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Show Journal of Neuro- Ophthalmology 19( 2): 144- 147, 1999. © 1999 Lippincott Williams & Wilkins, Inc., Philadelphia Occurrence of Familial Nonarteritic Anterior Ischemic Optic Neuropathy in a Case Series Mathew Y. Wang, M. D., Federico Sadun, M. D., Lori B. Levin, M. P. H., Laurie LaBree, M. S., and Steven E. Feldon, M. D. Objective: To report on the occurrence of familial nonarteritic anterior ischemic optic neuropathy ( NAION) in our NAION series. Methods: One hundred forty- eight consecutive retrievable cases of NAION were surveyed regarding the occurrence of NAION in other family members. Medical records of affected family members were reviewed, and clinical characteristics of documented familial NAION cases were described. Results: Of 79 patients who returned the survey, four reported one or more relatives with previously diagnosed NAION. There were nine cases of documented NAION in these four families. All cases occurred in siblings, with a mean age at onset of 55 years. Six patients had second eye involvement and in five, involvement became bilateral within 4 years after initial onset. None of the patients had diabetes; two had hypertension. Conclusion: A small number of patients with NAION may belong to a familial subclass. Three previous reports of familial NAION further support this hypothesis. Key Words: Case series- Familial- Nonarteritic anterior ischemic optic neuropathy- Optic neuropathy. Nonarteritic anterior ischemic optic neuropathy ( NAION) is an infarction of the prelaminar portion of the optic nerve. Often occurring in patients between 50 and 70 years of age, it is characterized by disc swelling and acute painless visual loss. Although NAION is thought to be a microvascular occlusive disease, its precise cause is unknown ( 1). However, the number of patients with NAION who have a congenital absence of a physiological cup in the optic disc is greater than would be expected ( 2). Associated diseases are arteriosclerosis, diabetes, hypertension, and hyperlipidemia. Investigators in recent studies have suggested a ge- Manuscript received July 15, 1998; accepted January 13, 1999. From the Doheny Eye Institute and the Departments of Ophthalmology ( M. Y. W., L. B. L., S. E. F.), Preventative Medicine ( L. L.), and Neurological Surgery ( S. E. F.), University of Southern California School of Medicine, Los Angeles, California; and the Department of Ophthalmology ( F. S.), University of Rome, " La Sapienza," Italy. Presented in part at the North American Neuro- Ophthalmology Society Annual Meeting, Snowbird Resort, Utah, February 13, 1996. Address correspondence and reprint requests to Steven E. Feldon, MD, Doheny Eye Institute, 1450 San Pablo Street DEI- 5803, Los Angeles, CA 90033, U. S. A. netic predisposition for NAION. Johnson and Arnold ( 3) showed a decreased likelihood of NAION among black people in comparison with whites. The annual incidence of NAION in subjects 50 or more years of age was 0.32/ 100,000 in blacks compared with 2.3/ 100,000 in whites. Johnson et al. ( 4) showed that the presence of the genetic marker HLA- A29 on chromosome 6 is a potential risk factor for the development of NAION ( P = 0.006). There have been sporadic reports of familial NAION in the literature. In 1974, Berggren et al. ( 5) reported on a man, three of whose seven children born in his second marriage had NAION. The children were healthy except for possible hypertension. In 1990, Manor ( 6) reported a case of identical female twins with NAION who had no detectable systemic, vascular, or hematologic abnormalities. Deutsch et al. ( 7) also reported a sister of the aforementioned twins who had received the erroneous diagnosis of papillophlebitis. We investigated the occurrence of familial NAION at the University of Southern California Doheny Eye Institute by retrieving the medical records of patients diagnosed with NAION from January 1985 through July 1995. Efforts were made to obtain information about relatives with NAION. Clinical characteristics of familial NAION cases were compared with those of isolated NAION cases. PATIENTS AND METHODS One hundred forty- eight consecutive retrievable cases of NAION diagnosed at the University of Southern California Doheny Eye Institute from January 1985 through July 1995 ( including patients participating in the Ischemic Optic Neuropathy Decompression Trial) were reviewed, with special attention to family history. Some family histories were incomplete, and some family members may have had onset of NAION after the patient's initial diagnosis. Therefore, a short survey