Original article
Nonarteritic anterior ischemic optic neuropathy: associations with homozygosity for the C677T methylenetetrahydrofolate reductase mutation

https://doi.org/10.1016/j.lab.2003.10.015Get rights and content

Abstract

The association between nonarteritic anterior ischemic optic neuropathy (NAION) and coagulation disorders was prospectively assessed at least 3 months after the occurrence of ocular vascular events in 12 white patients in an outpatient clinical research center. Two community-based ophthalmologists evaluated the 12 NAION patients in the consecutive order of their referral. Polymerase chain reaction–complementary DNA assays of gene mutations associated with coagulation disorders and serologic coagulation measurements in study patients were compared with those in 36 healthy, normal race-, sex-, and age-matched controls, with 3 controls matched for each case. Of the 12 patients, 4 men and 8 women (mean age 62 ± 15 years, 3 of them 55 years or older), 8 had unilateral NAION (bilateral in 4). The 12 patients with NAION were more likely than controls to demonstrate homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (50% vs 11 %; Fisher's P = .009, with the likelihood of a type I error quite small, 0.9%). Our sample size had a power of 80% to detect this case-control difference in C677T MTHFR homozygosity at an α value of .05. Of the 12 NAION patients, 7 (58%) had at least 1 gene mutation in the C677T MTHFR, G1691A V Leiden, or G20210A prothrombin gene, compared with 5 of 36 controls (14%) (χ2 = 9.48, P =. 002, with the likelihood of a type I error quite small, 0.2%). Our sample size had a power of 85% to detect this case-control difference at alpha =. 05. Of the 8 women with NAION, 5 (63%) first experienced the condition while taking hormone replacement therapy (n = 4) or during pregnancy (n = 1), with superposition of estrogen-induced thrombophilia on heritable thrombophilia and hypofibrinolysis. Confirmation of a causal relationship between coagulation disorders and NAION should facilitate its preven tion and treatment and help protect against thrombi in other vascular beds.

Section snippets

Study protocol

The Jewish Hospital Institutional Review Board approved this consecutive case study, which was carried out in accordance with the ethical standards for human experimentation established by the Declaration of Helsinki of 1975 and revised in 1983. Written informed consent was obtained from all subjects.

Over the course of 48 months (February 1999–March 2003), 2 community-based ophthalmologists prospectively and consecutively evaluated 12 patients with NAION in the sequence of their referral. The

Cases and controls

Demographic values for the patients and the 3:1 age-, sex-, and race-matched controls are summarized in Table III. This matching reduces the likelihood that differences in PCR measures are a result of these factors but does not entirely eliminate the possibility.

Twelve white patients (4 men and 8 women, mean ± SD age 62 ± 15 years old, 3 ≤ 55 years) had NAION (8 unilateral, 4 bilateral; Table I). Except for a 26-year-old woman whose NAION developed in her 22nd week of pregnancy (patient 9), 11

Discussion

In this study, NAION was associated with heritable thrombophilia, homozygosity for the C677T mutation of the MTHFR gene. The 12 patients with NAION were more likely than controls to have homozygosity for the C677T gene mutation of the MTHFR gene (50% vs 11%, P = .004, Fisher's P = .009). Homozygosity for the C677T MTHFR was associated with NAION patients (OR 8.0, 95% CI 1.72–37.19). We examined type I and type II errors and power. The declaration that a significant difference existed with

References (38)

  • S.E. Feldon

    Anterior ischemic optic neuropathytrouble waiting to happen

    Ophthalmology

    (1999)
  • R.W. Beck et al.

    Aspirin therapy in nonarteritic anterior ischemic optic neuropathy

    Am J Ophthalmol

    (1997)
  • N.J. Newman et al.

    The fellow eye in NAIONreport for the ischemic optic neuropathy decompression trial follow-up study

    Am J Ophthalmol

    (2002)
  • C.J. Glueck et al.

    Interaction of heritable and estrogen-induced thrombophiliapossible etiologies for ischemic optic neuropathy and ischemic stroke

    Thromb Haemost

    (2001)
  • S. Reino et al.

    Optic neuropathy in the “primary” antiphospholipid syndromeReport of a case and review of the literature

    Clin Rheumatol

    (1997)
  • N. Besbas et al.

    Optic neuropathy in primary antiphospholipid syndrome in childhood

    J Child Neurol

    (2001)
  • H.E. Killer et al.

    Bilateral non-arteritic anterior ischemic optic neuropathy in a patient with autoimmune thrombocytopenia

    Eur J Ophthalmol

    (2000)
  • A. Kawasaki et al.

    Hyperhomocysteinemia in young patients with non-arteritic anterior ischaemic optic neuropathy

    Br J Ophthalmol

    (1999)
  • M. Weger et al.

    Hyperhomocyst(e)inemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy

    Br J Ophthalmol

    (2001)
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    Supported in part by a Jewish Hospital Medical Research Council Grant and by the Lipoprotein Research Fund of Jewish Hospital.

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