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Show Journal of Clinical Neuro- ophthalmology 9( 4): 285- 288, 1989. Isolated, Pupil- Sparing Third Nerve Palsy as Initial Manifestation of Systemic Lupus Erythematosus Elliot D. Rosenstein, M. D., Joseph Sobelman, M. D., and Neil Kramer, M. D. © 1989 Raven Press, Ltd., New York A 29- year- old woman had an isolated, pupil- sparing third cranial nerve palsy, Serologic and CSF abnormalities and the subsequent course were consistent with systemic lUpus erythematosus, Corticosteroid therapy resulted in improvement of ocular palsy within 4 weeks, The pathogenesis of cranial neuropathy in systemic lupus erythematosus and the unique presentation in this patient are discussed, Key Words: Systemic lUpus erythematosus- Cranial neuropathy- Oculomotor nerve, From the Division of Rheumatology and Department of Neurology, UMDNJ- New Jersey Medical Center, Newark, New Jersey, U. S, A, Address correspondence and reprint requests to Dr. E, D. Rosenstein at Division of Rheumatology and Chmcal Immunology, Newark Beth Israel Medical Center, 201 Lyons Ave" Newark, NJ 07112, U. S, A. 285 Systemic lupus erythematosus is a chronic inflammatory disease of unknown etiology, characterized by autoantibody formation and immune complex deposition resulting in diverse and variable clinical presentation. Neurologic manifestations of systemic lupus erythematosus are often prominent and dramatic and have been appreciated since the earliest descriptions by Kaposi ( 1) and Osler ( 2). Since the original descriptions, a wide spectrum of neurologic findings have been reported involving almost every level of the neuraxis, from disorders of cortical function ( e, g., psychosis or dementia) to the neuromuscular junction ( e. g., myasthenia gravis), Cranial neuropathies, consisting most commonly of ophthalmoplegias, trigeminal neuralgia, or facial palsy, have been reported in 3- 16% of patients in several large series ( 3- 5), In our case, a common neuro- ophthalmologic abnormality, an isolated third nerve palsy with pupillary sparing, represents a novel initial manifestation of systemic lupus erythematosus, CASE REPORT A previously well 29- year- old woman presented in September 1985 with progressive horizontal and vertical diplopia with associated dizziness for several weeks, unresponSive to trifluoperazine and meclizine. Single binocular vision occurred only in left lateral gaze, There was no prior personal or family history of diabetes, hypertension, hypercholesterolemia, or vascular disease. The patient smoked one pack of cigarettes daily for 12 years. There was no use of oral contraceptive medications. Physical examination was notable for normal visual acuity. Pupils were equal in size and reacted to light and accommodation. Visual fields were 286 E. D. ROSENSTEIN ET AL. full. Ptosis was present on the left. The left eye was deviated outward and slightly depressed. There was inability to move the eye upward or downward. There was no nystagmus, and ocular motility was full in the right eye. The remainder of the neurologic and general physical examination was normal. There was no improvement in ocular motility after administration of edrophonium chloride. Computed tomography of the head and orbits, with and without contrast, and cerebral angiography were normal. Cerebral spinal fluid analysis revealed protein 76 mg/ dl ( normal, 14- 45 mg/ dl) and slight lymphocytosis, 12 cells/ mm3 ; oligoclonal bands were absent. Erythrocyte sedimentation rate was 63 mm/ h ( Westergren). Complete blood count, 4- h glucose tolerance, and thyroid function tests were normal. Serologic testing for syphilis [ rapid plasma reagin ( RPR)] and Lyme disease [ enzyme- linked immunosorbent assay ( ELISA)] were negative. LE prep was positive. Anti- nuclear antibody was positive at titer 1: 2,560, homogeneous pattern; antibodies to DNA, RNP, Smith, SS- A ( Ro), and SS- B ( La) were absent. Anticardiolipin antibody determination was not done. The level of C3 was 65 mg/ dl ( normal, 84- 140 mg/ dl), C4 was 12 mg/ dl ( normal 18- 45 mg/ dl). Prednisone, 1 mg/ kg, was administered with improvement of gaze palsy within 3- 4 weeks. During the following 4 months, her regimen was reduced to alternate day corticosteroids and eventually discontinued. During the next 8- 12 months, she subsequently noted the onset of periods of morning stiffness with painful swelling of her digits; cold- and emotion- induced Raynaud's phenomenon of her fingers; pleuritic chest pain without documented effusion- all of which have been treated with nonsteroidal medications and supportive measures. Renal function and urinalysis remained normal. There has been no recurrence of her ocular palsy or development of other neurologic findings. DISCUSSION Isolated pupil- sparing third nerve palsies in adults are most often caused by microvascular infarction ( 6). In the patient presented here, there was no identifiable vasculopathic risk factor other than the history of smoking. The presence of tumor or aneurysm was excluded by the radiographiC procedures. Systemic lupus erythematosus seemed the most plausible explanation for her presenta tion. Neuro- ophthalmologic manifestations of lupus I Gin Neuro- ophthalmol, Vol. 9, No. 3, 