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Show J. Clill. Neuro-ophthalmol. 4: 265-273, 1984. Optic Neuritis or Ophthalmic Artery Aneurysm? Case Presentation with Histopathologic Documentation Utilizing a New Staining Method ALFREDO A. SADUN, M.D., Ph.D. BARBARA A. SMYTHE JUDITH D. SCHAECHTER Abstract An elderly woman was admitted to the hospital with a presumptive diagnosis of optic neuritis following abrupt loss of vision in her left eye. Noninvasive studies were unrevealing, and she was put on a course of prednisone. Further visual loss 2 weeks later prompted a second course of prednisone therapy. Six years later the patient died from cardiac arrest. The autopsy revealed an aneurysm arising from the origin of the left ophthalmic artery. Selected brain specimens were histologically examined by application of a newly developed staining technique capable of identifying degenerated axons in human brain tissue even after long survival periods. We traced degeneration from the site of compression at the left optic nerve to five primary visual nuclei. Furthermore, transsynaptic cellular changes were observed in the lateral geniculate nucleus. Introduction The present case report deals with an optic neuropathy in which the nerve damage occurred several years prior to death. Histopathological assessment of the optic nerve required a method to identify degenerated axons in man. The Bodian stain is routinely employed in the microscopic analysis of human brain tissue. However, this is a fiber stain and does not delineate degenerated axons. Silver impregnation methods, such as the Nauta method, are used to identify degenerating axons in experimental animals. However, the silver methods do not reliably stain degenerated axons in the human brain. Recently, a new staining technique, paraphenylene-diamine (PPD), has been developed which reliably identifies de- From the Department of Ophthalmoltlgy, Harvard Medical School, Boston, Massachusetts. December 1984 generated axons and degenerated axon preterminals in human autopsy brain tissue even after long survival periods.1 The ability of paraphenylene- diamine to reliably stain degeneration in the human brain is probably due to the relative persistence of lipid remnants of degenerated axons after a central nervous system lesion. This is in contrast to the transitory phase of neurofibrillar axonal degeneration which the silver impregnation methods stain. Thus, the paraphenylenediamine method has been employed to assess histologically the full extent of neuronal damage incurred in this case of optic neuropathy. Optic Neuritis Optic neuritis is an inflammatory disorder of the optic nerve. The inflammation produces nerve conduction delay and some axonal destruction, typically leading to both transient and residual visual failure. Partial remyelination of viable fibers occurs and marks the recovery phase. There is no known etiology for this disorder. Optic neuritis initially presents in patients between the ages of 21 and 50,:: 3 and occurs more often in females'::- 5 Seasonal patterns of occurrence of optic neuritis have been noted,"" althoug~ this has not been found by all investigators.' Optic neuritis is often an early manifestation of multiple sclerosis (MS). Approximately one-third of all optic neuritis patients develop probable or definite MS.:: H The likelihood of progression to MS after an episode of optic neuritis is much higher among the young (ages 21-40) and among women.::'" Ophthalmic Artery Aneurysms Aneurysms of the internal carotid artery, posterior communicating artery, anterior cerebral artery, and ophthalmic artery have been described as causing visual disturbances.' However, it is the 265 Aneurysm from Ophthalmic Artery Figure 1. (A) Right fundu, Optic di" ~h\lI\" hL',llthl' rim \\'lth nl)rmal Lllioration (B) Left fundus, Marked pallor of the optIc dl~(, nlll:-.t pnIIlUUTlL'L'd tl'nlplHll1Iy. presentation of ophthalmic artery aneurysm that is most frequently confused with that of optic neuritis," Cases of congenital, trauma-induced, and