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Show ORIGINAL CONTRIBUTION The Visual Impact of Fractionated Stereotactic Conformal Radiotherapy on Seven Eyes With Optic Nerve Sheath Meningiomas Monika Landert, MD, Brigitta G. Baumert, MD, PhD, Martina M. Bosch, MD, Urs M. Liitolf, MD, and Klara Landau, MD Background: Treatment of primary optic nerve sheath meningiomas ( ONSMs) remains controversial. Although recent studies have suggested a favorable outcome of radiotherapy, controlled data on the efficacy of fractionated stereotactic conformal radiotherapy ( SCRT) in primary ONSMs are still lacking. Methods: Seven eyes treated with SCRT ( total dose: 54 Gy) were compared with six eyes that were not treated because of patient or physician preference. The indication for intervention was deterioration of visual function with or without imaging evidence of tumor progression. Patients with secondary ONSMs and those with neurofibromatosis type 2 were excluded. The mean follow- up period was 57 months for the treated eyes and 61 months for the untreated eyes. Results: Among the seven treated eyes, visual acuity improved in six, five of which sustained improvement of three or more Snellen lines. One eye deteriorated by two lines. Visual field improved in four eyes, remained stable in two, and deteriorated in one. Four untreated eyes showed worsening of visual acuity and two remained stable. Visual field deteriorated in three eyes and was stable in three. None of the untreated eyes experienced improvement in visual acuity or visual field. No complications of treatment were documented. Conclusions: In agreement with previous reports, these results indicate that SCRT is superior to observation in its impact on visual function in eyes with primary ONSMs. ( J Neuro- Ophthalmol 2005; 25: 86- 91) Department of Ophthalmology ( ML, MMB, KL), University Hospital Zurich, Zurich, Switzerland; Radiation Oncology ( BGB), University Hospital Zurich, Zurich, Switzerland; Department of Radiation Oncology ( MAASTRO), University Hospital Maastricht, Maastricht, The Netherlands; Radiation Oncology ( UML), University Hospital Zurich, Zurich, Switzerland. Address correspondence to Klara Landau, Department of Ophthalmology, University Hospital Zurich, Frauenklinikstr. 24, 8091 Zurich Switzerland; E- mail: Klara. Landau@ usz. ch Optic nerve sheath meningiomas ( ONSM) represent 1% to 2% of all meningiomas diagnosed in the general population ( 1), 95% of which are unilateral ( 2). Primary optic nerve sheath meningiomas develop from meningo-thelial cap cells of arachnoid villi along the intracanalicular or intraorbital portions of the optic nerve. Visual loss and visual field defects tend to be slowly progressive and long-term survival is common ( 2). Secondary ONSM arise from a neighboring intracranial site and extend into the subdural and/ or subarachnoid spaces of the optic nerve sheath ( 3). The formerly controversial issue of management of primary ONSM, with recommendations ranging from simple observation to surgery and radiotherapy, is now being revised. There is an accumulating literature in support of radiation ( 4- 16). Because of the low incidence of this tumor, however, outcome measurements of radiation therapy are limited and no prospective studies have yet been published. Conventional radiotherapy has been used to treat ONSM with some success ( 1,17- 19). A large retrospective comparative series by Turbin et al ( 16) showed a more favorable outcome for conventional fractionated radiation therapy than for surgery or observation. Newer treatment techniques of radiotherapy are able to tailor or, conform, dose better to the tumor itself while sparing surrounding non-tumoral healthy tissue. These techniques are known as three- dimensional conformal radiotherapy, which is based on three- dimensional patient data, treatment planning, and treatment delivery. Stereotactic radiotherapy represents a highly accurate form of three- dimensional conformal radiotherapy. Eight studies have suggested short- term beneficial results from three- dimensional conformal radiotherapy ( 12) or the more precise fractionated stereotactic conformal radiotherapy ( SCRT) ( 4- 7,10,14,15). Of the seven studies of SCRT, only the two by Andrews et al ( 4) and by Saeed et al ( 15) compared radiation treatment to observation alone. In the current study, we report the outcome of seven eyes with ONSM treated by fractionated SCRT at the University Hospital of Zurich and compare it to a similar group of six eyes that were not treated. 