Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

21.2.4.3 Diagnosis

Fluorescein angiography is usually necessary in CRVO. The filling of the veins is typically delayed, producing the picture of black veins on a bright choroidal background during the early phase. Sinclair and Gragoudas [153] correlated a venous filling time

21 III of more than 20 s (between first appearance of the dye on the papilla and maximum filling of the temporal veins) to ischemic CRVO. Intensive staining of the large veins’s wall occurs during the late phase, even if no generalized leakage of the small vessels is present (Fig. 21.2.9a). Strong leakage often blurs the petal form of the cystoid macular edema, which can always be found in eyes with a drop in visual acuity, but later will become obvious (Fig. 21.2.9b). Prognostically important areas with capillary occlusion/ non-perfusion are difficult to discern during the first weeks because they are often concealed by heavy retinal bleedings. This seriously limits the information about capillary occlusion [69] and, hence, the prognostic value of the early angiogram (see Sect. 21.2.4.2). Lower retinal fluorescence with a smooth

a

b

Fig. 21.2.9. Fluorescein angiography in CRVO with a wall staining of large veins of mild type, and b cystoid macular edema in a non-ischemic CRVO after 6 months

choroidal background combined with bud-like abortive vessels later points to massive ischemia (Fig. 21.2.8c) and allows for better classification.

Visual acuity may be quite normal initially and usually drops within a fortnight. Twenty-five to 30 % are still able to read (visual acuity 0.4), while roughly 50 % have fallen to 0.1 or less [62, 134]. Considering the degree of ischemia, 70 – 80 % of patients with non-ischemic CRVO are seen with 0.1 or better while only 7 – 14 % of ischemic eyes present with this visual acuity [71, 134]. Thus, a low visual acuity of less than 0.1 is a marker for the ischemic type with a high sensitivity [71, 168] (Fig. 21.2.2). This marker is less predictive [136] in patients younger than 50 years, with a better range in the initial visual acuity.

Perimetry can be helpful in patients with indeterminate CRVO. Almost all eyes have a central scotoma but only the peripheral fields allow for some distinction. Ischemic eyes always show considerable defects in kinetic perimetry. Hayreh et al. [71] found that 71 % of non-ischemic eyes but only 8 % of ischemic ones presented unremarkable Goldmann visual fields.

The relative afferent pupillary defect (RAPD) can be tested easily and is a reliable functional test for differentiating of ischemic from non-ischemic CRVO [152]. Hayreh et al. found a sensitivity of 80 % and a specificity of 97 % when using RAPD with a cutoff of 0.9 log units [71]. The prerequisite of this objective test is normal pupils and a normal fellow eye.

Electroretinography may also be useful in the differentiation of the types of CRVO. Routine ERG parameters yield a sensitivity of 80 – 90 % and a specificity of 70 – 80 % [70] for the b-wave amplitude under photopic and scotopic conditions. Matsui et al. [118] found that a reduced b/a-wave amplitude ratio correlated significantly with the presence of capillary dropout on fluorescein angiogram in CRVO. Williamson et al. [182] confirmed the data and simplified and shortened the protocol, thereby making the application of ERG more practical in the clinical setting. An increased photopic cone b-wave implicit time in the 30 Hz flicker ERG seems to be a good predictor for iris neovascularization. Larsson et al. [105] recommend the 30 Hz flicker ERG is best done after 3 weeks and found it superior to fluorescein angiogram.

Venous collapse pressure, as measured by an ophthalmodynamometric device in conjunction with a special Goldmann contact lens, seems to be a promising new functional test. The collapse pressure is significantly higher in eyes with ischemic CRVO than in the non-ischemic variant [90].

Laboratory testing is not necessary beyond evaluating risk factors for atherosclerotic vascular disease.

Blood pressure should always be checked and blood taken for hematocrit. In young patients, blood for APC resistance might be taken to exclude thrombophilia. History of vein thrombosis elsewhere should alert for a more extensive check-up by the specialist.

21.2.4.4 Differential Diagnosis

Differential diagnosis of CRVO is usually not a difficult problem (Table 21.2.3). Entities like diabetic and hypertensive retinopathy as well as hyperviscosity syndromes occur bilaterally. If both eyes are affected, a medical examination is mandatory! Most difficulties are encountered with early, mild non-ischemic CRVO and late forms and complications.

