudative maculopathy, additional laser may be considered. Subretinal hemorrhagic components can be treated by adjunctive pharmacologic therapy or surgical removal.

22.3.8.2.3 Surgery for Submacular Hemorrhage

Prognosis for restoration of vision in the presence of submacular hemorrhage is generally poor, regardless of the primary cause [21]. The duration and amount of blood deposition under the fovea is crucial for photoreceptor cell damage. Thus, surgical intervention is worth considering for those cases. However, subretinal blood removal has remained a challenge for some time. Direct and indirect approaches to submacular hemorrhages of various origins [ARMD, angioid streaks, presumed oscular

histoplasmosis syndrome (POHS), RAM, trauma] have been suggested.

Mechanical removal via retinotomy using forceps to grasp the clot was used in the 1990s, but includes a high risk of retinal trauma and RPE damage [22, 24]. Furthermore, we found that blood adheres firmly to the aneurysm, and attempts to remove clots often

remain incomplete. We also observed that postoper- III 22 ative complications, such as marked scarring, pucker

formation and PVR, frequently occur despite careful surgical manipulations (Fig. 22.3.12). Accordingly, this method is largely abandoned today.

A step toward a more atraumatic technique to remove submacular hemorrhages was achieved by injection of recombinant tissue plasminogen activator (rt-PA) subretinally into the blood coagulum [18, 23, 33, 39, 45, 53, 71]. The injected solution must be kept subretinally up to 1 h intraoperatively, to allow clot lysis. Blood evacuation is then performed using a fluid cannula, removing clot remnants with a forceps. Perfluorocarbon liquid (PFCL) may assist atraumatic blood displacement toward the retinotomy. Complications, as mentioned above, were reduced significantly (Figs. 22.3.12d, 22.3.13b, 22.3.14b).

As an alternative, techniques to dislocate subfoveal blood have been advocated, as direct elimination of subfoveal blood was thought not to be necessary. Removal of the hemorrhage from the macular area may be sufficient to protect foveal photoreceptors from toxic damage and nutritious deficiency by the

Fig. 22.3.9. a RAM with predominantly preretinal hemorrhage which is surrounded by a rim of subretinal blood. Intravitreal injection of SF6 and rt-PA was performed, but sufficient blood dislocation was not achieved (b). During vitrectomy the major blood component was found to be encapsulated between the retina and ILM. After ILM peeling and removal of the liquefied blood remnants, severe macular edema and lipid deposits due to an active RAM became evident, and laser treatment to the RAM was performed (arrow) (c). Three months later, vision has improved to 0.6, the macula is dry and the RAM is occluded (d)

a

c

b

d