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

bleeding while working on other areas of epiretinal tissue.

Another approach for vitreous surgery in Stage 5 ROP has been open sky vitrectomy, which requires concomitant lensectomy or an aphakic eye [7, 15]. We reserve open sky vitrectomy for eyes in which corneal opacity precludes closed vitrectomy. The

20 III technique of open sky vitrectomy allows access to more peripheral dissection of membranes with direct visualization through the open cornea.

Even if retinal reattachment is achieved, visual outcome is limited. As reported, the best vision achieved in Stage 5 eyes has been 20/200 to 20/600, and these results are quite rare [19]. The majority of eyes achieve visions of 20/800 or less. In addition, eyes can have no light perception despite having a completely attached retina. In the future, these eyes may be candidates for other types of therapy such as microelectronic or other biologic approaches.

20.3.4.5 Follow-up Care

It is important to realize that the premature children present postoperative challenges not seen in the adult population. The eye must be protected from digital damage, which can lead to bleeding. This is done with a Fox shield and elbow restraints. The child is positioned sitting up for several weeks after surgery so they cannot burrow their head, again causing the eye to bleed. In our practice, the child does not receive sedation, but the family is asked to comfort the child as much as possible to avoid extensive periods of crying with the potential for intraocular bleeding. Bleeding in the postoperative period is certainly not desirable, although in a smaller percentage of eyes, some bleeding can reabsorb, leaving the child with reasonable retinal anatomy.

In summary, the surgical management of the retinal detachment of retinopathy of prematurity has improved tremendously over the last 15 years. The child who is appropriately screened receives peripheral ablation at this point and perhaps in the future pharmacologic treatment. Early vitreous surgery will be anticipated to achieve good anatomic and visual function. In the past the association of late rhegmatogenous retinal detachment and retinopathy of prematurity has been clinically recognized. It will be interesting to follow these children who have had vitrectomy to see if their risk of rhegmatogenous retinal detachment is reduced. One of the major difficulties with vitreous surgery in children of this age is the inability to remove the posterior hyaloid despite sheets of tissue being peeled from the retina. These sheets of tissue reflect the sheet of solid and liquid vitreous that is present in the vitreous cavity of all

premature children. Hopefully, the development of enzymatic products to separate the posterior hyaloid from the retina may prevent the problems of late rhegmatogenous retinal detachment. We have seen several children 3 – 5 years after vitrectomy who show a sheet of tissue in their vitreous cavity which may be transparent or somewhat opalescent, reflecting the detached posterior hyaloid, and thus supporting the observation that the hyaloid is generally not removed at the time of vitreous surgery. With all these considerations, however, the fate of the premature child with retinopathy of prematurity and retinal detachment is much better today than it was 2 decades ago.

References

1.Capone A, Trese MT (2001) Lens-sparing vitreous surgery for tractional Stage 4A retinopathy of prematurity retinal detachments. Ophthalmology 108:2068 – 2070

2.Coats D, Miller A, Brady McCreery K, Holz E, Paysse E (2004) Involution of threshold retinopathy of prematurity after diode laser photocoagulation. Ophthalmology 111: 1894 – 1898

3.Cryotherapy for Retinopathy of Prematurity Cooperative Group (2001) Multicenter trial of cryotherapy for retinopathy of prematurity: Ophthalmological outcomes at 10 years. Arch Ophthalmol 119:1110 – 1118

4.Early Treatment for Retinopathy of Prematurity Cooperative Group (2003) Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 121:1684 – 1694

5.Greven C, Tasman W (1990) Scleral buckling in stages 4B and 5 retinopathy of prematurity. Ophthalmology 97:817 – 820

6.Hartnett MI, McColm JR (2004) Retinal features predictive of progressive stage 4 retinopathy of prematurity. Retina 24:237 – 241

7.Hirose T, Katsumi O, Mehta MC, Schepens CL (1993) Vision in stage 5 retinopathy of prematurity after retinal reattachment by open-sky vitrectomy. Arch Ophthalmol 111:345 – 349

8.Hubbard GB, Cherwick H, Burian G (2004) Lens-sparing vitrectomy for stage 4 retinopathy of prematurity. Ophthalmology 111:2274 – 2277