Table 21.2.3. Differential diagnosis of central retinal vein occlusion

AMD age-related macular degeneration

a

Fig. 21.2.10. Differential diagnosis of CRVO: a ocular ischemia in a patient with complete carotid stenosis, and b hyperviscosity syndrome in a patient with plasmocytoma

21.2Central Retinal Vein Occlusion

21.2.4.4.1Early CRVO

Anterior ischemic neuropathy (AION) with marked swelling of the papilla may simulate a mild CRVO, but can easily be discerned by the typical altitudinal visual field defect. Retinal bleedings extending to the mid-periphery strongly favor the diagnosis of CRVO, although strong swelling of the papilla may also lead to vein engorgement.

Ocular ischemia with venous stasis retinopathy [94] induced by severe carotid artery obstructive disease should not be mistaken for non-ischemic CRVO (Fig. 21.2.10a). Features that help to distinguish the two are the absence of optic disk swelling, more deeply located dot and blot bleedings, and decreased retinal artery perfusion pressure on ophthalmodynamometry. Furthermore, the bleedings in ocular ischemia are less frequent and spread over the midperiphery. Anterior chamber flare and rubeosis iridis, combined with fair visual acuity, support ocular ischemia.

Diabetic retinopathy does not reveal papilla swelling. Furthermore, hard exudates are commonly seen with diabetic retinopathy and are rarely encountered in CRVO. When diabetic retinopathy seems more pronounced in one eye, a CRVO may be excluded by angiogram, which in turn will reveal the later vein filling in the CRVO eye.

Hypertensive retinopathy and hyperviscosity syndrome (Fig. 21.2.10b) can be easily ruled out by taking the blood pressure and performing laboratory tests such as sedimentation rate, blood cell count, and plasma proteins. A thorough history will reveal general symptoms not corresponding to CRVO.

b

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454

21 III

with only 13 %. This reflects the latter’s better IVA, which does not always allow an improvement of > 2 lines.

When taking into account the final visual outcome with regard to reading ability (VA 0.4, 20/ 50), the CRVO’s poor prognosis becomes evident. The data is not obtainable from the published CVOS results, but Quinlan et al. [134] found that 24 % were initially able to read, while this rate fell to 15 % after 1 year. No patient with ischemic CRVO reached this goal at the end of the study, while the rate in the nonischemic variant fell from 35 % to 23 %. In the CVOS group the rate of patients with a visual acuity 0.5 fell from 29 % to 26 %, which corresponds somewhat to Qinlan’s data. Thus one must stress that even nonischemic CRVO cannot be regarded as a benign disease!

21.2Central Retinal Vein Occlusion

21.2.4.5.2Neovascular Disease

The CVOS used the non-perfusion area ( 10 disk areas) in the fluorescein angiogram as a basal parameter for the risk of developing neovascular disease [168]. This has been justifiably criticized by Hayreh [69], and is supported by the CVOS data itself. It has been clearly demonstrated that all types of CRVO can progress to neovascular disease (Fig. 21.2.11a–d). The non-perfusion criteria applied to 18 % of the 714 patients enrolled; 7 % were indeterminate. Of the 714 eyes enrolled in the CVOS, 117 (16 %) developed iris or anterior angle neovascularization (INV). These INV eyes were only partly in accordance with the non-perfusion criteria (Table 21.2.5). While 33 % of the non-perfused CRVOs developed INV, the rates were 40 % in the indeter-

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Table 21.2.5. Incidence of iris and/or angle neovascularization (INV) in correlation to initial visual acuity (VA) and perfusion [168]

minate and 9.5 % in the perfused type. This clearly demonstrates the difficulties in providing a reliable prognosis based solely on a fluorescein angiogram.

The lower the initial visual acuity, the higher the rate of INV (Table 21.2.5). The rates were 5 % (eyes with IVA > 0.4), 15 % (IVA 0.1 – 0.4) and 31 % (IVA < 0.1). The lower the IVA, the sooner the INV develops. Twenty percent of the INV evolves within the first 4 months, but only 7 % in the group with an IVA > 0.4, while this rate is 44 % in eyes with an IVA < 0.1. Though some correlation between the IVA and neovascular disease exists, development of INV cannot be excluded in patients with a good IVA! Patients with low vision must be observed closely during the first weeks and months.

