Delayed Radiation Injury to the Retrobulbar Optic Nerves and Chiasm

Delayed Radiation Injury to the Retrobulbar Optic Nerves and Chiasm Clinical Syndrome and Treatment with Hyperbaric Oxygen and Corticosteroids DERMOT RODEN, FRCSI,t THOMAS M. BOSLEY, MD,t BARBARA FOWBLE, MD/ JAMES CLARK, MD, 3 PETER J. SAVINO, MD,t ROBERT C. SERGOTT, MD,t NORMAN J. SCHATZ, MD 1

Abstract: Thirteen patients with delayed radiation injury to the optic nerves and chiasm were treated with hyperbaric oxygen (HBO) and corticosteroids. These patients experienced painless, abrupt loss of vision in one (6 patients) or both (7 patients) eyes between 4 and 35 months after receiving radiation doses of at least 4500 cGy to the region of the chiasm. Diagnostic evaluation including neuro-imaging and lumbar puncture showed no recurrent tumor and no other cause for visual loss. No patient's vision improved during treatment or follow-up lasting between 1 and 4 years. There were no serious complications of treatment. Ophthalmology 1990; 97:346-351

Forrest and colleagues, 1 in 1956, first described delayed injury to the optic nerves or chiasm months to years after external beam radiation therapy. Subsequent reports involved small numbers of patients, radiation techniques that may no longer be used, and diagnostic evaluations that do not meet current standards. Visual outcome is typically poor. There is no proven therapy, but Guy and Schatz2 suggested hyperbaric oxygen (HBO) as a possible treatment. We review the clinical syndrome and response to treatment with HBO and corticosteroids in 13 patients with radiation injury to the anterior visual pathways.

Originally received: November 28, 1988. Revision accepted: November 20, 1989. 1 2 3

Neuro·Ophthalmology Service, Wills Eye Hospital, Philadelphia. Department of Radiation Therapy, Hospital of the University of Pennsylvania, Philadelphia. Environmental Medicine, Hospital of the University of Pennsylvania, Phil· adelphia.

Reprint requests to Thomas M. Bosley, MD, Neuro-Ophthalmology Service, Wills Eye Hospital, 9th & Walnut Sts, Phiiadelphia, PA 19107.

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METHODS From July 1979 to September 1987, 21 patients with presumed radiation damage to the optic nerves or chiasm were referred to the Neuro-Ophthalmology Service at Wills Eye HospitaL Details of the initial clinical presentation, radiation dosage and portals, and postradiation visual loss were obtained from the patient and pertinent records. Evaluation in each case consisted of complete neuro-ophthalmologic examination, Goldmann kinetic perimetry, high-resolution computed tomography (CT) and/or magnetic resonance imaging (MRI), and lumbar puncture. Eight patients were excluded from this report because of alternative explanations of visual loss including tumor mass contiguous with the intracranial optic nerves or chiasm in five, possible optic neuritis in one, possible malignant meningitis in one, and occipital lobe radiation damage in one. Two patients reported by Guy and Schatz2 were among those excluded; the other two patients in that report were treated at the University of Florida. Table 1

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Table 1. Radiation Therapy and Sequellae Patient No.

Age (yrs)/Sex

1 2 3 4 5 6 7 8 9 10 11 12 13

55/F 70/M 63/M 68/F 72/M 70/F 58/F 46/F 72/F 75/M 56/M 58/M 60/M

Tumor

Total Dose (cGy)

Radiation Therapy Daily Fraction (cGy)

Energy (MeV)

Radiation to Visual Loss (mos)*

Other CNS Damage

Pituitary adenoma Pituitary adenoma Esthesioneuroblastoma Pituitary adenoma Lymphoma Pituitary adenoma Pituitary adenoma Astrocytoma Pituitary adenoma Pituitary adenoma Craniopharyngioma Meningioma Squamous cell carcinoma

5000 5000 6000 5000 5142 4500 4500 5600 4500 4500 6500 6400 7200

200 NA 200 200 200 180 180 200 180 180 180 200 180

6oco NA 4 4 6 10 6 6oco NA 4 6 18 6

9 15 35 19 11 11 4 6 14 25 19 13 11

N N F N N N N N F, p T N T, p N

NA = not available; N = no; F = frontal lobe; P = parietal lobe; T = temporal lobe. * Delay from beginning of radiation therapy to onset of visual loss.