mycotic ophthalmic artery aneurysms have been reported to occur in both sexes in a variety of ages,llI The ophthalmic artery is the first intracranial branch of the internal carotid artery arising just as the internal carotid pierces the dura after traversing the cavernous sinus. The ophthalmic artery originates anterior to the optic chiasm and runs inferior and lateral to the optic nerve (Fig. 3), passing to the medial side of the optic nerve before entering the orbit through the optic foramen. Aneurysms of the ophthalmic artery characteristically arise from the superior wall of the artery at, or near, its origin from the internal carotid artery and may expand in a number of different directions. Ophthalmic artery aneurysms account for only 3-5% of all intracranial aneurysms.ll. 1C Ophthalmic artery aneurysms may be large when clinically apparent. Most are greater than 25 mm in diameter at the time of surgery or at autopsy.q Their large size may reflect the fact that an ophthalmic artery aneurysm is less apt to rupture due to the protection afforded by the clinoid processesD Intracranial arteries are unusually thin-walled. There is a paucity of elastic fibers in the media, and the adventitia is sparse. However, the internal elastic membrane is well developed. The initial defect leading to an aneurysm is thought to be a developmental absence or depletion of smooth muscle in the media. D The wall of a large aneurysm is formed by initima and layers of connective tissue. 266 Case Report A 66-year-old woman presented to the emergency ward of the Massachusetts Eye and Ear Infirmary complaining of loss of vision in the left eye. She denied pain, numbness, paresthesias, or headache. Her visual acuity was hand motions on the left (20/25 on the ~ight). There was no proptosis, ophthalmoplegia, or bruits. A left afferent pupillary defect was noted; pupillary responses on the right were normal. Funduscopic examination revealed a pale left optic disc (Figs. lA and IB). Goldmann perimetry of the left eye depicted a central scotoma to 30°; whereas perimetry of the right eye was normal. Neurological exam was normal. The presumptive diagnosis was optic neuritis and the patient was started on prednisone 60 mg for 3 days, and admitted for further evaluation. X-ray studies included a skull series and orbital films, all of which appeared normal. The patient refused tomography of the optic canals. Carotid and periorbital examinations by ultrasound were normal. Visual-evoked responses of the left eye did not produce a peak. Three days after admission the patient's visual acuity had improved to 20/400 on the left, but she still failed to appreciate color. A retinal fluorescein angiogram of the left eye revealed a pale optic disc with slight sludging of vascular flow. Despite this finding, the diagnosis remained optic neuritis, and the patient was discharged on a prednisone taper to extend over 1 week. Nine days later, the patient returned with vision in the left eye reduced to counting fingers at one foot. This was thought to reflect an exacerbation of the optic neuritis. She was restarted on the original prednisone taper regimen, but this Journal of Clinical Neuro-ophthalmology Sadun, Smythe, Schaechter 3 (Jp'/.c ~rr' .Cafol'l A (,"".J!y/ "fer."" ..,.,c:-./t For.. :;S ,'Lt;.rr'UJ','LJ/f Bt:<1. Figure 2. Ophthalmic artery aneurysm (A). Vascular pouch at inferior border of left L)ptiC nerve. 5 mm anterior to chiasm (e). Right optic nerve (RN) and infundibulum (I). Figure 3. Schematic drawing of sagittal section through chiasmal region. Origin of ophthalmic artery from internal carotid is inferior to optic nerve and anterior to chiasm. time there was no visual improvement. No other neurological deficits developed. Six years later the patient died of cardiac arrest. At autopsy, a vascular pouch 6-7 mm in diameter was found adjacent to and inferior to the left optic nerve and slightly anterior to the optic chiasm. The vascular attachments to the pouch were in the region of the bifurcation of the ophthalmic artery from the