9.Maguire AM, Trese MT (1992) Lens-sparing vitreoretinal surgery in infants. Arch Ophthalmol 110:284 – 286

10.Mandriota SJ, Menoud PA, Pepper MS (1996) Transforming growth factor beta 1 down-regulates vascular endothelial growth factor receptor 2/flk-1 expression in vascular endothelial cells. J Biol Chem 271:11500 – 11505

11.Multicenter trial of cryotherapy for retinopathy of prematurity (1990) One-year outcome – structure and function. Cryotherapy for Retinopathy of Prematurity Cooperative Group (1990) Arch Ophthalmol 108:1408 – 1416

12.Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB, Tung B (1991) The cryotherapy for retinopathy of prematurity cooperative group: Incidence and early course of retinopathy of prematurity. Ophthalmology 98:1624 – 1640

13.Prenner JL, Capone A, Trese MT (2004) Visual outcomes after lens-sparing vitrectomy for stage 4A retinopathy of prematurity. Ophthalmology 111:2271 – 2273

14.Saunders RA, Donahue ML, Christmann LM, Pakalnis AV, Tung B, Hardy RJ, Phelps DL (1997) Racial variation in retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 115: 604 – 608

15.Tasman W, Borrone RN, Bolling J (1987) Open sky vitrectomy for total retinal detachment in retinopathy of prematurity. Ophthalmology 94:449 – 452

16.Trese MT (1984) Surgical results of Stage V retrolental

20.Zhao S, Overbeek PA (2001) Elevated TGF beta signaling inhibits ocular vascular development. Dev Biol 237:45 – 53

Core Messages

The initial history should focus on a careful review of systems to detect associated vasculitic/uveitic disease

Middle age and older adults presenting with ocular vascular occlusive disease should have a referral to primary care physicians for evaluation of their blood pressure (acute measurement can be performed in the clinic), blood sugar and probably an assessment of serum lipids and cholesterol. Periodic visits to a family practitioner are appropriate for patients with retinal vascular disease, and patients who do not see a primary care physician should consider doing so

In arterial ocular occlusive disease, the carotid and cardiac sources are most likely. Sedimentation rate measurement is usually appropriate

Although no level one evidence exists, when these common risk factors have been eliminated in young patients, Hcy, APA, FVL and perhaps ATIII, protein C and S may be evaluated, especially in cases of bilateral disease, positive family history or previous thrombotic disorders

If deficiency in one of the above parameters is identified, the management of the systemic components of the disease should be addressed by referral to a specialist familiar with this type of disorder

The finding of an anomaly in one of the coagulation proteins could have an impact on peroperative management of thrombosis prophylaxis and birth control pill management, and lead to greater consideration being given to quit smoking

Although no prospective randomized trial has proven the efficacy of oral folates for preventing any kind of systemic or ocular vascular event, some authorities recommend 400 μm of oral folates daily for patients with elevated plasma Hcy and low folate levels. We regard this as a CII level recommendation – and as such would not criticize doctors who do not screen for hyperhomocysteinemia or advise their patients to supplement with folates

The ophthalmologist plays an important role in the follow-up of the eye disease itself and in managing further complications such as glaucoma, macular edema and neovascularization

21.1.1 Introduction

A complicated well-regulated balance exists between the thrombosis and fibrinolysis systems. This chapter will cover the two main categories of retinal vascular occlusive disease (RVOD): central (CVO) or branch retinal vein occlusion (BVO) and central (CAO) or branch retinal artery occlusion (BAO). This chapter will not address the overall diagnostic evaluation of patients with retinal vascular disease. Patients with CAO/BAO should be evaluated by their medical doctor for common underlying causes such as ipsilateral carotid disease and heart disease. Patients with bilateral, simultaneous CVO/BVO of course should be evaluated for common causes of hypercoagulable states such as Waldenström’s or

multiple myeloma. Basic evaluation should include a medical review of systems, testing for high blood pressure and diabetes for all patients, and sedimentation rate, carotid Doppler and cardiac sonogram should always be obtained for retinal arterial disease (RAO). After a basic evaluation, many patients with RAO or retinal venous disease (RVO) are said to have idiopathic conditions. In recent years, there have been a large number of papers citing possible associations of RAO and RVO with abnormalities of plasma proteins. Are these associations real? Which should be considered and looked for in which patients? It will be some years before we can offer clear guidance on this subject, and there is a strong need for large prospective studies with contemporaneous wellmatched control groups. Until these studies are

available, in this chapter we summarize the pertinent literature and offer some thoughts on whether and how patients with RAO and RVO who do not have obvious causes after a “basic” evaluation should be worked up.

