The prevalence of retinal vein occlusion (RVO) depends strongly on age, becoming more common with increasing age (see Chap. 5). Younger patients with RVO form an important subset of patients because the common risk factors are less common in this group (see Chap. 6).35 The definition of “younger” varies among reports. The cutoff point between younger and older ages varies from 40 to 60.2,16,28 Estimates for the size of this subgroup vary and are somewhat weak because of the absence of population-based data.28 Case series have reported that 5–12% of patients with RVO are under age 45.16,28

Abbreviations commonly used in the discussion of RVO in the younger patients are listed in Table 14.1. Each abbreviation is spelled out at its first occurrence.

14.1Pooled Retinal Vein Occlusions in the Young

The association of pooled RVO with hypertension depends on age. In a study of 87 patients with RVO divided into those less than 50 years old and those 50 years or older, hypertension occurred three times as frequently in the older group, but other systemic factors were approximately similar in frequency.6 Younger patients had a higher prevalence of alcohol consumption than older patients (21% vs. 8%, P < 0.01) in this study.6 The prevalence of hyperlipidemia, diabetes, and smoking were similar between the two age groups.6

Table 14.1 Abbreviations used in retinal vein occlusions in the young

It has been suspected that searches for thrombophilic genetic mutations or an inflammatory etiology might be more fruitful in younger patients with pooled RVO under the assumption that the more common risk factors – hypertension, hyperlipidemia, diabetes mellitus, and cardiovascular disease – would be less important in younger patients.6,8,24 However, the evidence suggests that this is not the case.1,8 Associations of the 5,10-methylenetetrahydrofolate reductase 677T mutation and prothrombin 20210A mutation and pooled RVO were not significant in patients under age 60 years.2 Most studies examining the association of the factor V Leiden mutation (FVLM) with pooled RVO in younger patients have not found an association,3,17,18,31 although a minority have (see Chaps. 3 and 6).5,20 Indices of a systemic inflammatory state, such as the erythrocyte sedimentation rate, have not differed between younger and older patients with RVO.6

The role of oral contraceptives in the genesis of pooled RVO is an issue confined to younger patients. In one series, 10% of the patients of age 49 or less who developed RVO were taking oral contraceptives.6 Because there was no agematched control group, it is not possible to assess whether this percentage differs from that persons without RVO.

Important differences in prognosis exist between pooled RVO in younger and older age cohorts. In general, younger patients have an improved prognosis compared to older patients if they develop nonischemic RVO. For both groups, however, onset of an ischemic RVO portends a guarded VA outcome. Whereas in the older group, an ischemic RVO usually implies more severe associated vascular risk factors, in the young it implies a higher probability of finding associated vascular risk factors.

14.2Branch Retinal Vein Occlusion in Younger Patients

In a clinic-based study of 375 consecutive BRVOs, 5% occurred in patients of 45 years old and younger.16 In a case-control study of 60 patients with BRVO of age 49 or less and 123 age-matched controls,therewerethreeindependentlysignificant systemic associations – hypertension, hyperlipidemia, and increased body mass index (BMI).23

Subgroup analyses of younger patients with BRVO showed no association of any of the six following thrombophilic genetic risk factors: factor II 20210A, factor V 506Q, fibrinogen b-455A, factor XII 46T, GPIa 807T, and GPIIIaPIA2.35 In another case-control study of patients with BRVO of age 55 or less, low protein C, protein S, and antithrombin levels (all of which would be procoagulant) were not more prevalent in cases than in controls.22 Prevalence of antiphospholipid antibodies was not higher compared to controls.22 Paradoxically, an elevated protein C was more common in CRVO in patients of age 55 and younger compared to controls reflecting activation of systemic thrombolysis, perhaps related to an acute thrombotic event.22

