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4 Practical Neurology
Pract Neurol 2010; 10: 415
NeurolupusFady G Joseph,1 Neil J Scolding2Systemic lupus erythematosus (SLE) is not an uncommon condition. Most neurologists are well aware that it can cause a wide range of neurological complications, and SLE almost invariably appears on differential diagnosis lists in cases of clinical uncertainty. However, the precise nature of the manifestations of SLE in the central and peripheral nervous systems is perhaps less widely understood, and misperceptions about phenomenology and treatment are common. Here we survey some of the main primary neurological complications of SLEneurolupuswhile acknowledging that secondary problems, either iatrogenic or relating to other consequences of SLE (eg, hypertensive CNS disease, for example, secondary to renal lupus) are neither less serious nor less treatable.
iNTrODUCTiONSystemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations ranging from trivial and ephemeral to life threatening. Improved therapeutic options in recent years have enhanced survival rates in the face of a rising incidence over the past four decades (the last probably in part due to better recognition). The current estimated prevalence of SLE ranges from 6 to 150 per 100 000, and depends on sex and racial origin there is a 510 times higher risk in females, AfricanCaribbeans and Asians.1 The diagnosis is usually based on the American College of Rheumatology (ACR) criteria (table 1) which require at least four of the 11 listed features at some time in the course of the illness.2 Involvement of the nervous system cognitive and psychiatric, central and peripheral nervous, all inclusively referred to as neurolupus in this brief accountrepresents a much dreaded complication, and is common.3 Precisely how common has proved difficult if not impossible to establish. Published studies give figures ranging (remarkably) from 14% to over 90% of SLE patients developing neurological or psychiatric symptoms at
some time during their illness, the unhelpfully large range a result of studying fundamentally different populations and of substantial
TABLe 1 Diagnosis of systemic lupus erythematosus based on the American College of rheumatology criteriaFour out of the 11 features are required: Malar rash Discoid rash Photosensitivity (see figure 1) Oral ulcers Arthritis Serositis (pleurisy or pericarditis) Renal disorder (proteinuria >0.5 g/24 h or cellular casts) Neurological disorder Haematological disorder (haemolytic anaemia, leucopenia or lymphopenia on two or more occasions, or thrombocytopenia) Immunological disorder Antinuclear antibody
Consultant Neurologist, Neville Hall Hospital, Abergavenny and the Royal Gwent Hospital, Newport, UK Burden Professor of Clinical Neurosciences, Department of Neurology, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK Correspondence to Professor N Scolding, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK; n.j.scolding@bristol. ac.uk
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differences in the definition and criteria used to designate nervous system involvement.46 Many authorities, possibly depending more on resigned guesswork than sound epidemiology, suggest 50% may be about right. Despite its gravity, however, SLE is potentially treatable, making it important for neurologists to be aware of the spectrum of neurolupus and its management.
PATHOLOGY AND PATHOGeNeSiSIn order to understand neurolupus and to rationalise investigations and treatment, it is useful to have a basic understanding of the underlying disease mechanisms.7 The principal neuropathological changes are those of infarction in the territory of small vessels, particularly in the cerebral cortex and brainstem (table 2). Vasculitis (true inflammatory infiltrate and destructive change within the blood vessel wall) is rare in neurolupus. There is extravasation of fibrin and red blood cells, together with endothelial cell proliferation, hypertrophy and the appearance of fibrin thrombi9 (figure 2). These non-inflammatory proliferative changes appear to be responsible for the numerous areas of microinfarction. Less commonly, macroscopic infarction or haemorrhage occurs, the former occasionally due to embolism from LibmanSacks endocarditis, or to the consequences of antiphospholipid antibodies (APAs). A common suggestion is that focal manifestations, including stroke, are predominantly
Figure 1 One of the features of lupus (see table 1). Credit: SPL.