describes 13 patients with presumed delayed radiation damage to the optic nerves or chiasm in the order in which they were treated. No patient had serologic evidence of systemic inflammatory disease or infection, and none was taking medicine known to be toxic to the visual system. One patient with a growth hormone secreting pituitary adenoma (patient 4) refused surgery, but all other patients underwent biopsy or excision of the tumor mass before radiation therapy. All 13 patients received HBO therapy consisting of repeated treatments in a hyperbaric chamber with 100% oxygen at two atmospheres for 2 hours in a modification of a protocol shown to be effective in treating radionecrosis of bone. 3 Visual acuity and visual field were reassessed weekly, and HBO was continued if vision appeared to be stable or improved. Eleven patients were treated with corticosteroids simultaneous with HBO. Six patients received oral corticosteroids for 14 to 25 days, whereas five patients were treated with methylprednisolone 250 mg intravenously every 6 hours for 3 days.

RESULTS RADIATION THERAPY AND SEQUELLAE

Table 1 describes the radiation dosage and protocol in 12 patients; details of radiation other than total dose were unavailable in patient 2. Total radiation dosage varied from 4500 to 7200 cGy, but no patient received daily radiation fractions greater than 200 cGy to the area of the optic nerves and chiasm. Time between completion of radiation therapy and onset of new visual symptoms varied from 4 to 35 months. Four patients had CT and/or MRI evidence of radiation damage to areas of the brain outside of the afferent visual system. Two of these patients

had stroke-like neurologic syndromes compatible with this parenchymal damage. No patient experienced ocular or periorbital pain around the time of visual loss. One patient reported transient diffuse visual blurring of variable severity lasting less than 1 minute for approximately 3 weeks before permanent visual loss. Many patients were not aware of visual loss in the first eye and orily became aware of a visual disturbance when the second eye was involved. Permanent visual loss was reportedly instantaneous in one eye of one patient but was gradual over a period ofless than 3 weeks in all other affected eyes. Two to 24 weeks lapsed between the involvement in the first arid second eyes in four patients for whom accurate information was available. Patients were examined between 2 and 12 weeks after loss of vision in the most recently affected eye. Table 2 shbws that 20 eyes (one eye in six patients, both eyes in seven patients) had evidence of damage to the pregeniculate afferent visual system with decreased visual acuity, dyschromatopsia, loss of visual field, and altered optic nerve appearance on funduscopy. Four eyes had no visual loss at the time of initial examination (patients 1, right eye; 7, left eye; 9, left eye; and 12, left eye), and two eyes were excluded from consideration because of visual loss due to other ocular processes (patients 3, left eye; and 13, right eye). Visual acuity was better than 20/100 in five affected eyes (25% of affected eyes) of four patients and worse than 20/400 in nine eyes (45%) of seven patients. Visual field defects included cecocentral scotomas, temporal field loss, and altitudinal nerve fiber bundle defects. Patients 4 and 11 had unequivocal visual field evidence of new chiasma! damage without recurrent tumor, and patient 2 also may have had chiasma! damage with only a nasal visual field remaining in the right eye. Both optic discs were swollen in patient 8, and the other ten patients had visual field loss most compatible with damage to one or both retrobulbar optic nerves. 347

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Table 2. Ocular Examination Results Patient No.

2 3 4 5 6 7

8 9 10 11 12 13

Eye

Visual Acuity

00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS 00 OS

20/20 20/400 HM CF 20/70 NLP§ CF 20/100 HM NLP 20/100 20/200 20/25 20/25 20/200 20/200 HM 20/20 20/30 LP 20/50 20/40 CF 20/20 CF~

CF

Color Vision*

Pupillary Reactiont

Visual Fieldst

Optic Disc

10 0 0 0 0 0 0 0 0 0 0 0 4 10 0 7 0 10

4 2 1 0 1 0 1 3 2 1 2 2 3 4 2 3 1 4 4 1 3 4 1 4 0 1

0 1, 2, 4, 5 1, 4 1 1' 2, 5 6 1, 3 1' 3 1, 2, 5 6 1 1 2 0 1' 2 1 1, 4 0 1, 2 6 4 4 1' 2, 3 0 1' 2, 4 1, 2, 4

Normal Pale Pale Pale Pale No view Pale Pale Pale Pale Pale Pale Pale Normal Swollen Swollen Pale Normal Pale Pale Pale Pale Pale Normal Pale Pale

9

0 7 6 0 10 0 0

00 = right eye; OS = left eye; HM = hand motions; CF = counting fingers; NLP = no light perception; LP = light perception. * Number identified out of ten Ishihara isochromatic plates. t 0 (no reaction to light) to 4 (normal reaction). t 0 = normal; 1 = central or cecocentral scotoma; 2 = altitudinal scotoma; 3 = superotemporal scotoma; 4 = total temporal hemianopia; 5 = constricted visual field; 6 = not obtainable. § Postradiation neovascular glaucoma. ~ Proliferative diabetic retinopathy.

