Primary Optic Nerve Sheath Meningioma in Children

SURVEY OF OPHTHALMOLOGY

VOLUME 53  NUMBER 6  NOVEMBER–DECEMBER 2008

MAJOR REVIEW

Primary Optic Nerve Sheath Meningioma in Children Hui Bae Harold Lee, MD,1 James A. Garrity, MD,1 J. Douglas Cameron, MD,1 Diego Strianese, MD,2 Giulio Bonavolonta`, MD,2 and James R. Patrinely, MD3 1 3

Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA; 2Universita0 Degli Studi, Naples, Italy; and Plastic Eye Surgery Associates, Houston, Texas, USA

Abstract. Primary optic nerve sheath meningioma represents a proliferation of meningothelial cap cells of the arachnoid villi within the optic nerve sheath. Patients younger than 20 years of age make up less than 5% of all cases of pediatric primary optic nerve meningiomas. Histopathologically, the most common subtypes in children are transitional (54%) and meningotheliomatous (38%). This tumor has been called aggressive in the pediatric population, with surgical excision recommended. However, the tumor may spread intraorbitally, intracranially, or intraocularly after subtotal surgical resection. Recent studies examined the use of fractionated, stereotactic radiation in children with this tumor; however, follow-up is limited. Neurofibromatosis type 2 is concomitantly diagnosed in 28% of patients with pediatric primary optic nerve sheath meningioma. There have been no known deaths attributed primarily to this tumor. (Surv Ophthalmol 53:543--558, 2008. Ó 2008 Elsevier Inc. All rights reserved.) Key words. children



meningioma



optic nerve

I. General Considerations



orbit



pediatric



sheath



tumor

sphenoidale, frontal-parietal area, or olfactory groove.40,59 Rare forms of meningioma may develop apart from the optic nerve and intracranial extension from ectopic orbital arachnoid, other intraorbital nerve sheaths, or orbital mesenchymal cells. Previously reported cases of primary pediatric nerve sheath meningioma (PPONSM) in persons younger than 20 years of age have addressed two clinical features: the relative rarity of this type of neoplasm and its aggressive behavior in this age group. A retrospective review of the Mayo Clinic patient database, searched using diagnostic codes for the period between 1960 and 2005, identified seven patients with PPONSM. Seven additional patients with PPONSM were identified by our colleagues at Universita0 Degli Studi in Naples, Italy, and at Plastic Eye Surgery Associates in Houston, Texas. Cumulatively, the 14 cases we report, along

Tumors of the optic nerve are uncommon. They affect either the optic nerve sheath (typically, a meningioma) or the optic nerve itself (typically, a glioma). Optic nerve sheath meningioma is a proliferation of meningothelial cells within the nerve sheath of the orbital or intracanalicular portion of the optic nerve. This type of proliferation is found more frequently in adults than in children.17 Orbital meningioma may be either a primary tumor of the optic nerve arachnoid or a secondary tumor due to extension of a meningioma into the orbit from a primary intracranial meningioma. Only 10% of orbital meningiomas are primary to the optic nerve (92% intraorbital optic nerve; 8% intracanalicular optic nerve).17 Intracranial meningiomas may arise from the cavernous sinus, falciform ligament, clinoid, sphenoid wing, pituitary fossa, planum 543 Ó 2008 by Elsevier Inc. All rights reserved.

0039-6257/08/$--see front matter doi:10.1016/j.survophthal.2008.08.022

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with the 39 previously reported cases (total 53 patients), underscore both the uncommon nature of this condition and the loss of ocular function caused by tumor progression or treatment. A. HISTORICAL PERSPECTIVES

PPONSM (see Table 1 for summary) was first studied in detail by Walsh,61 who reported in 1970 on seven patients whose clinical course appeared to be more rapid and aggressive than that of older patients. Two patients in the series also had neurofibromatosis type 2 (NF-2). In 1971, Lloyd37 presented the case of a 10-yearold boy with proptosis and blindness in the affected eye. Plain film radiographs showed hyperostosis of the orbit and calcification of the optic nerve sheath. Pathologic studies confirmed an intracanalicular nerve sheath meningioma. In 1974, Karp et al32 studied 25 cases of ONSM accessioned at the Armed Forces Institute of Pathology between 1925 and 1968; 10 (40%) occurred in patients younger than 20 years of age. Data were compiled on the basis of histopathologic studies, predating the advanced radiographic studies available today. Seven years later, Alper2 reviewed these 10 cases and 5 of his own, and found that 15 of 55 PPONSM patients (27%) were younger than 20 years of age. Both series advocated surgical resection for PPONSM because of its aggressive course in young persons. In 1979, Cooling and Wright13 described an 8-yearold girl who initially was diagnosed with an optic nerve meningioma after excision of the intracranial portion of the optic nerve. The diagnosis was changed to an optic nerve glioma after a second operation wherein the entire orbital portion of the optic nerve was removed and examined histologically. Arachnoid proliferation, a reactive response in the meninges, not meningioma, was found in the glioma. This finding indicates the difficulty in diagnosing the tumor even with tissue sampling. The authors questioned whether the large number of cases previously reported could be explained by misdiagnoses, since only 1 in 20 patients (5%) in their own study was younger than age 20.13 Their findings demonstrated the difficulty in diagnosing PPONSM, particularly without advanced neuroimaging techniques, and the difficulty in identifying its accurate incidence. In 1984, Sibony et al56 reported one case of PPONSM in an 18-year-old female patient with bilateral optic nerve sheath meningiomas that severely affected visual acuity. This report was followed by one by Cibis et al12 that documented the only case to date of intraocular extension of an optic nerve sheath meningioma in a child. They attributed the

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intraocular invasion to the aggressive nature of this tumor in children. In 1989, Wright et al63 summarized their experience with 50 cases of optic nerve sheath meningioma treated at Moorfields Hospital, London. Six of the 50 patients (12%) were 20 years old or younger, including a 10-year-old boy who underwent exenteration with craniotomy to remove the invasive tumor and who was alive and tumor free at 8-year follow-up. In 1990, Kuroda et al34 reported two cases of PPONSM. One patient was a 6-year-old boy who was previously misdiagnosed with an optic nerve glioma on the basis of the radiographic appearance of ‘‘kinking’’ in the optic nerve. Both patients underwent fine-needle biopsy for diagnosis and ultimately had subtotal transcranial excision. Of note, the second patient, an 11-year-old boy, underwent biopsy, orbitotomy, and transcranial resection without any visual symptoms preoperatively. Two more cases of PPONSM were reported in 1991. A 4-year-old boy and an 11-year-old boy presented with decreased vision, proptosis, and extraocular motility deficits. Both patients underwent transfrontal craniotomies, and one underwent exenteration. In the largest review of optic nerve sheath meningiomas in all ages, Dutton17 surveyed all the medical literature up to 1991. In this large series of 256 optic nerve meningiomas, the mean age at presentation was 40.8 years (range, 2.5--78 years). Only 4% of these patients were younger than age 20. In 2002, Pitz et al47 reported the first case of PPONSM treated with stereotactic fractionated irradiation. The patient, a 13-year-old boy, was diagnosed 5 months before treatment with visual acuity at the counting fingers level in the affected eye. The tumor was confined to the orbit and vision improved to 20/ 200 at 37 months follow-up. In 2004, Baumert et al4 treated a 9-year-old with stereotactic fractionated radiation therapy. Before these two cases, the standard of care was surgical resection by an anterior orbital approach or transfrontal craniotomy. There has been no report to date on the use of observation alone in PPONSM. B. DEMOGRAPHICS