Many patients with RAO have an underlying cause that is known or found after a basic medical evaluation. In contrast, although retinal venous occlusive disease is common, most patients are told their condition is idiopathic. This is neither satisfying to the patient nor to the doctor. Patients want to know “Why did this happen?” and doctors want to find causes in case there are modifiable risk factors that if altered, would reduce the likelihood of a second similar event. Many consultants order a wide range of medical tests, although the classic teaching has been that for patients with BVO and CVO, unless there are simultaneous bilateral events, the only underlying medical diseases that are more common are diabetes (less true for BVO), hypertension, hypercholesterolemia, smoking, glaucoma, and atherosclerosis [15, 60 – 62]. Throughout this chapter those will commonly be referred to as major risk factors. Since patients who see their primary care practitioner will be evaluated for diabetes, hypercholesterolemia, atherosclerosis and hypertension even in the absence of venous occlusive disease, it has been our practice simply to confirm that patients do periodically see their doctor and no special testing has been advised. The ophthalmologist will consider underlying glaucoma, and both the ophthalmologist and the family physician should counsel against smoking.

In recent years, there have been a large number of papers written about possible underlying hematological risk factors which might explain why a particular patient had their retinal vascular event – the cause might not be idiopathic. Many of the papers that point out or claim an association have substantial opportunities for improvement and their conclusions may not be valid. In general, sample sizes are small, control groups are absent or not as comparable as they ought to be, the studies are retrospective, or there are other possible causes of bias or confounding that complicate the analyses and interpretations. To cite just one example of a paper that may not be correctly interpreted, consider the work of Marcucci and colleagues who write on “Thrombophilic risk factors in patients with central retinal vein occlusion [45].” They compared 100 cases and controls and conclude there is a potential role of hemostatic risk factors in the pathophysiology of CVO. After considering the article, most readers might agree. However, the methods section states “we investigated 100 consecutive, unselected patients ...

referred to our Thrombosis Center.” The authors did not study patients with CRVO; they studied patients

with CRVO referred to thrombosis experts. This will be a select group of patients and will not likely generalize to the overall population of patients with CRVO seen by ophthalmologists.

In this chapter, we will review the literature on plasma proteins and retinal vascular disease. Levels or abnormalities of homocysteine (Hcy), methylene-

tetrahydrofolate reductase (MTHFR), activated pro- III 21 tein C resistance (aPCR), antithrombin (AT) III defi-

ciencies, protein C and S deficiencies, antiphospholipid antibodies (APA), factor II G20210A polymorphisms, lipoprotein A, factor V Leyden (FVL), factor VIII, factor XII deficiencies and von Willebrand factor will be reviewed and, where possible, we will offer guidance on which patients might be evaluated for what abnormalities and why.

We believe that the associations discussed generally remain uncertain and our comments should be viewed as guidelines and there remain patients with retinal vascular disease for whom no workup at all would be reasonable and correct. Some of the putative disease states that may increase the risk of retinal vascular disease can be managed relatively easily with a favorable risk/benefit ratio. Others may require lifelong anticoagulation with the likelihood of a severe adverse event during a patient’s lifetime being a near certainty. We will offer a very brief introduction to the systemic management of these conditions since it will be necessary to weigh risks and benefits before making management decisions. In general, the medical knowledge required to counsel patients about whether to search for risk factors and if such factors are found, if they should be treated, will be beyond the expertise of most ophthalmologists. It is our prejudice that the ophthalmologist should introduce the issues to the patient, help the patient decide if further consultation with an expert is appropriate, and as needed, follow the patient along for the ophthalmic issues such as the diagnosis and management of macular edema, new vessels or glaucoma while the consultant knowledgeable in coagulation issues manages possibly associated systemic disease.