TREATMENT AND FOLLOW-UP

Table 3 provides details of HBO and corticosteroid therapy. Hyperbaric oxygen was discontinued in patients 2 and 3 because of bothersome dysesthesias with no permanent sequellae. Patient 11 experienced severe headaches due to a fistula between a previously operated frontal sinus and the subarachnoid space. Intracranial air was visible on CT. Patients 9 and 10 both underwent two separate courses of HBO separated by weeks because of progressive neurologic symptoms. No patient experienced major side effects of steroid therapy. No patient's vision improved in either eye during the treatment or follow-up periods (Table 4). Visual acuity in 18 eyes remained within two lines of pretreatment levels. Patient 7 lost vision in the right eye during treatment, but vision in that patient's left eye remained unaffected during treatment and follow-up. Five eyes in four patients (patients 8, right eye; 9, left eye; 11, right eye; 12, bbth eyes) lost visual acuity during the follow-up period. Patients 9 and 12 each lost vision in the left eye 2 weeks after completing treatment and 12 to 18 weeks after losing vision in the right eye. Timing 348

of visual loss in the other two patients was uncertain. These patients were treated 3 to 8 weeks after onset of symptoms, and continued visual loss may have been the natural course of delayed radiation injury (Fig 1).

DISCUSSION At least 6I cases of delayed radiation injury to the anterior visual pathways have been reported (Table 5). 1•4 - 16 In the current series, visual loss was invariably painless and permanent, often progressing over a period as long as 3 weeks. Visual loss was commonly profound, although 25% of affected eyes had visual acuity better than 20/ I 00. When both eyes were involved, initial visual loss was usually monocular with a delay of 2 to 24 weeks before development of symptoms in the second eye. Although radiation equipment and dosage schedules differed from patient to patient, affected individuals received doses of at least 4500 cGy to the afferent visual system. The time between radiation therapy and development of new visual symptoms was never shorter than 4 months or longer than 3 years (mean, I year).

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Table 3. Treatment with Hyperbaric Oxygen and Corticosteroids Patient No. 1 2 3 4 5 6 7 8

9

10 11 12 13

Visual Loss to Treatment (wks)

Steroid Treatment

HBO Treatment (hrs)

Compound

Dose (mg/day)

Duration (days)

NA 20 18 76 36 30 48 32 81 160 28 40 36

Prednisone Prednisone Prednisone Decadron (dexamethasone) No No Prednisone Prednisone Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone

100 100 100 16

14 21 21 14

60 100 1000 1000 1000 1000 1000

25 21 3 3 3 3 3

2 NA 3 4 6 NA

9

3 12 4 8 2 5

HBO = hyperbaric oxygen; NA = not available. Table 4. Results of Treatment Patient No.

2 3 4 5 6 7 8

9 10 11 12 13

Eye OD OS OD OS OD OS* OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS*

Follow-up (yrs)

3 3 4 4 3 3 3 3 2 2 2

Visual Acuity Before Treatment

After Treatment

Latest

20/20 20/400 HM CF 20/70 NLP CF 20/100 HM NLP 20/100 20/200 20/25 20/25 20/200 20/200 HM 20/20 20/30 LP 20/50 20/40 CF 20/20 CF CF

20/20 CF HM CF 20/80 NLP CF 20/200 HM NLP 20/200 20/200 CF 20/25 20/200 20/200 CF 20/20 20/30 LP 20/50 20/40 HM 20/20 CF CF

20/30 CF HM CF 20/80 NLP CF 20/200 LP NLP 20/200 20/200 CF 20/25 LP 20/200 CF CF 20/40 LP 20/400 20/60 NLP 20/40 CF CF

OD = right eye; OS = left eye; CF = counting fingers; HM = hand motions; NLP = no light perception; LP = light perception. * Excluded because of other causes of visual loss.