Additional risk factors for neovascular disease besides low visual acuity and extensive capillary dropout seem to be venous tortuosity and extensive retinal hemorrhage. The latter may explain the high rate of INV in indeterminate CRVO because the obscured non-perfusion areas are difficult to assess. Retinochoroidal collateral veins are negatively associated with INV in late CRVO and may function in a protective manner against such an outcome [42].

Younger patients (50 years) with CRVO in general have a slightly better visual outcome [38, 149], with 42 % ending up with VA 0.4 [135], and show a more variable clinical course. IVA in younger patients does not appear to be as predictive of visual or anatomic outcome as it does in older patients. On the other hand, 42 % of young patients end up with a FVA 0.1 and 18 % develop neovascular disease. These data do not differ much from that obtained for outcomes of older patients, thus highlighting how important careful follow-up of these patients is.

21.2.5 Treatment

Essentials

Lowering of risk factors may inhibit CRVO’s progression from a non-ischemic to the ischemic form, or reduce the frequency of recurrences or involvement of the second eye

Randomized studies on fibrinolysis and hemodilution have demonstrated some positive effect on visual outcome but they did not prevent neovascular disease Isovolemic hemodilution has few contraindications, and can be used as basic treatment in most cases

Selective or local thrombolysis continues to evolve as a potentially effective treatment Whether there is a definite place for intraocular steroids remains controversial and has to be evaluated in randomized studies

The laser-induced, but often restricted, cilioretinal anastomosis formation with its wide spectrum of complications cannot be recommended

The role of radiary optic neurotomy can only be evidenced by randomized studies and up to now cannot be recommended

As has been demonstrated above, CRVO has a wide range of outcomes and few reliable parameters for a clear-cut differentiation between a benign and an unfavorable course in the initial stage of the disease. This makes it difficult to assess the real benefit of one particular therapy and to decide on a treatment with definite risks, instead of waiting for a fortuitous course, as has always been advocated by Hayreh [69]. This also explains why there are only a few eye diseases for which such a wide range of different treatment modalities has been tried (Table 21.2.6); however, most of them were applied in preliminary pilot studies without definite success. For a review of earlier studies with additional treatment modalities including vasodilation, see Sedney [151]. Most of the studies are not only non-randomized, but have a variety of limitations which make it hard to evaluate the benefits claimed. These limitations include the lumping together of CRVO and branch vein occlusion, not differentiating between ischemic and nonischemic CRVO or using mistaken criteria to do so, problems with study design and personal biases.

The goal of CRVO therapy should be to prevent:

(1) chronic macular edema and macular scarring and (2) neovascular complications. Currently there

Table 21.2.6. Overview of recent medical therapies (controlled [CS] and prospective [PS] studies tried for CRVO). For review of earlier studies with additional treatment modalities, see Sedney [190] and for details see text [30, 99]

aTreatment not recommended by the authors because of adverse effects

is no generally accepted treatment for the first, while the latter can be achieved by timely laser treatment, although there is debate concerning the time of intervention. The main treatments can be divided into two categories: (1) early intervention to improve the visual outcome, and (2) late treatment to avert painful blinding.

21.2.5.1 Early Treatment

As has been explained above, CRVO is a subacute or chronic disease that does not require urgent intervention within hours. Nevertheless, early treatment within the first weeks might be important to improve the chances of a reasonable visual acuity. Factors known to initiate and exacerbate the course should be dealt with aggressively within days or weeks.

21.2.5.1.1 Medical Treatment

Lowering of Risk Factors

Treatment of cardiovascular risk factors or associated medical or ocular conditions will not reverse the visual effects of CRVO [98] unless a real causal relationship such as with hyperviscosity syndromes is responsible for the occlusion ([112, 155], see below). However, lowering of risk factors may inhibit its progression from a non-ischemic to the ischemic form, or reduce the frequency of recurrences or involvement of the second eye [28]. Accordingly, arterial hypertension should be treated and cardiovascular risk factors (e.g., obesity, smoking, low physical activity, dehydration) reduced. While sleeping, the patient’s upper part of the body should

be slightly elevated to avoid high central venous pressure.