In this chapter, the relevant studies will be evaluated regarding the importance of their recommendations to clinical outcomes and the overall strength of evidence supporting these recommendations using the rating scheme of Minckler. This scheme is used as part of the manuscript submission guidelines for Ophthalmology, the journal of the American Academy of Ophthalmology, and is summarized in Tables 21.1.1 and 21.1.2 [31]. The system uses a “I, II, III” grading scale for the strength of the evidence and an “A, B, C” rating for the level of importance with respect to the clinical outcome.

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inversely to Hcy plasma concentration. Methylenetetrahydrofolate reductase (MTHFR), a pivotal enzyme involved in Hcy metabolism, is discussed in the following section. The reader is referred elsewhere for more detailed biochemistry discussions [13, 54].

The biological explanation of how Hcy is implicated in atherogenesis is not well understood. A growing body of experimental evidence points toward endothelial cell damage either by direct exposure to high levels (1 – 10 mmol/L) of Hcy or by generation of reactive oxygen species. This damage leads to endothelial dysfunction creating a prothrombotic state by promoting platelet aggregation or altering the coagulation cascade [13]. To give the reader a reference frame, the generally accepted normal plasma Hcy level is below about 9 – 12 μmol/L; there is some variation on “normal” levels across laboratories. Hyperhomocysteinemia is divided in the literature into mild (9 – 15 μmol/L), moderate (15 – 20 μmol/L) or severe (over 20 μmol/L). As the reader delves into specific studies, different levels are used to define hyperhomocysteinemia, which makes it hard to draw uniform conclusions.

In congenital homocysteinuria, Hcy plasma levels can reach as high as 400 μmol/L. The early observation of thrombotic events and arterial lesions in these young patients led to a search for its association with various kinds of vascular occlusions. Although still debated, a large amount of data has been gathered, showing, more often than not, that even mild hyperhomocysteinemia is independently associated with heart, brain and peripheral atherosclerosis. It is noteworthy that these associations have been made through epidemiological studies and causality still remains to be demonstrated [54].

Multiple studies have established that there are higher Hcy plasma levels in male and elderly patients [54]. In the Framingham Offspring cohort, people over 65 years of age had a 23 % higher Hcy plasma level compared to those younger than 45 [32]. Acquired factors can increase Hcy plasma concentration: elevated serum creatinine; low folate, vitamin B6 or B12 intake; diabetes; anti-hypertensive medication; alcohol; caffeine; smoking; psoriasis; methotrexate; tricyclic antidepressant; dilantin; carbamazepine; fibrates; metformin; cyclosporin A; and trimethoprim [13, 20, 32].

21.1.2.2Methylenetetrahydrofolate Reductase Gene 677 CT Polymorphism:

the Thermolabile Form (TT MTHFR)

Mutations that result in severely reduced MTHFR activity and hyperhomocysteinemia are rare. A succession of demonstrations led to the current association of MTHFR with thrombotic events and hyper-

homocysteinemia. At first, a MTHFR with 50 % specific activity in vitro and thermolability was associated with moderate elevation of Hcy and low folate levels. Then MTHRF thermolability was found to be inherited as a recessive trait in about 5 % of the population compared to 17 % of individuals with coronary artery disease. Subsequently, the thermolability was

explained by identifying a single DNA point muta- III 21 tion at a polymorphic site (677 C to T transmission).

This mutation causes a valine to take the place of an alanine in the MTHFR protein backbone.

The impact of thermolabile MTHFR (TT MTHFR) variant on plasma Hcy levels is unclear. A large proportion of studied populations with TT MTHFR have normal plasma Hcy concentrations. In those same samples, when people did have hyperhomocysteinemia, it was mild and certainly did not correspond with the 50 % in vitro decrease in enzyme activity previously mentioned. This lack of correlation points toward other factors regulating the enzyme activity in vivo.

