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Tolosa-Hunt Syndrome and Antinuclear Factor
TOLOSA-HUNT SYNDROME AND ANTINUCLEAR FACTOR ROBERT LESSER, M.D.,
AND LEE M. JAMPOL,
M.D.
New Haven, Connecticut 1
Hunt and associates described the condi tion of unexplained retro-orbital pain and extraocular muscle palsy in a review of six cases. They attributed the symptoms to a low-grade inflammation in the anterior cav ernous sinus. This report describes a patient with corticosteroid-responsive Tolosa-Hunt syn drome who had a positive antinuclear factor (antibody) associated with exacerbations of her disease. CASE REPORT
A 58-year-old white woman was admitted to the Neurology Service at the Yale-New Haven Hos pital in February 1970 for evaluation of pain in the left eye, and diplopia. The patient's past medical history included tuberculosis, thyroid adenoma, and duodenal ulcer. In addition, she had had a left mas tectomy in 1953 for a carcinoma of the breast. Sub sequent wedge resections of her right breast at Yale-New Haven Hospital in 1964 and 1967 showed only cystic mastitis. In 1969, the patient had had an episode of retro-orbital pain in the left eye, which apparently spontaneously improved over a period of two months. At that time, ophthalmic evaluation showed bilateral subepithelial corneal opacities and a left sixth nerve palsy. These symptoms resolved, and the patient was doing well until 11 days before admission, when she developed a constant, severe left-sided aching retro-orbital pain. This persisted without relief, and six days prior to admission, she developed diplopia, and her left pupil was larger than her right. She noted no decrease in vision. Ophthalmic evaluation at the time of admission re vealed bilateral vision of 20/20. The pupils, at the time of our evaluation, were equal and reactive to light. No Marcus Gunn pupil was present. External examination revealed no evidence of blepharoptosis or orbital inflammation. There was limitation of ab duction of the left eye; extraocular muscle evalua tion was otherwise normal. Corneal sensation was intact bilaterally. Slit-lamp examination revealed bi lateral discrete corneal subepithelial opacities. General physical examination showed a thin feFrom the Department of Ophthalmology and Vis ual Science, Yale University School of Medicine, New Haven, Connecticut. Reprint requests to Lee M. Jampol, M.D., De partment of Ophthalmology and Visual Science, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06S10.
male in extreme discomfort. She had a left mastec tomy scar as well as a scar on the right breast. The remainder of her examination was unremarkable. Laboratory findings on admission included a C-reactive protein of 3 mm. The antinuclear factor was positive on two separate occasions (indirect immunofluorescent test). Rheumatoid factor was negative. The sedimentation rate was 41 mm per hour. A glucose tolerance test was normal. The lupus prepa ration (LE test), VDRL for syphilis, and FTAABS were negative. A temporal artery biopsy was negative. Skull x-ray films were unremarkable, and a lumbar puncture showed a normal pressure and glucose level, with a protein of 56 mg/100 ml. A diagnosis of Tolosa-Hunt syndrome was made, and the patient was started on 60 mg of prednisone per day. Within eight hours the pain and the left sixth nerve paresis dramatically improved. Four days later the prednisone was discontinued. Two days later, she again developed a headache. She was put back on prednisone, but she stopped the medica tion herself and the headache and diplopia again re curred. This required readmission at which time she again responded to prednisone. The patient was gradually tapered off her corticosteroid regimen and did well until April 1972, when she had another at tack manifested by retro-orbital pain in the left eye and left sixth nerve palsy. She again responded dra matically to prednisone treatment and again had a positive antinuclear factor and elevated sedimenta tion rate. DISCUSSION
According to H u n t and his colleagues, 1 the Tolosa-Hunt syndrome is characterized by a steady, unilateral, retro-orbital gnawing pain with ophthalmoplegia. Cranial nerves I I I , I V , V, and V I , and occasionally the optic nerve and sympathetics, may be involved. Charac teristically the attacks recur at intervals of months to years with symptoms lasting for days or weeks. Spontaneous remissions oc cur, but a dramatic improvement in symp toms is often seen when the patient is given prednisone over a 48-hour period. 2 Most evi dence points to an inflammatory lesion in the anterior cavernous sinus. 3 A t postmortem examination in a single case, Tolosa 4 found periarteritic lesions in the intracavernous sinus. Laake 5 reported a case in which he found at operation a localized low-grade
732
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TOLOSA-HUNT SYNDROME