1. Epidemiology Demographic information about children with optic nerve sheath meningioma is difficult to obtain because of the rarity of this disorder. There is also controversy in the medical literature about potentially misdiagnosed cases. The incidence of intracranial meningioma for all age groups is 2 per 100,000 per year,49 or 18% of all

Clinical Presentation of Primary Pediatric Optic Nerve Meningiomas Reported in the Medical Literature (1970--2008) Sex Reference (year) 61

Walsh (1970) Lloyd37 (1971) Karp et al32 (1974) Alper2 (1981) Sibony et al56 (1984) Cibis et al 12(1985) Ito etal29 (1988) Wright et al63 (1989) Kuroda et al64 (1990) Dailey14 (1991) Perilongo et al46 (1992) Pitz et al47 (2002) Saced et al53 (2003) Baumert et al4 (2004) This report Total *

Visual Field OCS

No. Patients

Age,y

M

F

VA*

Propotosis

EOM*

Disk Edema

Disk Atrophy

7 1 10 2 1 1 2 1 2 2 2 1 6 1 14 53

4--11 10 3--19 17 18 13 5--12 10 6--11 4--11 13--15 13 7--15 9 9--18 3--19

1 0 2 0 0 0 0 1 2 2 1 1 2

6 1 8 1 1 1 2 0 0 0 1 0 4

6 of 7 1 of 1 8 of 10 1 of 1 1 of 1 1 of 1 2 of 2 1 of 1 1 of 2 2 of 2 1 of 2 1 of 1

5 of 7 1 of 1 4 of 10 1 of 1

2 of 7

2 of 7

5 of 7 1 of 1

1 of 1

1 of 1

8 20

6 31

10 of 14 36 of 45

Defects 4 of 7

Vessels

nf-2

0 of 7

2 of 7 1 of 1 3 of 10

1 of 1 1 of 1

1 1 1 2 2

of of of of of

1 2 1 2 2

1 of 1

1 of 1

1 of 1

1 of 1 2 of 2

0 of 1 1 of 2

1 of 1 1 of 2

2 of 2

1 of 1 1 of 2

1 of 1 1 of 2

2 of 2

PRIMARY OPTIC NERVE SHEATH MENINGIOMA IN CHILDREN

TABLE 1

1 of 1 2 of 6 10 of 14 28 of 41

6 of 14 11 of 24

5 of 14 10 of 26

7 of 14 17 of 27

4 of 14 13 of 27

3 of 14 7 of 25

4 of 14 15 of 42

EOM5extraocular movement; F5female; M5male; NF-25neurofibromatosis type 2; OCS5 optociliary shunt vessels; VA5visual acuity; y5year. Decreased

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intracranial neoplasms.48,52 Meningiomas generally occur in the fifth to eighth decades with a peak incidence at age 60.15 Meningiomas primary to the optic nerve sheath account for 1.7--10% of all orbital tumors,34,52,53,59,63 with a mean age at presentation of 40.8 to 44 years.4,17,56 Optic nerve sheath meningioma represents 33--42% of all optic nerve tumors in all age groups.52,53 Only 1--2.9% of all intracranial meningiomas occur in children 21 years of age or younger.4,22 In 318 patients, Sheikh et al55 found nine cases (2.6%) of central nervous system meningioma in children younger than age 16. Germano et al22 found that 5% (15 of 278) of all meningiomas in the first two decades of life were orbital. Patients younger than age 20 represent 4% of all cases of primary optic nerve meningioma.17 Using special algorithms, Levin and Jakobiec estimated the prevalence of pediatric optic nerve sheath meningioma as only 1 in 95,000 to 525,000.35 2. Sex Distribution In adults, there is a clear female predominance of primary optic nerve sheath meningioma. Previous studies have shown that 55--86% of these tumors occur in girls and women.2,4,17,21,32,34,53,55,56,60,63 The actual sex distribution in PPONSM is difficult to determine because of similar confounders in establishing incidence. When Germano et al22 reviewed pediatric meningiomas in all sites, they found that 154 (55%) of 278 cases were in male patients. However, only one (14%) of Walsh’s61 seven patients and only two (33%) of Saeed et al’s53 six patients younger than age 20 were male. Karp et al32 found the same sex distribution in children as in adults (8 females in 10 cases of primary pediatric intraorbital meningioma). Our review of the extant medical literature identified 39 cases, which, in addition to our own 14 cases, included 20 (38%) male patients and 31 (59%) female patients (two published reports did not indicate the sex of the patients; Table 1). Assuming, on average, that puberty begins at about 8 years of age in females and at about 9 years of age in males, children with PPONSM can be classified at presentation as prepubescent or postpubescent: 89% (8 of 9) of prepubescent children with PPONSM are female, compared with 63% (12 of 19) of postpubescent children. Taken as a whole, the sex distribution of affected persons appears to be similar in adults and children. 3. Association with Neurofibromatosis The association of meningioma with NF-2 has been well established. A strong relationship also

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exists specifically for primary optic nerve sheath meningioma in children with NF-2.7 In patients of all ages, Dutton17 found that 8% (12 of 142) who were specifically examined for neurofibromatosis had the disease (type not specified). Wright et al63 found only 1 of 50 patients (2%) of all ages with NF-2, and thus suggested that the association of neurofibromatosis with optic nerve meningioma in adults is far less significant. In a review by Bosch et al,7 27% (8 of 30) consecutive patients diagnosed with NF-2 were concomitantly diagnosed with ONSM. The incidence of NF-2 in PPONSM is greater than in adult optic nerve sheath meningioma. Saeed et al53 described 1 patient in 73 (1.4%) older than age 15 years with neurofibromatosis type not specified; however, 2 of 6 (33%) children were diagnosed with neurofibromatosis type not specified and two others had cafe´-au-lait spots. Walsh61 reported that two of seven (29%) patients younger than age 20 had signs of NF-2. In Karp’s study,32 3 of 10 (30%) patients younger than 20 had NF-2. In our series of 14 previously unreported cases, 4 patients (28.6%) had evidence of NF-2. One patient was diagnosed with NF-2 three years after presentation with optic nerve sheath meningioma. When our series was combined with reported cases, a total of 15 (28.3%) of 53 patients had concomitant diagnoses of NF-2 and PPONSM. The presence of PPONSM may be the first manifestation of NF-2.61 Walsh et al described two of seven (28.6%) cases with optic nerve sheath meningioma as the initial finding in patients later diagnosed with NF--2.61 Thus, the findings of neurofibromatosis in the context of orbital meningioma do not bode well for a positive outcome in regard to tumor growth and mortality. 61 Two of our four patients with NF-2 initially presented with nerve sheath tumor. The concomitant diagnosis of NF-2 and optic nerve tumor may well change both management strategy and prognosis. Treatment of the optic nerve tumor should therefore be conducted with awareness that there may be additional primary sites of meningioma.

