Internuclear ophthalmoplegia in systemic lupus erythematosus

CLINICAL SCIENCE

Internuclear Ophthalmoplegia in Systemic Lupus Erythematosus Maria Galindo, Josd L. Pablos, and Juan J. Gomez-Reino Objectives: To describe and review internuclear ophthalmoplegia (INO) in systemic lupus erythematosus (SLE). Patients and Methods: A population of 268 SLE patients was retrospectively studied. INO was clinically defined as palsy of the ipsilateral rectus muscle and failure in contralateral eye adduction with dissociated nystagmus. A systematic review of the literature was made using MEDLINE (Silver-Platter) between 1966 and 1997, and for completeness, earlier references cited in identified articles. Results: Four women with INO were identified. Their mean age at INO diagnosis was 38 years, and mean delay from diagnosis of SLE to INO was 6 years. INO was unilateral in all and coincided with disease activity in three. Cardiovascular risk factors were present in three. Magnetic brain resonance showed multiple and hyperintense (T2) lesions in white matter without correlation with clinical features. Other ancillary tests were not helpful for diagnosis. Corticosteroid therapy resulted in full resolution of INO in three cases. Review of 14 additional cases from the literature showed a similar experience. Conclusions: INO is uncommon in SLE, but it should be suspected in young patients with active disease and impairment of ocular movements. Diagnosis relies largely on clinical grounds. Neuroimaging is of little help. Steroid therapy seems effective in improving eye movements. Semin Arthritis Rheum 28:179-186. Copyright © 1998 by W.B. Saunders Company

INDEX WORDS: Systemic lupus erythematosus; central nervous system; internuclear ophthalmoplegia; neuroophthalmology; magnetic resonance. 'EUROPSYCHIATRIC INVOLVEMENT in systemic lupus erythematosus (NPSLE) may present as psychosis, organic brain syndrome, neurocognitive disorders, headaches, seizures, strokes, basal ganglia disregulation, myelitis, cranial or peripheral neuropathy, and neuromuscular union disorders. The frequency of NPSLE is estimated to range from 25% to 75% (1-3). No objective diagnostic criteria for NPSLE have been established (4). One of the focal manifestations of NPSLE is internuclear ophthalmoplegia (INO). It is defined as a lesion of the medial longitudinal fascicle (MLF), which connects the nucleus of the VI cranial nerve pair with the contralateral III pair during horizontal movements. Clinically, INO results in palsy of the ipsilateral rectus muscle and failure in contralateral eye adduction, with dissociated nystagmus. Usually, there is preservation of

N

medial rectus function on convergence. However, horizontal (worst in the abducting eye), rotatory, and vertical nystagmus are present. Vertical divergence of the eyes (skew deviation) often occurs. The onset of eye-related symptoms may- be accompanied by vertigo, nausea, and vomiting. INO occurs in several diseases, multiple sclerosis being From the Servicio de Reumatologfa, Hospital 12 de Octubre, Madrid, Spain; and the Servieio de Reumatolog{a, Complejo Hospitalario Universitario, Santiago de Compostela, Spain. Maria Galindo, MD: Research fellow, Servicio de ReumatoIogfa, Hospital 12 de Octubre, Madrid; Jos6 L. Pablos: Senior Staff Rheumatologist, Servicio de Reumatolog{a, Hospital 12 de Octubre, Madrid," Juan J. G6mez-Reino: Professor and Chief Servicio de Reumatologfa, Complejo Hospitatario Universitario, Santiago de Compostela, Spain. Address reprint requests to Marfa Galindo, MD, Servicio de Reumatolog{a, Hospital 12 de Octabre, 28041 Madrid, Spain. Copyright © 1998 by W.B. Saunters Company 0049-0172/98/2803-000458. 00/0

Seminars in Arthritis and Rheumatism, Vo128, No 3 (December), 1998: pp 179-186

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GALINDO, PABLOS, AND GOMEZ-REINO

the most frequent in young patients (5). There are several cases reported in association with systemic lupus erthymatosus (SLE), but information regarding suitable diagnostic methods, therapy, and prognosis is meager. In this article, we describe the clinical presentation, results of diagnostic methods, and treatment of four SLE patients with INO. In addition, we have systematically reviewed the information accumulated in the literature between 1966 and 1997 and earlier reports cited in identified articles. PATIENTS AND METHODS

Patients Patients were retrospectively identified by reviewing the charts of 268 SLE patients diagnosed according to the 1982 revised American College of Rheumatology criteria (6) and followed-up at the rheumatology unit of our university hospital between 1979 and 1997. Clinical, laboratory, and neuroimaging data were extracted from their records. Special attention was paid to previous events and symptoms at INO onset. Reviewed laboratory data included full blood counts, biochemistry, clotting tests, and the results of serologic assays. Computerized axial tomography (CAT) and magnetic resonance imaging (MRI) of the brain were available in all identified patients.