TABLe 2 Neuropathology of systemic lupus erythematosus: a summary of four published papersJohnson and richardson (1968)8 No of cases Vasculopathy (%) Vasculitis (%) Gross infarcts (%) Microinfarcts (%) Large haemorrhage (%) Microhaemorrhages (%) Infection (%) Heart: endocardial lesions/mural thrombi (%) ND, not determined.www.practical-neurology.com
ellis and verity (1979)9 57 65 7 12 35 42 29 28 ND
Devinsky et al (1988)10 50 ND 0 22 ND 6 ND 16 50
Hanly et al (1992)11 10 ND 10 10 40 0 30 10 ND
24 83 13 25 71 21 25 0 33
6 Practical NeurologyFigure 2 (A, B) Cerebral microvascular thrombosis in the antiphospholipid syndrome, clinically and angiographically mimicking CNS vasculitis. Reprinted with permission from Lie and others (1997).50
caused by vascular occlusion, while diffuse manifestations, such as psychiatric features, may result from pathogenic antineuronal antibodies. Indeed, a hallmark of SLE is autoantibody production (table 3, figure 3). In principle, in neurolupus, antibodies could mediate neurological injury by reacting against neuronal, astroglial or endothelial cells.7 Changes could also be induced in the cerebral vasculature, either through immune complex deposition or effects on the coagulation system leading to infarction. These proposals are not mutually exclusive. In addition, well recognised abnormalities of cytokines, complement components, immune related
TABLe 3 The common and diagnostically helpful antibodies in neurolupusAntinuclear antibodies (ANA) are the serological hallmark of systemic lupus erythematosus (SLE), present in the serum of virtually every patient at some time during the course of the disease. They may also be found in normal individuals where their prevalence increases with age; they are therefore sensitive but not specific for the disease: Anti-DNA antibodies include anti-single stranded (ssDNA) antibodies that target purine and pyrimidine bases of denatured DNA and anti-double stranded (dsDNA) antibodies that seek the ribose phosphate backbone of native DNA. Anti-dsDNA antibodies are reasonably specific for SLE but are only present in about 70% of patients; they can be used to monitor disease activity. They may contribute to disease pathology7 but are sometimes found in normal individuals and those with rheumatoid arthritis and Sjgrens syndrome. Anti-ribonuclear P (anti-P) antibodies have been associated with neurolupus, in particular psychosis and severe depression. However, more rigorous meta-analysis casts serious doubt on their value.12 Anti-sn ribonucleoprotein (sn-RNP) antibodies are linked with disease activity, in particular with lupus psychosis and various rheumatic processes such as myositis, oesophageal hypomotility, Raynauds phenomenon, arthralgia, arthritis, sclerodactyly, nephritis and pneumonitis. Anti-Sm antibodies attack the Smith antigen, a soluble nuclear component. They are relatively specific and associated with milder renal and CNS disease and flare-up of SLE. Anti-Ro (SSA) and anti-La (SSB) antibodies target ribonucleoprotein particles. Anti-Ro is implicated in photosensitivity, lung disease, lymphopenia and nephritis. Anti-La, on the other hand, is associated with neonatal and late onset SLE, and secondary Sjgrens syndrome. It may offer protection from anti-Ro associated nephritis. Anti-histone antibodies are found in all cases of drug induced SLE. These are directed against several of the protein components of nucleosides. A small minority of those with rheumatoid arthritis, primary biliary cirrhosis and scleroderma carry these antibodies. Antiphospholipid antibodies13 may be of IgG, IgM or IgA isotypes and form part of a spectrum of circulating antibodies. Originally thought to be directed against phospholipids or cardiolipin (hence anticardiolipin antibodies), they are now recognised to attach to a serum protein called 2 glycoprotein 1 (B2GP1) which in turn attaches to cardiolipin in vitro. These antibodies are also involved in the lupus anticoagulant which may coexist or occur even if antiphospholipid antibody/ 2GP1 levels are normal. Antiphospholipid antibodies compete with clotting factors and enhance aspects of the coagulation cascade, with prolongation of the prothrombin time that is not corrected by mixing the sample with normal plasma. This is a paradox as in vitro they cause an anticoagulant effect but in vivo they are associated with arterial and venous thrombosis.10.1136/jnnp.2009.200071
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genes and hormones could all contribute to lupus related processes. Much recent interest has focused on apoptosis (programmed cell death) in SLE. Antibodies to C1q complement protein are common in SLE, and can cause a functional deficiency of C1q and so defective clearance of apoptotic cells leading to an increase in circulating nucleosomes (essentially circulating DNA fragmentation products of apoptosis) and so to antinucleosome antibody production.7 These theories could help explain some of the precipitants of disease activity (for example, sunlight and viral infections) may increase the number of apoptotic cells in the skin and blood with release of intracellular antigens leading to increased autoanti