left internal carotid artery (Fig. 2). The left optic nerve was atrophic, with a diameter approximately half of its counterpart. No other aneurysms were found at autopsy. No plaques suggestive of MS were seen in any of December 1984 her brain sections. In short the neuropathological exam was entirely normal except for the descriptions above and the histological examination to be described. Histopathology Methods The brain was obtained from the Massachusetts General Hospital Department of Pathology, 20 hours after death. Relevant visual structures were removed in blocks. Small tissue blocks were set aside for the paraphenylene-diamine staining 267 Aneurysm from Ophthalmic Artery method tlf Sadun and Smith. I The larger remaining bk)(ks (about 1 cm X 2 cm X 2 cm) were prepared for paraffin processing. Representative sections were stained with luxolfast blue, hematoxylin and eosin, cresyl violet, periodic acidSchiff, and the Bodian stain. The smaller tissue blocks (0.5 mm X 5 mm X 5 mm) selected for paraphenylene-diamine staining were stored in a buffered glutaraldehyde/paraformaldehvde fixative for 4 days at 4°C. The tissue was -rinsed in buffer and placed in osmium tetroxide overnight. The blocks were processed through a graded series of alcohols and propylene oxides and infiltrated with Embed 812. Followmg polymerization, the blocks were trimmed and sectioned at 1-2 J.l. on an ultramICrotome and mounted on glass slides. The slides were immersed in 1% paraphenylene-diamine in methanol, rinsed, and coverslipped. Findings The 6-mm vascular pouch found at autopsy was adherent to the inferior aspect of the left optic nerve, slightly anterior to the optic chiasm. The lumen of the aneurysm was empty; the wall was comprised of an intima, media, and adventitia. The intima was largely intact and essentially normal in appearance, with little evidence of focal thickening. The media was well defmedand composed predominately of connectIve tissue elements. The elastica was largely broken down and most of the smooth muscle cells were degenerated. Cholesterol clefts were noted to be surrounded by foamy macrophages. The adventitial layer was abnormally wide; serosal strands extended to the left optic nerve (Figs. 4 and 5). The left optic nerve showed compression with marked fibrosis and gliosis at this site. , . L t .. "1-'" - ...~. •I ... ~ . - ,. " . -' - '. ;"', '; ·1 .. " ..1 ,. ",. I"~.'·._, 'III".. .fII •• I •• ~..... ~ ", , I " Figure 4. Cross section thrl1ugh aneurysm ShllWS lumen (L). Area surrounding cholesteral cleft (arrow) is infiltrated with foamy macrophagl" and fibroblasts. (H&E, original magnification X200.) Figure 5. Aneurysm wall with adjacent optic nerve (N). Smooth muscle (M) cells are organized and associated with fibroblasts and Cllnnt'ct;ve tissue. Adwntitia (A) adjoins llptic nerve. (H&E, original magnification X400.) 268 Journal of Clinical Neuro-ophthalmology Microscopic examination of the intact right optic nerve demonstrated fascicles of axon bundles supported by connective tissue septae. Paraphenylene- diamine staining demonstrated dark rings of myelin surrounding the unstained axoplasm of normal axons (Fig. 6A). In contradistinction, the paraphenylene-diamine-stained left optic nerve showed disruption of fascicles and loss of intact myelin rings. Dark circular profiles were seen scattered throughout the left optic nerve and were followed, anterogradely, to the optic chiasm. These darkly stained profiles represent the remnants of degenerated axons and correspond to degenerated axons identified by electron-microscopic criteria 1 (Figs. 6B-6D). Transsynaptic effects of optic nerve degeneration were observed in the lateral geniculate nucleus. Cells within laminae 2, 3, and 5 of the left lateral geniculate nucleus, known to receive input from the left (damaged) optic nerve, were small and atrophic. In contrast, laminae 1, 4, and 6 had normal, large neurons (Fig. 7A). The reverse pattern of atrophy was seen in the right lateral geniculate nucleus, with atrophic cells contained in laminae 1, 