Clear demonstration has now been made that the hyperhomocysteinemia in patients homozygous for the 677 CT mutation related to their low folate plasma levels and could be reversed by folate supplementation. By the same token, only those with low folate levels harbored Hcy plasma elevations. This possible explanation, that the phenotypic expression of the MTHFR genotypes is dependent on the folate availability, suggests a benefit of higher folate intake of patients with the TT MTHFR.

21.1.2.3 Literature Evidence on Homocysteine

We have not identified level one evidence, that is, evidence from randomized trials that reliably confirm a relationship between elevated Hcy and retinal vascular occlusions. Table 21.1.3 describes the quality and the findings of various studies on this topic.

Cahill et al. [13] in a meta-analysis of pooled data from one prospective and 9 retrospective case-con- trol studies compared 614 patients with any type of venous occlusive disease and 762 controls to find a significant combined difference between the two groups in Hcy plasma concentrations. A statistically significant elevation in plasma Hcy levels was found in seven of those studies comparing 465 central vein occlusions to 658 controls, in three addressing 129 branch vein occlusions with 256 controls and similarly when pooling 154 retinal artery occlusions and 358 controls. In the only prospective study [46] included in Cahill’s review, they state there was no statistical significance between their subgroups age, sex and major risk factors. When looking closer, their pooled CVO/BRVO group had a mean age of 65.6 years, their retinal artery occlusion group was

69.8 and those were compared to a 51.5-year-old control group. They did though control very well for other major risk factors. This is an example taken from the multiple studies used in Cahill’s meta-anal- ysis to explain why, although encompassing a large number of patients; it should be regarded as level II evidence.

In this same meta-analysis, no association was found between vitamin B12 and ocular vascular events but serum folate levels tended to be lower in 287 cases compared to the controls. Furthermore, the data compilation from 11 studies regarding thermolabile (TT genotype) MTHFR led to the impression Hcy levels were more likely the true risk factor than the presence of the TT genotype. Similarly, five of the studies [13, 46, 64 – 66] included in this meta-analysis identified Hcy as an independent risk factor for retinal vascular occlusive disease.

In a level II study, Lahey et al. evaluated 55 consecutive patients with CRVO less than 56 years old without any of the major risk factors and no personal or familial history of thrombosis. Four of those (9.5 %) had a plasma Hcy level > 12 μmol/L compared to none of their 59 healthy age-matched controls. They concluded that whether there was an association between elevated Hcy plasma levels and CVO needed further investigation.

In the level III study of Adamczuk, patients and controls were evaluated for major risk factor but hypertension and hypercholesterolemia were over five times more prevalent in their patient group. However, this study may not generalize well. Although “37 consecutive patients with CVO” were evaluated, we later read “patients were referred to our thrombosis center for ... thrombophilia screening. As discussed in the “Introduction,” we need to

know better who was referred and who was not referred to eliminate the referral bias.

In 2004, Di Crecchio et al. [20] published a welldesigned prospective case-control level II study on 31 patients younger than 50 and concluded that Hcy was not an independent risk factor for CVO. The main point of interest of their study was that the statistically significant difference of Hcy plasma concentration between CVO patients and age-sex matched controls (10.60 vs 9.34 μmol/L, p = 0.003) disappeared when the same patients were compared to controls also matched for body mass index, diabetes, hypertension and cholesterolemia (10.60 vs 10.39 μmol/L, p = 0.674). eaders should remember those levels are almost in the normal range of Hcy plasma concentration. Di Crecchio concluded that Hcy should be considered as a marker of atherosclerosis and the consequence of those other well-established risk factors.

Marcucci et al. investigated 100 consecutive unselected Italian patients referred to their Thrombosis Center, 6 – 24 months after they had a CVO. In this retrospective level III study discussed in the “Introduction,” they did find elevated plasma Hcy as an independent risk factor for CVO after conducting a multivariate analysis. Although the cases and the 100 controls appeared well matched for age, sex, family history of coronary artery disease and smoking, they were nearly completely mismatched with respect to other important cardiovascular variables such as hypertension (48 % of cases vs 6 % of controls), hypercholesterolemia (37 % of cases vs 8 % of controls) and diabetes (12 % vs 0 %). These cardiovascular factors may relate to the prevalence of relevant plasma proteins such as lipoprotein (a) and Hcy and those imbalances call into question the certainty of some of their observations.