questionnaire was developed to ascertain the number of family members with possible NAION. The questionnaire regarding the occurrence of NAION in first- and second- degree relatives was mailed to all patients with NAION in our 144 FAMILIAL NAION 145 series. Follow- up phone calls were made to patients who reported possible family members with NAION for further clinical details and contact information. Medical records were released, with permission, to the Doheny Eye Institute and reviewed for documentation of NAION. A family member was documented as having NAION if the following diagnostic criteria were met: sudden onset of painless visual loss, arcuate and/ or alti-tudinal visual field loss, Westergren sedimentation rate less than 40 mm/ hr and/ or negative results of a temporal artery biopsy to rule out temporal arteritis, and ophthalmoscopic appearance of optic neuropathy. One familial patient was available for mDNA testing for Leber's hereditary optic neuropathy, the result of which was negative. Clinical information from NAION- documented familial patients was collected on the following variables: age, gender, family configuration, bilaterality with time to second eye involvement, visual acuity, presence of hypertension and diabetes mellitus, cup- to- disc ratio, and visual field. Cases were separated into two groups: familial NAION cases with affected siblings and isolated NAION cases without affected siblings. This allowed for a comparison of clinical characteristics between known familial cases to known isolated cases ( Table 1). RESULTS Of the 148 surveys mailed to patients with NAION, 79 ( 53%) were completed and returned to the Doheny Eye Institute. Four ( 2.7%) patients reported relatives with NAION. There were 10 familial patients with NAION in these four families, 9 of whom released their medical records for our review. Seventy patients reported knowing of no relatives with NAION. Five patients reported relatives ( some parental) with visual loss but were unsure of the diagnosis, and we were unable to obtain their medical records. Of those who responded to the survey, 44 ( 55%) were men, and the average age was 69 years. Of the nonrespondants, 43 ( 62%) were men, and the average age was 71 years. TABLE 1. Clinical comparison of familial NAION cases to isolated NAION cases Familial Isolated ( n = 9 patients) ( n = 144 patients)" Mean age ( years) 6 Gender (% male) Bilaterality (%) Cumulative incidence of bilaterality (%) Visual acuity'' (%) £ 20/ 64 20/ 64 > VA > 20/ 200 £ 20/ 200 Hypertension (%) Diabetes mellitus (%) 55.0 ± 1 l yr 4 yrs ( n = 66 67 14.9 = 22.2% = 55.5% 15 40 7 53 22 0 eyes) 63.3 ± 10.5 60 28 22% 16% ( n = 422 eyes) 45 9 47 35 22 " Does not include the four familial cases ( n = 144). * At time of first NAION attack. c Snellen visual acuity at onset of attack. NAION, nonarteritic anterior ischemic optic neuropathy; VA, visual acuity. Familial Occurrence In our series, the number of patients with NAION who had an affected family member was 4 of 148 or 2.7%. Family Configuration All of the familial NAION cases occurred among siblings. Two male patients reported fathers with possible NAION ( as described by their signs and symptoms), but the diagnoses could not be confirmed. No NAION-affected offspring were reported. The familial cases were from large families ( four or more siblings). Of the four families with NAION, family 1 had 11 siblings ( 3 affected), family 2 had 7 siblings ( 2 affected, with the possibility of a third), and families 3 and 4 had 4 siblings each ( each with 2 affected). The onset of NAION did not always occur sequentially in accordance with the birth placement. Both sexes were represented among the affected siblings. Familial Versus Isolated NAION Table 1 presents a clinical comparison of familial cases to isolated cases on the following variables: age, gender, second eye involvement ( bilaterality), visual acuity, and systemic disease. The age at onset of NAION in familial cases ranged from 32 to 81, with 55% occurring before the age of 60. Mean age of onset in the familial patients was 55.0 ± 14.9 years compared with 63.3 ± 10.5 years in the isolated NAION series. When compared with isolated cases, the familial patients had a higher rate of second eye involvement. The cumulative incidence of second eye involvement over time is shown in Figure 1. Four years after onset, five ( 56%) of the nine familial cases were bilateral, compared with only 23 ( 16%) of the 144 isolated cases. Initial Snellen visual acuity in familial affected eyes were reviewed. Of the familial patients ( 15 eyes), 6 eyes ( 40%) had initial