International Journal of Rheumatic Diseases 2014; 17: 494–501

REVIEW ARTICLE

Neuro-ophthalmologic manifestations of systemic lupus erythematosus: a systematic review Bik Ling MAN, Chi Chiu MOK and Yat Pang FU Department of Medicine, Tuen Mun Hospital, Hong Kong, China

Abstract Herein we summarize the clinical presentation, treatment and outcome of neuro-ophthalmologic manifestations in patients with systemic lupus erythematosus (SLE). We performed a systematic review of the neuro-ophthalmologic manifestations of SLE reported in the English literature from 1970 to 2010 by a Medline search. The prevalence of neuro-ophthalmologic manifestations is 3.6% in adult and 1.6% in childhood SLE patients. Neuro-ophthalmologic manifestations of SLE are highly variable, with the commonest presentation being optic neuritis, followed by myasthenia gravis, visual field defects and pseudotumor cerebri. The underlying pathology was thought to be either SLE activity or its vascular complications. Most neuro-ophthalmologic manifestations of SLE are responsive to high-dose glucocorticoids. Anticoagulation is indicated when there is concomitant antiphospholipid syndrome. SLE-related neuromyelitis optica is often refractory to treatment and 92% of patients require multiple immunosuppressive protocols. Neuro-ophthalmologic manifestations of SLE are uncommon but heterogeneous. The prognosis of neuro-ophthalmologic manifestations in SLE is generally good because of their rapid response to glucocorticoids. Relapses of these manifestations may be reduced by the use of maintenance immunosuppression. Cyclophosphamide, azathioprine, plasmapheresis, intravenous immunoglobulin and rituximab can be considered in glucocorticoid-dependent or refractory cases. Anticoagulation is indicated when there is concomitant antiphospholipid syndrome. Key words: lupus, myasthenia, neuromyelitis optica, neuro-ophthalmologic, optic neuritis, pseudotumor cerebri.

INTRODUCTION Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease that may affect any organ of the body. Neurological manifestations are fairly common and the American College of Rheumatology (ACR) has defined 19 neuropsychiatric syndromes that may occur in patients with SLE.1 Neuro-ophthalmologic manifestations refer to those that arise from primary lesions in the ocular muscles, neuromuscular junction, optic nerves and visual pathways, and the central nervous system, resulting in ptosis, visual symptoms or visual field defects. Neuro-ophthalmoCorrespondence: Dr Chi Chiu Mok, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, China. Email: [email protected]

logic manifestations in SLE are heterogeneous and up to the present, there are still no consensus criteria for their classification. Neuro-ophthalmologic manifestations of SLE are related to either SLE activity or its vascular complications. The underlying pathogenetic mechanisms include vasculitis or vascular thrombosis, autoantibodies directing against neural tissues such as the neuromuscular junction, inflammation or ischemia of the optic nerve, vasogenic edema of the brain in the territory of the posterior cerebral circulation and intracranial hypertension. Only a small number of SLE patients with neuro-ophthalmologic manifestations have been reported in the literature. Although these manifestations are uncommonly encountered in SLE, they are important causes of disability and impairment of quality of life. In this article, we summarize the prevalence, clinical presentation,

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

SLE neuro-ophthalmologic manifestations

treatment and outcome of SLE patients with neuro-ophthalmologic manifestations by performing a Medline search.

METHODS We performed a systematic review of neuro-ophthalmologic manifestations in SLE by performing a Medline search for publications from January 1970 to March 2010 using the keywords ‘lupus’, ‘neuro-ophthalmology’, ‘neuro-psychiatric’, ‘optic neuritis’, ‘optic neuropathy’, ‘neuromyelitis optica’, ‘ischemic optic neuropathy’, ‘eye movement disorders’, ‘orbital pseudotumor’, ‘pseudotumor cerebri’, ‘myasthenia’, ‘intracranial hypertension’ and ‘visual field defect’. Searches were limited to human trials and articles written in English.

RESULTS Prevalence of neuro-ophthalmologic manifestations in SLE Table 1 summarizes the prevalence of neuro-ophthalmologic manifestations in SLE patients reported in 12 studies.2–13 There are eight adult3,5,6,8,9,11–13 and four childhood SLE2,4,7,10 series, with a total number of 1433 patients (1067 adult and 366 pediatric patients). The mean age at the onset of neuro-ophthalmologic manifestations was 34.6  6.8 years in adult patients and 12.6  1.0 years in childhood patients. The reported prevalence of neuro-ophthalmologic manifestations in childhood SLE2,4,7,10 was between 0.5% and 4%, whereas in adult-onset SLE patients,3,5,6,8,9,11–13 the prevalence figures ranged from 1% to 23%. A pool-