II. Clinical Features The correct interpretation of clinical signs and symptoms in primary optic nerve meningioma is vital because lesions of this type, particularly in adults, are not always confirmed by tissue sampling.59 The clinical features of our 14 previously unreported cases are summarized in Table 2. Table 1 summarizes the clinical features of our 14 patients as

Clinical Feature of 14 Previously Unreported Cases—Present Series Intracranial Involvement Patient

Age. y

Sex

VA*

Pain

Disk Pathologic Without After Proptosis Findings Findings Presentation Surgery Surgery

1

16

M

H/M

No

2.5 mm

P, OCS

T

Yes

NR

2y 3

18 6

F M

20/20 NLP

No No

4 mm 6 mm

None P, OCS

None T

No No

4y

13

F

20/400

Yes

7 mm

E

T

5y 6 7 8 9 10y 11 12 13

14 18 11 15 15 17 9 17 13

M F M F M F M F M

20/20 LP NLP NLP 20/20 LP 20/20 HM 20/40

No No No No No No No No No

1.5 mm No No 2 mm 3 mm 5 mm 5 mm 1 mm No

E,COS P,OCS E,P P E P E P None

14

11

M

20/80

No

No

None

Intraorbital Spread Without Surgery

After Surgery

NR

NR

NR

No NR

NR Yes

NR NR

NR Yes

No

Yes

NR

NR

NR

T Psa Me T T Me Me T Me

No Yes Yes No No No No No No

NR NR NR No No Yes No No No

Yes NR NR NR NR Yes No No NR

Yes NR NR NR NR NR NR NR NR

NR NR NR NR NR Yes No No NR

Me

Yes

NR

NR

Yes

NR

Treatment

Outcome

Followup

Subtotal2 with section of ON None Subtotal3, enucleation, radiation Subtotal, the enucleation Subtotal Subtotal Total Total Subtotal Subtotal Total Total Biopsy, conformal radiation Biopsy, conformal radiation

AND

31 y

AWD AND

13 y 20 y

AWD

9 mo

AWD AWD AND AND AND AWD AND AND AWD

13 y 5y 18 y 7y 13 y 18 y 10 y 12 y 3 mo

AWD

3 mo

PRIMARY OPTIC NERVE SHEATH MENINGIOMA IN CHILDREN

TABLE 2

AND5active with no disease; AWD5alive with disease; E5edema; a; F5female; HM5 hand motion; LP5light perception; M5male; Me5meningotheliomatous; NLP5no light perception; NR5not reported; OCS5optociliary shunt vessels; ON5optic nerve; P5pallor; Psa5psammomatous; T5transitional; subtotal5subtotal resection; total5total resection; VA5visual acuity. * In affected eye at presentation. y Neurofibromatosis type 2.

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well as those of the cases previously reported in the medical literature. A. VISUAL ACUITY

In patients of all ages with optic nerve sheath meningiomas, decreased vision is a common symptom. It is the initial complaint in 65--100% of patients.2,17,21,34,53,61,63 Most patients with PPONSM also present with visual loss. Wright et al63 described three patients younger than age 20 with loss of vision. Six of Walsh’s61 seven patients had visual acuity reported; five of these six had 20/200 or worse sight and one patient had normal vision that deteriorated to light perception only over two years. Other studies have shown considerable loss to counting fingers vision or worse.14,34,47,56 Overall, 36 of 45 patients (80%) with PPONSM had visual loss as a presenting symptom (Table 1). B. VISUAL FIELDS

In all ages, the visual field may be markedly decreased at presentation because of the compressive nature of the tumor. Visual field loss may affect many patients and has been reported in 83--95% of patients of any age.17,56,60 Sibony et al 56 reported that compression of the optic nerve leads first to an increase in the size of the blind spot, then to peripheral constriction; however, arcuate defects, temporal or nasal islands, altitudinal defects, and cecocentral and paracentral defects have also been described.33,53,56,61 Visual field loss is a common finding in pediatric patients at presentation. Of Walsh’s seven patients with PPONSM who were 4 to 11 years old, 57% had field defects, including an enlarged blind spot and central scotoma (1 patient was already blind at presentation).61 Sibony et al’s 18-year-old female patient had peripheral constriction in both eyes,56 and one of Dailey’s two patients had nonspecified field loss.14 Overall, 13 of 27 pediatric patients (48%) who were tested had visual field defects at presentation.

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This finding occurs with similar frequency in younger patients. Wright et al described two of three patients younger than age 2 years who had 3 mm and 5 mm of proptosis, respectively.63 Proptosis measured 2 to 5 mm in four of five patients identified by Walsh61 (this particular finding not reported for two of the seven). Dailey’s two patients had marginal proptosis described as ‘‘slight’’ and as 2 mm, respectively.14 The only documented proptosis greater than 5 mm was in an 11-year-old boy who had 11 mm.34 Overall, 68% (28 of 41) of pediatric patients presented with proptosis. D. EXTRAOCULAR MOTILITY

Restriction of extraocular movement is another common presenting sign of PPONSM. This finding has been reported to occur in 9--100% of patients of any age.17,21,34,53,56,60,61 Details of extraocular motility in children were included in only a few reports. Walsh described two of seven patients with ophthalmoplegia.61 Dailey noted this finding in both of his two male patients.14 Thus, extrapolating the frequency of its presentation in PPONSM is not possible. E. OPTIC NERVE FINDINGS

Dutton found that disk atrophy occurred at a rate of 45% in patients of all ages,17 whereas disk edema occurred in 48%. Although some studies do not report negative findings, younger patients with primary optic nerve sheath meningioma appear to have a similar proportion of these two disk findings. Five of the seven (71%) pediatric patients reported by Walsh had optic disk atrophy, whereas only two of the seven (29%) had disk swelling.61 Alper documented the case of a 17-year-old female patient with both findings.2 Chronic disk swelling may be an early manifestation of optic nerve compression secondary to nerve sheath meningioma.17 Optic atrophy may be a subsequent finding that evolves after prolonged compression. Cumulatively, 17 of 27 (63%) patients with PPONSM had evidence of optic disk atrophy, whereas 10 of 26 (38%) had disk edema.2

C. PROPTOSIS

Proptosis may be a frequent finding on external examination. Typically, this sign follows visual loss, but it can occasionally be the presenting symptom alone.17 Walsh found no correlation between the degree of proptosis and the visual acuity in all age groups.61 This finding shows some variability and is reported to occur in 30--100% of all patients.17,21,34,56,59,63 Dutton’s large series showed that 59% (142 of 241) of patients in all age groups presented with proptosis, typically of 2--5 mm.17

F. OPTOCILIARY SHUNT VESSELS

The Hoyt-Spencer triad of disk swelling, optic atrophy, and optociliary shunt vessels, although described in association with adult optic nerve meningioma, is not sensitive or specific for this entity in pediatric patients.57 Rather, other causes of optic nerve compression, usually chronic, can result in these clinical findings. Optociliary shunt vessels due to optic nerve meningioma are described with and without

