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Malignant Gliomas of the Optic Nerve Pathways
MALIGNANT GLIOMAS OF THE OPTIC NERVE PATHWAYS THOMAS
C. SPOOR, M.D., JOHN S. KENNERDELL, M.D., A. JULIO MARTINEZ, M.D., AND DAVID ZORUB, M.D.
Pittsburgh, Pennsylvania
Malignant gliomas of the optic nerve pathways are rare in adults,1.2 and differ from benign optic gliomas that occur in childhood and are considered by some to be hamartomas with self-limiting growth and morbidity.F':" Adult optic glioblastomas are aggressive, causing rapid visual deterioration and subsequent death. They are rarely diagnosed before craniotomy or autopsy.1.2.5 Hoyt and associates 1 examined the clinical and pathologic nature of this tumor and defined a characteristic syndrome consisting of the following: (1) occurrence in middle-aged men; (2) initial signs and symptoms resembling optic neuritis; (3) blindness in two to four months; (4) death in six to nine months. Recent reports indicate that this tumor can occur with visual loss in older individuals of either sex despite normal ophthalmologic and neuroradiologic results.v" We describe herein five cases of malignant optic pathway gliomas, from a single institution, all diagnosed before death. We compared the clinical courses and pathologic features with those in other series. MATERIAL AND METHODS
Biopsy specimens from four cases were examined. In three patients (Cases 2-4),
From the Eye and Ear Hospital, Pittsburgh, Pennsylvania (Dr. Spoor); the Department of Ophthalmology and Neurology (Dr. Kennerdell), Department of Pathology-Neuropathology Division (Dr. Martinez), and Department of Neurosurgery (Dr. Zorub), University of Pittsburgh, Pittsburgh, Pennsylvania. . Reprint requests to John S. Kennerdell, M.D., Eye and Ear Hospital, 230 Lothrop St., Pittsburgh, PA 15213. 284
fragments for paraffin embedding techniques were fixed in buffered 10% formalin; sections were stained with hematoxylin and eosin, and studied by light microscopy. In one patient (Case 5) the biopsy specimen from the left optic nerve was fixed in Karnovsky (4% paraformaldyhyde and 2% glutaraldehyde in Sorenson's buffer) and embedded in plastic for ultrastructural studies. Plastic-embedded sections (l1J.) stained with toluidine blue were studied by light microscopy. Ultrathin sections were mounted in 240-hole copper grids, stained with lead citrate and uranyl acetate, and observed in a Philips 200 electron microscope. CASE REPORTS
Case I-A 69-year-old woman complained of bilaterally blurred vision in December 1970. Results of ophthalmologic examination were normal except for the visual acuity, which was R.E.: hand motions and L.E.: 6/60 (20/200). The left eye was amblyopic, Skull x-rays and brain scan were normal. The patient was treated with systemic prednisone. One month later, she was referred for examination. Examination revealed visual acuity of R.E.: hand motions and L.E.: 6/60 (20/200) with marked dyschromatopsia. A right inferior, total altitudinal fixation defect was present as was a left inferior, dense paracentral scotoma. A right afferent pupillary defect was present. The fundus and optic disks appeared normal bilaterally. A tentative diagnosis of right ischemic optic neuritis was made. Two months later, the right eye was amaurotic and visual acuity in the left eye remained 6/60 (20/200). Optic disks and fundi remained normal. A corrected sedimentation rate was 15 mm/hr. X-rays of the skull and optic foramen were normal. The sella turcica was somewhat enlarged and demineralized, suggesting an infrasellar mass. Bilateral carotid angiograms were normal. Pneumoencephalography showed an extrinsic impression of the anterior right third ventricle, suggesting a small suprasellar mass. Exploratory craniotomy revealed a smooth enlargement and a red-gray discoloration of the optic nerves and chiasm. Histologic examination of a biopsy specimen confirmed the operative impres-
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sion of a malignant astrocytoma. There was no evidence for extension beyond the optic nerve pathways. Postoperatively, the chiasmal region was irradiated (5,000 rads during five weeks). Vision continued to deteriorate. She was totally blind eight months after her initial examination and died a few months later. Permission for autopsy was not granted. The histopathologic specimen was not available for examination. Case 2-A 64-year-old woman was referred for examination in March 1975 for progressive bilateral visual dysfunction attributed to venous stasis retinopathy. Two weeks before referral, examination revealed decreased vision and a hemorrhagic papillopathy in the left eye. Skull x-rays, brain scan, electroencephalogram, and lumbar puncture were reported as normal. Our initial examination revealed visual acuity was R.E.: 6/60 (20/200) and L.E.: light perception. The pupils were sluggishly reactive. Ophthalmoscopic examination revealed bilateral disk edema and an appearance similar to venous stasis retinopathy. Skull x-rays and bilateral carotid arteriograms were normal. Pneumoencephalography revealed blunting of the anterior recess of the third ventricle by a suprasellar mass. Craniotomy revealed swelling and discoloration of the optic nerves and chiasm with extension to the adjacent hypothalmus, A biopsy was performed. Histopathologic examination revealed a highly cellular, malignant neoplasm, composed of atypical, bizarre astrocytes with giant cells and occasionally spindle-shaped and multi-polar astrocytes with pleomorphic and hyperchromatic nuclei. Disrupted myelin sheaths and axons were present within the neoplastic elements (Fig. 1). The diagnosis of malignant astrocytoma was made. Postoperatively, she was treated with radiation therapy. She was totally blind one month after the onset of her visual symptoms. Dementia and lethar-
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gy followed and she died nine months after the onset of symptoms. Autopsy was not permitted. Case 3-A 59-year-old man was first examined in March 1978 three weeks after the onset of bilateral blurred vision. No other ocular symptoms were noted. General health was excellent except for adult-onset diabetes mellitus which was well controlled with oral hypoglycemtcs. Visual acuity on initial examination was R.E.: hand motions and L.E.: 6/60 (20/200) with marked dyschromatopsia. Visual fields revealed bilateral inferior altitudinal defects with loss of fixation. An afferent pupillary defect was present in the right eye. Motility was normal. The optic disks appeared normal. The arterioles were slightly attenuated; the fundi were otherwise unremarkable. Skull x-rays were normal. Computed axial tomography revealed an enhancing mass in the sellar region. This was confirmed by carotid angiography. The mass was believed to be a meningioma. At craniotomy, the optic nerves and chiasm appeared enlarged and elevated. Examination of a biopsy specimen from the region of the chiasm revealed a moderately cellular tumor with numerous foci of mucoid degeneration with frequent hyperchromatic, bizarre, malignant glial cells (Fig. 2). The patient was blind four weeks after the onset of his visual symptoms and he died six months later. Permission for autopsy was not granted. Case 4-A 64-year-old man was referred to us in April 1978 with a three-week history of pain and loss of vision in the right eye. Neuro-ophthalmologic examination revealed an amaurotic right eye with an afferent pupillary defect, 3 mm of proptosis, and a right lateral rectus palsy. Visual acuity was 6/12 (20/40) in the left eye with mild dyschromatopsia. The left visual field was normal. Ophthalmoscopic examination of the right eye revealed a markedly edematous disk and hemorrhagic retinopathy with attenuation of the arterioles. The left fundus was unremarkable. Computed axial tomography re-
Fig. 1 (Spoor and associates). Case 2. Photomicrograph showing a poorly differentiated glial neoplasm with numerous malignant multinucleated giant cells. Atypism and pleomorphism of glial elements are obvious (hematoxylin and eosin, x250).
