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Should a Hypercoagulable Work-Up Be Performed on Young Patients With Nonarteritic Anterior Ischemic Optic Neuropathy?

Francis, Courtney E. MD; Patel, Vivek R. MD

Editor(s): Lee, Andrew G. MD; Van Stavern, Gregory MD

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Journal of Neuro-Ophthalmology: December 2019 - Volume 39 - Issue 4 - p 523-528
doi: 10.1097/WNO.0000000000000840
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The pathophysiology and pathogenesis of nonarteritic anterior ischemic optic neuropathy (NAION) is not completely understood. There is a lack of consensus as to whether a hypercoagulability work-up should be performed in patients with nonarteritic anterior ischemic optic neuropathy, particularly in patients with atypical presentations or atypical demographics. Two experts discuss this topic.

Pro: Courtney E. Francis, MD

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in older patients. The Ischemic Optic Neuropathy Decompression Trial (IONDT) yielded significant information on the natural history of the disease in addition to identifying common risk factors, including hypertension, diabetes mellitus, and other conditions that lead to microvascular disease (1). However, the IONDT in addition to many other studies of patients with NAION exclude patients younger than 50 years. This is likely due to the relatively rare incidence of NAION in younger patients and to ensure patients with optic neuritis or other etiologies for anterior optic neuropathy are excluded. However, the question arises if younger patients have a different set of risk factors which lead to NAION.

NAION is generally considered to occur as a result of an ischemic event related to transient nonperfusion or hypoperfusion. A hypercoagulable state is not regarded as a common etiology; however, over the years, there have been multiple reports of a hypercoagulable state in some patients with NAION, including Factor V Leiden, lipoprotein (a), glycoprotein IIIa, MTHFR mutation, homocysteine, fibrinogen, and Factor VIII (2–6).

In his American Ophthalmological Society thesis, Anthony Arnold beautifully described several differences between patients younger and older than 50 years with NAION (7). His conclusions were that NAION in younger patients is not as rare as previously thought and actually carried a higher risk of second eye involvement compared with older patients observed in the IONDT. This increased risk of sequential NAION was associated with a concurrent diagnosis of diabetes. He hypothesized that younger patients may have a different vasculopathic risk factor profile. He did note that in a small subset of patients tested, 20.8% had abnormal studies, including Factor V Leiden, antithrombin III, anticardiolipin antibodies, protein C, and protein S; however, his study was not powered to fully evaluate the role of prothrombotic risk factors.

Preechawat et al (8) also tried to characterize NAION in younger patients through a retrospective chart review of all patients with NAION presenting to a single tertiary care center. They noted 23% of patients were younger than 50 years at presentation. As in Arnold's review, they also found a higher risk of fellow eye involvement in younger patients with NAION but concluded the systemic risk factors were similar to those described in older patients. In their study, 5% of patients were found to have a hypercoagulable state including antiphospholipid antibodies, hyperhomocysteinemia, and heterozygosity for the methylenetetrahydrofolate reductase (MTHFR) gene.

Hyperhomocysteinemia is a vascular risk factor independent of diabetes mellitus, hypertension, hypercholesterolemia, and tobacco, with elevated levels of homocysteine associated with atherosclerosis and carotid artery stenosis (9,10). Hyperhomocysteinemia impairs synthesis and bioavailability of nitric oxide, leading to endothelial dysfunction, which in turn can impair perfusion and lead to ischemia at the optic nerve head. Furthermore, a point mutation in the MTHFR gene has been associated with increased levels of homocysteine.

Kawasaki et al (11) first reported a potential association between hyperhomocysteinemia and young patients with NAION in 1999. In their series, 12 patients younger than 50 years were included, with 2 (17%) noted to have elevated serum homocysteine levels. Neither patient had a history of hypertension or tobacco use; however, both patients went on to have contralateral eye involvement. The study was limited by the number of patients and the fact that homocysteine levels were not drawn at the time of presentation with NAION, making the association less clear-cut.

To further evaluate the role of homocysteine levels in the risk of NAION, Weger et al (12) studied 59 consecutive patients with NAION and an equal number of age- and gender-matched controls. Of note, this study was not specifically evaluating patients younger than 50 years at the time of their vision loss—the mean age of patients was 69.1 years. Plasma homocysteine levels were significantly higher in patients with NAION compared with controls (11.8 vs 9.8, P = 0.020). They did not find an increased incidence of the MTHFR genotype in their cohort of patients with NAION.

