Neuro-ophthalmologic manifestations of systemic lupus erythematosus: a systematic review

REVIEW ARTICLE

Neuro-ophthalmologic manifestations of systemic lupuserythematosus: a systematic review

Bik Ling MAN, Chi Chiu MOK and Yat Pang FU

Department of Medicine, Tuen Mun Hospital, Hong Kong, China

AbstractHerein we summarize the clinical presentation, treatment and outcome of neuro-ophthalmologic manifesta-

tions in patients with systemic lupus erythematosus (SLE). We performed a systematic review of the neuro-oph-

thalmologic 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 anti-

phospholipid 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 mainte-

nance 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 multi-

systemic autoimmune disease that may affect any organ

of the body. Neurological manifestations are fairly com-

mon and the American College of Rheumatology

(ACR) has defined 19 neuropsychiatric syndromes that

may occur in patients with SLE.1 Neuro-ophthalmo-

logic manifestations refer to those that arise from pri-

mary lesions in the ocular muscles, neuromuscular

junction, optic nerves and visual pathways, and the cen-

tral nervous system, resulting in ptosis, visual

symptoms or visual field defects. Neuro-ophthalmo-

logic manifestations in SLE are heterogeneous and up

to the present, there are still no consensus criteria for

their classification. Neuro-ophthalmologic manifesta-

tions of SLE are related to either SLE activity or its vas-

cular 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 intra-

cranial hypertension.

Only a small number of SLE patients with neuro-oph-

thalmologic manifestations have been reported in the

literature. Although these manifestations are uncom-

monly encountered in SLE, they are important causes of

disability and impairment of quality of life. In this arti-

cle, we summarize the prevalence, clinical presentation,

Correspondence: Dr Chi Chiu Mok, Department of Medicine,Tuen Mun Hospital, Tsing Chung Koon Road, New Territories,Hong Kong, China.Email: [email protected]

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

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

treatment and outcome of SLE patients with neuro-oph-

thalmologic manifestations by performing a Medline

search.

METHODS

We performed a systematic review of neuro-ophthalmo-

logic manifestations in SLE by performing a Medline

search for publications from January 1970 to March

2010 using the keywords ‘lupus’, ‘neuro-ophthalmol-

ogy’, ‘neuro-psychiatric’, ‘optic neuritis’, ‘optic neuropa-

thy’, ‘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.

RESULTSPrevalence of neuro-ophthalmologicmanifestations in SLETable 1 summarizes the prevalence of neuro-ophthal-

mologic 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 manifes-

tations 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

(%)

Mean age

(years)

Prevalence

(%)

Manifestations

(no. of patients)

Petri M, 20088 Adult 111 C (55)

B (15)

H (21)

A (5)

33 3 (3) CN (2), MG (1)

Hershko AY, 20089 Adult 651 A 24 10 (2) PTC (10)

Hanly JG, 200811 Adult 572 C (52)

B (13)

H (16)

A (16)

35 5 (1) CN (5)

Yu HH, 20064 Childhood 185 A 13.5 1 (0.5) CN (1)

Harel L, 200610 Childhood 106 C (20)

B (8.5)

H (26)

A (37)

M (8.5)

12.3 4 (4) CN (1), PTC (3)

Al-mayouf SM, 20037 Childhood 52 A 11.3 14 (27) ON (3), VFD (11)

Brey RL, 200213(13) Adult 128 C (30)

B (8)

H (56)

43 2 (2) CN (2)

Sibbitt WL, 20022 Childhood 75 C (27)

B (8)

H (61)

A (4)

13.3 1 (1) CN (1)

Ainiala H, 20016 Adult 46 C 45 4 (9) CN (3), MG (1)

Yap EY, 19985 Adult 70 A 32.9 2 (3) ON (2)

Keane JR, 19953 Adult 113 NS 33.5 26 (23) Ptosis (8), PTC (2)

CN(4), spontaneous

eye movements (12)

Feinglass EJ, 197612 Adult 140 C (52)

B (48)

30 22 (16) 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.

International Journal of Rheumatic Diseases 2014; 17: 494–501 495

SLE neuro-ophthalmologic manifestations

ing of these figures reveals that the prevalence of neuro-

ophthalmologic manifestations is 3.6% and 1.6% in

adult and childhood SLE patients, respectively.

Clinical presentation and treatment outcomeof neuro-opthalmologic disease in SLEOptic neuropathy

The commonest and most well-known neuro-ophthal-

mologic manifestation of SLE is optic neuropathy. This

may present as isolated optic neuritis, neuromyelitis op-

tica (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 ret-

robulbar ischemic optic neuritis or papillitis. The most

common presentations are decreased visual acuity, orbi-

tal 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 subse-

quent demyelination and axonal necrosis. The degree

of axonal loss correlates to visual outcome. The optic

neuritis responds dramatically to corticosteroid treat-

ment.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 anti-

aquaporin-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 immuno-

suppressive agents. One patient had poor response after

multiple immunosuppressants and was relapse-free

after use of immunoablative cyclophosphamide proto-

col 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 cil-

iary 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.