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Fig. 2 (Spoor and associates). Case 3. Photomicrograph showing an anaplastic astrocytoma containing numerous foci of mucoid degeneration. Frequent hyperchromatic, bizarre malignant glial cells are seen (hematoxylin and eosin, x250).
vealed an enlarged right optic nerve. Tomograms of the optic foramina were normal. Three weeks later, visual acuity in the left eye decreased to 6/15 (20/50) and the visual fields revealed both a peripheral and central superior temporal defect. A fine needle aspiration biopsy of the enlarged right optic nerve under computed axial tomography visualization disclosed cytologic evidence of a malignant astrocytoma. The right orbit was subsequently explored through a medial orbitotomy. The optic nerve was markedly enlarged and violaceously discolored. A biopsy was performed. Histopathologic examination showed a scantily cellular neoplasm composed of sparsely located spindle-shaped, astrocytic cells with irregular, mild pleomorphism, and moderate hyperplasia of blood vessels (Fig. 3). No Rosenthal fibers were evident. Postoperatively, the left optic nerve and chiasm were irradiated and the patient was treated with
systemic prednisone. Visual acuity in the left eye improved initially to 6/9 (20/30). Subsequently, visual acuity and visual field rapidly deteriorated in the left eye and the left optic nerve became atrophic. Total occlusion of the retinal arterioles and venules developed in the right eye, followed by rubeosis of the iris and marked increase of intraocular pressure, necessitating cyclocryotherapy for relief of pain. Six months after the onset of visual symptoms, he was totally blind. Seizures, dementia, and hyperglycemia developed and death occurred three months later. Permission for autopsy was not granted. Case 5-A 60-year-old woman was referred to us in August 1978 with a three-week history of rapidly decreasing vision and bifrontal headaches. Medical history revealed mild hypertension and adult onset diabetes mellitus. Results of neurologic examination, including an electroencephalogram and computed axial tomography before referral were normal.
Fig. 3 (Spoor and associates). Case 4. This tumor is composed of elongated, spindle-shaped hyperchromatic astrocytes. Relative ahundant intercellular glial processes are seen within neoplastic elements (hematoxylin and eosin, x250).
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Initial ophthalmologic examination revealed visual acuity of counting fingers in both eyes and marked dyschromatopsia. There was a dense central scotoma with peripheral constriction in the right eye and a total inferior altitudinal defect with loss of central fixation in the left eye. Pupils were equal but sluggishly reactive. Results of slit-lamp examination and intraocular pressures were normal as was ocular motility. Ophthalmoscopic examination revealed minimal background diabetic retinopathy and normal optic disks in both eyes. The sedimentation rate was 49 mm. Temporal artery biopsy specimens were normal. Skull x-rays and computed axial tomography were normal. A trial of systemic prednisone relieved the headaches and it subjectively improved vision. Subsequently, visual acuity and visual fields progressively deteriorated. Minimal pallor of the disks became evident. An electroretinogram was normal. Repeat enhanced computed axial tomography (American Science and Engineering 512 matrix) with coronal sectioning was normal. Visually evoked response was markedly diminished bilaterally. Polytomography of the optic foramina and sella turcica was also normal. Bilateral carotid angiography, metrizamide cistemography, and pneumoencephalography with midline tomography were also normal. Visual acuity and visual fields continued to deteriorate and pupillary responses became amaurotic. The chiasmal and prechiasmal regions were explored through a right frontal craniotomy. At craniotomy, the optic nerves and chiasm appeared grossly normal, although the left optic nerve was questionably distended. A biopsy specimen was taken of the left optic nerve. The' specimen was characteristic of a highly cellular malignant neoplasm composed of atypical, bizarre astrocytes with disrupted myelin sheaths and axons within neoplastic elements (Fig. 4). Postoperative irradiation treatment was given.
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The patient was blind two months after her initial visual symptoms and she died four months later. DISCUSSION
Since Hoyt and associates! defined the syndrome of malignant glioma of the optic nerve pathway, six additional cases have been reported. 2,5-7 In our five cases as in previous cases, the initial diagnoses were erroneous. All five cases were diagnosed by surgical exploration; four by craniotomy and one by fine needle aspiration biopsy of the enlarged optic nerve under computed axial tomography." This diagnosis was subsequently confirmed by open biopsy of the optic nerve via a medial orbitotomy. After reviewing our cases and those previously reported, we found that malignant optic gliomas do not appear to comprise a remarkably uniform neuroophthalmologic entity as previously reported.' Our patients ranged in age from 59 to 65 years (average, 63.4 years). Three were women and two were men. These data combined with those previously publishedl.2.s-7.9.lo gave a total of 26 patients whose ages ranged from 22 to 79 years (average, 51.9 years). Of these 26,15 were men and 11 were women. Our series did
Fig. 4 (Spoor and associates). Case 5. Photomicrograph revealing numerous disrupted myelin sheath intermingling with bizarre, atypical astrocytes. Plastic-embedded tissue (toluidine blue, x250).