Other than homocysteine, there have been multiple other thrombophilic factors which have been reported in association with NAION in younger patients. In a case–control prospective study of patients with NAION younger than 60 years, Kuhli-Hattenbach et al (13) found thrombophilic abnormalities in 46% of patients compared with 18% of controls. The most common etiologies found included Factor VIII, lipoprotein (a), and homozygous resistance to activated protein C. In patients with NAION younger than 65 years, the same research group noted thrombophilic factors in 51.4% of patients, with Factor VIII and lipoprotein (a) the most common (14).

There are several case reports of young patients with NAION found to have laboratory testing consistent with a hypercoagulable state. Serrador-García et al (15) reported a 49-year-old man who presented with NAION. Extensive work-up was performed as the patient had no known cardiovascular risk factors. The patient was found to have significantly elevated anticardiolipin antibodies and was started on antiplatelet therapy. Örnek et al (16) presented a case of a 39-year-old man with bilateral sequential NAION who was found to have hyperhomocysteinemia, a heterozygous MTHFR A1298C mutation and a positive lupus anticoagulant.

Although NAION is not considered a thromboembolic disease, it is possible that thrombogenic risk factors may trigger an attack in NAION in some patients. For a typical patient older than 50 years with diabetes, hypertension, and a contralateral disc-at-risk, minimal further laboratory testing is required to confirm the diagnosis. However, it is reasonable to proceed with additional work-up in a younger patient, especially in one who does not have a clear history of typical risk factors. Given the risk of second eye involvement is higher in young patients with NAION, the added cost of further laboratory testing to evaluate for a hypercoagulable state (and potentially a treatable cause) is likely justified.

Laboratory tests to consider

  1. Homocysteine;
  2. Protein C and protein S;
  3. Anticardiolipin IgG/IgM antibody and lupus anticoagulant;
  4. Factor V Leiden;
  5. Fibrinogen;
  6. Factor VIII;
  7. Lipoprotein (a);
  8. Antithrombin III.

Con: Ischemic Optic Neuropathy: Hypercoagulable Work-up Is not Routinely Required for Young Patients With NAION: Vivek R. Patel, MD

Nonarteritic ischemic optic neuropathy (NAION) is widely recognized as the leading cause of acute optic neuropathy in patients older than 50 years. However, relatively few studies have systematically evaluated patients younger than 50 years, who present with a clinical constellation of symptoms and signs consistent with NAION (17–21). Fortunately, series reporting on this younger cohort are relatively well powered, ranging from 21 to 169 patients, constituting an overall incidence of 10.5%–23.2% of their cases across all age groups (8,18–21). Overall, a morphologically small or “crowded” disc is the most prevalent local predisposing factor while diabetes mellitus, hypertension, hyperlipidemia, and smoking are well-established systemic risk factors, irrespective of age cohort (22). Other studies have suggested potential associations with comorbidities including anemia, hypotension, and hypercoagulability (8,23).

Here, we will take the opportunity to review the quality and quantity of evidence establishing a link between thrombophilia and the development of NAION in patients younger than 50 years. Is there enough to draw a pathophysiologically sound connection, behooving clinicians to routinely look for such conditions in this subset of patients, or are the data coincidental and anecdotal at best?

To set the basis for discussion, if we agree for this purpose that we consider “young” patients to be those younger than 50 years at the time of initial presentation, what are we defining as a hypercoaguable work-up? Although there is considerable mechanistic overlap and complexity, hypercoagulable disorders predisposing to venous vs arterial thromboses differ (24). While local perioptic venous congestion likely plays a role, NAION is considered by most to be a condition precipitated by a critical level of arterial hypoperfusion to the optic nerve head and is not a thromboembolic condition (25). Nonetheless, several reports have commented on a potential contributory role of hypercoagulable conditions traditionally believed to predispose to primarily venous thrombosis. These include protein C, protein S, Factor V Leiden, antithrombin III, and prothrombin G20210A mutations (24). Even if an anecdotal association is suggested in reviews and small retrospective series (2,3,26,27), reconciling a cause–effect relationship without a plausible pathophysiological basis is precarious. For example, Srinivasan et al (28) report on a single of case of a 52-year-old woman presenting with a unilateral NAION thought to the precipitated by Factor V Leiden deficiency and concurrent antiphospholipid antibody syndrome (APLA). APLA is recognized as a risk factor for both venous and arterial thrombosis (24). Definitively determining which factor is contributory, if any, is simply not possible. Several series have demonstrated an increased risk of developing myocardial infarctions, cerebrovascular ischemia, and peripheral arterial disease in patients with APLA antibodies, compared with controls (29,30).