14.3Central Retinal Vein Occlusion in Younger Patients

CRVO is not rare in young persons and many cases have been documented in patients younger than 20.8 In various large case series, the percentages of patients with CRVO under age 40 and 50 were 8–10% and 10–20%, respectively.10,16,19,26,33 In a case series of 667 patients, 16% of the nonischemic cases and 7% of the ischemic cases were under age 45 years, respectively.15 In a clinicbased study of 154 consecutive HCRVOs, 10% occurred in patients 45 years old or younger.16

There has been inconsistent information published regarding gender differences in younger patients with CRVO. Some studies report male predominance, but others report no difference.8,21,29,30,34 After CRVO in a younger person, it is not uncommon to discover unsuspected hypertension, diabetes, hyperlipidemia, or primary openangle glaucoma (POAG). Therefore, investigation for these conventional risk factors is indicated routinely after the diagnosis of CRVO.7,8,21,30 The prevalence of associated systemic disease in young adults with CRVO has ranged from 40% to 91% in various reports depending on the compulsiveness of the search.7,8,21,30 Although some unsuspected cases of vascular risk factors will be discovered in young patients who present with CRVO, in many cases the search will be unproductive. In these cases, it has been speculated that the patients have a congenital anomaly of the central retinal vein predisposing to turbulent blood flow at the lamina cribrosa, but evidence

for this has not been reported.34

Systemic and ocular associations with CRVO in younger patients may be dependent on ethnicity and environmental factors. In one study of 103 younger Americans with CRVO, the top three associated conditions were hypertension (25%), hyperlipidemia (21%), and POAG (7%).8 In a second study of 67 younger Americans with CRVO, the top three associated conditions were hypertension (22%), diabetes mellitus (12%), and hypercholesterolemia (6%).30 In contrast, a study of 25 younger Chinese with CRVO found the top three associated conditions to be hypercholesterolemia

(65%), hypertriglyceridemia (64%), and hyperhomocysteinemia (42%).21

As in older patients with CRVO, the literature is inconsistent with regard to prevalence of hyperhomocysteinemia in younger patients with CRVO. In those cases of CRVO in which plasma homocysteine is elevated, it is unknown whether elevated homocysteine is a marker for increased risk of thrombosis or is the cause of the thrombosis.21,22 For example, one study found that 42% of 22 patients age 40 or less with CRVO had hyperhomocysteinemia, but many of them had renal failure, stroke, and hypertension, which could have caused secondary elevations of homocysteine.21 Because of uncertainty as to cause, it is controversial whether to treat elevated homocysteine in younger patients with CRVO with folic acid, vitamin B6, or vitamin B12 (see Chaps. 6 and 13).22 When authors recommend such treatment, it is generally a weak recommendation.32

The literature is inconsistent about whether resistance to activated protein C from the FVLM is more prevalent in patients with CRVO who are younger than 50.10,20,24 Two of these studies lacked an internal control group, making interpretation difficult. In a young patient with bilateral RVO, or a personal or family history of thromboses, a search for this thrombophilic trait may be indicated because the carrier frequency of the FVLM in white Americans is 5.27%. If the FVLM were to be found, it would be reasonable to advise the patient to avoid other risk factors that might compound risk for thrombosis. For example, all of the following might be advised if applicable: cessation of smoking, elimination of obesity, avoidance of oral contraceptives or postmenopausal estrogen replacement therapy, and anticoagulation if surgery or immobilization must occur.10

Baseline VA may be informative regarding systemic associations in these patients. In one series, when the VA at baseline was 20/40 or better, there were few systemic associations.4 When the VA at baseline was less than 20/40, associated hypertension was found in 43% compared to none in an age-matched control group (P = 0.005).