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not show the marked statistical tendency for middle-aged men, as previously described.! Visual loss in our patients was rapid and unrelenting; with blindness ensuing in a matter of months (average, 3.6; range, one to eight months) and death following shortly thereafter. This sequence of events and rapid course is similar to that described by others. I.2.5- 7,9.10 Our patients all had blurred or dimming vision as the initial symptom, bilaterally in four of the five. Bilateral involvement has been reported by others.v" although initial monocular involvement has been described as characteristic.t-P'-'? As in other reports, periorbital pain was a common early symptom in our patients. Table 1 shows the initial ocular findings in our patients and those previously reported. I,2.5-7.9.10 There is an equal incidence of unilateral and bilateral visual dysfunction as the initial symptom. It was also evident that optic disk edema was present on initial ophthalmologic examination in slightly over one half of these patients. Three of our patients and all of Harper and Stewart-Wynne's" patients had nearly normal appearing disks and fundi throughout their illness. The failure of these patients to develop disk edema and venous stasis probably results from a tumor located more centrally in the anterior visual pathways. Our three patients with normal fundi (Cases TABLE I INITIAL OCULAR FINDINGS IN 18 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Initial Symptom
No.
Decreased Vis ion l'nilateral Bi lateral Disk Edema Normal or mild atrophy
18 9 9
10 8
Percent
100 50 50 55.5 44.5
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1, 3, and 5) all had bilateral severe visual dysfunction and bilateral inferior altitudinal visual field defects with loss of central vision. Table 2 relates the visual field defects found in 13 patients to the ophthalmoscopic appearance of their optic disks. Those patients with optic disk edema in one eye and a normal appearing contralateral disk, had dense central defects in the eye with the edematous disk, and a contralateral temporal hemianopia, progressing to involve central visual acuity. Those patients with similar defects and bilaterally normal optic disks probably had tumors originating more centrally in the optic nerve or chiasm. Two patients (Harper and StewardWynne's- Cases 2 and 3) with homonymous hemianopia had extensive involvement of their cerebral hemispheres with tumor and appropriate neurologic deficits. Their fundi were normal. Autopsy showed infiltration of the optic tract, chiasm, and right cerebral hemispheres. One of our patients (Case 4), had extensive ocular and orbital involvement; proptosis, conjunctival chemosis, ophthalmoplegia, optic disk swelling, central retinal vein occlusion, ischemic signs of the anterior segment, and hemorrhagic glaucoma. At orbitotomy, the intraorbital optic nerve was enlarged, violaceously discolored, and involved with tumor. A similar case has been described." Table 3 summarizes ocular and orbital complications reported in 26 malignant gliomas of the optic nerve pathways.I.2.5-7.9.10 We agree with a previous review! that orbital and ocular complications are not frequent and result from invasion of tumor into the orbit. Only one of our patients (Case 4) had such involvement. He also had partial ophthalmoplegia as did the case reported by Hamilton and associates." The initial symptoms in all of our patients were ocular. Neurologic complica-
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TABLE 2 INITIAL VISUAL FIELDS AND OPTIC DISKS IN 13 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Visual Field Defect Inferior altitudinal in both eyes Central scotoma Contralateral temporal Homonymous hemianopia Central scotoma Contralateral temporal
Percent
3
23.1
Normal, both eyes
2 2
15.4 15.4
6
46.1
Normal, both eyes Normal, both eyes Edema and stasis Normal (contralateral)
tions occurred late, were mild in the early stages in some (Cases 1, 3, and 5), and marked in others (Cases 2 and 4). The predominance of ocular symptoms with the late occurrence of neurologic symptoms suggests that these tumors originated in the optic nerve pathways. Adult-onset diabetes mellitus was present before the development of ocular symptoms in two of our patients (Cases 3 and 5). The patient in Case 4 developed marked hyperglycemia before death with marked personality changes. Skull and optic foramina x-rays were not abnormal in any of our patients. In one case (Case 1), the sella turcica was thought to be enlarged, indicating a possible intrasellar mass. Carotid angiography showed an enhancing sellar mass in Case 3, but was normal in three others. Computed axial tomography was performed on three patients and was abnormal in two. The computed axial tornogra-
TABLE 3 ORBITAL AND OCULAR COMPLICATIONS IN 26 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Complication
No.
Percent
Proptosis Edema/chemosis Ophthalmoplegia Glaucoma (hemorrhagic)
6 3
23 11.5 26.9 11.5
7 3
Disk Appearance
No.