Glaucoma is regarded as a risk factor for CRVO, but we do not know whether a reduction in increased intraocular pressure will improve the prognosis of the disease, as supposed by Fong et al. [38]. There is little evidence that lowering intraocular pressure improves retinal blood flow in CRVO [67, 74].

Anticoagulation and Thrombolysis

Anticoagulant therapy cannot reverse thrombosis, so the rationale would, at the most, prevent the thrombus growth and stop the deterioration of CRVO. Past therapeutic regimens have included anticoagulant therapy with heparin sodium [29, 81, 171], bishydroxycoumarin [29, 140, 171] and acetylsalicylic acid [145]. Although these results were interpreted by the authors as positive, theirs and subsequent studies were not conclusive ([82], for review see [151]) and in no way fulfilled requirements of evi- dence-based data.

Thrombolysis seems a far more reasonable approach to dissolving a thrombus than anticoagulant therapy. Hence, there have been many attempts over the last 40 years using a variety of lytic agents [streptokinase, urokinase, recombinant tissue-type plasminogen activator (rt-PA)] and different types of access (systemic, intravitreal, retinal vessels) to restore blood flow and improve vision. Ideally, these agents should be given as soon as possible to prevent dreaded complications such as retinal ischemia and its sequelae. On the other hand, the induced lytic state places the patient at a considerable risk for systemic bleeding that can be life-threatening [30].

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Table 21.2.7. Course of visual acuity (with regard to initial visual acuity but not ischemia). N = number of patients (all data taken from the scatter plots from the studies [59, 61, 62, 134, 168, 187])

Table 21.2.8. Course of visual acuity (with regard to initial visual acuity and ischemia). N = number of patients (all data taken from the scatter plots of the studies [61, 134])

VA visual acuity, IVA initial visual acuity, IHD isovolemic hemodilution, Perf. perfusion, ni non-ischemic, i ischemic

(hemodilution period shorter, blood replacement 0.9 % saline instead of hydroxyethylstarch, thus creating a kind of hypovolemia) differed considerably. Furthermore, Luckie et al. [110] did not publish their original data, so that their outcome cannot be compared to the large studies on the natural course [134, 168]. On the other hand, the positive randomized studies [59, 62, 187] were small and not blinded, but their entrance data were comparable to those of the natural-course studies. In addition they were also supported by larger prospective non-randomized studies [51, 61].

Table 21.2.7 provides an overview over these studies’ results in comparison to the natural course. The CVOS [168] has shown that initial visual acuity (IVA) is important for the final outcome (FVA). Although the percentage of control/untreated eyes with an IVA 0.5 varies from 18 % to 40 %, their FVA is very similar and only 10 – 14 % improve more than two lines after 3 – 12 months. This rate is changed by hemodilution to 37 – 45 %, indicating a better outcome after this rheologic treatment. The comparison of ischemic to non-ischemic types reveals that the effect is even more pronounced in ischemic types (Table 21.2.8). This adheres well to the principle that hemodilution is more effective in low flow states.

In summary, hemodilution slightly improves the final visual outcome of eyes with CRVO, but one should bear in mind at the same time that it does not prevent neovascular disease. Thus we strongly advocate isovolemic hemodilution as a basic treatment starting within the first 4 – 6 weeks after symptoms appeared [51]. This regimen does not interfere negatively with additional treatment modalities (intravitre-

al steroids, retinal endovascular lysis, radial optic neuropathy) that are still not evidence based (see below).

Steroids

Corticosteroids can reduce the permeability of leaky vessels independent of whether this is caused by inflammation or by engorgement. Thus the macular edema can be reduced irrespective of the primary cause of CRVO and bridge the transient imbalance between inflow and outflow, which can last several months or even years (see Sect. 2.3.3). Routes of administration may be systemic, subtenon (not investigated with newer steroid generations) and intravitreal. The latter can be a crystalline triamcinolone acetonide deposit or an implanted sustainedrelease fluocinolone acetonide device [87].