In his study on 54 RVOs, Hansen et al. [29] were able substantially to decrease plasma Hcy in 100 % of 14 hyperhomocysteinemic patients by prescribing 5 mg daily of folic acid over at least 2 weeks. Cahill et al. concluded estimation of plasma Hcy and folate levels should be considered for ocular vasculopathic patients. According to the actual findings in the literature discussed above, they hypothesized that reduction of plasma Hcy level by folate supplementation could decrease the occurrence of the disease in the fellow eye or other systemic vascular events. Although no prospective randomized trial has proven the efficacy of oral folates at preventing any kind of systemic or ocular vascular event, Cahill et al. recommended 400 μm of oral folates daily for patients with elevated plasma Hcy and low folate levels. We regard this as a CII level recommendation – and as such would not criticize doctors who do not screen for hyperhomocysteinemia or advise their patients to supplement with folates. Recent experience suggests that vitamin supplementation may not always be “benign.” Vitamin A supplementation, for example, has been associated with increased risk of lung cancer in smokers [47, 57].

We did not find any study looking exclusively at BVO. All studies grouped them with CVO under “venous retinal disease.” We have identified four studies looking more specifically for an association between BVO and Hcy levels. One from Backhouse included only three BVO patients and had no control group. The three other ones were included in Cahill’s meta-analysis discussed previously. His review included all the major existing studies on Hcy and MTHFR and their association with vascular retinal diseases. He consistently found an association between hyperhomocysteinemia whether he was looking at CVO, BVO or retinal arterial occlusion. No distinction could be made in the results of each study

looking at multiple types of vascular retinal occlusions, whether arterial or venous.

Despite the existence of studies pointing to mild hyperhomocysteinemia as a risk factor for systemic occlusive vascular disease, thrombosis, and stroke, the question as to whether Hcy is responsible for these events or if it is just an atherosclerosis marker

remains to be answered. Most of the authors who III 21 have studied this topic have lumped together CVO,

BVO, CAO and BAO and since the etiologies and pathogenesis likely differ, additional studies splitting out the various groups will be needed. The relationship, if any, with RVO remains unclear.

21.1.2.4Literature Evidence Concerning MTHFR

In the meta-analysis by Cahill et al. discussed above in the Hcy section, no statistically significant difference was found in the proportion of the 690 patients with CVO or BVO harboring the TT MTHFR and comparing them to 2,754 controls. Nine case-control studies were reviewed and four of them did not have age-matched controls. Furthermore, all studies contained in Table 21.1.4 are also in agreement with the conclusion that MTHFR is not an independent risk factor for CVO.

Cahill’s meta-analysis of the three major studies looking at CAO and BAO found no significant difference as to the prevalence of the TT MTHFR in 152 cases compared to 435 controls. Based on three level II and two level III studies evaluating 838 patients and 3,226 controls with arterial and venous retinal occlusions, the authors conclude there is a CII level of evidence and do not recommend screening for MTHFR 677CT mutation.

21.1.3Antiphospholipid Antibodies: Lupus Anticoagulant and Anticardiolipin Antibodies

Antiphospholipid antibodies (APAs) are autoimmune immunoglobulins recognizing phospholipids in in vitro laboratory test studies that can activate the coag-

21 III ulation cascade and cause thrombosis. The two immunoglobulins described so far are the lupus anticoagulant (LA) and the anticardiolipin antibody (ACA). LA was originally named after plasma from lupus patients failed coagulating appropriately using in vitro phospholipid coagulation assays. For unknown reasons, activated partial thromboplastin (aPTT) time is prolonged in the presence of LA. It was later found the majority of people harboring LA did not have lupus. ACA got its name from the original radioimmunoassay test using cardiolipin as the antigen.