phy in Case 4 showed a swollen optic nerve and a biopsy specimen was taken, sparing the patient a craniotomy. An enhancing sellar mass was shown in Case 3. In Case 5, computed axial tomography combined with metrizamide cisternography was normal. This same patient had relatively normal appearing visual pathways at craniotomy, the diagnosis was made from a biopsy specimen of a questionably distended left optic nerve. Pneumoencephalography revealed subtle abnormalities in Cases 1 and 2, and was normal in Case 5. Table 4 summarizes the diagnostic value of various neurologic procedures in 11 recently reported cases 1 •2 •5 - 7 and five of our own. Computed axial tomography appears to be a good diagnostic modality; but has not been used often in these cases. It revealed· abnormalities in two of the three cases described previously. In one other (Harper and Stewart-Wynne's" Case 2) a large enhancing mass was indicated in the right cerebral hemisphere. Cerebral angiography and pneumoencephalography yielded inconclusive results in approximately one half of the cases. Plain skull x-rays of the optic foramina and chiasm were generally unrevealing. Exploratory craniotomy and biopsy were necessary to make a diagnosis in four of our five cases. In Case 4 the diagnosis was made by fine needle aspira-
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TABLE 4 NEURORADIOLOGIC EVALUATION IN 16 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Procedure
Percent Abnormal
No. of Patients
X-rays Skull series Optic canals Sella turcica Computed axial tomography Angiography Pneumoencephalogram
6.2 16.6 15.4 75 41.6 54.5
16 12
tion biopsy of an enlarged optic nerve; this was subsequently confirmed by open biopsy through a medial orbitotomy. Our experience supports the premise that malignant gliomas may originate in either optic nerve, tract, or chiasm and extend proximally and distally.':" Patients with gliomas of proximal origin have bilateral visual dysfunction and normal appearing fundi (Cases 1,3, and 5). A patient with a tumor originating more distally in an optic nerve may have unilateral visual dysfunction, ophthalmoscopic signs of optic disk edema, and venous stasis. As growth proceeds proximally, a contralateral superior temporal hemianopia develops and the inferior nasal crossing fibers are involved in the proximal optic nerve. With further growth and extension into the chiasm, subsequent loss of central visual acuity ensues. The optic disk will appear normal or slightly atrophic. However, if the predominent growth extends distally along the contralateral optic nerve, disk edema and venous stasis will accompany contralateral visual dysfunction. A patient with a tumor originating more proximally and extending in a predominantly posterior direction, may have hemiparesis and hypothalamic symptoms preceding visual loss (Hoyt and associates, I Case 3) or accompanying it (Harper and Stewart-Wynne'sf Cases 2 and 3). We believe that the method of explora-
13
4 12 II
tion and diagnosis depends on the location of the tumor and the clinician's judgment. In a patient with a distally located tumor and rapid, unilateral, progressive visual loss and ophthalmoscopic signs of disk swelling and venous stasis, a diagnosis may be made either by fine needle aspiration biopsy" or orbitotomy (medial or lateral). Patients with more proximally located tumors and progressive, bilateral visual loss, and negative findings of ophthalmologic and neuroradiologic examinations should undergo exploratory craniotomy with biopsy of the optic nerve. All five of our patients were treated with a course of radiation therapy. It was not effective in any patients. As in other reports,I,2,5 the tumor progressed rapidly and no known treatment has had any beneficial effect. Permission for autopsy was not granted in any of our cases. Histologic diagnosis was made from biopsy specimens obtained at craniotomy or orbitotomy. Table 5 compares the histopathologic features observed in four of our five biopsy specimens (Cases 2-5). The specimen from Case 1 was unavailable for examination. Microscopic features of severe malignancy showing pleomorphic, atypical, and mitotically active astrocytes were evident in Cases 2, 3, and 5 (Figs. 1, 2, and 4). One specimen (Case 4) (Fig. 3) ap-
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MALIGNANT GLIOMAS TABLE 5 HISTOPATHOLOGIC FEATURES IN FOUR CASES OF MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Case No. 2
3
4
5
Histologic Diagnosis
Histologic Features Densely cellular; marked atypia; pleomorphism, hyperchromatism; giant cells; rare mitosis; and vascular and endothelial proliferation Less cellular; modest atypism; mild cellular pleornorphorisrn, foci of mucoid degeneration; hyperplasia of blood vessels, severe Densely cellular, elongated, spindle-shaped astrocytes; modest atypism; mild pleomorphism hyperchromatism; rare mitosis Myelin sheaths separated by bizarre, atypical, and pleomorphic astrocytes
peared to be a well-differentiated astrocytoma. Biopsy specimens of a welldifferentiated glial neoplasm without significant atypical astrocytes, obtained from a clinically aggressive lesion, have been previously described! and the aggressive nature of the tumor subsequently confirmed at autopsy.' Extensive vascular and endothelial proliferation, as well as disruption of myelin sheaths and axons, were also noted and have been described by others.t-? We also believe that adult-onset optic gliomas are acquired and originate primarily in the optic nerve pathways, although this premise cannot be established by histopathologic evidence alone.' Supporting this premise, Hoyt and associates! stated that initial symptoms occur during adulthood and originate in the anterior visual pathways. Initially, all our patients had symptoms of visual dysfunction referable to the optic nerves or chiasm as the sole manifestation of their tumor. Additionally, neurosurgical exploration in two patients (Cases 1 and 5) revealed abnormalities confined to the optic nerve or chiasm and
Glioblastoma multiforme
Anaplastic astrocytoma
Well-differentiated astrocytoma
Glioblastoma multiforrne
no evidence for extension to adjacent structures. SUMMARY
We compared the clinical course and histopathologic findings in five patients with malignant gliomas originating from the optic nerve pathways with those in previously reported cases to elucidate further the clinical features of this tumor and facilitate future diagnoses. Patients with malignant optic nerve pathway gliomas had unilateral or bilateral visual dysfunction, which was often accompanied by periorbital discomfort in an otherwise asymptomatic adult. Regardless of origin, the clinical course invariably was bilateral blindness rapidly followed by death. Occasionally, the diagnosis was made preoperatively and was confirmed by surgical exploration and biopsy. REFERENCES 1. Hoyt, W. F., Meshel, L. G., Lessel, S., Schatz, N. J., and Suckling, R.: Malignant optic gliomas of adulthood. Brain 96: 121, 1973. 2. Manor, R. S., Israeli, J., and Sandbank, U.: Malignant optic glioma in a 70-year-old patient. Arch. Ophthalmol, 94:1142, 1976.
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3. Verhoefl, F. H.: Primary intraneural tumours (gliomas) of the optic nerves. Arch. Ophthalmol, 51:120,1922. 4. Hoyt, W. F., and Baghdassarian, S. A.: Optic glioma of childhood. Br. J. Ophthalmol. 53:793, 1969. 5. Harper, C. G., and Stewart-Wynne, E. G.: Malignant gliomas in adults. Arch. Neurol. 35:731, 1978. 6. Gibberd, F. B., Miller, T. N., and Morgan, P. D.: Glioblastoma of the optic chiasm. Br, J. Ophthalmol. 57:788, 1973. 7. Hamilton, A. M., Garner, A., Tripathi, R. C.,
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and Sanders, M. D.: Malignant optic nerve glioma. Report of a case with electronmicroscopic study. Br. J. Ophthalmol, 57:253, 1973. 8. Kennerdell, J. S., Dekker, A., Johnson, B. L., and Dubois, P. J.: Fine needle aspiration biopsy. A report of its use in orbital tumors. Arch. Ophthalmol. 97:1315, 1979. 9. Saeb, J.: Primary tumors of the optic nerve (glioblastoma multiformi). Br. J. Ophthalmol. 33: 701,1949. 10. Mattson, R. H., and Peterson, E. W.: Glioblastoma multiform of the optic nerve. J.A.M.A. 196:799, 1966.