Table 1 Prevalence of neuro-ophthalmologic manifestations in SLE Author, year

Patient Characteristics

No. of patients

Ethnicity (%)

Petri M, 20088

Adult

111

Hershko AY, 20089 Hanly JG, 200811

Adult Adult

651 572

Yu HH, 20064 Harel L, 200610

Childhood Childhood

185 106

Al-mayouf SM, 20037 Brey RL, 200213(13)

Childhood Adult

52 128

Sibbitt WL, 20022

Childhood

75

Ainiala H, 20016 Yap EY, 19985 Keane JR, 19953

Adult Adult Adult

46 70 113

C (55) B (15) H (21) A (5) A C (52) B (13) H (16) A (16) A C (20) B (8.5) H (26) A (37) M (8.5) A C (30) B (8) H (56) C (27) B (8) H (61) A (4) C A NS

Feinglass EJ, 197612

Adult

140

C (52) B (48)

Mean age (years)

Prevalence (%)

33

3 (3)

24 35

10 (2) 5 (1)

13.5 12.3

1 (0.5) 4 (4)

11.3 43

14 (27) 2 (2)

13.3

1 (1)

45 32.9 33.5

4 (9) 2 (3) 26 (23)

30

22 (16)

Manifestations (no. of patients) CN (2), MG (1)

PTC (10) CN (5)

CN (1) CN (1), PTC (3)

ON (3), VFD (11) CN (2)

CN (1)

CN (3), MG (1) ON (2) Ptosis (8), PTC (2) CN(4), spontaneous eye movements (12) CN (16) Scotoma (4), PTC (2)

A, Asian; C, Caucasian; B, Black; H, Hispanic; M, mixed; NS, not specified; MG, myasthenia gravis; CN, cranial neuropathy; ON, optic neuropathy; PTC, pseudotumor cerebri; VFD, visual field defects.

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ing of these figures reveals that the prevalence of neuroophthalmologic manifestations is 3.6% and 1.6% in adult and childhood SLE patients, respectively.

Clinical presentation and treatment outcome of neuro-opthalmologic disease in SLE Optic neuropathy The commonest and most well-known neuro-ophthalmologic manifestation of SLE is optic neuropathy. This may present as isolated optic neuritis, neuromyelitis optica (NMO) (optic neuritis together with myelitis) or ischemic optic neuropathy. Isolated optic neuritis occurs in about 1% of SLE patients. It is typically unilateral and may present as retrobulbar ischemic optic neuritis or papillitis. The most common presentations are decreased visual acuity, orbital pain and central scotoma.14 SLE-optic neuritis is not due to a primary inflammatory demyelinating process but rather an ischemic process that can cause subsequent demyelination and axonal necrosis. The degree of axonal loss correlates to visual outcome. The optic neuritis responds dramatically to corticosteroid treatment.15 Early diagnosis and prompt treatment with high-dose corticosteroids is associated with better visual outcomes. In patients with NMO, aquaporin-4 antibody could be detected in 60% of cases, and higher titers of antiaquaporin-4 were associated with poorer prognosis, such as complete blindness and more extensive cerebral and spinal cord lesions on magnetic resonance imaging (MRI). Florid antibody-mediated inflammatory response could be demonstrated in NMO lesions.16 Neuromyelitis optica is well known for its resistance to treatment. Table 2 summarizes the outcomes of NMO in 12 patients with SLE.17–28 All except one patient were treated with a combination of immunosuppressive agents. One patient had poor response after multiple immunosuppressants and was relapse-free after use of immunoablative cyclophosphamide protocol without stem cell rescue.20 The coexistence of SLE and multiple sclerosis (MS) has rarely been described29 and the activity of lupus remained quiescent in all patients while on standard immunomodulatory MS therapy.29 Ischemic optic neuropathy is rare in SLE. The cause is thought to be due to vasculitis of the short posterior ciliary artery with resultant hypoperfusion and infarction of the anterior optic nerve.30 Ischemic optic neuropathy usually responds to glucocorticoid treatment. Patients with concomitant antiphospholipid syndrome should be treated with anticoagulation.