visual acuity of 20/ 64 or better, 1 eye ( 7%) had initial visual acuity worse than 20/ 64 but better than 20/ 200, and 8 eyes ( 53%) had initial visual acuity of 20/ 200 or worse. This pattern of initial visual acuity was approximately the same in the isolated cases. The percentage of patients with hypertension ( 22%) and diabetes mellitus ( 0%) was much lower in the familial group. Two familial patients had known heart disease. In those familial patients ( five eyes) with cup- to- disc ratio data, the ratio in three eyes was below 0.2. One bilaterally affected patient had cup- to- disc ratios of 0.4 and 0.5. Initial visual field reports were available for 13 eyes in the familial group. Of these eyes, 10 ( 76.9%) had an altitudinal defect. DISCUSSION Occurrence The prevalence of familial NAION ( number of patients with NAION who had NAION- affected relatives) in our series was 4 of 148 or 2.7%. This number may be an underestimation of familial NAION cases, because patients often were not aware of the ocular status of their relatives. Also there were possible but unconfirmed J Neuro- Ophthalmol. Vnl. 19 Nn ? 1QQQ 146 M. Y. WANGETAL. Q Familial • Isolated FIG. 1. Cumulative incidence of second eye involvement ( bilateral-ity) at 1 and 4 years from first reported onset of nonarteritic anterior ischemic optic neuropathy ( NAION) in familial and isolated cases. 1 year 4 years NAION- affected relatives ( including parents). The prevalence of NAION in the general population is 4.1/ 10,000 or 0.0405% for all ages and 5.8/ 10,000 or 0.0575% in those aged 50 or more years, calculated from the annual incidence rates reported by Johnson and Arnold ( 3). Thus, it is highly unlikely that family members are affected by chance. The effect of nonresponses on the data is unclear. There was essentially no difference demographically ( age and gender) between respondents and nonrespon-dents. Because the responding and nonresponding groups are similar, it is likely that one or two of the 69 nonre-spondants, would have relatives with NAION. However, nonresponse may suggest that they have no relatives with NAION, and they therefore did not bother to respond. Hereditary Pattern All of our nine cases of familial NAION were sibling relationships. The earlier age of onset ( mean age of 55 for familial cases vs. 63 years for isolated cases) and the increased incidence of bilateral disease ( 56% vs. 16%) noted in patients with familial NAION are consistent with a genetic component in the pathogenesis. In addition, the cumulative incidence of second eye involvement at 4 years from initial onset for familial cases was higher than that in isolated cases. Moreover, rates of hypertension and diabetes in the general NAION population reported in the literature ( 8- 11) and in our isolated case series were much higher than that found in familial NAION cases. Some parents of patients with NAION may have had NAION, but we could not confirm any diagnoses. Possible parental disease is further confounded by changes in diagnostic criteria for NAION over the years. The absence of NAION- affected children in our series may be explained by their young ages. Prospective, generational studies and DNA analysis are needed to delineate any inheritance pattern fully. Clinical Characteristics The familial cases did not differ in cup- to- disc ratio from the general NAION population. Low cup- to- disc ratio may be the most important common characteristic ( 12). One potential concern is that the familial incidence of disease can be explained solely by the inherited anomalous disc. However, Leibowitz et al. ( 13) reports that 50% of optic discs for all age groups, including the elderly, have cup- to- disc ratios of less than 0.25. Also consistent with the general NAION population, altitudinal defects were the most common visual field pattern deficit occurring in familial patients with NAION ( 11,14,15). We suggest that NAION may be a syndrome encompassing different diseases with similar manifestations of signs and symptoms, disc swelling, and sudden painless visual loss based on the differences between familial and isolated NAION. However, retrospective survey studies and genetic typing studies are needed to delineate the characteristics of patients with the disease. Additional studies on larger NAION series would allow for statistical testing of these differences, which may indicate that familial NAION has a different pathogenesis than non-familial NAION. Acknowledgment: Supported in part by grant EY03040 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. 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