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Editor-in-Chief AMERICAN JOURNAL OF OPHTHALMOLOGY
C. SPOOR, M.D., JOHN S. KENNERDELL, M.D., A. JULIO MARTINEZ, M.D., AND DAVID ZORUB, M.D.
Pittsburgh, Pennsylvania
Malignant gliomas of the optic nerve pathways are rare in adults,1.2 and differ from benign optic gliomas that occur in childhood and are considered by some to be hamartomas with self-limiting growth and morbidity.F':" Adult optic glioblastomas are aggressive, causing rapid visual deterioration and subsequent death. They are rarely diagnosed before craniotomy or autopsy.1.2.5 Hoyt and associates 1 examined the clinical and pathologic nature of this tumor and defined a characteristic syndrome consisting of the following: (1) occurrence in middle-aged men; (2) initial signs and symptoms resembling optic neuritis; (3) blindness in two to four months; (4) death in six to nine months. Recent reports indicate that this tumor can occur with visual loss in older individuals of either sex despite normal ophthalmologic and neuroradiologic results.v" We describe herein five cases of malignant optic pathway gliomas, from a single institution, all diagnosed before death. We compared the clinical courses and pathologic features with those in other series. MATERIAL AND METHODS
Biopsy specimens from four cases were examined. In three patients (Cases 2-4),
From the Eye and Ear Hospital, Pittsburgh, Pennsylvania (Dr. Spoor); the Department of Ophthalmology and Neurology (Dr. Kennerdell), Department of Pathology-Neuropathology Division (Dr. Martinez), and Department of Neurosurgery (Dr. Zorub), University of Pittsburgh, Pittsburgh, Pennsylvania. . Reprint requests to John S. Kennerdell, M.D., Eye and Ear Hospital, 230 Lothrop St., Pittsburgh, PA 15213. 284
fragments for paraffin embedding techniques were fixed in buffered 10% formalin; sections were stained with hematoxylin and eosin, and studied by light microscopy. In one patient (Case 5) the biopsy specimen from the left optic nerve was fixed in Karnovsky (4% paraformaldyhyde and 2% glutaraldehyde in Sorenson's buffer) and embedded in plastic for ultrastructural studies. Plastic-embedded sections (l1J.) stained with toluidine blue were studied by light microscopy. Ultrathin sections were mounted in 240-hole copper grids, stained with lead citrate and uranyl acetate, and observed in a Philips 200 electron microscope. CASE REPORTS
Case I-A 69-year-old woman complained of bilaterally blurred vision in December 1970. Results of ophthalmologic examination were normal except for the visual acuity, which was R.E.: hand motions and L.E.: 6/60 (20/200). The left eye was amblyopic, Skull x-rays and brain scan were normal. The patient was treated with systemic prednisone. One month later, she was referred for examination. Examination revealed visual acuity of R.E.: hand motions and L.E.: 6/60 (20/200) with marked dyschromatopsia. A right inferior, total altitudinal fixation defect was present as was a left inferior, dense paracentral scotoma. A right afferent pupillary defect was present. The fundus and optic disks appeared normal bilaterally. A tentative diagnosis of right ischemic optic neuritis was made. Two months later, the right eye was amaurotic and visual acuity in the left eye remained 6/60 (20/200). Optic disks and fundi remained normal. A corrected sedimentation rate was 15 mm/hr. X-rays of the skull and optic foramen were normal. The sella turcica was somewhat enlarged and demineralized, suggesting an infrasellar mass. Bilateral carotid angiograms were normal. Pneumoencephalography showed an extrinsic impression of the anterior right third ventricle, suggesting a small suprasellar mass. Exploratory craniotomy revealed a smooth enlargement and a red-gray discoloration of the optic nerves and chiasm. Histologic examination of a biopsy specimen confirmed the operative impres-
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sion of a malignant astrocytoma. There was no evidence for extension beyond the optic nerve pathways. Postoperatively, the chiasmal region was irradiated (5,000 rads during five weeks). Vision continued to deteriorate. She was totally blind eight months after her initial examination and died a few months later. Permission for autopsy was not granted. The histopathologic specimen was not available for examination. Case 2-A 64-year-old woman was referred for examination in March 1975 for progressive bilateral visual dysfunction attributed to venous stasis retinopathy. Two weeks before referral, examination revealed decreased vision and a hemorrhagic papillopathy in the left eye. Skull x-rays, brain scan, electroencephalogram, and lumbar puncture were reported as normal. Our initial examination revealed visual acuity was R.E.: 6/60 (20/200) and L.E.: light perception. The pupils were sluggishly reactive. Ophthalmoscopic examination revealed bilateral disk edema and an appearance similar to venous stasis retinopathy. Skull x-rays and bilateral carotid arteriograms were normal. Pneumoencephalography revealed blunting of the anterior recess of the third ventricle by a suprasellar mass. Craniotomy revealed swelling and discoloration of the optic nerves and chiasm with extension to the adjacent hypothalmus, A biopsy was performed. Histopathologic examination revealed a highly cellular, malignant neoplasm, composed of atypical, bizarre astrocytes with giant cells and occasionally spindle-shaped and multi-polar astrocytes with pleomorphic and hyperchromatic nuclei. Disrupted myelin sheaths and axons were present within the neoplastic elements (Fig. 1). The diagnosis of malignant astrocytoma was made. Postoperatively, she was treated with radiation therapy. She was totally blind one month after the onset of her visual symptoms. Dementia and lethar-
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gy followed and she died nine months after the onset of symptoms. Autopsy was not permitted. Case 3-A 59-year-old man was first examined in March 1978 three weeks after the onset of bilateral blurred vision. No other ocular symptoms were noted. General health was excellent except for adult-onset diabetes mellitus which was well controlled with oral hypoglycemtcs. Visual acuity on initial examination was R.E.: hand motions and L.E.: 6/60 (20/200) with marked dyschromatopsia. Visual fields revealed bilateral inferior altitudinal defects with loss of fixation. An afferent pupillary defect was present in the right eye. Motility was normal. The optic disks appeared normal. The arterioles were slightly attenuated; the fundi were otherwise unremarkable. Skull x-rays were normal. Computed axial tomography revealed an enhancing mass in the sellar region. This was confirmed by carotid angiography. The mass was believed to be a meningioma. At craniotomy, the optic nerves and chiasm appeared enlarged and elevated. Examination of a biopsy specimen from the region of the chiasm revealed a moderately cellular tumor with numerous foci of mucoid degeneration with frequent hyperchromatic, bizarre, malignant glial cells (Fig. 2). The patient was blind four weeks after the onset of his visual symptoms and he died six months later. Permission for autopsy was not granted. Case 4-A 64-year-old man was referred to us in April 1978 with a three-week history of pain and loss of vision in the right eye. Neuro-ophthalmologic examination revealed an amaurotic right eye with an afferent pupillary defect, 3 mm of proptosis, and a right lateral rectus palsy. Visual acuity was 6/12 (20/40) in the left eye with mild dyschromatopsia. The left visual field was normal. Ophthalmoscopic examination of the right eye revealed a markedly edematous disk and hemorrhagic retinopathy with attenuation of the arterioles. The left fundus was unremarkable. Computed axial tomography re-
Fig. 1 (Spoor and associates). Case 2. Photomicrograph showing a poorly differentiated glial neoplasm with numerous malignant multinucleated giant cells. Atypism and pleomorphism of glial elements are obvious (hematoxylin and eosin, x250).