pachymeningitis involving primarily the superior orbital fissure as well as the wall of the cavernous sinus. The cavernous sinus itself, however, was spared. Recently Schatz and Farmer 6 described two patients with Tolosa-Hunt syndrome who had granulomas in the cavernous sinus. Sondheimer and Knapp 7 added further support for the disease being localized to the cavernous sinus by re viewing the venographic findings in three patients and finding complete ipsilateral oc clusion of the superior ophthalmic vein and partial obliteration of the cavernous sinus. T h e patient in this report appears to fit the clinical diagnosis of the Tolosa-Hunt syn drome. There was a history of retro-orbital pain with ophthalmoplegia which responded consistently and dramatically to corticosteroid treatment. Characteristically, the signs and symptoms recurred with rapid corticosteroid withdrawal. Metastatic disease, dia betes mellitus, aneurysm, and nasopharyngeal tumor were all carefully ruled out. Although the patient did not have evidence of a sys temic vasculitis, a striking clinical feature was the association of flare-ups of the syn drome with an increased sedimentation rate and a positive antinuclear factor. T h e antinuclear factor (antibody) is not a specific immunologic test. A positive test indicates the presence of antibodies to nuclei or nu cleic acid in the fluid tested. At least three subcategories have been delineated. T h e most commonly used method of testing for this antibody is the indirect immunofluorescence technique. 8 Antinuclear factor is invariably positive in patients with systemic lupus erythematosus, and a patient with a positive L E preparation should have a positive antinuclear factor. T h e antinuclear factor is also positive in a size able proportion of patients with rheumatoid arthritis ( 3 0 % ) and scleroderma (50 to 6 0 % ) . ° Other causes of a positive antinu clear factor include medications 1 0 ' 1 1 (hydralazine hydrochloride, isoniazid, anticonvulsants, and others), and occasionally derma tomyositis, polyarteritis, Hashimoto's thy-
733
roiditis, hepatitis, ulcerative colitis, or pul monary fibrosis. Malignancy has also been associated with positive antinuclear fac tor, 12 ' 13 and patients above 65 years of age have a higher incidence of positive antinu clear factor. 14 O u r patient had none of the diseases described above. W e found no prev ious reports of the association of TolosaH u n t syndrome with a positive antinuclear factor. However, Mathew and Chandy, 1 5 in reporting 22 cases of painful ophthalmo plegia in India, did find positive L E prepara tions in five of eight patients tested. Anti nuclear factor was negative in eight patients tested. However, the five patients with a posi tive L E test should have had positive anti nuclear factor. Like our patient, there was no evidence in their patients of collagen vascular disease. Although it seems unlikely that the antinuclear factor elevation in our patient with Tolosa-Hunt syndrome indicates gen eralized collagen vascular disease, this lab oratory test may help diagnose this rare cause of ophthalmoplegia. SUMMARY
A 58-year-old woman had corticosteroidresponsive Tolosa-Hunt syndrome mani fested by episodes of severe retro-orbital pain in the left eye and left sixth nerve palsy. Elevated sedimentation rate and a positive antinuclear factor accompanied exacerbations of her disease. Testing for antinuclear factor may help diagnose this rare cause of ophthalmoplegia. REFERENCES
1. Hunt, W. E., Meagher, J. N., Lefever, H. E., and Zeman, W.: Painful ophthalmoplegia. Its rela tion to indolent inflammation of the cavernous sinus. Neurology 11:56, 1961. 2. Smith, J. L., and Taxdal, D. S. R.: Painful ophthalmoplegia. The Tolosa-Hunt syndrome. Am. J. Ophthalmol. 61:1466, 1966. 3. Walsh, F. B., and Hoyt, W. F.: Clinical Neuro-Ophthalmology, 3rd ed. Baltimore, Williams and Wilkins, 1969, p. 398. 4. Tolosa, E.: Periarteritic lesions of carotid siphon with the clinical features of a carotid infraclinoidal aneurysm. J. Neurol. Neurosurg. Psychiatr. 17:300, 1954.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
5. Laake, J. P. W. F.: Superior orbital fissure syndrome. Report of a case caused by local pachymeningitis. Arch. Neurol. 7:289, 1962. 6. Schatz, N., and Farmer, P.: Tolosa-Hunt syn drome. The pathology of painful ophthalmoplegia. In Smith, J. L. (ed.) : N euro-Ophthalmology, vol. 6. St. Louis, C. V. Mosby, 1972, p. 102. 7. Sondheimer, F. K"., and Knapp, J.: Angiographic findings in the Tolosa-Hunt syndrome. Pain ful ophthalmoplegia. Radiology 106:105, 1973. 8. Friou, G. J.: Antinuclear antibodies. Diagnostic significance and methods. Arthritis Rheum. 10:151, 1967. 9. Wohl, M. J., and Castleman, B.: Pulmonary hypertension in a 21-year-old woman. N. Engl. J. Med. 288:204, 1973. 10. Alarcon-Segovia, D., Fishbein, E., Reyes,
MAY, 1974
P. A., Dies, H., and Shwadsky, S.: Antinuclear antibodies in patients on anticonvulsant therapy. Clin. Exp. Immunol. 12:39, 1972. 11. Cetina, J. A., Fishbein, E., and AlarconSegovia, D.: Antinuclear antibodies and propylrhiouracil therapy. J.A.M.A. 220:1012, 1972. 12. Burnham, T. K.: Antinuclear antibody in pa tients with malignancies. Lancet 2:436, 1972. 13. Zeromski, J. O., Gorny, M. K., and Jarczewska, K.: Malignancy associated with antinuclear antibodies. Lancet 2:1035, 1972. 14. Cammarata, R. J., Rodnan, G. P., and Fennell, R. H.: Serum anti-y-globulin and antinuclear factors in the aged. J.A.M.A. 199: 455, 1967. 15. Mathew, N. T., and Chandy, J.: Painful ophthalmoplegia. J. Neurol. Sci. 11:243, 1970.