Literature Review The review was made using MEDLINE (SilverPlatter) between 1966 and 1997. For completeness, references cited in all identified articles were also reviewed. For the search, subject terms used were systemic lupus erythematosus, neurological manifestations, and ophthalmopIegia. To increase sensitivity regarding information on diagnostic methods, subject terms were combined with the following mesh terms: brain scan, radionuclide brain imaging, brain magnetic resonance imaging, or diagnosis. A total of eight articles meeting the purpose of our search were retrieved (7-14). All were case reports, totaling 14 patients. The characteristics of reported patients are summarized in Table 1. CASE REPORTS

Case 1 A 27-year-old woman was admitted with fever, myalgia, headaches, and malar rash. She had been diagnosed as having SLE 14 years earlier, when she

developed fever, malar rash, alopecia, polyarthralgia, pancytopenia, and diffuse proliferative glomerulonephritis with high blood pressure. She also had positive tests for antinuclear antibodies (ANA), anti-dsDNA, anti-ribonucleoprotein, and anticardiolipin antibodies immunoglobulin G, (ACA). She presented with downward vertical deviation of the right eye, vertical nystagmus of the left eye, and rotatory conjugated nystagmus with limited supraversion of the right eye. On admission, she was on prednisolone (15 mg daily) and aspirin (200 mg daily) therapy. Laboratory tests showed thrombocytosis, hypergammaglobulinemia, elevated erythrocyte sedimentation rate (ESR), and C-reactive protein levels, and positive ANA and ACA. Chest radiograph, electrocardiogram (ECG), echocardiogram, and cerebrospinal fluid (CSF) analysis were normal. The electroencephalogram (EEG) showed nonspecific irregularities. A left thalamic lacunar infarction was found on brain CAT. The brain MRI showed hyperintense lesions in semioval centers, left frontal and right parietal areas, and left thalamus. Treatment with prednisolone (1 mg/kg/day) and ticlopidine was followed by complete INO resolution.

Case 2 A 39-year-old woman with a history of cigarette smoking was admitted with severe thrombocytopenia and bleeding complications. She also had left eye paresis in abduction on left conjugated gaze and horizontal nystagmus of this eye toward the same side without paresis in monocular gaze. She was diagnosed as having SLE 2 years earlier, when she developed subacute cutaneous lupus, polyarthralgia, thrombocytopenia, and positive ANA, anti-DNA, anti-Ro and ACA antibodies. On admission, she had an elevated ESR, low complement levels and positive ACA. At this time, chest radiograph, ECG, CSF analysis and brain CAT were normal. She was treated with prednisolone (2 mg/kg/day) but INO did not improve. A brain MRI performed 3 years later, when she developed hypertensive encephalopathy, revealed multiple hyperintense lesions in the white matter.

Case 3 A 51-year-old woman was admitted with acute diplopia and dizziness. SLE had been diagnosed 5 years prior to admission when she developed pleuropericarditis, alopecia, cutaneous vasculitis,

INTERNUCLEAR OPTHALMOPLEGIA IN SLE

organic brain syndrome (OBS), diffuse proliferative glomerulonephritis, anemia and lymphopenia. She had positive ANA, anti-DNA and anti-Ro antibodies, and low complement levels. In addition, she had high blood pressure and hypertrophic subaortic cardiomyopathy with severe calcification of the mitral annulus. On admission, she was on prednisolone (10 mg daily) therapy. The ECG showed a regular rhythm with signs of left ventricle hypertrophy and repolarization abnormalities. All laboratory tests, EEG, and brain CAT were normal. Brain MRI showed multiple hyperintense lesions of the left hemisphere white matter. She was treated with prednisolone (1 mg/kg/day), and oral anticoagulation and INO resolved. Case 4 A 34-year-old woman was admitted with cutaneous vasculitis, visual scintillation, blurred vision, and unsteadiness. The diagnosis of rheumatoid arthritis/SLE overlap syndrome was made 4 years earlier when she developed chronic, erosive, and nodular polyarthritis, malar rash, mouth ulcers, pleuropericarditis, mesangial glomerulonephritis, anemia, and leukopenia. She had low complement levels and positive ANA, anti-DNA, anti-ribonucleoprotein, and anti-Sin antibodies. On admission, chest radiograph, ECG, EEG, CSF analysis, and brain CAT were normal. Brain MRI was not available. She was treated with prednisolone (1 mg/kg/day) and oral anticoagulation. INO resolved, but headaches and unsteadiness remained. Additional characteristics of the patients are summarized in Table 1. RESULTS