4, and 6 (Figs. 7B and 8). Paraphenylene- diamine staining demonstrated more degenerated axons in the atrophied laminae of both lateral geniculate nuclei than in the healthy laminae (Fig. 9). Some degenerated axon preterminals were seen adjacent to neurons or large dendrites in the lateral geniculate nucleus (Fig. 9). Degenerated axons and axon preterminals were also found bilaterally in the pretectum, pulvinar, superior colliculi, and suprachiasmatic nuclei of the hypothalamus. Discussion Optic Neuritis Optic neuritis typically presents as blurred vision, progressing over a few days with concurrent or antecedent ocular pain. The initial visual symptom of optic neuritis is often described as fogging or blurring of vision. In the first attack, most patients have a visual acuity of worse than 20/ 100.2.3 Further deterioration of vision often occurs during the next few days2.3 and improvement usually begins to occur at 1 week. Ocular and periocular pain, usually exacerbated by e.r movement, is present in about 70% of cases2 . h The pain may precede, develop simultaneously, or not occur until after visual 10ss.2.3 Exacerbation of symptoms with heat or exercise (Uhtoff's phenomenon) is often encountered in optic neuritis. Color vision is typically lost even when the visual actuity deficit is mild. Nikoskelainen I' found that 26% of cases of optic neuritis had an impaired direct pupillary response, and 44% had December 1984 Sadun, Smythe, Schaechter an afferent pupillary defect. The most common visual field defects are paracentral or central scotomas3 . 7 The frequency of different optic disc changes described varies with the examiner and include blurred disc margins, papillitis, and optic disc pallor. 2.3 7 The diagnosis of optic neuritis is essentially clinical. The patient's history is singularly important, supported by appropriate physical findings. Studies are done more to exclude other possible causes than to confirm the diagnosis of optic neuritis. Evaluation of optic neuritis commonly includes skull and orbit films, and optic canal polytomography. In recent years, CT scanning may have supplanted other radiological examinations. A VORL, ESR, vitamin Blevels, and other blood studies may be valuable, if suggested by the history. Long VER latencies, and defects in contrast sensitivity are seen in optic neuritis; however, similar abnormalities are commonly found in compressive optic neuropathies. Ophthalmic Artery Aneurysm The clinical presentation of ophthalmic artery aneurysm characteristically includes visual loss, accompanied by headaches and retrobulbar or deep orbI·taI pam. . 10.1h.17 Visual loss may occur suddenly, or may develop gradually over days or months. 1O · IR.lq Three characteristic patterns of visual loss progression are seen corresponding to three distinct locations of the aneurysm: 1) an aneurysm anterior to the chiasm usually involves one optic nerve only. The lesion typically produces a central scotoma or ipsilateral superior nasal defect; 2) an aneurysm anterior to the chiasm and extending across the midline, encroaches upon the contralateral optic nerve producing an initial central scotoma or ipsilateral superior defect with development of a contralateral upper temporal defect; and 3) an aneurysm at the level of the chiasm causes an ipsilateral nasal and a contralateral temporal defect. The pain associated with ophthalmic artery aneurysm may be severe. lh . 17 It is often abrupt in onset and concomitant with visual loss. Ill. Ih The physical signs seen in ophthalmic artery aneurysm include a decreased, or even absent pupillary response. Ill. IR. 14 Funduscopic changes include optic atrophy, which may be noted at the initial exam, indicating that the lesion considerably antedated presentation. An orbital bruit may be heard. lh Proptosis, which is occasionally noted, need not imply that the aneurysm has expanded into the optic canal. 