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Myasthenia gravis Myasthenia gravis (MG) has long been reported in association with SLE. Most patients presented as generalized MG with ptosis, ophthalmoplegia and proximal muscle weakness. In some patients, SLE developed after thymectomy for MG.31 The thymus is important in maintaining tolerance to self-antigens by clonal depletion of self-reactive T cells32 or rendering the self-reactive T cells anergic.33 It was postulated that thymectomy leads to loss of central tolerance and over-production of autoantibodies, which triggers the onset of SLE in susceptible individuals.31 Most SLE patients with concomitant MG responded well to pyridostigmine, glucocorticoid and thymectomy treatment. Some patients required additional immunosuppressive agents for disease control such as cyclophosphamide, azathioprine, plasmapheresis, immunoglobulin, mycophenolate mofetil, tacrolimus and cyclosporin A. Visual field defects Optic chiasmal and retro-chiasmal lesions may cause visual field defects. Symptoms included homonymous hemianopia due to occipital infarcts and posterior reversible encephalopathy syndrome (PRES). SLE patients are prone to arterial thromboembolism that includes cerebrovascular accidents. This is due to the increased prevalence of traditional vascular risk factors and lupus-specific factors such as the antiphospholipid antibodies.34 Posterior reversible encephalopathy syndrome is a reversible neurological condition characterized by headache, nausea, vomiting, altered mental status, visual disturbances, and seizures. MRI shows the typical features of vasogenic edema at the parieto-occipital areas in the ‘watershed’ areas of the posterior circulation of the brain which reduces after subsidence of the underlying causes.35 PRES has been associated with a variety of clinical conditions such as malignant hypertension in SLE patients due to active renal disease. The pathophysiology of PRES is elevation of arterial pressure that exceeds the limit of cerebral auto-regulation which leads to hydrostatic brain edema or brain ischemia.36 In SLE patients with concomitant active disease, increase in inflammatory cytokine production may further up-regulate cell adhesion molecules, leading to chemotaxis of leukocytes and cerebral microcirculatory dysfunction.36 These further aggravate the leakage of cerebral circulation and cause PRES. The posterior circulation is more involved in PRES because of a relative lack of sympathetic innervation of the arterioles.37

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Table 2 Treatment and outcome of neuromyelitis optica in SLE Author, year

No. of patients

Treatment

Karim S, 200918

1

Mottaghi P, 200921

1

Nasir S, 200923

1

Mok CC, 200820

1

Birubaum J, 200828

1

Jacobi C, 200624

1

Hagiwara N, 200525 Ferrerira S, 200526

1 1

Gibbs AN, 200217

1

Margaux J, 199922

1

Bonnet F, 199927

1

Cordeiro MF, 199419

1

Steroid Plasmapheresis Steroid Plasmapheresis Cyclophosphamide Steroid Cyclophosphamide Rituximab Steroid Immunoglobulin Mycophenolate Mofetil Tacrolimus Cyclophosphamide Steroid Cyclophosphamide Rituximab Steroid Immunoglobulin Cyclophosphamide Steroid Steroid Cyclophosphamide Plasmapheresis Immunoglobulin Steroid Cyclophosphamide Steroid Anticoagulation Azathioprine Steroid Plasmapheresis Cyclophosphamide Steroid Cyclophosphamide Warfarin

Posterior reversible encephalopathy syndrome is a reversible condition and management mainly focuses on the control of the underlying conditions, such as treatment of hypertension. Supportive care for other complications such as control of seizures is also needed.35 PRES is also related to medications used for the treatment of SLE. A possible link between PRES and a number of offending drugs, such as cyclosporine, mycophenolate mofetil, tacrolimus, intravenous immunoglobulin and rituximab have been suggested. Pseudotumor cerebri (PTC) is a complex syndrome consisting of: (i) elevated intracranial pressure over 200 mmH2O; (ii) normal cerbrospinal fluid (CSF)

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Outcome Partial reponse Full response

Full response with relapses

No response to multiple immunosuppressants and finally responded to immunoablative cyclophosphamide Partial response with relapses

Partial response with relapses

Full response Partial response with relapses

No response Full response

Partial response with relapses

Partial response

compositions; (iii) papilloedema with occasional sixth nerve paresis; and (iv) absence of a space-occupying lesion in the brain or ventricular enlargement.38 Headache and papillodema (Fig. 1) are the most common presentations. PTC is associated with antiphospholipid antibodies and dural sinus thrombosis. It was suggested that absorptive failure of the CSF, and thrombosis of the venous sinuses, may be involved in the pathogenesis of PTC in SLE.39 The anti-phospholipid antibodies are associated with cerebral venous thrombosis or stenosis which causes disruption of the blood–brain barrier and thus decreases CSF adsorption.

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(a)

(b)

Figure 1 Fundi photos. (a) Optic atrophy in neuromyelitis optica. (b) Papilledema in pseudotumor cerebri (Courtesy of Dr. Andy Cheng, the Hong Kong Eye Hospital, Hong Kong).