Granted the common implication of arterial pathophysiology between NAION and these systemic ischemic conditions, can the cardiovascular and neurological literature be extended to suggest that increased levels of APLA antibodies portend an elevated risk of NAION, and should we be ordering APLA antibodies for our young patients with NAION? There is a lack of data to draw this link definitively. In fact, there is more direct evidence that APLA antibodies may be associated with autoimmune optic neuropathy (31,32), which carries a clinical phenotype quite distinct from NAION.

Hyperhomocysteinemia and homozygosity for the C677T methylenetetrahydrofolate reductase (MTHFR) mutation deserve particular attention with respect to their potential role in the development of NAION in certain patients. Patients with hyperhomocysteinemia carry an increased risk of early-onset (before the age of 50 years) vascular occlusive disease, stroke, and myocardial infarction, through the promotion and acceleration of atherosclerotic changes (9,33–35). Hence, there is a potentially tenable pathophysiological link. However, there is only 1 article which specifically reports on the association of hyperhomocysteinemia and NAION in patients younger than 50 years (11). In their case series of 12 patients with NAION younger than 50 years, Kawasaki et al report that 2 (17%) had hyperhomocysteinemia. Although their series lacked a control arm, the reported incidence of hyperhomocysteinemia in the general population is 5%–7%. More convincingly, in their series, 6/12 and 3/12 patients developed bilateral disease and recurrent NAIONs, respectively. Both hyperhomocysteinemic patients were among those with bilateral and recurrent disease and were not hypertensive, diabetic, or smokers, but optic disc morphology was not reported for these patients. Although the findings reported in this study are suggestive of an association, one must note that serum homocysteine levels can fluctuate—measurements in this report were taken years after the initial NAION episode(s). In addition, determination of the clinical effects attributable to homocysteine must take into account vitamin B12, vitamin B6, and particularly serum folate levels, as these are cofactors in its metabolism. In this study, one of the hyperhomocysteinemic patients revealed normal levels of these cofactors, while levels were not reported for the second patient. Importantly, homocysteine levels are well controlled by supplementation of these nutrients.

Biousse et al reported on 14 patients with acute NAION (mean age 42.8 years with range of 28–68 years) for whom they measured B6, B12, folate, and homocysteine levels as well as the C677T polymorphism of the MTHFR gene (36). Thirty-six percent (5/14) developed fellow eye involvement, but there was no association with MTHFR mutation rate or type, homocysteine levels, folate or vitamin levels, and risk of bilateral or recurrent involvement. All patients had a “disc at risk” conformation, rendering it impossible to determine whether these factors could independently predispose to NAION development for patients with disc morphologies atypical for NAION. Family history of thrombotic conditions was not reported in these studies.

Further studies investigating the potential role of MTHFR gene mutations as a risk factor for NAION have failed to achieve consensus (12,37,38). Glueck et al discovered that 50% (6/12) of their patients with NAION harbored homozygous MTHFR mutations; however, the clinical relevance of this finding is brought into question, given that none of these patients had elevated homocysteine levels. MTHFR mutations predispose to hyperhomocysteinemia (by impairing remethylation of methionine), which in turn is the proposed pathophysiological substrate promoting atherogenesis through endothelial damage. More interestingly, the youngest patient in the cohort (age 26 years, unilateral NAION) was homozygous for the MTHFR mutation, bringing up the possibility of estrogen-induced thrombophilia potentially exacerbated by this additional genetic factor. In another well-powered study, Salomon et al reported on 61 patients with NAION but found no difference in protein C, protein S, antithrombin III, lupus anticoagulant, prothrombotic polymorphisms (V G1691A, Factor II G20210A, and C677T MTHFR polymorphisms), compared to controls. Granted this study population mostly consisted of patients older than 50 years, there was no report of greater risk of hypercoagulable abnormalities in younger patients within the overall group.

Preechawat et al (8) have provided the largest study systematically evaluating the clinical characteristics of NAION in younger patients. Structural characteristics (cup-to-disc ratio and optic disc drusen), and most systemic risk factors, including hypercoagulabilty (5%), did not differ between the under 50 years group and the over 50 years group. Anemia, however, was found to strongly associate with the risk of sequential bilateral involvement and was present in 20% (3/15) of young patients presenting without optic disc anomalies, including a small physiologic cup. The authors do comment on the relative variability in the hypercoagulability work-up performed over the retrospective study period; however, among these 15 patients without the typical optic disc conformation, only 1 patient had APLA antibody positivity, and no other hypercoaguable condition was noted within this subset. This study corroborates what other large series reporting on this younger cohort have found: The rate of bilaterality (41%) is higher in younger patients than their older counterparts (15%) (1), with similar associated factors. Hence, bilateral involvement in a young patient need not signal the need to perform an exhaustive work-up for additional risk factors, including hypercoagulability. No matter how “logical” it may be, there is certainly a paucity of literature to support such a practice.