Systemic Corticosteroids. Brückner [9] advised as early as 1955 the use of systemic corticosteroids in the treatment of CRVO. Hayreh [66, 69] claimed that among the patients with CRVO there is a small group that would respond favorably to prolonged systemic steroid treatment (up to 3 years). This group seems to be found more often in patients 50 years of age. However, the value of systemic steroids has never been evaluated within a large prospective and/or controlled study, and with the additional possibility of adverse reactions this has led to some reservations about the use of systemic steroids. We consider their use in young patients only [149].

Intravitreal crystalline triamcinolone, with its prolonged efficacy and lack of association with systemic adverse effects, was originally employed to reduce pro-

liferative vitreoretinopathy [161, 162], but it has only been recently that ophthalmologists have taken advantage of its stabilizing effect on the blood-retinal barrier [187] to treat all kinds of macular edema [91].

Recent studies have also reported success in the treatment of cystoid macular edema in CRVO [55, 83, 91], and a series of pilot studies [6, 84, 85, 92, 100,

21 III 130, 183] ensued. In summary, 65 patients with nonischemic CRVO and a duration of symptoms from 2 to 9 months made a significant gain of 3 – 5 lines in distance visual acuity. The reduction in macular edema was proven by optical coherence tomography. Both effects lasted for a maximum of 6 months and repeat injections were necessary for prolonged action, although Jonas detected triamcinolone in low, yet measurable concentrations up to 1.5 years after the intravitreal injection [91].

A rise in intraocular pressure was observed in most patients, but only one patient with intractable glaucoma was reported, in whom the triamcinolone had to be removed [93]. One must be aware of other possible complications (cataract, pseudoendophthalmitis, endophthalmitis, central artery occlusion, retinal detachment [88]).

Although the early use of triamcinolone is convincing, further study in the form of a randomized controlled study [150] is warranted to evaluate this new therapy’s safety and efficacy. This NIH-funded trial (SCORE) includes patients with macular edema and a duration of symptoms of 3 – 8 months.

21.2.5.1.2 Surgical Treatment

Medical treatment modalities may help occasionally, but if at all, they only modestly improve visual outcome and they never prevent neovascular disease (see above). Thus early surgical treatment of CRVO based on various rationales has been attempted over the last 10 years: (1) dissolution of the thrombus as a causal treatment may circumvent the dangerous adverse reactions [30] when selectively applied (retinal endovascular lysis, REVL, intravitreal lysis, see above). This may permit the inclusion of patients who would otherwise not be recruitable for systemic low-dose lysis regimens [65]; (2) the creation of a chorioretinal anastomosis (CRA) may improve the outflow by bypassing the partly occluded central vein; (3) compression of the central vein against the lamina cribrosa fostered by an arteriosclerotic central artery may be relieved by enlarging the scleral outlet [172] and improving the outflow.

Chorioretinal Venous Anastomosis

McAllister et al. [119, 120] have advocated laserinduced iatrogenic chorioretinal anastomosis (CRA)

as a treatment modality in CRVO. In eyes with nonischemic CRVO, they created this bypass using a transretinal venipuncture technique. CRA formation via a surgical approach in ischemic CRVO [124] has also been recently tried in a pilot study.

Successful laser-induced creation of collaterals was reported in 33 % [119], 37.5 % [35] and 20 % [13] and led to overall improvement rates > 2 lines of 20 – 38 %, which were not always associated with CRA formation [12]. Using refined techniques, investigators [108, 120, 121] later achieved CRA formation in 54 – 100 %, and visual increase was observed in 49 % of all treated patients. These results were not based on randomized studies and at best matched the visual acuity gain yielded by hemodilution (Tables 21.2.7, 21.2.8).

However, that procedure is by no means benign [12, 13, 35, 119]; it can cause immediate (intraretinal, subretinal, vitreal bleeding) and late complications (secondary neovascularization of the retina, choroid and anterior segment, subretinal fibrosis, non-clearing vitreous hemorrhage, traction retinal detachment). Because of the often restricted anastomosis formation and the wide spectrum of complications, attempts to create a CRA cannot be considered advisable.

Radial Optic Neurotomy

Opremcak et al. [128] have picked up on the idea of Vasco-Posada [172] to decompress the central vein by pushing a lancet with a sharp cutting edge on one side and an opposing blunt edge through an equal portion of the nasal optic nerve head and the adjacent sclera approximately 2 mm deep.