Most patients need glucocorticoid treatment as concomitant active SLE was almost universally present. This contrasts with acetazolamide as the first-line treatment of PTC not related to SLE. Ventriculoperitoneal shunting may be indicated for sight-threatening papilloedema. Relapse of PTC and persistent papilloedema were reported in some patients.9

DISCUSSION Neuro-ophthalmologic manifestations of SLE are uncommon but heterogeneous and the diagnostic para-

digm is shown in Figure 2. Optic neuropathy is the most common neuro-ophthalmologic presentation in SLE. Most patients respond completely to glucocorticoid treatment. Optic atrophy may be found in patients with severe or recurrent optic neuritis (Fig. 1). The MRI orbit in optic neuritis may show contrast enhancement and swelling of optic nerves. New sequences such as diffusion tensor imaging (DTI) can quantitatively assess lesions to reveal alterations in tissue structure which may predict visual outcomes in patients with optic neuritis.40 Another modality is optical coherence tomography, which can be used to measure the thickness of the

Neuro-ophthalmologic manifestations in SLE Afferent pathway Symptoms: blurring of vision, visual field defects

Efferent Pathway Symptoms: diplopia, ptosis

Investigations: fundi examination, OCT, MRI brain and orbit, lumbar puncture, VEP, NMO antibody

Investigations: autoimmune markers, anti-AchR, Tensilon test, MRI brain, LP, SFEMG

Findings Optic neuropathy

Papilledema

Hemianopia

Cranial neuropathy

Fatigability

Etiology Isolated optic neuritis

PTC

Stroke

PRES NMO

INO MS

498

Vasculitis

MG

Figure 2 Diagnostic paradigm of neuroophthalmologic manifestations in SLE. OCT, Optical Coherence Tomography; Anti-AchR, anti-acetylcholine receptor antibody; VEP, visual evoked potential; NMO, Neuromyelitis Optica; INO, Ischemic optic neuropathy; MS, multiple sclerosis; PTC, pseudotumor cerebri; PRES, Posterior reversible leukoencephalopathy; MG, Myasthenia Gravis; SFEMG, single fiber electromyography.

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(a)

(b)

(c)

(d)

Figure 3 Magnetic resonance imaging in neuromyelitis optica. (a) Abnormal T2-weighted signal at bilateral thalami and midbrain. (b) Long segment abnormal T2 hyperintense cord signal from T1 to T8. C and D. Decreased T2-weighted abnormal signal in brain and spinal cord after plasma exchange.

retinal peripapillary nerve fiber layer which may be reduced in optic neuritis, and this reduction correlates well with findings from testing visual acuity and visual field and with the disability scores.41 Visual evoked potentials are prolonged in optic neuritis.42 Neuromyelitis optica is a less common but more serious neuro-ophthalmologic manifestations of SLE. NMO presents as optic neuritis and myelitis. MRI in NMO typically shows longitudinal and confluent spinal cord lesions across more than three vertebral segments. MRI brain abnormalities are present in with 60% of NMO cases and are quite distinct from MS lesions.43 The cerebral lesions are usually linear, as opposed to oval lesions with Dawson finger configuration in MS (Fig. 3). Special techniques such as diffusion tensor and magnetization transfer imaging may show abnormal findings due to axonal degeneration secondary to lesions in the spinal cord and optic nerves.40 Oligoclonal bands in CSF are negative in most NMO patients. NMO is associated with the aquaporin-4 antibody (NMO-IgG). NMO carries a poor prognosis because it is often refractory to treatment. Our analysis shows most patients required a combination of multiple immunosuppressive agents for treatment but despite this, relapse was usual. Prevention of relapse with longterm immunosuppressive drugs that include low-dose glucocorticoids, azathioprine, cyclophosphamide and rituximab, remains the cornerstone of therapy in NMO. Systemic lupus erythematosus and MG are part of the same autoimmune spectrum of diseases and coexistence

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of the two diseases is commonly encountered. Some MG patients developed SLE after thymectomy. When thymectomy is considered for patients with MG, one should be alerted to the possibility of onset of SLE. SLE patients with ocular or generalized muscular weakness and worsening symptoms during the day should be referred to the neurologist for work-up of MG. The prognosis of neuro-ophthalmologic manifestations in SLE appears to be good because of their rapid response to glucocorticoid treatment. Relapses may be reduced by the use of maintenance immunosuppression. Alkylating agents, azathioprine, plamapheresis, immunoglobulin and rituximab can be considered in glucocorticoid-dependent or refractory cases. Patients with antiphospholipid antibody syndrome should be treated with anticoagulation.

CONCLUSIONS Neuro-ophthalmologic manifestations of SLE are unusual but heterogeneous. The pathophysiology is probably multifactorial, including occlusive vasculitis, direct autoantibody cytotoxicity, antiphospholipid antibodies and non-inflammatory vasculopathy. The prognosis of neuro-ophthalmologic manifestations in SLE seems to be good because of its rapid response to glucocorticoids. Relapses may be reduced by the use of maintenance immunosuppression. Patients with concomitant antiphospholipid syndrome should be anti-coagulated.

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DISCLOSURE None.

13

FUNDING

14

The authors did not receive any external funding.

CONFLICTS OF INTERESTS None.

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