86 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Optic Nerve Sheath Meningiomas J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 FIG. 1. Axial T1- weighted magnetic resonance imaging showing extent of presumed primary optic nerve sheath meningiomas in 12 study patients. Case 1, right orbital lesion. Case 2, bilateral orbitocranial lesions. Case 3, right intraorbital lesion. Case 4, right orbitocranial lesion, Case 5, right orbitocranial lesion. Case 6, right orbitocanalicular lesion. Case 7, left orbitocanalicular lesion. Case 8, right orbitocranial lesion. Case 9, left orbitocranial lesion. Case 10, right orbitocranial lesion. Case 11, left orbitocanalicular lesion. Case 12, left orbital lesion. 87 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Landert et al TABLE 1. Clinical characteristics and outcomes in Case Age/ Sex Treated group 1 44/ F 2 27/ F 3 50/ F 4 34/ F 5 59/ F 6 66/ F 7 46/ M Untreated group 8 13/ M 9 35/ F 2 27/ F 10 76/ F 11 33/ F 12 53/ F Side affected OD OD OD OD OD OD OS OD OS OS OD OS OS 7 treated and 6 untreated Treatment SCRT SCRT SCRT SCRT SCRT SCRT SCRT None None None None None None eyes with primary optic nerve Radiation dose ( Gy) 31 X 1.7 = 52.7 30 X 1 30 X 1 28 X 1 30 X 1 30 X 1 30 X 1 8 = 54.0 8 = 54.0 8 = 50.4 8 = 54.0 8 = 54.0 8 = 54.0 - - - - - - sheath meningiomas Indication V A i , t VA i VA i VA i V A i , t VA i VA i, pain RT refused RT refused VA and VF stable Only eye RT refused VA and VF stable METHODS Patient Selection Only cases presenting clinically and radiologically with primary, rather than secondary, ONSM were included. Between 1989 and 2000, 18 cases were referred to the Department of Ophthalmology at the University Hospital of Zurich with the diagnosis of primary ONSM. Three patients were excluded because of previous surgical treatment, one because of neurofibromatosis type 2 with multiple meningiomas, and one because of previous conventional radiotherapy. One patient who received SCRT with no light perception before treatment was excluded because visual improvement after irradiation could not be expected. Diagnosis was based on the clinical findings and the characteristic appearance on magnetic resonance imaging ( 20). The 12 cases included in the study had repeated magnetic resonance imaging studies, the last of which was performed at the end of the follow- up period. All cases had detailed orbital investigations using high spatial-resolution pre- contrast and post- contrast T1 - weighted images with fat saturation, which allow improved visualization of meningiomas ( 21). Thirteen eyes of twelve cases met entry criteria. Seven tumors were located on the right side and four on the left. One case had bilateral ONSM, one symptomatic, the other discovered incidentally with magnetic resonance imaging. Seven eyes were treated with SCRT ( treated group). Six eyes were managed by observation only ( untreated group). The single case with bilateral optic nerve sheath meningiomas was represented in both groups. Indications for treatment were deterioration of visual function with or without radiologically documented tumor growth. Untreated patients included three with satisfactory and stable visual function and three who did not wish to be irradiated despite progressive visual loss ( Table 1). All treated patients gave informed consent before therapy. Our seven treated patients have been previously reported in a multicenter study published in a radiation oncology journal with emphasis on treatment technique and clinical outcome ( 5). Patient Baseline Characteristics There were 10 women ( 83%) and two men ( 17%). The female predominance prevailed in both treatment groups ( Table 1). The mean age of the entire patient group at the time of presentation was 44.7 years ( range: 13- 76). Treated patients were older than untreated patients. The mean and median age in the treated group was 46.6 and 46 years, respectively; the mean and median age in the untreated group was 39.5 and 34 years, respectively. In general, visual acuity at the time of diagnosis was better in the treated group than in the untreated group. All treated patients presented with 20/ 40 or better visual acuity immediately before treatment started. At initial presentation, half of the untreated eyes had a visual acuity ranging from 20/ 40 to 20/ 100, whereas the other half had normal vision. Radiation Treatment Seven cases were treated with highly focused irradiation in the form of fractionated SCRT at the Department of Radiation Oncology, University Hospital of Zurich. The 2005 Lippincott Williams & Wilkins Optic Nerve Sheath Meningiomas J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 TABLE 1. ( continued) Clinical sheath meningiomas VAat Case diagnosis Treated group 1 20/ 321 2 20/ 20 3 20/ 20 4 20/ 32 5 20/ 16 6 20/ 30 7 20/ 25 Untreated group 8 20/ 70 9 20/ 100 10 20/ 16 11 20/ 40 12 20/ 20 13 20/ 16 Visual VA before RT @ mo after diagnosis 20/ 40 @ 139 20/ 30 @ 62 20/ 30 @ 6 20/ 30 @ 4 20/ 25 @ 27 20/ 40 @ 4 20/ 30 @ 6 characteristics and outcomes in acuity ( VA) VA3mo