It is sometimes stated in the literature that one should consider testing for a hypercoagulable condition in a young NAION patient with a known personal or family history of thrombophilia, lacks a small physiological cup, and bilateral simultaneous or recurrent involvement. However, there is little, if any, substantive evidence to support this practice routinely. Although it is sensible that if a patient has had recurrent episodes of thrombosis elsewhere in the body, one should consider a causative to the subsequent development of NAION; reports of such occurrences are exceedingly rare, and if present, often multifactorial.

Rebuttal: Dr. Francis

Dr. Patel and I agree on the basic underlying mechanism of NAION being small-vessel ischemia from chronic vascular disease in the setting of a crowded optic nerve head. However, one must question if there are other factors at play in younger patients with fewer years of damage from chronic vascular disease, many of whom go on to develop contralateral disease at a much higher rate. Although NAION is not a thromboembolic disease, it remains possible that there are thrombogenic factors that initiate the cascade of events leading to NAION. In particular, hyperhomocysteinemia can lead to vascular endothelial dysfunction that can cause impaired perfusion and ischemia.

The limited data to support the role of hypercoagulable factors are largely due to the fact that NAION has a low incidence and an even lower number of patients younger than 50 years. This makes retrospective reviews and case series challenging to show a definitive causal relationship. In addition, the etiology of NAION in most patients is likely multifactorial—with a combination of systemic and local structural and vascular causes at play.

Although it may be challenging to definitively prove the association between hypercoagulable factors and the incidence of NAION in younger patients, we must be proactive in evaluating these patients. With increased morbidity given a longer life expectancy and the increased risk of second eye involvement, the added cost of additional laboratory studies is offset by the potential benefit of identifying a treatable condition to prevent bilateral disease and secondary complications.

Rebuttal: Dr. Patel

I enjoyed reading Dr. Francis' clear and comprehensive review of the literature reporting on hypercoagulable risk factors as potential contributors to the development of NAION. Although our arguments are designed to explore opposite sides of the spectrum, there is a great deal of consensus in our conclusions.

In both of our reviews, we comment on a notable absence of literature specifically looking at thrombophilia in younger patients. Even subgroup analyses of this cohort, extracted from larger studies fail to reliably demonstrate a higher risk of hypercoagulable conditions in younger patients with NAION. However, we can agree that the rate of bilaterality and recurrent disease may be greater in our younger patients. This raises the question of why… if not entirely explained by hypercoagulability, then are there are other contributors to this difference? Perhaps, greater crowding of the nerve in presenescent small optic nerves, increased symptomatic reporting, or other factors are at play.

I believe we can agree that irrespective of age, NAION patients with a relatively atypical presentation—those without the usual cardiovascular risk factors, larger cup‐to‐disc ratio, and recurrent or bilateral disease—warrant consideration of potentially contributory comorbidities, including thrombophilic conditions on a case-by-case basis guided by the history. Although such a finding may not be entirely causative, the ability of a hypercoagulable condition to elevate the risk of thrombogenesis in a susceptible individual cannot be uniformly excluded. For my younger patients presenting with recurrent or bilateral disease, or any patient without the typical crowded disc or systemic risk factors, I would not hesitate to empirically order homocysteine levels in particular, as I believe the evidence for a pathophysiological link is most plausible, relative to other thrombophilias. Evidence in support of a broader “shotgun” approach in search of a hypercoagulable condition is distinctly lacking. After all, adapting one's clinical judgment for each patient is inherent to the practice of neuro-ophthalmology, as so much of what we do is not guided by a mountain of prospective evidence.

Conclusion: Drs. Lee and Van Stavern

The experts nicely reviewed the literature regarding the incidence of thrombophilia in patients with NAION. At this point, there is no evidence supporting routine testing for hypercoagulable disorders in typical patients with NAION. There may be a role in patients with atypical presentations, particularly in the setting of a personal or family history of recurrent thrombosis. It should also be noted that NAION remains a clinical diagnosis, and other optic neuropathies can be misdiagnosed as NAION. This is an important point when reviewing case reports and case series. Larger and ideally prospective studies are needed to better answer this question.


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