PRIMARY OPTIC NERVE SHEATH MENINGIOMA IN CHILDREN

associated vision loss and optic atrophy. Shunt vessels may also develop in patients with compressive optic neuropathy from other causes.2,14,17,19,20,25,57,61 For example, optociliary shunt vessels have been related to optic nerve glioma, chronic atrophic papilledema, optic nerve drusen, retinal vein occlusion, and glaucoma, and as a developmental abnormality of optic disk tissue.8 Venous obstruction causes shunt vessels to develop from preexisting collateral channels between the retinal and choroidal circulation.17,25 Optociliary shunt vessels may appear many years after symptoms begin and can involute in patients with advanced optic atrophy; therefore, their true incidence may be underreported.17 Shunt vessels may occur in nearly 30% of adults with primary optic nerve sheath meningioma.17,53,56,63 Previous reports on children have found that the proportion who present with shunt vessels is similar to that for adults. Wright noted one (33%) in three pediatric patients with shunt vessels,63 whereas Walsh did not describe this finding in any of the seven patients he reported.61 Dailey reported two (100%) of two patients with prominent shunt vessels,13 and Alper reported 1 (7%) in 15.2 This finding is seldom reported in individual case reports.4,34,47,56 Four (29%) of our 14 patients had shunt vessels (Fig. 1). Overall, this clinical feature was found in 7 (28%) of 25 patients with PPONSM (Table 1).

III. Radiographic Features Neuroimaging studies, especially magnetic resonance imaging (MRI) with a gadolinium contrast

Fig. 1. Optociliary shunt vessels of the left optic nerve in patient 1.

549

agent and fat suppression, is an accurate method of establishing the diagnosis and extent of involvement in PPONSM. Current imaging methods are much more sensitive than previous radiographic techniques for determining the extent of intracranial extension. Neuroimaging is not pathognomonic, however. For example, a radiographic image of sarcoidosis may resemble that for PPONSM.28 The computed tomogram (CT) of a primary optic nerve sheath meningioma is characterized by a hyperdense or isodense mass with variable calcification, edema, and hyperostosis with homogeneous enhancement after injection of contrast material.55 Tram-tracking, where the denser and thickened optic nerve sheath outlines the residual optic nerve, is characteristic of nerve sheath meningiomas.17 High-resolution CT can be helpful in the early diagnosis and follow-up of optic nerve sheath meningiomas.56 Dutton suggested that CT can be used to identify 97% of tumors at presentation and 99% at follow-up.17 More recently, MRI imaging of these tumors has proved to be the most accurate way to diagnose and follow patients who have primary optic nerve sheath meningioma. Images of meningiomas are isohypointense on T1-weighted images and hyperintense on T2-weighted images (Fig. 2).55 Compared with CT, this modality may improve the diagnosis of intracanalicular meningioma with far less artifact.17 Fat suppression T1--weighted MRI with contrast material gives superior delineation of the tumor relative to adjacent orbital fat. Turbin and Pokorny called MRI with fat suppression and gadolinium contrast the procedure of choice for diagnosis of optic nerve sheath meningioma.59 Saeed et al reported four cases of optic nerve sheath meningioma in adult patients who had an MRI and a CT performed about the same time.53 MRI showed clear evidence of intracranial extension not observed on CT. Thus, CT may be more useful for assessing overall configurations, calcifications, and bony changes, whereas MRI may be superior for evidence of soft-tissue involvement in the orbit and intracranial extension. Of note, optic nerve sheath meningiomas have specific morphologic patterns on imaging. Saeed et al described the radiographic configuration of these tumors.53 Most nerve sheath meningiomas in patients of all ages had tubular configuration (63%). Tubular subtypes included patterns of diffuse expansion (45%), apical expansion (15%), or anterior expansion (3%). Other patterns were globular (23%), fusiform (11%), or focal enlargement (4%) of the optic nerve. Irregular margins in the orbit implied extradural invasion into the surrounding tissues: 8 (31%) of 26 patients with histopathologically proved

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Surv Ophthalmol 53 (6) November--December 2008

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Fig. 2. Orbital magnetic resonance imaging (MRI) and computed tomographic (CT) images of patient 2. A: T1weighted MRI of orbits, gadolinium enhanced, at presentation demonstrating axial view of left optic nerve mass on the medial aspect of the optic nerve. B: T1-weighted MRI of head, gadolinium enhanced, demonstrating sagittal view of left optic nerve mass. C: T1-weighted MRI of orbits, gadolinium enhanced, demonstrating coronal view of enlarged left optic nerve secondary to optic nerve sheath meningioma. D: CT scan with contrast demonstrating axial view of left optic nerve.

tumor invasion into the orbital fat showed irregular margins radiographically.53 Similarly, in Dutton’s review,17 diffuse tubular enlargement was observed in 64% of patients, a globular pattern in 25%, and a fusiform pattern in 10%. There is no clear evidence of specific patterns in the pediatric population. In the study by Saeed et al,53 two of six children had a globular pattern, whereas Sibony et al reported a tubular pattern in the bilateral sheath tumors in an 18-year-old.56 However, the lack of specific radiographic information and the small number of reported cases limit our ability to define specific radiographic patterns in children.

IV. Histologic Findings The arachnoid sheath is a two-layered membrane. The outer layer consists of cells that resemble

epithelium, and the inner layer consists of stratified fibrous tissue. Meningothelial cells are present in large collections that project into the intracranial dural sinuses and veins (pacchionian bodies or arachnoid granulations).57 Meningiomas have different histologic characteristics, depending on the layer in which the neoplasm arises. In the optic nerve sheath, meningothelial cells are concentrated throughout regions within the arachnoid space. Primary optic nerve sheath meningiomas arise from meningothelial cap cells of the arachnoid villi in the optic nerve sheath.17 Meningiomas in all sites are histologically heterogeneous. The 15 different subtypes of tumors that have been reported include meningotheliomatous, fibrous, transitional, psammomatous, angiomatous, metaplastic, microcystic, secretory, lymphoplasmacyte-rich, clear cell, chordoid, rhabdoid, papillary, atypical, and anaplastic.38

PRIMARY OPTIC NERVE SHEATH MENINGIOMA IN CHILDREN A. WORLD HEALTH ORGANIZATION CRITERIA

The World Health Organization (WHO) classification of meningioma includes well-differentiated (grade I), atypical (grade II), and malignant (grade III).38 Histologic and immunohistochemical patterns suggesting unfavorable prognostic features include hypercellularity, loss of lobular architecture, cytologic atypia, prominent nucleoli, increased mitotic activity, increased MIB-1 labeling index, necrosis, small-cell changes, and anaplasia.9 The well-differentiated subtype (WHO grade I), often lobular and lacking these poor prognostic features, is generally meningotheliomatous, transitional, psammomatous, fibrous, or microcystic. The meningothelial subtype (WHO grade I) has distinct characteristics that include clearly defined polygonal cells arranged in sheets separated by vascular trabeculae. The cytoplasm is homogeneous and has spherical nuclei. Cells, divided into large lobules by bundles of vascular tissue or hyalinized collagen, show rare mitoses and reticulin fibers. The transitional subtype (WHO grade I) is characterized by a whorl formation of concentrically arranged spindle or oval cells (Fig. 3). Psammoma bodies, from hyalinization and deposition of calcium salts in the degenerated centers of the whorls, are typical of this transitional subtype but can also be found in the meningothelial variant (Fig. 4). Saeed et al found a correlation between significant psammoma bodies in biopsy specimens with evidence of calcification on CT,53 and Dutton found

