In 2001, we conducted a retrospective investigation of the ophthalmological, neurosurgical, and radiation therapy records of 77 patients who had undergone surgery and external beam radiation treatment of NFA from 1985 to 1998 at the University Hospital, Gro-ningen, The Netherlands (n = 52) and four regional institutions with equivalent radiation therapy protocols (n = 20).
The median age of our cohort at the start of radiation therapy was 52 years. The sex distribution was 41 males (57%) and 31 females (43%). All 72 patients were treated with a combination of surgery and radiation therapy. Sixty patients had one, ten patients had two, and one patient had four operations before radiation therapy. One patient had a second operation for tumor recurrence after operation and radiation therapy. Median ophthalmological follow-up time after radiation therapy was 51 months (range, 19-171 months). Total radiation dose ranged from 45 to 55.8 Gy. The daily radiation fraction size varied from 1.8 to 2 Gy. Median overall treatment time was 35 days (range, 30-42 days). The radiation fractionation schemes used were 45 Gy in 25 daily fractions (n = 49; 68%), 50 Gy in 25 daily fractions (n = 9; 13%), 50.4 Gy in 28 daily fractions (n = 7; 10%), 46 Gy in 23 daily fractions (n = 6; 8%) and 55.8 Gy in 31 daily fractions (n = 1; 1%). All radiation treatment fields were applied daily.
Patients were treated with linear accelerators with 4-MV photons (n = 5), 6-MV photons (n = 45), 8-MV photons (n = 11), 10-MV photons (n = 5), and 16 to 18 MV photons (n = 6). A two-field opposed lateral technique was used in 10 patients, a three-field technique in 30 patients, a five-field technique in 20 patients, and a combination of these techniques in 22 patients. The most frequent combination was opposed lateral fields, followed by a three-field (n = 13) or a five-field technique (n = 5). In the time period 1985 to 1990, the radiation dose to the tumor was prescribed at the tumor encompassing isodose, and from 1991 to 1998 it was prescribed at a central point in the tumor accor-ding to the recommendations of the International Commission on Radiation Units and Measurements (ICRU)20.
Ophthalmological follow-up, defined as the period between the first day of irradiation and the last ophthalmological examination, had to be at least 18 months. Five patients were excluded because they were lost to follow-up before 18 months, reducing the cohort to 72.
Visual fields were obtained with Goldmann kinetic perimetry. The visual field data of all patients at diagnosis, after neurosurgery, radiation therapy, and in follow-up were reviewed by one neuro-ophthalmologist (J.-W.R.P.).
The diagnosis of RON was based on the criteria of Kline et al.18 and Parsons et al.19; 1) irreversible visual loss with visual field defects of optic nerve or chiasmal origin; 2) absence of visual pathway compression caused by recurrence or progression of tumor, radiation-induced neoplasm, arachnoidal adhesions around the chiasm, radiation retinopathy, or other ophthalmologic disease; 3) absence of optic edema; 4) optic disc pallor noted within six to eight weeks after onset of symptoms. The diagnosis of RON was also based on review of visual fields, visual acuity, and fundoscopic examinations in combination with brain imaging.
For our review of the published literature on RON, we performed a search of Medline between 1966 and May 2003 and a search of Embase between 1989 and May 2003. Key words were radiation optic neuropathy, nonfunctioning pituitary adenoma, and radiotherapy. All articles that included patients with NFA were checked for vision loss caused by radiation therapy. The references retrieved by Medline and Embase were screened for other references not found using the aforementioned key words.
To estimate the incidence of RON in NFA, we included only cohort series of patients in which RON was studied. In reports that included functioning and nonfunctio-ning pituitary adenomas, we included only those in which the number of NFA and RON cases were reported. To evaluate risk factors for RON, we included only those cases from series and case reports in which radiation treatment data were available. Our calculations include our own series as well as previous reports. The 95% confidence interval was calculated assuming a binomial distribution.