Review Article
The neurology of lupus

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Highlights

  • •

    SLE can affect the nervous system, most frequently the brain, in up to 50% of patients and the first step in assessment should be to ensure a robust diagnosis of SLE.

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    Heterogeneity and lack of specificity of clinical neuropsychiatric (NP) events in SLE patients obliges clinicians to consider and exclude non-SLE causes.

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    Pathogenetic mechanisms for NPSLE includes vascular ischemia and inflammation mediated by autoantibodies, inflammatory mediators and microglial activation.

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    The clinical diagnosis of NPSLE may be may be supported by neuroimaging, autoimmune serologycerebrospinal fluid and neuropsychological testing.

  • •

    Treatment of NPSLE includes anticoagulation, corticosteroids and immunosuppression in addition to symptomatic therapies and treatment of relevant comorbidities.

Introduction

Systemic lupus erythematosus (SLE) is a chronic, autoimmune-inflammatory disease [1] characterized by autoantibody production and protean clinical manifestations. These include common features such a skin rashes and inflammatory polyarthritis and less frequent involvement of internal organs such as the kidneys, lungs and nervous system. There is a 9:1 female predominance and peak incidence occurs during childbearing years although it may present at any age of life. The frequency and severity of the disease also varies across racial/ethnic groups with increased vulnerability in individuals with African, Asian and Hispanic ancestry compared to Caucasians. Internal organ involvement accounts for most of the morbidity and mortality attributed to SLE [[2], [3], [4]]. Nervous system involvement presents with a variety of neurological and psychiatric features, collectively called neuropsychiatric SLE (NPSLE).

It is critical to ensure a robust diagnosis of SLE per se prior to considering if nervous system abnormalities can be attributed to lupus. Although this can be done by any physician with appropriate skills and expertise, rheumatologists are the medical subspecialists who perform this task most frequently. The diagnosis rests upon the identification of a composite of clinical and laboratory abnormalities resulting from a systemic autoimmune inflammatory process, for which other reasonable causes have been considered and excluded. Classification criteria for SLE have been derived and validated [[5], [6], [7]] but these are not intended for use in the diagnosis of SLE in individual patients. Rather, they were developed primarily to ensure homogeneity of patient populations in clinical research studies. Moreover, in validation studies of the classification criteria it was the experienced physician's diagnosis that was the gold standard and this remains the case in clinical practice.

Section snippets

Frequency, classification and attribution of nervous system disease in SLE

Although involvment of the nervous system by SLE has been recognized for almost 150 years [8] the reported frequency has varied widely [[9], [10], [11]]. The reasons for this include lack of uniform classification criteria for NPSLE, failure to consider alternative causes for NP events, and improved awareness of the disease with enhanced diagnostic techniques and study design. In a meta-analysis including 5057 SLE patients, the prevalence of NPSLE varied from 17.6 to 44.5% in retrospective and

Pathogenesis of NPSLE

NP events that are primary manifestations of SLE (NPSLE) should be distinguished from NP events due to complications of SLE (e.g. hypertension in patients with lupus nephritis) complications of SLE therapies (e.g. infection in patients on high dose corticosteroids) or alternative causes (e.g. atherosclerosis). Experimental and human studies suggest two complementary autoimmune pathogenic mechanisms for NPSLE (Fig. 1); these pathways are associated with different clinical manifestations [10,11].

Clinical manifestations of neuropsychiatric systemic lupus erythematosus

In the absence of controlled clinical trials in patients with NPSLE, guidelines for diagnosis and treatment have been published by the European League Against Rheumatism [21,49]. These were developed by an international committee using a data-driven approach and expert opinion when required. Comments on selected clinical manifestations follow.

The neurology of antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis (arterial, venous, small vessel) and pregnancy morbidity (recurrent early pregnancy loss, fetal loss, preeclampsia, eclampsia, placental insufficiency) in the presence of persistent aPL antibodies [104]. Widely used tests for aPL antibodies include lupus anticoagulant and/or moderate/high titer anticardiolipin antibodies and/or anti-β2glycoprotein I antibodies. Classification criteria including these

Approach to diagnosis and treatment of neuropsychiatric systemic lupus erythematosus (Fig. 2)

In the absence of a diagnostic standard for most of the NP manifestations of SLE, the decision on attribution is achieved largely by a process of exclusion through careful analysis of the clinical, laboratory, and imaging data as appropriate for each case. Examination of the cerebrospinal fluid (CSF) is helpful to exclude infection, measure CSF pressure, IgG index and oligoclonal bands. Measurement of CSF autoantibodies [42,[129], [130], [131]], cytokines [132,133], and biomarkers of neurologic

Neuroimaging in neuropsychiatric systemic lupus erythematosus

Superior to CT brain scanning, structural MRI is widely available and used to diagnose overt cerebral pathology, including global and regional atrophy as well as changes in the appearance and integrity of gray and white matter. However, the relationships between structural changes and clinical NP manifestations of SLE, particularly cognitive dysfunction, are relatively limited [140]. This has been a significant limitation of structural MRI for measuring disease progression or treatment

Conclusion

SLE, the prototypic systemic autoimmune disease, has the potential to affect all components of the nervous system with a wide variety of clinical presentations, most of which are not specific for SLE. Approximately one-third of all NP events that occur in SLE patients are attributable to the disease and most occur early in the course of the illness. Potential non-SLE causes for each type of NP event need to be considered in the differential diagnosis of NPSLE that is based upon clinical

Funding support

Canadian Institutes of Health Research (Operating grant MOP-88526).

Declaration of Competing Interest

The authors declare no conflicts of interest.

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