551

a relation between these histologic findings and calcifications shown on plain radiographs.17 These calcifications, best seen by CT, may be an indicator of slower growth for ONSM. B. ADULT SUBTYPES

Most investigators agree that the transitional subtype, with both meningotheliomatous and fibrous features, is the most commonly occurring type of optic nerve sheath meningiomas in all age groups.2,59 Saeed et al found the transitional subtype to be the most common type in 13 (50%) of 26 patients,53 with the meningothelial type representing only 5 (19%) of 26 patients in all ages. However, a few reports suggest that the meningotheliomatous subtype may occur more frequently.61,63 Most authors agree that only three types of this primary tumor of the optic nerve sheath should be considered: meningothelial (syncytial), transitional with or without psammoma bodies, and a mixed variant.2,17,32,59 They suggest that other histologic types of meningioma, including fibroblastic or angiomatous, are found in the orbit only because of invasion from intracranial sites. Germano et al found no definitive relation between histologic type and incidence of recurrence. 22 In fact, meningiomas classified as benign make up the most frequent category of recurrence. Although certain histologic features, including necrosis, invasion of adjacent tissue, and mitotic figures, may foreshadow a more aggressive behavior, meningiomas that lack these features may recur after subtotal resection.22 C. PEDIATRIC SUBTYPES

Fig. 3. Histologic findings of left optic nerve meningioma, transitional type, in patient 1 included whorled meningothelial cells (arrows) and elongated fibroblastic elements. (Hematoxylin and eosin 40.)

The dominant histopathologic subtype in optic nerve meningioma in the pediatric population is not clearly defined. There have been individual reports of transitional, meningothelial, and fibrous subtypes,12,34 but no clear dominant type has been established because of the small numbers reported. In patients of all ages who have optic nerve sheath meningioma, however, most subtypes fit the WHO grade I category.38 Sheikh et al reported that 34% (45 of 131) of meningiomas from all sites were meningotheliomatous in patients younger than 16 years of age.55 Of 131 meningiomas identified, 30 (23%) were fibroblastic and 30 were transitional. In a review of meningiomas from all sites in patients younger than 20 years of age, Germano et al found that the histologic features in pediatric meningiomas were no more malignant than those found in adults.22 Pathologic findings of past

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Fig. 4. Histologic sections of right optic nerve meningioma, transitional type, in patient 3. A: Meningioma circumscribes optic nerve (ON). (Hematoxlyin and eosin 10.) B: Hematoxylin-and-eosin stain (20) shows lesion near right optic nerve (ON). C: Alizarin red stain (10) shows calcified psammoma bodies (arrows). D: Hematoxylin-and-eosin stain (40) demonstrates psammoma bodies.

reports documented no malignant characteristics in pediatric optic nerve sheath meningiomas. It is difficult to identify the proportion of pediatric patients with a specific type of optic nerve sheath meningioma because this information is often not included by the ages of patients. Scattered histologic details include mixed-cell optic nerve sheath meningioma in a 17-year-old female patient2 and meningothelial meningioma in a 6-year-old male patient.34 However, the prominence of one pathologic variant over another cannot be concluded from published reports of optic nerve meningiomas in the pediatric population. Tissue was obtained from 13 of our 14 previously unreported cases; all 13 cases were reviewed and current WHO classification criteria were applied. Of the 13 tumors, 7 (54%) were transitional subtype, 5 (38%) were meningothelial, and 1 (8%) was psammomatous.

V. Treatment The treatment approach for PPONSM should be individualized to each patient on the basis of functional state, lesion location, and intracranial extension. A. OBSERVATION

To this date, there have been no other published reports of children with optic nerve sheath meningioma who have been observed throughout the course of their disease. Patient 2 in our series was an 18-year-old female patient with NF-2 who presented with 2 mm of proptosis in the left eye. Her vision was 20/20, bilaterally. No optic disk edema or pallor was noted. However, a mass in the left orbital apex that was confined to the orbit was identified on MRI as optic nerve sheath meningioma (Fig. 2). The tumor was observed for 13 years, during which time the

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1 0 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 2 1 1 1 2 2 0 1 1 2 0 5 0 2 0 0 2 2 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 3 1 0 0 0 1 0 1 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 7 5 0 1 0 1 2 2 2 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7 10 12 1 2 1 2 2 2 1 1 Walsh (1970) Karp et al32 (1974) Alper2 (1981) Cibis et al 12(1985) Ito et al29 (1988) Wright et al63 (1989) Kuroda et al64 (1990) Dailey14 (1991) Perilongo et al46 (1992) Pitz et al47 (2002) Baumert et al4 (2004)

Tumor WOD WD Unknown SR Exenteration Enucleation OR Craniotomy ONS Observe No. Patients Reference (year)

The recent trend has been toward primary irradiation using stereotactic, three-dimensional, conformal, and fractionated techniques.4--6,42,47,58,59 These have been well established in adults. Long-term side effects of radiation therapy include local dermatologic changes, radiation retinopathy or optic neuropathy, central retinal artery occlusions, encephalopathy, and premature atherosclerosis.1,10,11,24,44 Induction of secondary orbital and intracranial meningiomas after radiation therapy has been documented.23,27,31,41,45,51,52,62 Moss et al reported three separate pediatric cases with a radiation-induced intracranial meningioma.41 These secondary meningiomas are often histologically benign and typically calvarial.52 The limited use of radiation therapy has been advocated for children with recurrent tumors to minimize organic and psychological complications.55 However, the newer localized techniques have side effects that are far improved over those of conventional irradiation, with reports of radiation optic neuropathy occurring in less than 2%.30,58 However, one must always consider the risk of radiation, particularly to the cortical and hypothalamic-pituitary system, especially in a developing child.16

Methods of Treatment for PPONSM and Outcomes Reported in the Medical Literature (1970--2004)

C. RADIATION THERAPY

TABLE 3

The standard treatment modality reported in the medical literature is clearly surgical resection in young patients (Table 3). A few early reports documented stripping the tumor from the nerve when the tumor was localized anteriorly.2,61 This surgical technique was later abandoned for complete surgical excision after follow-up showed that it led to substantial visual loss and almost universal recurrence of the tumor. Stripping the tumor from the sheath was thought to compromise the blood flow to the pial vessels, which supply the intraorbital optic nerve. Alper described a 17-year-old female patient with 20/30 vision that declined to no light perception after biopsy and stripping of the tumor.2 Based on their understanding that PPONSM is aggressive, earlier authors suggested aggressive therapy, such as surgical excision.61 Three of Walsh’s seven patients underwent exenteration,61 whereas the rest had some other form of surgical removal. Overall, 40 (88%) of 45 patients for whom we could determine treatment received some form of surgical therapy. Of these 40, 27 (68%) had procedures that included craniotomy.

Alive

B. SURGERY

61

Dead

patient had no change in visual function and no change shown on MRI.