Clinical and Laboratory Data of Present Series Four of our 268 SLE patients had INO; all were women. The mean age at INO development was 38 years (range, 27 to 51). The mean delay from SLE diagnosis to INO diagnosis was 6 years (range, 2 to 14). INO was unilateral in all. In three patients, it was associated with SLE activity manifested by low complement levels, cutaneous lesions (in two), and hematological involvement (in two). Cardiovascular risk factors were found in three cases, high blood pressure in two, cardiomyopathy and cardiac valve disease in one, and smoking habit in one. Patient 2 developed INO without any other neuro-

181

psychiatric manifestation and associated with SLE activity. INO in patient 3 was likely of cardioembolic origin and was not accompanied by other signs of disease activity. Immunoglobulin G ACA were detected in two patients at the time INO was diagnosed. Other laboratory abnormalities were thrombocytopenia and low complement levels. CSF analysis was performed in three patients, with normal results. EEG in three patients showed diffuse nonspecific irregularities. Neuroimaging Brain CAT was normal in three patients. In case 1, it showed a left thalamic lacunar infarction. MRI was performed in three patients. At diagnosis of INO, it showed multiple hyperintense lesions in the white matter in patients 1 and 3. Despite clinical improvement, repeat MRI in patient 1 remained unchanged. In case 2, MRI was performed 3 years later because of hypertensive encephalopathy and showed multifocal hyperintense lesions in the white matter. Treatment All patients were treated with 1 to 2 mg/kg/day prednisone for 1 month. One patient also received platelet antiaggregation; and two, anticoagulation. In patients 1, 2, and 4, SLE activity improved after 1 month of corticosteroid therapy. In patients 1, 3, and 4, INO resolved with therapy, and it persisted in patient 2 despite treatment (Table 1). Literature Review Fourteen cases of SLE with INO have been reported in the literature between 1950 and 1997. All were women with ages between the second and the fifth decades. INO was unilateral in ten (7-9, 12-14) and bilateral in four (10, 11, 14). Clinical, laboratory and neuroimaging data at INO were reported in nine cases (7-13). In eight, INO coincided with activity of SLE (7-13). In two patients (7, 8), INO was the exclusive neurological manifestation. In seven cases (9-13), other neurological symptoms were present (Table 1). ACA were positive in three patients who were studied. Treatment was reported in four cases; all received corticosteroids and one also was given azathiopfine. In all, INO improved concomitantly with therapy. Additional characteristics are summarized in Table 1.

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GALINDO, PABLOS, AND GOMEZ-REINO

Table 1: Characteristics of the Patients Reference

No. patients

Cogen et al, 1950 (7) Meyer, 1975 (8) Lessell, 1979 (9)

1 1 3

Age/Sex 25/F 49/F (1) 26/F

Cardiovascular Risk Factors NA NA NA

SLE activity + +

(2) 24/F

+

(3) 13/F

+

Jackson et al, 1985 (10)

1

25/F

NA

+

Cogen etal, 1987 (11)

1

23/F

NA

+

Sugie et al, 1989 (12)

1

15/F

NA

+

Hisashi et al, 1993 (13)

1

Adolesc/F

NA

+

Keane, 1995 (14)

5

NA

NA

NA

Present series

4

(1) 27/F

HBP

+

(2) 39/F (3) 51/F

Smoker HBP; HTCM

+ -

(4) 34/F

NA

+

Abbreviations:F, female; HBP, high blood pressure; HTCM, hypertrophic cardiomyopathy; INO, internuclear ophthalmoplegia; NA, not available; OAC, oral anticoagulation.