Factors previously reported to predispose irradiated patients to injury of the afferent visual system include daily doses greater than 250 cGy, 9 growth hormone secreting pituitary adenomas, 11 •13 and total tissue dose in excess of6000 cGy. 15 None of our patients received daily

doses greater than 200 cGy, and only three (23%) had growth hormone-secreting tumors. Eight patients (62%) received less than 6000 cGy total tissue dose, implying that higher doses are not absolutely necessary for delayed radiation injury to occur. The patients described here did 349

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3:

g

6LL 20/50 20/100

;

20/400

20/70

o cr

<( HM <(LP

......J

~

>

NLP NLP

HM

~

~

400

100

20 70

20 50

~

30

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Hyperbaric oxygen stimulates fibroplasia and angiogenesis in radionecrotic bone with clinical improvement within 2 weeks in most patients3 using an HBO protocol similar to the one used in this study. Although similar histologic changes would not be expected in neural tissue, an earlier report of HBO for radiation damage to the afferent visual system was encouraging. 2 Corticosteroid therapy was often instituted by referring physicians and was included in this study because of difficulties in separating the effects of HBO and corticosteroids in these cases and because of indications that corticosteroids may be effective in treating certain inflammatory diseases of the pregeniculate afferent visual system. 18- 20 Hyperbaric oxygen and steroid therapy in the protocols described here did not improve vision in this series of patients with radiation injury to the optic nerves and chiasm. No patient's vision improved, and visual acuity declined more than two lines in 25% (6/24) of eyes at risk during the treatment and follow-up periods. Several qualifications to these results must be recognized. Much of the data was collected retrospectively, and follow-up information was to some extent incomplete. This preliminary trial was not randomized, and it is possible that vision would have been worse after follow-up in these patients if they had not received treatment. Finally, it is possible, although unlikely, that either HBO or corticosteroid therapy alone would have been more effective than the two therapies delivered together. Treatment might have been more successful if instituted more rapidly after visual loss. In general, treatment was undertaken as quickly as possible, but visual loss in the first eye was often unrecognized, and referral from widespread geographic locations added to the delay. Despite these problems, 6 of the 13 patients were treated within 1 month of recognized visual loss. Patients treated earlier had no better visual outcome than those treated later. It is unlikely that longer follow-up would have yielded dif-

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VISUAL ACUilY BEFORE TREATMENT Fig I. Results of treatment. Comparison of visual acuity before treatment with visual acuity after follow-up in each eye at risk. Two eyes (patients 3 and 13, left eyes) were excluded because of other causes of visual loss. The solid line indicates where pretreatment visual acuity would equal visual acuity after follow-up. CF = counting fingers; HM = hand motions; LP = light perception; NLP = no light perception.

not share an overt vasculopathic tendency or any other obvious risk factor for optic nerve damage. Radiation injury to the anterior afferent visual system is thought to begin in the microvasculature with perivascular lymphocytic cuffing, hyalinization, and loss of endothelial cells eventually causing thrombosis and fibrosisY Subsequent damage consists of infarction of neural tissue with loss of axonal bundles, demyelination, reactive gliosis, and mild chronic inflammatory infiltration.ll,l?

Table 5. Reports of Radiation Injury to Anterior Visual Pathways Radiation (cGy)

Time to Symptoms (mos)

Reference

No. of Patients

Minimum

Maximum

Minimum

Forrest et al 1 (1956) Buys and Kerns 4 (1957) Rosengren 5 (1958) Crompton and Layton 6 (1961) Ghatak and White7 (1969) Shukovsky and Fletcher8 (1972) Harris and Levene 9 (1976) Aristizabal et al 10 (1977) Atkinson et al 11 (1979) Fitzgerald et al 12 (1981) Brown et al 13 (1982) Hammer14 (1983) Parsons et al 15 (1983) Singh and Vashist16 (1984) Current study

4 2 2 2 1 2 6 4 4 1 6 4 9 1 13

10000 12500 5950 4500 7995 7000 4500 5000 4240 8060 3600 4250 6000 6500 4500

15000 13000 5950 6250

NA 2 NA 12 5 48 5 10 10 11 5 8 11 18 4

7500 7000 5000 4520 7200 4250 8000 7200

NA = not available; NLP = no light perception; CF = counting fingers; LP = light perception.