Other

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The application of irradiation in children has not been studied thoroughly. Pitz et al reported the case of a 13-year-old male patient with counting fingers acuity in the biopsy-proved eye at presentation.47 His vision improved to 20/200 after treatment without evidence of radiographic progression at 37-month follow-up. Baumert et al described a child with biopsy-proved optic nerve meningioma who had improvement in visual acuity with only 1 month of follow-up.4 Other reports of pediatric treatment give few or no specific case details.5 Two (14%) of our 14 patients underwent conformal radiation therapy: one with tumor confined to the orbit, and the other with intracanalicular spread. Both had biopsyproved nerve sheath meningioma. However, followup for each patient was only 3 months. D. FUTURE THERAPIES

As a whole, the pathologic characteristics of optic nerve sheath meningioma in children are as benign as they are in adults. However, proliferation of meningiomas has been reported to result from growth factors that mediate the activation of intracellular signaling cascades, similar to the effect of pregnancy.57 Growth factor receptors (e.g., progesterone, somatostatin, platelet-derived, and epidermal growth factor receptors) are expressed in intracranial meningiomas.26,39,50,54 Although histologically similar to their adult counterparts, optic nerve meningiomas in pediatric patients show a greater propensity to spread within the orbit and intracranially.2,53,61,63 This behavior may be due to hormonal influences in the growing child. To date, hormone therapy has not had a clear role in the treatment of primary optic nerve

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meningiomas, and no cases of treatment of children have been reported. However, as research continues, growth factor inhibitors may be a substantial advancement in the treatment of children.

VI. Prognosis A. INTRACRANIAL EXTENSION

In adults with optic nerve sheath meningioma, 20% of patients have either intracanalicular or intracranial extension.14 Younger patients may have a higher incidence of intracranial extension.2,53,61,63 Wright et al reported that intracranial disease developed in four (68%) of six patients younger than age 20. 63 Dailey reported similar findings and concluded that, in younger patients, optic nerve sheath meningioma tends to spread intracranially, intraneurally, intraocularly, and intraorbitally.14 Nine (28%) of 32 patients among the 53 patients reported in the medical literature, including our 14 patients, for whom data were available had intracranial disease at presentation. Five (31%) of 16 patients with no previous evidence of intracranial disease had invasion after surgical resection. Overall, intracranial disease developed in 44% (14 of 32) at some point in their treatment course (Table 4). Although the risk of intracranial extension may be greater for younger patients, tumor-related mortality among young patients is no greater than that among older persons.17 Furthermore, there is no evidence of any substantial effect on prognosis for life or vision in the contralateral eye in patients younger than 20 years. This notion appears to conflict with recommendations of other authors who advocate early complete excision of both the

TABLE 4

Disease Extension from PPONSM Reported in the Medical Literature (1970--2008) Intracranial Spread

Reference (year) Walsh61 (1970) Alper2 (1981) Dailey14 (1991) Cibis et al 12(1985) Ito et al29 (1988) Wright et al63 (1989) Kuroda et al94 (1990) Perilongo et al46 (1992) This report Total * y

Postsurgery*

No. patients

On presentation

Without Surgery*

Intraoccular, Intraorbital or Bony Spread without Surgery

7 1 2 1 2 1 2 2 14y 32

1 0 0 1 2 0 0 2 3 9

1 0 0 0 0 1 0 0 3 5

1 0 0 0 0 0 0 0 2 3

Intracranial Spread

Intraocular, Intraorbital, or Bony Spread

0 1 1 0 0 0 0 0 3 5

3 1 1 0 0 0 0 0 2 7

Surgery defined as either craniotomy, orbitotomy, biopsy, or other surgical intervention. Only 13 of the 14 patients has surgical intervention.

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tumor and the optic nerve in patients younger than age 20.2,32,55,62 Saeed et al suggested that optic nerve sheath meningiomas are primarily indolent tumors except in young persons.53 Wright et al stated that the younger the patient, the more aggressive the growth and spread of the tumor; thus, the correct recognition of these tumors is imperative so that they can be removed as soon as possible.63 Walsh described a case where radical resection with exenteration should have been performed initially to prevent possible spread to the contralateral eye and concluded that an assumption of slow growth does not seem justifiable in young patients.61

last examination in 2005, vision in the affected eye was 20/20 with normal color plates and extraocular motility. This is the only known case with documented long-term follow-up for an untreated optic nerve sheath meningioma in a child. D. MORTALITY

The only documented deaths due to optic nerve sheath meningioma were reported by Alper2 in a follow-up of Karp et al’s32 cases. These five deaths (in 15 patients) were all associated with complications from other coexisting intracranial tumors or operative complications.2 Thus, there have been no deaths caused by this tumor in children.17

B. GROWTH

Saeed et al used radiographic imaging to study the rates of intracranial involvement and tumor growth in patients with nerve sheath meningioma.53 In patients 30 years of age or younger, intracranial spread developed in 53% (9 of 17), with a growth rate of 829 mm3 per year.59 However, only 25% (16 of 65) of patients who were 31 to 60 years old had intracranial spread, with a growth rate of 344 mm3 per year. Although these findings provide objective evidence of the higher rates of tumor growth in younger patients, they do not explain why this rapid growth occurs. Furthermore, Saeed et al looked at the MIB-1 staining index, a marker for cell proliferation, in ONSM.53 Although there was no statistically significant correlation between this index and intracranial extension, Saeed et al noted a low MIB-1 index in nerve sheath meningiomas with extensive psammoma bodies. This finding may suggest a lower rate of growth when calcification is visualized on CT. C. VISUAL OUTCOME

Because much of the past medical literature supports early surgical resection for children with optic nerve sheath meningioma, the visual outcomes are quite poor. Typically, the nerve is sectioned from globe to optic canal. However, there have been some promising reports of stereotactic fractionated radiation therapy. Pitz et al treated a 13year-old boy with counting fingers vision before treatment who regained 20/200 vision.47 Baumert et al reported visual improvement in a 9-year-old boy treated with radiation therapy.4 However, these two patients had relatively short follow-up times of 37 months and 1 month, respectively.4,47 Our patient who was observed for 13 years (patient 2) had no decline in vision over time. She did have NF-2 with multiple central nervous system meningiomas and other tumors. However, on her

VII. Summary The approach to optic nerve sheath meningioma should be individualized for each patient with consideration of age and any comorbid conditions. As a whole, the current medical literature advocates primary surgical removal of the tumor in children at presentation, a treatment approach that contrasts with adult management. Possible consequences of orbital surgery, including incisional biopsy, for primary optic nerve meningioma include loss of vision, visual field defects, central artery occlusions, motility disturbances, phthisis bulbi, and ptosis.2,17,21 Transcranial surgery involves further risks of seizures, leaks in cerebral spinal fluid, and meningitis.17 Surgical intervention, including tissue biopsy, may also lead to tumor spread into the orbit and adjacent structures.59 In our review of the medical literature and our own cases, we found 7 (30%) of 23 patients who had subsequent intraorbital, intraocular, or bony spread of their tumors. However, before any surgical intervention 3 (9%) of 32 patients had extradural invasion of these structures (Table 4). Surgical intervention does not appear to increase the risk of intracranial spread: 5 of 16 patients (31%) demonstrated intracranial extension of the meningioma after surgical resection, compared with 14 of 32 (44%) without intervention in whom the tumor spread intracranially. Technological advances have improved the ability to diagnose pediatric optic nerve sheath meningiomas. However, these tumors continue to present a therapeutic dilemma. Fat suppression MRI with a gadolinium contrast agent is the imaging modality of choice, although scattered case reports of optic nerve glioma,36 metastases to the optic nerve,3 inflammatory perioptic neuritis,18 hemangioblastoma,43 or even sarcoid,28 provoke uncertainty about absolute diagnostic accuracy. We support the need