DISCUSSION

Focal neurological manifestations represent between 10% and 35% of all NPSLE (15). Among them, cranial nerve neuropathies are the most frequent. Ocular movements may be impaired by lesions at any level between the first motor neuron and ocular muscles (16, 17). INO results from structural or functional lesions of the MLE Its prevalence in SLE is low, and only 14 cases have been reported since 1950. We herein present four additional cases. INO presents almost invariably during periods of SLE activity, either isolated or, more often, associated with other neurological symptoms. Its etiopathogenesis is unknown, owing in part to inacces-

sibility of brain tissue specimens for study. Focal neurological disorders were first described in SLE as secondary to vasculopathy by Johnson and Richardson in 1968 (1). Predominant lesions were multifocal microinfarcts and increased microglial cells around small arteries (< 100 pm) and capillaries, with fibrin thrombi occluding their lumens. Hyalinization of the meningeal, subcortical, and cortical arterioles, perivascular lymphocytic infiltrates, endothelial proliferation, thrombosis, and capillary wall thickening also were seen. This initial description has been repeatedly confirmed by others (2, 18-20). True large vessel vasculitis is rare (less than 10% in postmortem studies) and has been documented in patients with severe and often

183

INTERNUCLEAROPTHALMOPLEGIAIN SLE

Table 1: Characteristics of the Patients (Cont'd} Neurological symptoms

Uni/bilateral INO

Treatment

Outcome

Unilateral Unilateral Unilateral

NA NA (1) NA

INO improvement NA (1) No improvement

Unilateral

(2) NA

(2) No improvement

Unilateral

(3) Steroids and azathioprine

(3) No improvement and death

Bilateral

NA

Bilateral

Prednisolone (120 mg daily) and intravenous methylprednisolone (1 g/day, 3 days) NA

Unilateral

Prednisolone (40 mg/day)

Improvement

Unilateral

Prednisolone NA

NA

(1) Right INO

Unilateral(3) Bilateral(2) Unilateral

(2) Left INO (3) Left INO

Unilateral Unilateral

(4) Visual scintillation, blurred vision, unsteadiness. Right INC.

Unilateral

(1) Prednisolone (1 mg/kg day), ticlopidine (2) Prednisolone (2 mg/kg/day) (3) Prednisolone (2 mg/kg/day), OAC (4) Prednisolone (1 mg/kg/day), OAC

(1) Improvement and INO resolution (2) Persistent INO (3) Improvemnt and INO resolution (4) INO resolution, recurrent headaches and unsteadiness

Left INO Right INO (1) Bilateral Babinski and left quadrantonopia. Right INC. (2) Left motor and sensory defect due to infectious endocarditis. Headaches, scotomas, diplopia. Left INC. (3) Headaches, recurrent facial numbness, ptosis, recurrent diplopia. Right INC. Facial nerve palsy, asymmetrical sensory loss, motor weakness, areflexia Dysarthria, hemifacial weakness, hemiparesis, dysmetria Left face hemiparesis, right hemiparesis Left lateral medullary syndrome, sensorineural hearing loss NA

fatal infarction or hemorrhage (21, 22). Inflammatory involvement of small vessels without immune complex deposition, Shwartzman-like phenomenon, may develop in vascular beds without fenestrations such as those in central nervous system (CNS) (23). This may be due to the presence of the blood-brain barrier, which prevents the access of circulating immune complexes to the perivascular tissues. Systemic activation of endothelial cells and complement can promote diffuse microvascular injury and microinfarction in the absence of immune complex deposition. During SLE flares, this mechanism may induce expression of adhesion molecules and neutrophil-endothelial cell adhesion, leading to leukoocclusive vasculopathy (24). Primary thrombotic vasculopathy also may occur, preferentially in SLE patients with positive

Improvement

ACA or additional cardiovascular risk factors (2532). The middle cerebral artery is the vessel affected most commonly. Histologically, endothelial cell edema, hyperplasia, and thrombovascular angiomatold complexes may be found. Sometimes, thrombotic and inflammatory vasculopathy develop together (33). Activation of endothelial cells may act as a unifying pathogenetic factor. They can express both adhesion molecules that promote leukothrombosis and membrane-associated coagulation proteins, a target for antiphospholipid antibodies (34). Histopathologic diagnosis was made only in a few cases of INC. In three cases, mild pretectal infarction was confirmed angiographically or at postmortem examination (14). In two cases, limitation of eye movements resembling INO was due to myositis in the periorbita and, in the other patient,