Several early reports of CRVO in the young posited an inflammatory etiology, terming the condition benign retinal vasculitis, papillophlebitis,

optic disc vasculitis, and presumed phlebitis of the optic disc. More recently, the lack of evidence to support an inflammatory etiology has led to the conclusion that these patients simply have typical CRVO.6,8,12,34 Whereas the sheathing occasionally seen after resolution of the acute phase was formerly considered to indicate a vasculitis, it is recognized now that such sheathing can occur in nonvasculitic CRVO (see Fig. 7.6).11,25,34 In most cases, the presentations described by earlier authors are consistent with a nonischemic CRVO.34

The clinical picture of CRVO in the young has some differences from that in the older patient. In young patients, the retinal capillaries can withstand high transmural pressure gradients with few intraretinal hemorrhages and little or no ME, at least for a period of time.27 The main finding in nonischemic cases may be venous dilation and a darkening of the venous blood column (Fig. 14.1). More ischemic cases and cases that persist over time may evolve to a fundus picture similar to that of CRVO in older patients (Fig. 14.2). Other anecdotal differences include observations of an increased proportion of optic disc edema in the young compared to the old and an impression that resolution of edema may take longer in the young to resolve. Statistical support for these suggestions is lacking.25,34

The literature regarding the capillary perfusion status of CRVO in young patients is inconsistent. Some reports state that the proportions of CRVOs that are nonischemic and ischemic in younger patients are approximately similar to the proportions noted in older patients. Nonischemic cases make up 64–73% of the total.

Others document a greater proportion of nonischemic CRVOs in younger patients. Consistently documented lower rates of ASNV (ASNV) and NVG (NVG) following CRVO in younger patients tend to support the validity of the latter perspective. Two case series suggest that the rate of conversion of CRVOs from nonischemic to ischemic is lower in younger than in older patients.

Cilioretinal arteriolar insufficiency or occlusion may be more common in younger patients than older patients with CRVO (Fig 14.3). In a case series of 21 patients of age 40 or less, 10% had

cilioretinal artery occlusion.34 In series without an age criterion, the analogous figure was 4%.8,13

Some data on initial VAs and final VAs of younger patients with CRVO are reproduced in Table 14.2. The overall theme is that younger patients with CRVO who present with good VA

will worsen approximately 45% of the time.30 Patients with poor baseline VA will uncommonly improve (20% of the time). Patients with intermediate baseline VA can evolve in either direction with roughly equal probability.30 The baseline VA in younger patients with CRVO is less predictive

Fig. 14.1 Fundus images of a 32-year-old man with treated hypertension who developed a shimmering quality to his vision in the right eye and was found to have a nonischemic central retinal vein occlusion. The VA was 20/16. The blood pressure was 138/96. He had seen an ophthalmologist who had placed him on levobunolol 0.5% to the right eye twice daily. (a) Color fundus photograph of the right eye shows darkened venous blood and dilated veins (the black arrow). A few cotton wool spots are present (green arrow). The nasal optic disc shows mild edema and a punctuate peripapillary hemorrhage. (b) Frame from the early-phase fluorescein angiogram shows good capillary perfusion of the macula. (c) Frame from the latephase fluorescein angiogram of the right eye shows prominent leakage of fluorescein from the optic disc and the peripapillary major veins (yellow arrow). This appearance led earlier clinicians to suggest that this entity was a

primary papillophlebitis, although investigation for inflammatory disorders was usually negative. (d) Line scan from the spectral domain OCT (SD-OCT) at the initial visit shows no overt macular edema. (e) False-color maps from the SD-OCT at the initial visit (5/19/2010) and follow-up visit (7/28/2010) showing that some subclinical edema was present at presentation that has resolved over 2 months of follow-up off the levobunolol. All subfields show reduced thickness. The patient had no evidence of primary open-angle glaucoma in either eye at presentation, therefore the levobunolol was discontinued. Ocular hypotensive therapy is commonly used for acute CRVO, but this practice is irrational. It does not help to resolve the thrombus, and it will worsen macular edema by lowering intraocular pressure in the face of an elevated intraocular venous pressure (see Sect. 2.3.2)

e

Thickness [7/28/2010]