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Fig. 2 (Spoor and associates). Case 3. Photomicrograph showing an anaplastic astrocytoma containing numerous foci of mucoid degeneration. Frequent hyperchromatic, bizarre malignant glial cells are seen (hematoxylin and eosin, x250).
vealed an enlarged right optic nerve. Tomograms of the optic foramina were normal. Three weeks later, visual acuity in the left eye decreased to 6/15 (20/50) and the visual fields revealed both a peripheral and central superior temporal defect. A fine needle aspiration biopsy of the enlarged right optic nerve under computed axial tomography visualization disclosed cytologic evidence of a malignant astrocytoma. The right orbit was subsequently explored through a medial orbitotomy. The optic nerve was markedly enlarged and violaceously discolored. A biopsy was performed. Histopathologic examination showed a scantily cellular neoplasm composed of sparsely located spindle-shaped, astrocytic cells with irregular, mild pleomorphism, and moderate hyperplasia of blood vessels (Fig. 3). No Rosenthal fibers were evident. Postoperatively, the left optic nerve and chiasm were irradiated and the patient was treated with
systemic prednisone. Visual acuity in the left eye improved initially to 6/9 (20/30). Subsequently, visual acuity and visual field rapidly deteriorated in the left eye and the left optic nerve became atrophic. Total occlusion of the retinal arterioles and venules developed in the right eye, followed by rubeosis of the iris and marked increase of intraocular pressure, necessitating cyclocryotherapy for relief of pain. Six months after the onset of visual symptoms, he was totally blind. Seizures, dementia, and hyperglycemia developed and death occurred three months later. Permission for autopsy was not granted. Case 5-A 60-year-old woman was referred to us in August 1978 with a three-week history of rapidly decreasing vision and bifrontal headaches. Medical history revealed mild hypertension and adult onset diabetes mellitus. Results of neurologic examination, including an electroencephalogram and computed axial tomography before referral were normal.
Fig. 3 (Spoor and associates). Case 4. This tumor is composed of elongated, spindle-shaped hyperchromatic astrocytes. Relative ahundant intercellular glial processes are seen within neoplastic elements (hematoxylin and eosin, x250).
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Initial ophthalmologic examination revealed visual acuity of counting fingers in both eyes and marked dyschromatopsia. There was a dense central scotoma with peripheral constriction in the right eye and a total inferior altitudinal defect with loss of central fixation in the left eye. Pupils were equal but sluggishly reactive. Results of slit-lamp examination and intraocular pressures were normal as was ocular motility. Ophthalmoscopic examination revealed minimal background diabetic retinopathy and normal optic disks in both eyes. The sedimentation rate was 49 mm. Temporal artery biopsy specimens were normal. Skull x-rays and computed axial tomography were normal. A trial of systemic prednisone relieved the headaches and it subjectively improved vision. Subsequently, visual acuity and visual fields progressively deteriorated. Minimal pallor of the disks became evident. An electroretinogram was normal. Repeat enhanced computed axial tomography (American Science and Engineering 512 matrix) with coronal sectioning was normal. Visually evoked response was markedly diminished bilaterally. Polytomography of the optic foramina and sella turcica was also normal. Bilateral carotid angiography, metrizamide cistemography, and pneumoencephalography with midline tomography were also normal. Visual acuity and visual fields continued to deteriorate and pupillary responses became amaurotic. The chiasmal and prechiasmal regions were explored through a right frontal craniotomy. At craniotomy, the optic nerves and chiasm appeared grossly normal, although the left optic nerve was questionably distended. A biopsy specimen was taken of the left optic nerve. The' specimen was characteristic of a highly cellular malignant neoplasm composed of atypical, bizarre astrocytes with disrupted myelin sheaths and axons within neoplastic elements (Fig. 4). Postoperative irradiation treatment was given.
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The patient was blind two months after her initial visual symptoms and she died four months later. DISCUSSION
Since Hoyt and associates! defined the syndrome of malignant glioma of the optic nerve pathway, six additional cases have been reported. 2,5-7 In our five cases as in previous cases, the initial diagnoses were erroneous. All five cases were diagnosed by surgical exploration; four by craniotomy and one by fine needle aspiration biopsy of the enlarged optic nerve under computed axial tomography." This diagnosis was subsequently confirmed by open biopsy of the optic nerve via a medial orbitotomy. After reviewing our cases and those previously reported, we found that malignant optic gliomas do not appear to comprise a remarkably uniform neuroophthalmologic entity as previously reported.' Our patients ranged in age from 59 to 65 years (average, 63.4 years). Three were women and two were men. These data combined with those previously publishedl.2.s-7.9.lo gave a total of 26 patients whose ages ranged from 22 to 79 years (average, 51.9 years). Of these 26,15 were men and 11 were women. Our series did
Fig. 4 (Spoor and associates). Case 5. Photomicrograph revealing numerous disrupted myelin sheath intermingling with bizarre, atypical astrocytes. Plastic-embedded tissue (toluidine blue, x250).