after RT 20/ 30 2 20/ 20 20/ 22 20/ 30 20/ 25 20/ 22 Final VA @ mo after RT or @ end of follow- up 20/ 25 @ 14 20/ 20 @ 24 20/ 20 @ 40 20/ 25 @ 36 20/ 32 @ 8 20/ 25 @ 23 20/ 16 @ 13 HM @ 118 NLP @ 94 20/ 16 @ 87 20/ 70 @ 23 HM @ 28 20/ 16 @ 16 A VA T T T T i T T i i < r-> i i < r-> 7 treated and 6 untreated Visual field ( VF) Goldmann No change + 20° + 70° No change No change Octopus No change - 9.0 dB + 11.5 dB - 11.4 dB + 11.6 dB + 22.8 dB + 14.9dB No change eyes with primary optic nerve A VF < r-> T < r-> T i T T i i < r-> < r-> i < r-> Imaging Location/ change during follow- up Intraorbital/ stable Intracranial/ stable Intraorbital/ stable Intracranial/ stable- regressive3 Intracranial/ stable Intracanalicular/ stable Intracanalicular/ stable Intracranial/ stable Intracranial/ stable Intracranial/ stable Intracranial/ stable Intracanalicular/ progressive Intraorbital/ stable SCRT, stereotactic conformal radiotherapy; RT, radiotherapy; HM, hand motion; NLP, no light perception; f, radiographic tumor progression. Visual field was considered as improved when expansion of at least 20° of the V- 4- e isopter was recorded by Goldmann perimetry, or a decrease of at least 5 dB of mean deviation ( MD) resulted on Octopus computerized perimetry . Therefore, + 20° ( Case # 2) indicates improvement on Goldmann perimetery, whereas - 9.0 dB ( Case # 4) indicates improvement on Octopus perimetry. VA at time of diagnosis not available, VA of 20/ 32 was recorded 15 mo before radiotherapy; not recorded; less uptake in contrast. median total dose was 54 Gray ( 50- 54 Gray) with fractions of 1.7/ 1.8 Gray daily over 6 weeks. Patients were immobilized and scanned in a relocatable stereotactic mask with integrated custom- made bite- block. The gross tumor volume was defined as visible tumor mass on the planning computed tomography scan and was expanded by 3 mm three- dimensionally for the calculation of the planning target volume. Irradiation was performed with non- coplanar fixed beams conformed to the treatment volume. Critical structures ( contralateral optic nerve, optic chiasm, lens, central retina) were identified to keep the radiation dose to these structures below the organ- specific critical dose. This was achieved by the use of dose restrictions that were defined by the maximum reported tolerance dose for a defined organ. For example, in a given case, the accepted dose was the minimum possible for the contralateral optic nerve, and for the optic chiasm it was aimed to be kept as low as possible but not exceeding 50 Gy. In general, maximum dose used was lower than usual, because ONSMs are benign tumors. The irradiation and planning techniques are described in detail elsewhere ( 5). The dose to the chiasm, the contralateral optic nerve, and the contralateral eyeball were always less than 20% of the prescription dose. Main Outcome Measures Baseline and follow- up assessments of visual acuity were performed by the same experienced neuro- ophthal-mologist ( K. L.). Best- corrected visual acuity was measured using Snellen charts and noted in a 20/ 20 ratio equivalent. At least three out of four letters had to be correctly identified for the patient to be given full credit for that line. If worse than 20/ 200, visual acuity was graded as counting fingers, hand motions, light perception, or no light perception. In the treated group, visual acuity was recorded at 3 months after treatment in six of seven eyes and at the last follow- up visit (" final VA") in all seven eyes. The visual field was tested either by Goldmann kinetic perimetry or by automated static perimetry with the Octopus program G2. A change in visual function was defined as change in visual acuity or visual field. A change in visual acuity 89 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Landert et al consisted of improvement or worsening by two or more lines. A change in visual field consisted of an expansion or contraction of 20 degrees or more in the V- 4- e isopter on Goldmann perimetry or a change of at least 5 dB in mean deviation ( MD) on automated fields ( 22). The mean follow- up time was 57 months ( range: 21- 142) in the treated group, and 61 months ( range: 16- 118) in the untreated group. The mean follow- up time after radiotherapy in the treated group was 23 months ( range: 8- 40). Statistical Analysis Changes in visual function were classified as improvement, stabilization, or worsening. The treatment groups were compared with each other by the Mann- Whitney [/ test. RESULTS Visual Outcome Among the seven treated eyes, six experienced improvement in visual function. Five eyes had an increase in visual acuity of three lines or more; one eye improved by one Snellen line. At 3 months after treatment, visual acuity had improved in five out of the six eyes in which it was