In their first uncontrolled retrospective pilot study [128], 11 patients with CRVO (five non-per- fused) underwent radial optic neurotomy (RON) without complications. Seventy-three percent of patients demonstrated improved visual acuity after 9 months, but two developed neovascular glaucoma. This study has prompted innumerable pilot studies on RON with small patient numbers reporting positive [44, 126, 154, 176, 184] and negative results [117]. Roider et al. [139] summarized the data from five retinal centers and found a significant mean increase from logMAR 1.3 (Snellen 20/400) to 1.1 (Snellen 20/ 250) in 107 patients after a mean follow-up time of 6 months. Patients with angiographically identified collaterals (18/30) even showed a mean increase of 6 lines, supporting the observation of earlier studies [4, 41, 44, 154].

The procedure in no way is as benign as claimed by the initial investigators [128] as central artery injury [139, 176, 189], peripapillary retinal detachment [142], and choroidal neovascularizations [176] were described. Williamson et al. [184] were the first to report on visual field defects. This finding was

anticipated by Hayreh [72] and also reiterated by Feltgen et al. [37]. When one constantly looks for this complication, it occurs in 87 % of cases [139]. The role of RON can only be evidenced by randomized studies and up to now cannot be recommended.

21.2.5.2 Late Treatment

The goal of late treatment is twofold: (1) to prevent long-standing macular edema ending up in macular scar or serous central retinal detachment with visual acuities between 0.05 (20/400) and 0.005 (hand movements) when other treatment modalities have failed, and (2) to avert painful blinding with neovascular glaucoma. The Central Vein Occlusion Study was designed to answer these questions [165].

Macular edema usually decreases spontaneously within 1 – 3 years, but irreversible damage of the photoreceptors often starts after as early as 3 months. The SCORE study [150] already mentioned with intravitreal triamcinolone will answer our question whether local steroids will be of value once other early interventions have failed.

Initial reports suggested that the grid pattern of laser photocoagulation may improve macular edema due to capillary leakage in CRVO [57, 95]. The CVOS [166] addressed this question in eyes with CRVO of at least 3 months duration and a visual acuity of 0.4 or less. Long-term results showed that the grid laser reduced angiographic leakage, but there was no visual benefit demonstrated at any point during the randomized study. Hence laser grid coagulation is not recommended in chronic macular edema of CRVO.

The intravitreal injection of inhibitors of vascular endothelial growth factor (bevacizumab, ranibizumab, pegabtanib) seems to be another upcoming, very promising treatment of macular edema [86, 157] with less adverse reactions than found with triamcinolone. However, randomized studies still lack and have to answer the question, whether it works better than other treatments and how often intravitreal have to be repeated.

Neovascular complications usually start with iris/ angle neovascularization (INV/ANV) and culminate in secondary neovascular glaucoma (NVG). Several studies have evaluated whether prophylactic laser panretinal photocoagulation (PRP) in eyes with ischemic CRVO can reduce the long-term risk of INV/ANV and NVG. Some studies recommended early prophylactic PRP in eyes with ischemic CRVO [103, 114, 115], but Hayreh [71] claimed that early treatment leads to a worse outcome without prevention of neovascular disease.

In this context the CVOS [167] answered two questions: (1) does early PRP prevent anterior segment neovascularization in eyes with non-perfused CRVO

(for definition see Sect. 21.2.4.5), and (2) is early PRP more effective than delaying treatment until INV/ ANV is first observed? While early PRP did not prevent INV/ANV development in 20 % of the eyes, the rate was only 30 % in the non-treated eyes. There was an even greater resolution of INV/ANV by 1 month after PRP in non-early treatment eyes compared to

early treatment eyes. Thus, PRP is useful only after III 21 INV/ANV has developed. On the other hand, this

requires careful observation of eyes with ischemic or indeterminate CRVO, with monthly examinations necessary in order not to overlook INV/ANV, as well as promptly carrying out PRP in eyes with INV/ANV. If close follow-up is not possible, early PRP may be considered in high-risk patients.

When neovascular glaucoma cannot be prevented, additional cycloablations (cyclophotoor cryocoagulation) may help to save the eye [69]. In desperate cases, peripheral retinectomy has been attempted with some success [5].

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