10 Ptosis and ipsilateral ophthalmoplegia are rare features of an ophthalmic artery aneurysm Hl Spontaneous improvement has been described for this lesion. ]h. k]4 269 Aneurysm from Ophthalmic Artery s 6A • Figure 6. Cross sections through normal right (A) and damaged left (8-0) optic nerves. (A) Normal axons grouped into fascicles separated by septal' (s). Darkly stained myelin rings about unstained axoplasm. (8) Few normal axons. (PPO, original magnification x500). (C) Widt·spread degeneration (arrows). (PPO, original magnification x300.) (0) Degenerated profiles (arrows) sometimes seen h.:lving an ensheathing ring. (PPO, original magnification Xl,OOO.) PPO = paraphenylene-diamine. 270 Journal of Clinical Neuro-ophthalmology Sadun, Smythe, Schaechter .~ ' ...... .. ' .. ' I '. , '. • ~ .J • ,', . .- ..... 4a' -, 5. • 4~• ..... 6a ;, ;- ... .' " ..~ , '6 ''- .'- ." - . ;- .. " ,- ,, Figure 7. (A) Left lateral geniculate nucleus (LGN). Cell bodies which were innervated by normal (contralateral) eye lie in laminae 1. 4. and 6. Cells which received input from affected (ipsilateral) eye occupy laminae 2, 3, and 5. and are atrophic (a). (H&E. original magnification x20.) (B) Right LGN. laminae J. 4. and 6 contain atrophic cell bodies (a). Reverse of pattern seen in (A). (H&E. original magnification x20.) Appropriate diagnostic studies include skull films, which may show bone erosion, optic canal tomography, and CT scanning with contrast. However, angiography remains the definitive investigation. Features of the Present Case The history and physical findings of the present case can be compared to the clinical features described for optic neuritis and ophthalmic artery aneurysm. Consistent with either diagnosis, this patient noted sudden monocular visual loss and had an afferent pupillary defect. Despite these nonspecific findings, there was clinical evidence highly suggestive of ophthalmic artery aneurysm. Optic neuritis typically presents between the ages of 21 and 50 while ophthalmic December 1984 artery aneurysm may occur at any age. In a 66year- old patient, a tumor or aneurysm is more likely than optic neuritis. This patient had progressive visual deterioration lasting 1-2 months; a tempo uncharacteristic of optic neuritis. The failure of our patient to improve on high doses of prednisone and the subsequent deterioration of vision makes the diagnosis of optic neuritis still less warranted. The optic disc pallor was further evidence for a chronic process such as an aneurysm. Disc pallor is not seen initially in optic neuritis and is infrequently noted even in follow-up examinations of optic neuritis.~·' In contradistinction, ophthalmic artery aneurysm typically produces optic atrophy which may be seen even on presentation. The patient's age and the initial presence of disc pallor should have aroused strong suspicion 271 Aneurysm from Ophthalmic Artery .. "" '," J," .. ,i I ;'" .. "I I II ~ t "11I I ': Figure 8. Right LGN, laminae 5 and 6 (separated by arrows). Lamina 5 received input from the normal right eye; cell bodies here are normally large (L). Cells in lamina 6 were innervated by the damaged left eye and are atrophic (A). (H&E, original magnification X200.) Figure 9. Right LGN. Cell bodies contain lipofuscin (L) granules, which stain darkly with PPO. Dark profiles (arrows) represent degenerated axons and preterminals. (PPO, original magnification x800.) of a chronic compressive lesion. The minimal additional workup for her included a CT scan. The subsequent deterioration of the patient's vision should have increased the doubt in the diagnosis optic neuritis and have prompted further investigation. It is not uncommon for there to be some difficulty in distinguishing between optic neuritis and ophthalmic artery aneurysm. However, as demonstrated by this case report, many differences exist. It is imperative to attend to these differences to avoid misdiagnosis. This case has additional features of heuristic value. Histopathological assessment allowed for a definitive localization and characterization of the lesion. The extent of damage to the nerve at the site of compression was determined by special stains. Of special interest is the