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for both CT and MRI for diagnosis and monitoring of patients with PPONSM. A suspected diagnosis of optic nerve sheath meningioma should promote a search for evidence of NF-2. If NF-2 is discovered, conservative management is appropriate. If NF-2 is not present and the optic nerve sheath meningioma exists in isolation, therein lies a therapeutic dilemma. If vision is severely compromised and the tumor is localized within the orbit, the decision is more straightforward and should include resection of the optic nerve from globe to optic canal. If vision is relatively normal, we advocate no surgery on the initial visit. Rather, the first visit can establish rapport for eventual surgery, whereas multiple visits can establish a rate of progression. If there is progression (e.g., loss of vision or radiographic evidence of extension), complete surgical excision is advocated with an orbital approach for anterior tumors or a transfrontal craniotomy for posterior tumors. Conformal stereotactic radiation therapy is used routinely in adults; however, its use in children (as documented in sparse case reports and short followup) has not been studied in detail. One must consider the dose of radiation, the remaining lifespan of the patient, and the risk of secondary radiation-induced side effects. Furthermore, this modality should be considered only in cases with good visual outcome expected with only mild to moderate pretreatment vision loss. If the growth rate of primary optic nerve sheath meningioma is truly higher in pediatric than in adult patients, radiation therapy may play a vital role in treatment. The question of biopsy for PPONSM arises when considering radiation. According to Turbin and Pokorny,59 biopsy may not be necessary in adults when there is substantial clinical and radiographic evidence of an optic nerve sheath meningioma. However, this approach is more controversial in children. The rarity of the tumor and its presumed aggressive nature lead us to advocate tissue sampling in all cases of PPONSM before initiation of radiation therapy. Our review is limited by the small number of cases reported in the English-language medical literature. Creating statistically significant outcomes and drawing recommendations is difficult because of the retrospective nature of this study. However, there is nevertheless value in reviewing this uncommon tumor and adding recommendations about it from the medical literature.

VIII. Method of Literature Search To obtain the published reports summarized herein, we conducted a Medline search of the

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medical literature for the period between 1970 and 2006 using the following key words: optic nerve sheath meningioma, intracranial meningioma, meningioma, optic nerve tumor, orbit tumor, children, and pediatric. Pertinent articles were selected from the English-language medical literature. Reference lists from the selected articles were used to obtain further relevant articles not included in the electronic database. Other sources included textbooks mentioned in the review.

References 1. al-Mefty O, Kersh JE, Routh A, et al: The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg 73:502--12, 1990 2. Alper MG: Management of primary optic nerve meningiomas. Current status—therapy in controversy. J Clin Neuroophthalmol 1:101--17, 1981 3. Backhouse O, Simmons I, Frank A, et al: Optic nerve breast metastasis mimicking meningioma. Aust NZ J Ophthalmol 26:247--9, 1998 4. Baumert BG, Villa` S, Studer G, et al: Early improvements in vision after fractionated stereotactic radiotherapy for primary optic nerve sheath meningioma. Radiother Oncol 72: 169--74, 2004 5. Becker G, Jeremic B, Pitz S, et al: Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 54:1422--9, 2002 6. Berman D, Miller NR: New concepts in the management of optic nerve sheath meningiomas. Ann Acad Med Singapore 35:168--74, 2006 7. Bosch MM, Wichmann WW, Boltshauser E, et al: Optic nerve sheath meningiomas in patients with neurofibromatosis type 2. Arch Ophthalmol 124:379--85, 2006 8. Boschetti NV, Smith JL, Osher RH, et al: Fluorescein angiography of optociliary shunt vessels. J Clin Neuroophthalmol 1:9--30, 1981 9. Burger PC, Scheithauer BW, Vogel FS: Intracranial meninges, in Burger PC, Scheithauer BW, Vogel FS (eds): Surgical Pathology of the Nervous System and its Coverings. New York, Churchill Livingstone, 2002, pp. 49--112, ed 4 10. Capo H, Kupersmith MJ: Efficacy and complications of radiotherapy of anterior visual pathway tumors. Neurol Clin 9:179--203, 1991 11. Cheng SW, Ting AC, Ho P, et al: Accelerated progression of carotid stenosis in patients with previous external neck irradiation. J Vasc Surg 39:409--15, 2004 12. Cibis GW, Whittaker CK, Wood WE: Intraocular extension of optic nerve meningioma in a case of neurofibromatosis. Arch Ophthalmol 103:404--6, 1985 13. Cooling RJ, Wright JE: Arachnoid hyperplasia in optic nerve glioma: confusion with orbital meningioma. Br J Ophthalmol 63:596--9, 1979 14. Dailey RA, et al: Optic nerve sheath meningiomas of childhood. Ophthalmol Clin North Am 4:519--29, 1991 15. Drummond KJ, Zhu JJ, Black PM: Meningiomas: updating basic science, management, and outcome. Neurologist 10: 113--30, 2004 16. Durkin SR, Roos D, Higgs B, et al: Ophthalmic and adnexal complications of radiotherapy. Acta Ophthalmol Scand 85: 240--50, 2007 17. Dutton JJ: Optic nerve sheath meningiomas. Surv Ophthalmol 37:167--83, 1992 18. Dutton JJ, Anderson RL: Idiopathic inflammatory perioptic neuritis simulating optic nerve sheath meningioma. Am J Ophthalmol 100:424--30, 1985 19. Ellenberger C: Perioptic meningiomas. Syndrome of longstanding visual loss, pale disk edema, and optociliary veins. Arch Neurol 33:671--4, 1976