OPHTHALMIC MINIATURE
Well, what can you do if they make you an Orator ? Here is one subject which would be all right—atmosphere. I do not mean what you breathe but what makes one hospital pleasant and another hospital unpleasant. It is the most valuable thing any hospital can possess and yet very little has been said about its ingredients. They are numerous and interesting: Fronthall porters, newspaper boys and ward maids contribute much to it, depending on whether they are alert, polite, cheerful and friendly or not. The telephone operators of the hospital switchboard play an enormous part. These matters do far more for a hospital than a new electronic machine for scanning Rorsach responses. A large number of notices telling people all the things they must not do and warning them it is their fault if their property gets stolen, and a few gum-chewing attendants with soiled uniforms do more harm to a hospital than one missed diagnosis of pseudo-spontaneous hypoparathyroidism. The subject of hospital atmo sphere is vast, and a man with wisdom and the gift of handling words well could make a splendid oration on it. Richard Asher Talking Sense Pitman Medical, 1972
AND LEE M. JAMPOL,
M.D.
New Haven, Connecticut 1
Hunt and associates described the condi tion of unexplained retro-orbital pain and extraocular muscle palsy in a review of six cases. They attributed the symptoms to a low-grade inflammation in the anterior cav ernous sinus. This report describes a patient with corticosteroid-responsive Tolosa-Hunt syn drome who had a positive antinuclear factor (antibody) associated with exacerbations of her disease. CASE REPORT
A 58-year-old white woman was admitted to the Neurology Service at the Yale-New Haven Hos pital in February 1970 for evaluation of pain in the left eye, and diplopia. The patient's past medical history included tuberculosis, thyroid adenoma, and duodenal ulcer. In addition, she had had a left mas tectomy in 1953 for a carcinoma of the breast. Sub sequent wedge resections of her right breast at Yale-New Haven Hospital in 1964 and 1967 showed only cystic mastitis. In 1969, the patient had had an episode of retro-orbital pain in the left eye, which apparently spontaneously improved over a period of two months. At that time, ophthalmic evaluation showed bilateral subepithelial corneal opacities and a left sixth nerve palsy. These symptoms resolved, and the patient was doing well until 11 days before admission, when she developed a constant, severe left-sided aching retro-orbital pain. This persisted without relief, and six days prior to admission, she developed diplopia, and her left pupil was larger than her right. She noted no decrease in vision. Ophthalmic evaluation at the time of admission re vealed bilateral vision of 20/20. The pupils, at the time of our evaluation, were equal and reactive to light. No Marcus Gunn pupil was present. External examination revealed no evidence of blepharoptosis or orbital inflammation. There was limitation of ab duction of the left eye; extraocular muscle evalua tion was otherwise normal. Corneal sensation was intact bilaterally. Slit-lamp examination revealed bi lateral discrete corneal subepithelial opacities. General physical examination showed a thin feFrom the Department of Ophthalmology and Vis ual Science, Yale University School of Medicine, New Haven, Connecticut. Reprint requests to Lee M. Jampol, M.D., De partment of Ophthalmology and Visual Science, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06S10.