184

secondary to hypoxic encephalopathy after cardiac arrest (14). In one patient, a small infarct close to the sixth nerve nucleus destroyed the homolateral MLF (7). Laboratory tests are of little help in clarifying the pathogenesis of INO in SLE. In patients with organic brain syndrome, anti-ribosomal P antibodies have been detected (35), but they have not been tested in INO patients. The presence of antiphospholipid antibodies may identify patients at high risk of thrombosis. Increased levels of immunoglobulins (IgG, IgA, IgM), anti-DNA antibodies, complement factors, 132 microglobulin, and cyclic guanosine monophosphate have been found in the CSF of patients with diffuse NPSLE (35,36). CSF analysis was performed in four 1NO patients, two from our series and two from the literature (9), and it was always normal. EEG findings are usually nonspecific. Only one patient had delta activity over the right posterior temporal region, but he also suffered from seizures (9). Neuroimaging studies are sensitive in detecting structural changes. No characteristic patterns have been consistently observed in NPSLE. The heterogeneous nature of the disease could explain the inconsistent correlation between clinical symptoms and neuroimaging findings. Brain CAT detects morphological abnormalities such as large infarcts, intracranial hemorrhages, and cerebral atrophy (37). In SLE patients, microinfarcts are not detected by CAT. MRI is more sensitive in detecting focal lesions, but it lacks specificity. Small or large hyperintense lesions in subcortical areas and in the periventricular white matter are commonly found (38). In our patients, MRI showed multiple, small, punctate areas of increased signal in the periventricular or subcortical white matter of both hemispheres, without correlation with clinical features. None had lesions in the brainstem where the MLF is located. MRI showed brainstem lesions only in two of the literature-reported patients (9, 11) and was normal in one case (12). We have previously reported MRI lesions in SLE patients regardless of the presence or absence of NPSLE. The number of lesions correlated with patient age at study and SLE duration, but not with clinical manifestations, presence of ACA, or previous therapy (39). Similar lesions can be found in healthy volunteers and are frequently present in nonlupus patients with cardiovascular risk factors

GALINDO, PABLOS, AND G(~MEZ-REINO

(40, 41). Whether this represents subclinical vascular brain involvement remains unknown. Nevertheless, MRI may be useful when patients are divided into focal or diffuse clinical categories and, when used in conjunction with serological markers, may predict response to steroid therapy (35, 42). Additional evidence for microvascular involvement in NPSLE comes from radioisotope perfusion studies such as single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime or positron emission tomography, MR spectroscopy, and diffusion/perfusion MR techniques. They detect hypoperfused or hypometabolic areas, respectively, with a high sensitivity but low specificity. The high incidence of perfusion defects, their multiple locations, and their presence in asymptomatic patients all support the idea that NPSLE represents a primary and diffuse microvascular disorder. In fact, the absence of lesions is strong evidence against NPSLE (43-45). These studies were not performed in patients with INO. Finally, angiography is not useful because of the low sensitivity in detecting lesions of the small vessels likely involved in INO (46, 47). Treatment of NPSLE varies according to clinical features. Prospective and controlled studies are not available. Usually, in severe cases, high doses of intravenous methylprednisolone (1 g daily for 3 days) are widely used as a first step, followed by oral prednisolone as maintenance therapy (48). Cyclophosphamide and plasmapheresis are added in those patients who are (49-51) unresponsive. Early "high dose" cyclophosphamide regimens produce good results (49, 50) but are associated with significant morbidity, including herpes zoster infection and ovarian failure. Low-dose intravenous cyclophosphamide pulses have been used as a safe and effective alternative (51). When thromboric vasculopathy is suspected, platelet antiaggregation and anticoagulation also are used. Plasma exchange has produced variable results, although short-term plasmapheresis may be a useful adjunct for managing life-threatening complications along with corticosteroids and cytotoxic agents. Our patients and three from the literature were treated with high doses of steroids, and all but two improved. The two unresponsive patients had underlying thrombotic vasculopathy (9). INO, as most focal neurological disorders in NPSLE, seems to

INTERNUCLEAR OPTHALMOPLEGIA IN SLE

185

have a good prognosis that does not affect the outcome of SLE (15, 52). In summary, INO is an uncommon manifestation of SLE, is clinically well defined, and, almost

invariably, related to disease activity. Ancillary diagnostic tests are of little, if any, help in diagnosis. Usually, treatment with high-dose corticosteroids is followed by resolution of eye derangement.

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