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not show the marked statistical tendency for middle-aged men, as previously described.! Visual loss in our patients was rapid and unrelenting; with blindness ensuing in a matter of months (average, 3.6; range, one to eight months) and death following shortly thereafter. This sequence of events and rapid course is similar to that described by others. I.2.5- 7,9.10 Our patients all had blurred or dimming vision as the initial symptom, bilaterally in four of the five. Bilateral involvement has been reported by others.v" although initial monocular involvement has been described as characteristic.t-P'-'? As in other reports, periorbital pain was a common early symptom in our patients. Table 1 shows the initial ocular findings in our patients and those previously reported. I,2.5-7.9.10 There is an equal incidence of unilateral and bilateral visual dysfunction as the initial symptom. It was also evident that optic disk edema was present on initial ophthalmologic examination in slightly over one half of these patients. Three of our patients and all of Harper and Stewart-Wynne's" patients had nearly normal appearing disks and fundi throughout their illness. The failure of these patients to develop disk edema and venous stasis probably results from a tumor located more centrally in the anterior visual pathways. Our three patients with normal fundi (Cases TABLE I INITIAL OCULAR FINDINGS IN 18 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Initial Symptom
No.
Decreased Vis ion l'nilateral Bi lateral Disk Edema Normal or mild atrophy
18 9 9
10 8
Percent
100 50 50 55.5 44.5
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1, 3, and 5) all had bilateral severe visual dysfunction and bilateral inferior altitudinal visual field defects with loss of central vision. Table 2 relates the visual field defects found in 13 patients to the ophthalmoscopic appearance of their optic disks. Those patients with optic disk edema in one eye and a normal appearing contralateral disk, had dense central defects in the eye with the edematous disk, and a contralateral temporal hemianopia, progressing to involve central visual acuity. Those patients with similar defects and bilaterally normal optic disks probably had tumors originating more centrally in the optic nerve or chiasm. Two patients (Harper and StewardWynne's- Cases 2 and 3) with homonymous hemianopia had extensive involvement of their cerebral hemispheres with tumor and appropriate neurologic deficits. Their fundi were normal. Autopsy showed infiltration of the optic tract, chiasm, and right cerebral hemispheres. One of our patients (Case 4), had extensive ocular and orbital involvement; proptosis, conjunctival chemosis, ophthalmoplegia, optic disk swelling, central retinal vein occlusion, ischemic signs of the anterior segment, and hemorrhagic glaucoma. At orbitotomy, the intraorbital optic nerve was enlarged, violaceously discolored, and involved with tumor. A similar case has been described." Table 3 summarizes ocular and orbital complications reported in 26 malignant gliomas of the optic nerve pathways.I.2.5-7.9.10 We agree with a previous review! that orbital and ocular complications are not frequent and result from invasion of tumor into the orbit. Only one of our patients (Case 4) had such involvement. He also had partial ophthalmoplegia as did the case reported by Hamilton and associates." The initial symptoms in all of our patients were ocular. Neurologic complica-
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TABLE 2 INITIAL VISUAL FIELDS AND OPTIC DISKS IN 13 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Visual Field Defect Inferior altitudinal in both eyes Central scotoma Contralateral temporal Homonymous hemianopia Central scotoma Contralateral temporal
Percent
3
23.1
Normal, both eyes
2 2
15.4 15.4
6
46.1
Normal, both eyes Normal, both eyes Edema and stasis Normal (contralateral)
tions occurred late, were mild in the early stages in some (Cases 1, 3, and 5), and marked in others (Cases 2 and 4). The predominance of ocular symptoms with the late occurrence of neurologic symptoms suggests that these tumors originated in the optic nerve pathways. Adult-onset diabetes mellitus was present before the development of ocular symptoms in two of our patients (Cases 3 and 5). The patient in Case 4 developed marked hyperglycemia before death with marked personality changes. Skull and optic foramina x-rays were not abnormal in any of our patients. In one case (Case 1), the sella turcica was thought to be enlarged, indicating a possible intrasellar mass. Carotid angiography showed an enhancing sellar mass in Case 3, but was normal in three others. Computed axial tomography was performed on three patients and was abnormal in two. The computed axial tornogra-
TABLE 3 ORBITAL AND OCULAR COMPLICATIONS IN 26 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Complication
No.
Percent
Proptosis Edema/chemosis Ophthalmoplegia Glaucoma (hemorrhagic)
6 3
23 11.5 26.9 11.5
7 3
Disk Appearance
No.
phy in Case 4 showed a swollen optic nerve and a biopsy specimen was taken, sparing the patient a craniotomy. An enhancing sellar mass was shown in Case 3. In Case 5, computed axial tomography combined with metrizamide cisternography was normal. This same patient had relatively normal appearing visual pathways at craniotomy, the diagnosis was made from a biopsy specimen of a questionably distended left optic nerve. Pneumoencephalography revealed subtle abnormalities in Cases 1 and 2, and was normal in Case 5. Table 4 summarizes the diagnostic value of various neurologic procedures in 11 recently reported cases 1 •2 •5 - 7 and five of our own. Computed axial tomography appears to be a good diagnostic modality; but has not been used often in these cases. It revealed· abnormalities in two of the three cases described previously. In one other (Harper and Stewart-Wynne's" Case 2) a large enhancing mass was indicated in the right cerebral hemisphere. Cerebral angiography and pneumoencephalography yielded inconclusive results in approximately one half of the cases. Plain skull x-rays of the optic foramina and chiasm were generally unrevealing. Exploratory craniotomy and biopsy were necessary to make a diagnosis in four of our five cases. In Case 4 the diagnosis was made by fine needle aspira-
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TABLE 4 NEURORADIOLOGIC EVALUATION IN 16 PATIENTS WITH MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Procedure
Percent Abnormal
No. of Patients
X-rays Skull series Optic canals Sella turcica Computed axial tomography Angiography Pneumoencephalogram
6.2 16.6 15.4 75 41.6 54.5
16 12