350

Maximum 12 15 8 19 60 36 15 108 36 13 100 35

Visual Acuity Minimum

Maximum

NLP NLP NLP NLP NLP NLP NLP NLP NLP CF CF NLP NLP LP NLP

NLP CF NLP 20/200 NLP CF NLP CF 20/30 CF 20/400 20/25

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ferent results because all patients were followed for more than 1 year and the syndrome typically completes its course of visual loss within 1 to 6 months. Currently, there is no therapy for delayed radiation injury to the afferent visual system. Other types of ischemic damage to the optic nerve, such as ischemic optic neuropathy,21 also rarely permit spontaneous visual improvement and have no medical treatment. Optic nerve sheath decompression improves vision in certain individuals with nonarteritic ischemic optic neuropathy22 but seems unlikely to be effective in radiation injury that causes infarction of axons in the proximal optic nerves and chiasm. Even more conservative radiation protocols for treatment of tumors in the region of the optic chiasm may be the only method of preventing delayed radiation injury, but the possibility of reduced treatment effectiveness will have to be weighed against the relatively small incidence of this complication.

8.

9.

10.

11.

12.

13. 14. 15.

REFERENCES 16. 1. Forrest APM, Brown DAP, Morris SR, Illingworth CFW. Pituitary radon implant for advanced cancer. Lancet 1956; 1:399-401. 2. Guy J, Schatz NJ. Hyperbaric oxygen in the treatment of radiationinduced optic neuropathy. Ophthalmology 1986; 93:1083-8. 3. Marx RE, Johnson RP. Studies in the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol 1987; 64:379-90. 4. Buys NS, Kerns TC Jr. Irradiation damage to the chiasm. Am J Ophthalmol1957; 44:483-6. 5. Rosengren B. Two cases of atrophy of the optic nerve after previous roentgen treatment of the chiasma! region and the optic nerves. A_cta Ophthalrnol1958; 3(6):874-7. 6. Crompton MR, Layton DD. Delayed radionecrosis of the brain following therapeutic x-radiation of the pituitary. Brain 1961; 84:85-101. 7. Ghatak NR, White BE. Delayed radiation necrosis of the hypothalamus:

17. 18. 19. 20. 21.

22.

report of a case simulating craniopharyngioma. Arch Neurol 1969; 21:425-30. Shukovsky LJ, Fletcher GH. Retinal and optic nerve complications in a high dose irradiation technique of ethmoid sinus and nasal cavity. Radiology 1972; 104:629-34. Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976; 120: 167-71. Aristizabal S, Caldwell WL, Avila J. The relationship of time-dose fractionation factors to complications in the treatment of pituitary tumors by irradiation. lnt J Radial Oncol Bioi Phys 1977; 2:667-73. Atkinson AS, Allen IV, Gordon DS, et al. Progressive visual failure in acromegaley following external pituitary irradiation. Cl Endocrinol1979; 10:469-79. Fitzgerald CR, Enoch JM, Temme LA. Radiation therapy in and about the retina, optic nerve, and anterior visual pathway: psychophysical assessments. Arch Ophthalmol 1981; 99:611-23. Brown GC, Shields JA, Sanborn G, et al. Radiation optic neuropathy. Ophthalmology 1982; 89:1489-93. Hammer HM. Optic chiasma! radionecrosis. Trans Ophthalmol Soc UK 1983; 103:208-11. Parsons JT, Fitzgerald CR, Hood Cl, et al. The effects of irradiation on the eye and optic nerve. lnt J Radial Oncol Bioi Phys 1983; 9: 609-22. Singh J, Vashist S. Postirradiation optic neuropathy in antral carcinoma. J Clin Neuro Ophthalmol1984; 4:103-4. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. lnt J Radial Oncol Bioi Phys 1980; 6:1215-28. Beck RW. The optic neuritis treatment trial [Editorial]. Arch Ophthalmol 1988; 106:1051-3. lngestad R, Stigmar G. Sarcoidosis with ocular and hypothalamicpituitary manifestations. Acta Ophthalmol 1971; 49:1-10. Kirkham TH. Neuro-ophthalmic presentations of sarcoidosis. Proc R Soc Med 1973; 66:167-9. Repka MX, Savino PJ, Schatz NJ, Sergott RC. Clinical profile and long-term implications of anterior ischemic optic neuropathy. Am J Ophthalmol1983; 96:478-83. Sergott RC, Cohen M, Bosley TM, and Savino PJ. Optic nerve surgery improves progressive non-arteritic ischemic optic neuropathy. Arch Ophthalmol1989; 107:1743-54.

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