1989 are diverse and include disorders of the orbits, visual system, and oculomotor pathways. These abnormalities are listed in Table 1, based on anatomic localization. We are aware of only one prior report of ocular palsy as the sole initial clinical manifestation of lupus. Sedwick and Burde ( 18) reported a young women with an isolated sixth nerve palsy who additionally had leukopenia and positive fluorescent antinuclear antibody, consistent with lupus. Her symptoms improved without treatment, and she subsequently showed no further evidence of active lupus. Third nerve palsy has been noted in only a few previous reports ( 5,19,20). The best substantiated case was reported by Johnson and Richardson ( 5) ( case 3), who noted a transient, pupil- sparing, third nerve palsy in a patient with multisystem involvement due to lupus. Death was attributed to renal failure 7 years later, and postmortem examination revealed a totally normal brainstem. The peripheral portion of the cranial nerve was not examined. Isolated, nontraumatic, third nerve palsy, sparing the pupil, has traditionally been ascribed to microinfarction due to diabetes, hypertension, or atherosclerosis. The classic oculomotor lesion, as seen in diabetes, involves the nerve at the brain stern level in its subarachnoid and cavernous portion. Asbury et al. ( 21) found hyalinization and endothelial proliferation resulting in luminal narrowing in some of these vessels. Due to involvement of the vasa nervorum, central axons and myelin sheaths were destroyed. The nerve periphery, where the pupillary- motor fibers dominate and which receives its blood supply from the arachnoidal vessels, was spared. TABLE 1. Neuro- ophthalmologic manifestations of systemic lupus erythematosus Orbital lesions Orbital pseudotumor ( 7) Tolosa- Hunt syndrome ( 8) Anterior visual pathway Papilledema ( 9) Pseudotumor cerebri ( 10,11) Optic neu ropathy ( 12) Retinal vascular disease ( 13) Retrochiasmatic pathway Visual field defects ( 14) Cerebral blindness ( 14) Visual hallucinations and transient obscuration with or without migraine ( 14,15) Brainstem lesions Unilateral internuclear ophthalmoplegia ( 16) Bilateral internuclear ophthalmoplegia ( 17) Isolated sixth nerve palsy ( 18) Isolated third nerve palsy ( present case) SYSTEMIC LUPUS ERYTHEMATOSUS 287 In systemic lupus erythematosus, the pathogenesis of CNS manifestations has been similarly felt to be due to vaso- occlusive phenomenon in small vessels. As opposed to the characteristic inflammatory cell infiltration of blood vessel walls and fibrinoid necrosis, pathologic studies of patients with CNS lupus infrequently show these features. More typically, a bland vasculopathy with degenerative and proliferative changes in small vessels, similar to those seen in hypertensive encephalopathy, would be present ( 5,22). Since vasculitic lesions are conspicuously absent, alternative explanations for vaso- occlusive phenomenon have been examined. Recent investigations have suggested that even in the absence of local immune complex deposition, profound complement activation can result in a release of chemotactic factors ( C3a and C5a) resulting in the aggregation and activation of platelets and neutrophils, with subsequent release of toxic oxygen species and proteolytic enzymes, causing endothelial injury and vascular obstruction ( 23). Alternatively, thrombotic and/ or embolic events related to the presence of anti- phospholipid antibodies ( lupus anticoagulant, anti- cardiolipin) have been postulated ( 24). Other less likely causes of vascular compromise might include embolic phenomenon related to the presence of verrucous ( Libman- Sachs) endocarditis ( 25) and the presence of thrombotic thrombocytopenic purpura, which has been documented in a number of patients with lupus ( 26). This patient's serologic abnormalities and subsequent course satisfies ARA criteria for the diagnosis of systemic lupus erythematosus ( 27). However, her initial presentation was most uncharacteristic of patients with CNS involvement. Although neuropsychiatric manifestations may occur before or after the diagnosis of lupus is made, in only - 5% of patients are they the sole presenting features of the disease ( 28). In the series ~ f Feinglass ( 3), among 33 patients with neuropsychIatric manifestations preceding or occurring in the first year subsequent to the diagnosis of lupus, 32 had associated clinical symptoms or findings more suggestive of lupus. Furthermore, among those patients with cranial nerve findings, 88% had other acute neurologic features ( 3). The patient described here reported no other manifestations of lupus until 1 year after her initial presentation. The use of corticosteroids in this patient was predicated on not only the ocular palsy, but the serologic and CSF abnormalities suggesting more generalized lupus activity and possibly diffuse cerebral dysfunction. The patient's rapid improve-ment and benign course may indicate responsiveness to corticosteroid therapy. Since vasculopathic palsy often resolves spontaneously in ~ 12 weeks without treatment, we cannot be certain if this may have occurred, similar to the patient reported by Sedwick and Burde ( 18). 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