tion biopsy of an enlarged optic nerve; this was subsequently confirmed by open biopsy through a medial orbitotomy. Our experience supports the premise that malignant gliomas may originate in either optic nerve, tract, or chiasm and extend proximally and distally.':" Patients with gliomas of proximal origin have bilateral visual dysfunction and normal appearing fundi (Cases 1,3, and 5). A patient with a tumor originating more distally in an optic nerve may have unilateral visual dysfunction, ophthalmoscopic signs of optic disk edema, and venous stasis. As growth proceeds proximally, a contralateral superior temporal hemianopia develops and the inferior nasal crossing fibers are involved in the proximal optic nerve. With further growth and extension into the chiasm, subsequent loss of central visual acuity ensues. The optic disk will appear normal or slightly atrophic. However, if the predominent growth extends distally along the contralateral optic nerve, disk edema and venous stasis will accompany contralateral visual dysfunction. A patient with a tumor originating more proximally and extending in a predominantly posterior direction, may have hemiparesis and hypothalamic symptoms preceding visual loss (Hoyt and associates, I Case 3) or accompanying it (Harper and Stewart-Wynne'sf Cases 2 and 3). We believe that the method of explora-
13
4 12 II
tion and diagnosis depends on the location of the tumor and the clinician's judgment. In a patient with a distally located tumor and rapid, unilateral, progressive visual loss and ophthalmoscopic signs of disk swelling and venous stasis, a diagnosis may be made either by fine needle aspiration biopsy" or orbitotomy (medial or lateral). Patients with more proximally located tumors and progressive, bilateral visual loss, and negative findings of ophthalmologic and neuroradiologic examinations should undergo exploratory craniotomy with biopsy of the optic nerve. All five of our patients were treated with a course of radiation therapy. It was not effective in any patients. As in other reports,I,2,5 the tumor progressed rapidly and no known treatment has had any beneficial effect. Permission for autopsy was not granted in any of our cases. Histologic diagnosis was made from biopsy specimens obtained at craniotomy or orbitotomy. Table 5 compares the histopathologic features observed in four of our five biopsy specimens (Cases 2-5). The specimen from Case 1 was unavailable for examination. Microscopic features of severe malignancy showing pleomorphic, atypical, and mitotically active astrocytes were evident in Cases 2, 3, and 5 (Figs. 1, 2, and 4). One specimen (Case 4) (Fig. 3) ap-
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MALIGNANT GLIOMAS TABLE 5 HISTOPATHOLOGIC FEATURES IN FOUR CASES OF MALIGNANT GLIOMAS OF THE AFFERENT VISUAL PATHWAY
Case No. 2
3
4
5
Histologic Diagnosis
Histologic Features Densely cellular; marked atypia; pleomorphism, hyperchromatism; giant cells; rare mitosis; and vascular and endothelial proliferation Less cellular; modest atypism; mild cellular pleornorphorisrn, foci of mucoid degeneration; hyperplasia of blood vessels, severe Densely cellular, elongated, spindle-shaped astrocytes; modest atypism; mild pleomorphism hyperchromatism; rare mitosis Myelin sheaths separated by bizarre, atypical, and pleomorphic astrocytes
peared to be a well-differentiated astrocytoma. Biopsy specimens of a welldifferentiated glial neoplasm without significant atypical astrocytes, obtained from a clinically aggressive lesion, have been previously described! and the aggressive nature of the tumor subsequently confirmed at autopsy.' Extensive vascular and endothelial proliferation, as well as disruption of myelin sheaths and axons, were also noted and have been described by others.t-? We also believe that adult-onset optic gliomas are acquired and originate primarily in the optic nerve pathways, although this premise cannot be established by histopathologic evidence alone.' Supporting this premise, Hoyt and associates! stated that initial symptoms occur during adulthood and originate in the anterior visual pathways. Initially, all our patients had symptoms of visual dysfunction referable to the optic nerves or chiasm as the sole manifestation of their tumor. Additionally, neurosurgical exploration in two patients (Cases 1 and 5) revealed abnormalities confined to the optic nerve or chiasm and
Glioblastoma multiforme
Anaplastic astrocytoma
Well-differentiated astrocytoma
Glioblastoma multiforrne
no evidence for extension to adjacent structures. SUMMARY
We compared the clinical course and histopathologic findings in five patients with malignant gliomas originating from the optic nerve pathways with those in previously reported cases to elucidate further the clinical features of this tumor and facilitate future diagnoses. Patients with malignant optic nerve pathway gliomas had unilateral or bilateral visual dysfunction, which was often accompanied by periorbital discomfort in an otherwise asymptomatic adult. Regardless of origin, the clinical course invariably was bilateral blindness rapidly followed by death. Occasionally, the diagnosis was made preoperatively and was confirmed by surgical exploration and biopsy. REFERENCES 1. Hoyt, W. F., Meshel, L. G., Lessel, S., Schatz, N. J., and Suckling, R.: Malignant optic gliomas of adulthood. Brain 96: 121, 1973. 2. Manor, R. S., Israeli, J., and Sandbank, U.: Malignant optic glioma in a 70-year-old patient. Arch. Ophthalmol, 94:1142, 1976.
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3. Verhoefl, F. H.: Primary intraneural tumours (gliomas) of the optic nerves. Arch. Ophthalmol, 51:120,1922. 4. Hoyt, W. F., and Baghdassarian, S. A.: Optic glioma of childhood. Br. J. Ophthalmol. 53:793, 1969. 5. Harper, C. G., and Stewart-Wynne, E. G.: Malignant gliomas in adults. Arch. Neurol. 35:731, 1978. 6. Gibberd, F. B., Miller, T. N., and Morgan, P. D.: Glioblastoma of the optic chiasm. Br, J. Ophthalmol. 57:788, 1973. 7. Hamilton, A. M., Garner, A., Tripathi, R. C.,
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and Sanders, M. D.: Malignant optic nerve glioma. Report of a case with electronmicroscopic study. Br. J. Ophthalmol, 57:253, 1973. 8. Kennerdell, J. S., Dekker, A., Johnson, B. L., and Dubois, P. J.: Fine needle aspiration biopsy. A report of its use in orbital tumors. Arch. Ophthalmol. 97:1315, 1979. 9. Saeb, J.: Primary tumors of the optic nerve (glioblastoma multiformi). Br. J. Ophthalmol. 33: 701,1949. 10. Mattson, R. H., and Peterson, E. W.: Glioblastoma multiform of the optic nerve. J.A.M.A. 196:799, 1966.
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Editor-in-Chief AMERICAN JOURNAL OF OPHTHALMOLOGY