male in extreme discomfort. She had a left mastec tomy scar as well as a scar on the right breast. The remainder of her examination was unremarkable. Laboratory findings on admission included a C-reactive protein of 3 mm. The antinuclear factor was positive on two separate occasions (indirect immunofluorescent test). Rheumatoid factor was negative. The sedimentation rate was 41 mm per hour. A glucose tolerance test was normal. The lupus prepa ration (LE test), VDRL for syphilis, and FTAABS were negative. A temporal artery biopsy was negative. Skull x-ray films were unremarkable, and a lumbar puncture showed a normal pressure and glucose level, with a protein of 56 mg/100 ml. A diagnosis of Tolosa-Hunt syndrome was made, and the patient was started on 60 mg of prednisone per day. Within eight hours the pain and the left sixth nerve paresis dramatically improved. Four days later the prednisone was discontinued. Two days later, she again developed a headache. She was put back on prednisone, but she stopped the medica tion herself and the headache and diplopia again re curred. This required readmission at which time she again responded to prednisone. The patient was gradually tapered off her corticosteroid regimen and did well until April 1972, when she had another at tack manifested by retro-orbital pain in the left eye and left sixth nerve palsy. She again responded dra matically to prednisone treatment and again had a positive antinuclear factor and elevated sedimenta tion rate. DISCUSSION
According to H u n t and his colleagues, 1 the Tolosa-Hunt syndrome is characterized by a steady, unilateral, retro-orbital gnawing pain with ophthalmoplegia. Cranial nerves I I I , I V , V, and V I , and occasionally the optic nerve and sympathetics, may be involved. Charac teristically the attacks recur at intervals of months to years with symptoms lasting for days or weeks. Spontaneous remissions oc cur, but a dramatic improvement in symp toms is often seen when the patient is given prednisone over a 48-hour period. 2 Most evi dence points to an inflammatory lesion in the anterior cavernous sinus. 3 A t postmortem examination in a single case, Tolosa 4 found periarteritic lesions in the intracavernous sinus. Laake 5 reported a case in which he found at operation a localized low-grade
732
VOL. 77, NO. 5
TOLOSA-HUNT SYNDROME
pachymeningitis involving primarily the superior orbital fissure as well as the wall of the cavernous sinus. The cavernous sinus itself, however, was spared. Recently Schatz and Farmer 6 described two patients with Tolosa-Hunt syndrome who had granulomas in the cavernous sinus. Sondheimer and Knapp 7 added further support for the disease being localized to the cavernous sinus by re viewing the venographic findings in three patients and finding complete ipsilateral oc clusion of the superior ophthalmic vein and partial obliteration of the cavernous sinus. T h e patient in this report appears to fit the clinical diagnosis of the Tolosa-Hunt syn drome. There was a history of retro-orbital pain with ophthalmoplegia which responded consistently and dramatically to corticosteroid treatment. Characteristically, the signs and symptoms recurred with rapid corticosteroid withdrawal. Metastatic disease, dia betes mellitus, aneurysm, and nasopharyngeal tumor were all carefully ruled out. Although the patient did not have evidence of a sys temic vasculitis, a striking clinical feature was the association of flare-ups of the syn drome with an increased sedimentation rate and a positive antinuclear factor. T h e antinuclear factor (antibody) is not a specific immunologic test. A positive test indicates the presence of antibodies to nuclei or nu cleic acid in the fluid tested. At least three subcategories have been delineated. T h e most commonly used method of testing for this antibody is the indirect immunofluorescence technique. 8 Antinuclear factor is invariably positive in patients with systemic lupus erythematosus, and a patient with a positive L E preparation should have a positive antinuclear factor. T h e antinuclear factor is also positive in a size able proportion of patients with rheumatoid arthritis ( 3 0 % ) and scleroderma (50 to 6 0 % ) . ° Other causes of a positive antinu clear factor include medications 1 0 ' 1 1 (hydralazine hydrochloride, isoniazid, anticonvulsants, and others), and occasionally derma tomyositis, polyarteritis, Hashimoto's thy-
733