paraphenylenediamine technique which has recently been adapted for use with human brain tissue. This 272 method allowed us to delineate the neural degeneration which coursed anterograde to the lateral geniculate nucleus, pretectum, superior colliculus, pulvinar, and the suprachiasmatic nucleus of the hypothalamus. These latter three pathways have not been described previously in man. Thus, the paraphenylene-diamine technique is a powerful new method for human neuro-anatomical investigations. The paraphenylene-diamine method, by allowing for the precise localization of neuronal degeneration traced from the primary site of injury to distant nuclei in the human brain, provides a new dimension to clinical-pathological correlations. The comparison of functional deficits with neuropathologicallesions, assessed by the paraphenylene- diamine method, promises to be a great aid in understanding the structure and function of the human visual system. Journal of Clinical Neuro-ophthalmology References 1. Sadun, A.A., Smith, L.E.H., and Kenyon, K.R.: Paraphenylenediamine: A new method for tracing human visual pathways. f. Neuropathol. Exp. Neural. 42(2):200-206, 1983. 2. Cohen, M.M., Lessell, S. and Wolf, P.A.: A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. NeurologJj (Minn) 29(2): 208-213,1979. 3. Bradley, G., and Whitty, CW.M.: Acute optic neuritis: Its clinical features and their relation to prognosis for recovery of vision. f. Neurol. Neurosurg. Psychiatry 30: 531-538, 1967. 4. Adie, W.J.: The aetiology and symptomatology of disseminated sclerosis. Br. Med. f. 2: 907-1000, 1932. 5. Hyllested, K., and Moller, P.M.: Follow-up on patients with a history of optic neuritis. Acta Ophthalmol. 39: 655-662, 1961. 6. Hutchinson, W.M.: Acute optic neuritis and the prognosis of multiple sclerosis. f. Neurol. Neurosurg. Psychiatry 39: 283-289,1976. 7. Perkin, G.D. and Rose, E.C: Methodology and Epidemiology. Optic Neuritis mId Its DiffufIltial Diagnosis. Oxford University Press, Oxford, 1979, pp. 1928-1929. 8. Collis, W.}.: Acute unilateral retrobulbar neuritis. Arch. Neurol. 13: 409-412,1965. 9. Stern, W.H., and Ernest, }.T.: Intracranial ophthalmic artery aneurysm. Am. f. Ophthalmol. 80: 203-206,1975. 10. Walsh, F.B., and Hoyt, W.F.: Clinical Neuro-Ophthalmologl/, (2nd ed.). William & Wilkins Co, Baltimore, 1969, pp. 1748-1751. 11. Krayenbuhl, H., and Yasargil, M.G.: Das HimanaIleurysma. J.R. Basel, Geigy, 1958, p. 15. 12. Locksley, H.B.: Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. f. Neurosurg. 25: 219-239,1966. December 1984 5adun, Smythe, Schaechter 13. Sekhar, L.. and Heros, R.C: Origin, growth and rupture of saccular aneurysms: A review. Neurosurgery 8: 248-260,1981. 14. Forbes, W.O.: On the origin of miliary aneurysms of the superficial cerebral arteries. Bull. Johns Hopkins Hasp. 47: 239-284, 1930. 15. Nikoskelsinen, E.: Symptoms, signs and early course of optic neuritis. Acta. Ophthalmol. 53: 254271, 1975. 16. Meadows, S.P.: Optic nerve compression and its differential diagnosis. Proc. R. Soc. Med. 42: 10171034,1949. 17. Jefferson, G.: Compression of the chiasm, optic nerves, and optic tracts by intracranial aneurysms. Brain 60: 444-497, 1937. 18. Cunningham, R.D., and Sewell, J'}': Aneurysm of the ophthalmic artery with drusen of the optic nerve head. Am. f. Ophthalmol. 72: 743-745,1971. 19. Knight, CL., Hoyt, W.F, and Wilson, CB.: Syndrome of incipient prechiasmal optic nerve compression. Arch. Ophthalmol. 87: 1-11, 1972. Acknowledgments The authors thank Drs. E. P. Richardson and Stanley Schiff for their assistance and expertise in obtaining appropriate neuropathological specimens; and Elaine F. Cannon for her help with the manuscript. This study was supported in part by the HEED Foundation Fellowship (Dr. Sadun) and by NEI grant 1R23 EY04331-01A2 (Dr. Sadun). This work was presented in part at the 1984 Frank Walsh Society meeting, Cleveland, Ohio. Write for repri/!ts to: Alfredo A. Sadun, M.D., Ph.D., Estelle Doheny Eye Foundation, 1335 San Pablo Street, Los Angeles, California 90033. 273 |