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253 m

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Central Max

378 m

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100

0

800

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0

Fig. 14.1 (continued)

of final VA and clinical course than in older patients.30

The visual prognosis for nonischemic CRVO is better in young patients than in older patients (Table 14.3). In a series of 87 patients with CRVO and age less than 45, no patient with VA of 20/60 or better at presentation had VA deterioration and 80% of the patients with VA of 20/70 or worse improved by three or more Snellen lines by the end of 2- to 5-years of follow-up. This differed from the prognosis in 472 patients of age 45 or greater, in which 15% of the nonischemic CRVO eyes with better VA declined by three or more Snellen lines and only 56% of those in the initial worse VA group improved by three or more

Snellen lines.14 An independent clinical series of 19 patients under the age of 50 compared to 26 patients of age 50 or older echoed this theme.4 Smaller studies have reported less sanguine VA outcomes but had lower quality study designs subject to various forms of bias.8,21 The relatively good prognosis on average in CRVO among young patients may reflect the absence of concomitant arterial disease in this age group.4,11

For ischemic CRVO in the young, the literature on visual prognosis is less consistent (Table 14.3). In one series of 17 patients with mean follow-up of 35.3 months, baseline VA was 20/200 or less in 41% but final VA was 20/200 or less in 18%, suggesting an improved prognosis

Fig 14.3 Fundus images of a 36-year-old woman who developed acute blurring of the right eye from a nonischemic central retinal vein occlusion. The VA was 20/20. Cilioretinal arteriolar insufficiency was present. (a) Monochromatic fundus photograph of the right eye showing an area of ischemic retinal whitening (the yellow arrow) corresponding to the distribution of an inferotemporal cilioretinal artery (the turquoise arrow). (b) Frame from the early-phase fluorescein angiogram showing the cilioretinal artery (the turquoise arrow) and excellent capillary perfusion in spite of the ischemic retinal whitening (the yellow arrow). (c) Frame from

the late-phase fluorescein angiogram showing no leakage of fluorescein from the microvasculature in the area of whitening (yellow arrow). The orange arrow denotes a hypofluorescent intraretinal hemorrhage. (d) Monochromatic fundus photograph of the same eye taken 4 years later. All signs of CRVO have resolved. The cilioretinal artery is denoted by the turquoise arrow. The patient had no scotoma and the VA was 20/12.5. Ischemic retinal whitening in cilioretinal arteriolar insufficiency associated with nonischemic CRVO does not equal retinal infarction (see Chap. 7). The whitening can resolve with no residual ocular signs or symptoms

Fig. 14.2 Fundus images of a 53-year-old man with hypertension and a smoking habit who suddenly lost vision in the right eye from a central retinal vein occlusion. The VA was counting fingers. (a) Color fundus photograph of the right eye shows intraretinal hemorrhages and dilated veins in all quadrants. Ischemic retinal whitening is present not only in the distribution of a cilioretinal artery (the black arrow), but also in the distribution of the central retinal artery (the green arrow), implying a higher grade of venous occlusion, and by inference a higher retinal venous pressure (see Fig. 2.23). (b) Frame from the mid-phase fluorescein angiogram showing severe capillary nonperfusion (the yellow oval) with a disrupted foveal avascular zone border (the green arrow). (c) Frame

from the late-phase fluorescein angiogram showing little hyperfluorescence because the blood flow is reduced so much. (d) Line scan from a spectral domain OCT study that shows marked macular edema. The macular edema is cytotoxic, as can be discerned by the high reflectivity of the signal in the inner retina (the red arrow) that blocks visualization of the outer retinal structures (the green arrow denotes a faintly seen retinal pigment epithelial layer). There is little vasogenic edema as attested by few cysts. There is marked subretinal fluid (the turquoise oval). One month later, this patient returned with neovascularization of the iris. Panretinal photocoagulation was recommended to prevent NVG (see Chaps. 11 and 13)