From 0 % to 9 % of the general population of healthy individuals harbor APA without any noticeable consequence [17]. The incidence of APA increases in age and may be seen in up to 14 % of the healthy elderly population [62]. The ACA status is determined by identification of serum IgG or IgM. As a reference standpoint for the reader, normal values for ACA are below 10 glycopeptidolipids (GPL). Low titers are between 10 and 20 GPL and frank elevation is above 20. Usually used methods to assess the presence of LA were prolonged clotting time (mainly aPTT, Russell Viper Venom, Kaolin). Nowadays, direct LA antibody detection is possible.

It is also worth mentioning that LA tests are unreliable in individuals on anticoagulant therapy. For ACA and LA tests, sensitivity and standard values vary from one laboratory to the next and cut-off levels are relative to each study design. For this reason, sensitivity and cut-off values can explain some variability in the results from one study to the next. Furthermore, variability can be accounted for by the fact that a positive result can become negative over time and vice versa.

Primary APA syndrome is defined by the presence of ACA or LA on two occasions 6 weeks apart, associated with a triad of multiple recurrent arterial or venous thromboembolic events, thrombocytopenia and multiple fetal wastages. Livedo reticularis, renal insufficiency, pseudotumor cerebri, transverse myelitis and cardiomyopathy are also recognized features. The literature contains several case reports of retinal vascular occlusion associated with this syndrome or with established connective disease such as systemic lupus erythematosus (SLE). There seems to be general agreement to conduct blood screening for APA in patients with a positive personal history of clotting disease or systemic illness or with a positive familial history of thrombosis.

APAs can be secondary to connective tissue disease, malignancies, infection, pregnancy and AIDS. They can also be induced by medications such as steroids, phenytoin, hydralazine, quinidine, procainamide, chlorpromazine, interferon, cocaine and oral contraceptives.

Several studies have investigated the incidence of APA in patients with retinal vascular occlusive disease and found very disparate results ranging from 0 % to 64 %. Interesting enough though, all the studies detailed in Table 21.1.5 had a 0 – 8 % prevalence rate for the controls.

No level I study was found in the literature. The only level II study was the one from Lahey et al. discussed earlier in the Hcy section. They found three patients positive for LA and three for ACA out of their 56 CVOs, giving them a combined prevalence of 11 % of APA. None of their controls was positive. They concluded the search for APA in people < 56 years old could be helpful in counseling patients for thrombosis prophylaxis in high-risk situations.

Adamczuck’s study (discussed earlier) found a statistically significant higher prevalence of antiphospholipid antibodies in CVO patients compared to their controls (5/37 compared to 3/144, p < 0.01) [3].

In Cobo-Soriano’s study, only ACAs were found elevated and everyone in the study was negative for LA. Nine out of 40 patients (22.5 %) were ACA positive. Three of those had clinical APA syndrome. This article has been the subject of criticism in the American Journal of Ophthalmology by Williams and Sarrafizadeh, where they disagree with their conclusion to support the routine screening of APA on a routine basis [67].

Glueck et al. (discussed later in the FVL section) found the opposite. No one was positive for ACA, but 6 of 14 patients (43 %) had a Russell venom clotting time of over 39 s, therefore being positive for LA, compared to 1 of 30 controls.

We may be mistaken, but on close reading of the two papers by Abu-El-Arsrar et al., it appears obvious that the second larger paper included some or all patients from their first publication, casing some degree of duplicate data presentation. Their larger study harbored evident potential biases as 65 % of their patients had major risk factors compared to none of the controls. Also, one patient with Beh¸cet disease, one diagnosed with systemic lupus erythematosus (SLE) and four presenting with bilateral CVO were included in the cases group. In this same study, subgroup analysis showed no significant difference in high prevalence of APA, protein C or S and ATIII whether you were under or over 45 years of age. This may demonstrate just a general tendency of the lab results to turn out positive as they had surpris-

21.1 Plasma Proteins – Possible Risk Factors for Retinal Vascular Occlusive Disease

Table 21.1.5. Studies assessing APA’s possible relationship with RVOD

Retrospective or prospective: not matched

*Prospective study matched for sex and age

**Prospective study matched for sex, age, hypertension, and hypercholesterolemia

***Numbers following each specific RVOD represent the number of patients in each category of event

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