Myasthenia gravis

Myasthenia gravis (MG) has long been reported in asso-

ciation with SLE. Most patients presented as generalized

MG with ptosis, ophthalmoplegia and proximal muscle

weakness. In some patients, SLE developed after thy-

mectomy for MG.31 The thymus is important in main-

taining 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 autoan-

tibodies, 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 immuno-

suppressive agents for disease control such as cyclo-

phosphamide, 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 typi-

cal features of vasogenic edema at the parieto-occipital

areas in the ‘watershed’ areas of the posterior circula-

tion 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 hyper-

tension in SLE patients due to active renal disease. The

pathophysiology of PRES is elevation of arterial pres-

sure that exceeds the limit of cerebral auto-regulation

which leads to hydrostatic brain edema or brain ische-

mia.36 In SLE patients with concomitant active disease,

increase in inflammatory cytokine production may fur-

ther 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 cir-

culation is more involved in PRES because of a relative

lack of sympathetic innervation of the arterioles.37

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

B. L. Man et al.

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 immu-

noglobulin 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)

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 anti-

phospholipid 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 cere-

bral venous thrombosis or stenosis which causes dis-

ruption of the blood–brain barrier and thus decreases

CSF adsorption.

Table 2 Treatment and outcome of neuromyelitis optica in SLE

Author, year No. of

patients

Treatment Outcome

Karim S, 200918 1 Steroid

Plasmapheresis

Partial reponse

Mottaghi P, 200921 1 Steroid

Plasmapheresis

Cyclophosphamide

Full response

Nasir S, 200923 1 Steroid

Cyclophosphamide

Rituximab

Full response with relapses

Mok CC, 200820 1 Steroid

Immunoglobulin

Mycophenolate Mofetil

Tacrolimus

Cyclophosphamide

No response to multiple

immunosuppressants and

finally responded to

immunoablative cyclophosphamide

Birubaum J, 200828 1 Steroid

Cyclophosphamide

Rituximab

Partial response with relapses

Jacobi C, 200624 1 Steroid

Immunoglobulin

Cyclophosphamide


Hagiwara N, 200525 1 Steroid Full response

Ferrerira S, 200526 1 Steroid

Cyclophosphamide

Plasmapheresis

Immunoglobulin


Gibbs AN, 200217 1 Steroid

Cyclophosphamide

No response

Margaux J, 199922 1 Steroid

Anticoagulation

Azathioprine

Full response

Bonnet F, 199927 1 Steroid

Plasmapheresis

Cyclophosphamide


Cordeiro MF, 199419 1 Steroid

Cyclophosphamide

Warfarin

Partial response



Most patients need glucocorticoid treatment as con-

comitant active SLE was almost universally present. This

contrasts with acetazolamide as the first-line treatment

of PTC not related to SLE. Ventriculoperitoneal shunt-

ing may be indicated for sight-threatening papilloedem-

a. 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 glucocorti-

coid 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 dif-

fusion tensor imaging (DTI) can quantitatively assess

lesions to reveal alterations in tissue structure which

may predict visual outcomes in patients with optic neu-

ritis.40 Another modality is optical coherence tomogra-

phy, which can be used to measure the thickness of the

(a) (b)

Figure 1 Fundi photos. (a) Optic atro-phy in neuromyelitis optica. (b) Papille-dema in pseudotumor cerebri (Courtesyof Dr. Andy Cheng, the Hong Kong EyeHospital, Hong Kong).

Neuro-ophthalmologic manifestations in SLE

Afferent pathwaySymptoms: blurring of vision, visual field defects

Efferent PathwaySymptoms: diplopia, ptosis

Optic neuropathy

Papilledema Hemianopia

Isolated optic neuritis

NMO

INO

MS

Cranial neuropathy

Fatigability

MG

PRES

StrokePTC Vasculitis

Findings

Etiology

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

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

Figure 2 Diagnostic paradigm of neuro-ophthalmologic manifestations in SLE.OCT, Optical Coherence Tomography;Anti-AchR, anti-acetylcholine receptorantibody; VEP, visual evoked potential;NMO, Neuromyelitis Optica; INO,Ischemic optic neuropathy; MS, multiplesclerosis; PTC, pseudotumor cerebri;PRES, Posterior reversible leukoencepha-lopathy; MG, Myasthenia Gravis;SFEMG, single fiber electromyography.


B. L. Man et al.

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 seri-

ous 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 Oligoclo-

nal 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 long-

term 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

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 manifesta-

tions in SLE appears to be good because of their rapid

response to glucocorticoid treatment. Relapses may be

reduced by the use of maintenance immunosuppres-

sion. 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 unu-

sual but heterogeneous. The pathophysiology is prob-

ably 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.

(a) (b)

(c) (d)

Figure 3 Magnetic resonance imagingin neuromyelitis optica. (a) AbnormalT2-weighted signal at bilateral thalamiand midbrain. (b) Long segment abnor-mal T2 hyperintense cord signal from T1to T8. C and D. Decreased T2-weightedabnormal signal in brain and spinalcord after plasma exchange.



DISCLOSURE

None.

FUNDING

The authors did not receive any external funding.

CONFLICTS OF INTERESTS

None.

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Neuro-ophthalmologic manifestations of systemic lupus erythematosus: a systematic review