PRIMARY OPTIC NERVE SHEATH MENINGIOMA IN CHILDREN 20. Frise`n L, Royt WF, Tengroth BM: Optociliary veins, disc pallor and visual loss. A triad of signs indicating sphenoorbital meningioma. Acta Ophthalmol (Copenh) 51:241--9, 1973 21. Gabibov GA, Blinkov SM, Tcherekayev VA: The management of optic nerve meningiomas and gliomas. J Neurosurg 68: 889--93, 1988 22. Germano IM, Edwards MS, Davis RL, et al: Intracranial meningiomas of the first two decades of life. J Neurosurg 80: 447--53, 1994 23. Ghim TT, Seo JJ, O’Brien M, et al: Childhood intracranial meningiomas after high-dose irradiation. Cancer 71:4091--5, 1993 24. Goldsmith BJ, Rosenthal SA, Wara WM, et al: Optic neuropathy after irradiation of meningioma. Radiology 185:71--6, 1992 25. Hollenhorst RW, Hollenhorst RW, MacCarty CS: Visual prognosis of optic nerve sheath meningiomas producing shunt vessels on the optic disk: the Hoyt-Spencer syndrome. Trans Am Ophthalmol Soc 75:141--63, 1977 26. Huisman TW, Tanghe HL, Koper JW, et al: Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. Eur J Cancer 27:1453--7, 1991 27. Iacono RP, Apuzzo ML, Davis RL, et al: Multiple meningiomas following radiation therapy for medulloblastoma. Case report. J Neurosurg 55:282--6, 1981 28. Ing EB, Garrity JA, Cross SA, et al: Sarcoid masquerading as optic nerve sheath meningioma. Mayo Clin Proc 72:38--43, 1997 29. Ito M, Ishizawa A, Miyaoka M, et al: Intraorbital meningiomas. Surgical management and role of radiation therapy. Surg Neurol 29:448--53, 1988 30. Jeremic B, Pitz S: Primary optic nerve sheath meningioma: stereotactic fractionated radiation therapy as an emerging treatment of choice. Cancer 110:714--22, 2007 31. Jew SY, Bartley GB, Salomao DR, et al: Radiation-induced meningiomas involving the orbit. Ophthal Plast Reconstr Surg 17:362--8, 2001 32. Karp LA, Zimmerman LE, Borit A, et al: Primary intraorbital meningiomas. Arch Ophthalmol 91:24--8, 1974 33. Kennerdell JS, Maroon JC, Malton M, et al: The management of optic nerve sheath meningiomas. Am J Ophthalmol 106:450--7, 1988 34. Kuroda R, Nakatani J, Yorimae A, et al: Clinical experience of intraorbital optic nerve sheath meningioma--report of eight cases. Neurol Med Chir (Tokyo) 30: 468--75, 1990 35. Levin LA, Jakobiec FA: Optic nerve tumors of childhood: a decision-analytical approach to their diagnosis. Int Ophthalmol Clin 32:223--40, 1992 36. Liauw L, Vielvoye GJ, de Keizer RJ, et al: Optic nerve glioma mimicking an optic nerve meningioma. Clin Neurol Neurosurg 98:258--61, 1996 37. Lloyd GA: The radiology of primary orbital meningioma. Br J Radiol 44:405--11, 1971 38. Louis DN, Scheithauer BW, Budka H, von Deimling A, Kepes JJ: Meningiomas, in Kleihues P, Cavenee WK (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System. Lyon, IARC Press, 2000, pp. 176--84 39. Mawrin C, Sasse T, Kirches E, et al: Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas. Clin Cancer Res 11:4074--82, 2005 40. Miller NR: Primary tumours of the optic nerve and its sheath. Eye 18:1026--37, 2004 41. Moss SD, Rockswold GL, Chou SN, et al: Radiation-induced meningiomas in pediatric patients. Neurosurgery 22:758--61, 1988 42. Narayan S, Cornblath WT, Sandler HM, et al: Preliminary visual outcomes after three-dimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 56:537--43, 2003

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43. Nerad JA, Kersten RC, Anderson RL: Hemangioblastoma of the optic nerve. Report of a case and review of literature. Ophthalmology 95:398--402, 1988 44. Parsons JT, Bova FJ, Fitzgerald CR, et al: Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 30: 755--63, 1994 45. Partington MD, Davis DH: Radiation-induced meningioma after treatment for pituitary adenoma: case report and literature review. Neurosurgery 26:329--31, 1990 46. Perilongo G, Sutton LN, Goldwein JW, et al: Childhood meningiomas. Experience in the modern imaging era. Pediatr Neurosurg 18:16--23, 1992 47. Pitz S, Becker G, Schiefer U, et al: Stereotactic fractionated irradiation of optic nerve sheath meningioma: a new treatment alternative. Br J Ophthalmol 86:1265--8, 2002 48. Rachlin J, Rosenblum M: Etiology and biology of meningiomas, in Al-Mefty O (ed): Meningiomas. New York, Raven Press, 2001, pp. 22--37 49. Radhakrishnan K, Mokri B, Parisi JE, et al: The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 37:67--73, 1995 50. Reubi JC, Maurer R, Klijn JG, et al: High incidence of somatostatin receptors in human meningiomas: biochemical characterization. J Clin Endocrinol Metab 63:433--8, 1986 51. Rubinstein AB, Shalit MN, Cohen ML, et al: Radiationinduced cerebral meningioma: a recognizable entity. J Neurosurg 61:966--71, 1984 52. Russell D, Rubinstein L: Tumours of the meninges and related tissues, in Russell D, Rubinstein L (eds): Pathology of Tumours of the Nervous System. Baltimore, Williams and Wilkins, 1989, pp. 449--532, ed 5 53. Saeed P, Rootman J, Nugent RA, et al: Optic nerve sheath meningiomas. Ophthalmology 110:2019--30, 2003 54. Schulz S, Pauli SU, Schulz S, et al: Immunohistochemical determination of five somatostatin receptors in meningioma reveals frequent overexpression of somatostatin receptor subtype sst2A. Clin Cancer Res 6:1865--74, 2000 55. Sheikh BY, Siqueira E, Dayel F: Meningioma in children: a report of nine cases and a review of the literature. Surg Neurol 45:328--35, 1996 56. Sibony PA, Krauss HR, Kennerdell JS, et al: Optic nerve sheath meningiomas. Clinical manifestations. Ophthalmology 91:1313--26, 1984 57. Spencer WH: Primary neoplasms of the optic nerve and its sheaths: clinical features and current concepts of pathogenetic mechanisms. Trans Am Ophthalmol Soc 70:490--528, 1972 58. Stafford SL, Pollock BE, Leavitt JA, et al: A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 55: 1177--81, 2003 59. Turbin RE, Pokorny K: Diagnosis and treatment of orbital optic nerve sheath meningioma. Cancer Control 11:334--41, 2004 60. Turbin RE, Thompson CR, Kennerdell JS, et al: A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology 109:890--9, discussion 899--900, 2002 61. Walsh FB: Meningiomas primary within the orbit and optic canal, in Smith JL (ed): Neuro-ophthalmology. St. Louis (MO), Symposium of the University of Miami and the Bascom Palmer Eye Institute, 1970, pp. 240--66, Mosby 62. Wilson CB: Meningiomas: genetics, malignancy, and the role of radiation in induction and treatment. The Richard C. Schneider Lecture. J Neurosurg 81:666--75, 1994 63. Wright JE, McNab AA, McDonald WI: Primary optic nerve sheath meningioma. Br J Ophthalmol 73:960--6, 1989 The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Supported by an unrestricted grant from Research to Prevent

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Blindness, New York, New York. Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.

Outline I. General considerations A. Historical perspectives B. Demographics 1. Epidemiology 2. Sex distribution 3. Association with neurofibromatosis II. Clinical features A. B. C. D. E. F.

Visual acuity Visual fields Proptosis Extraocular motility Optic nerve findings Optociliary shunt vessels

III. Radiographic features

LEE ET AL Reprint address: James A. Garrity, MD, Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 e-mail: [email protected].

IV. Histologic findings A. World Health Organization criteria B. Adult subtypes C. Pediatric subtypes V. Treatment A. B. C. D.

Observation Surgery Radiation therapy Future therapies

VI. Prognosis A. B. C. D.

Intracranial extension Growth Visual outcome Mortality

VII. Summary VIII. Method of literature search