roiditis, hepatitis, ulcerative colitis, or pul monary fibrosis. Malignancy has also been associated with positive antinuclear fac tor, 12 ' 13 and patients above 65 years of age have a higher incidence of positive antinu clear factor. 14 O u r patient had none of the diseases described above. W e found no prev ious reports of the association of TolosaH u n t syndrome with a positive antinuclear factor. However, Mathew and Chandy, 1 5 in reporting 22 cases of painful ophthalmo plegia in India, did find positive L E prepara tions in five of eight patients tested. Anti nuclear factor was negative in eight patients tested. However, the five patients with a posi tive L E test should have had positive anti nuclear factor. Like our patient, there was no evidence in their patients of collagen vascular disease. Although it seems unlikely that the antinuclear factor elevation in our patient with Tolosa-Hunt syndrome indicates gen eralized collagen vascular disease, this lab oratory test may help diagnose this rare cause of ophthalmoplegia. SUMMARY
A 58-year-old woman had corticosteroidresponsive Tolosa-Hunt syndrome mani fested by episodes of severe retro-orbital pain in the left eye and left sixth nerve palsy. Elevated sedimentation rate and a positive antinuclear factor accompanied exacerbations of her disease. Testing for antinuclear factor may help diagnose this rare cause of ophthalmoplegia. REFERENCES
1. Hunt, W. E., Meagher, J. N., Lefever, H. E., and Zeman, W.: Painful ophthalmoplegia. Its rela tion to indolent inflammation of the cavernous sinus. Neurology 11:56, 1961. 2. Smith, J. L., and Taxdal, D. S. R.: Painful ophthalmoplegia. The Tolosa-Hunt syndrome. Am. J. Ophthalmol. 61:1466, 1966. 3. Walsh, F. B., and Hoyt, W. F.: Clinical Neuro-Ophthalmology, 3rd ed. Baltimore, Williams and Wilkins, 1969, p. 398. 4. Tolosa, E.: Periarteritic lesions of carotid siphon with the clinical features of a carotid infraclinoidal aneurysm. J. Neurol. Neurosurg. Psychiatr. 17:300, 1954.
734
AMERICAN JOURNAL OF OPHTHALMOLOGY
5. Laake, J. P. W. F.: Superior orbital fissure syndrome. Report of a case caused by local pachymeningitis. Arch. Neurol. 7:289, 1962. 6. Schatz, N., and Farmer, P.: Tolosa-Hunt syn drome. The pathology of painful ophthalmoplegia. In Smith, J. L. (ed.) : N euro-Ophthalmology, vol. 6. St. Louis, C. V. Mosby, 1972, p. 102. 7. Sondheimer, F. K"., and Knapp, J.: Angiographic findings in the Tolosa-Hunt syndrome. Pain ful ophthalmoplegia. Radiology 106:105, 1973. 8. Friou, G. J.: Antinuclear antibodies. Diagnostic significance and methods. Arthritis Rheum. 10:151, 1967. 9. Wohl, M. J., and Castleman, B.: Pulmonary hypertension in a 21-year-old woman. N. Engl. J. Med. 288:204, 1973. 10. Alarcon-Segovia, D., Fishbein, E., Reyes,
MAY, 1974
P. A., Dies, H., and Shwadsky, S.: Antinuclear antibodies in patients on anticonvulsant therapy. Clin. Exp. Immunol. 12:39, 1972. 11. Cetina, J. A., Fishbein, E., and AlarconSegovia, D.: Antinuclear antibodies and propylrhiouracil therapy. J.A.M.A. 220:1012, 1972. 12. Burnham, T. K.: Antinuclear antibody in pa tients with malignancies. Lancet 2:436, 1972. 13. Zeromski, J. O., Gorny, M. K., and Jarczewska, K.: Malignancy associated with antinuclear antibodies. Lancet 2:1035, 1972. 14. Cammarata, R. J., Rodnan, G. P., and Fennell, R. H.: Serum anti-y-globulin and antinuclear factors in the aged. J.A.M.A. 199: 455, 1967. 15. Mathew, N. T., and Chandy, J.: Painful ophthalmoplegia. J. Neurol. Sci. 11:243, 1970.
OPHTHALMIC MINIATURE
Well, what can you do if they make you an Orator ? Here is one subject which would be all right—atmosphere. I do not mean what you breathe but what makes one hospital pleasant and another hospital unpleasant. It is the most valuable thing any hospital can possess and yet very little has been said about its ingredients. They are numerous and interesting: Fronthall porters, newspaper boys and ward maids contribute much to it, depending on whether they are alert, polite, cheerful and friendly or not. The telephone operators of the hospital switchboard play an enormous part. These matters do far more for a hospital than a new electronic machine for scanning Rorsach responses. A large number of notices telling people all the things they must not do and warning them it is their fault if their property gets stolen, and a few gum-chewing attendants with soiled uniforms do more harm to a hospital than one missed diagnosis of pseudo-spontaneous hypoparathyroidism. The subject of hospital atmo sphere is vast, and a man with wisdom and the gift of handling words well could make a splendid oration on it. Richard Asher Talking Sense Pitman Medical, 1972