recorded. One eye lost two lines of visual acuity. Visual field improved in four eyes, remained stable in two, and deteriorated in one. Among the six untreated eyes, four showed moderate to severe worsening of vision. In three eyes with initial visual acuities ranging from 20/ 20 to 20/ 100, visual acuity declined to hand motion and no light perception, and one eye declined from 20/ 40 to 20/ 70. Two eyes with initially normal visual acuity maintained normal acuity over the follow- up period. Visual field deteriorated in three eyes and remained unchanged in three eyes. Non- parametric statistical analysis revealed significantly better visual outcome for the treated group than the untreated group ( p = 0.012). Imaging Characteristics and Outcome Three meningiomas were confined to the orbit, three involved the optic canal, and seven involved the intracranial space ( Fig. 1). There was no difference in these patterns of involvement between the two groups ( Table 1). Slight reduction in tumor size was noted in one treated patient. In the untreated group, one patient had enlargement of the tumor that extended both towards the globe and from the canal towards the chiasm. There were no long- term side effects of SCRT. One patient had acute eyelid edema and was treated with low- dose corticosteroids with subsequent symptom resolution. DISCUSSION The main finding in our series of 13 eyes with primary ONSM was a statistically significant improvement of visual function in the treated group as compared with the untreated group. Six of seven treated eyes ( 86%) experienced prompt improvement in visual acuity, visual field, or both. Five of those eyes ( 71%) had an increase in visual acuity of three lines or more and remained stable over a mean follow- up period of 23 months after SCRT. By contrast, three of six untreated eyes had profound visual loss. Consistent with other series, our results show that stereotactic conformal radiotherapy in patients with progressive optic neuropathy caused by primary ONSM is superior to observation in preserving visual function. This improvement appears to be greater than found in previous studies. For example, the percentage of eyes with an improvement in visual acuity of at least three Snellen lines is higher than that reported by Pitz et al ( 14) and Narayan et al ( 12). Pitz et al ( 14) found functional improvement in 7 ( 44%) of 16 eyes ( defined as improvement of visual acuity of two or more lines or change of at least 8% of visual field) over a mean follow- up period of 37 months, but only one eye ( 6%) gained more than two Snellen lines. Narayan et al ( 12) reported a three- line or greater visual acuity improvement in 5 ( 36%) of 14 patients treated with three- dimensional conformal radiation therapy with a mean observation time of 51.3 months. The relatively low rate of visual improvement in these reports might be a reflection of an under- representation of eyes with pre- treatment mild or moderate visual loss. Our patients with marked improvement all had pretreatment visual acuities ranging from 20/ 40 to 20/ 30, which may allow a greater potential for good treatment results. Based on our interval visual acuity data, improvement in visual function appears to occur early after treatment initiation, resembling rapid visual recovery after surgical decompression in compressive optic neuropathy ( 23). The number of eyes included in our study was small and our follow- up was short. Thus, no firm conclusions with regard to long- term risks of irradiation, visual preservation, or containment of tumor growth can be made. Our untreated group had worse baseline visual function than our treated group, so that conclusions about the beneficial effect of treatment must also be tempered. Despite these weaknesses, our study supports the accumulating data on the efficacy of SCRT for primary ONSMs ( 4- 6,10,14). We further confirm that without treatment, vision declines substantially in some cases ( 2,15, 16,24) but remains stable in others ( 24). Our findings support SCRT for eyes with primary ONSM in which progression of optic neuropathy has been documented, but before severe visual loss occurs. 90 © 2005 Lippincott Williams & Wilkins Optic Nerve Sheath Meningiomas J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Acknowledgment The authors thank Burkhardt Seifert, PhD, Department of Biostatistics, University of Zurich, Switzerland, for his expert statistical consultation. REFERENCES 1. Sibony PA, Krauss HR, Kennerdell JS, et al. Optic nerve sheath meningiomas. Clinical manifestations. Ophthalmology 1984; 91: 1313- 26. 2. Dutton JJ. Optic nerve sheath meningiomas. Surv Ophthalmol 1992; 37: 167- 83. 3. Miller NR. The evolving management of optic nerve sheath meningiomas. 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