University of Edinburgh
Neurological disease in lupus: towards a personalized medicine approachSarah McGlasson1,2,3Stewart Wiseman2Joanna Wardlaw2Neeraj Dhaun4David Hunt1,2,31MRC Institute of Genetics and Molecular Medicine 2The UK Dementia Research Institute, University of Edinburgh3The Anne Rowling Clinic, University of Edinburgh4Centre for Cardiovascular Science, Queen's Medical Research Institute, University of EdinburghAbstractThe brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Understanding and classifying nervous system disease in lupus pose significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in our understanding of the pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials. Correspondence to: david.hunt@igmm.ed.ac.ukIntroduction Systemic lupus erythematosus (SLE, lupus) is a multiorgan autoimmune disease, initially described on the basis of its cutaneous manifestations ADDIN EN.CITE <EndNote><Cite><Author>Tsokos</Author><Year>2011</Year><RecNum>6</RecNum><DisplayText>(1)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516357564">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsokos, G. C.</author></authors></contributors><auth-address>Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. gtsokos@bidmc.harvard.edu</auth-address><titles><title>Systemic lupus erythematosus</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>2110-21</pages><volume>365</volume><number>22</number><edition>2011/12/02</edition><keywords><keyword>Female</keyword><keyword>*Gene Expression</keyword><keyword>Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>Kidney/pathology/ultrastructure</keyword><keyword>*Lupus Erythematosus, Systemic/drug therapy/etiology/genetics/pathology</keyword><keyword>Lupus Nephritis/pathology</keyword><keyword>Male</keyword><keyword>Receptors, Antigen, T-Cell/metabolism</keyword><keyword>Sex Factors</keyword><keyword>Transcription, Genetic</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>22129255</accession-num><urls><related-urls><url>;(1). During the 19th century, the true multisystem nature of the disease was recognized with the initial descriptions of severe brain involvement ADDIN EN.CITE <EndNote><Cite><Author>M</Author><Year>1875</Year><RecNum>8</RecNum><DisplayText>(2, 3)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516359256">8</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Kaposi M</author></authors><tertiary-authors><author>Hebra F, Kaposi M</author></tertiary-authors></contributors><titles><title>Lupus Erythematosus</title></titles><dates><year>1875</year></dates><orig-pub>On Diseases of the Skin Including the Exanthemata</orig-pub><urls></urls></record></Cite><Cite><Author>Osler</Author><Year>1895</Year><RecNum>7</RecNum><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516359050">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Osler, W.</author></authors></contributors><titles><title>On the visceral complications of erythema exudativum multiforme</title><secondary-title>Am J Med Sci</secondary-title></titles><periodical><full-title>Am J Med Sci</full-title></periodical><pages>629-646</pages><number>110</number><dates><year>1895</year></dates><urls></urls></record></Cite></EndNote>(2, 3). The first dedicated clinical studies of neurological dysfunction in lupus were reported in 1945 by David Daly ADDIN EN.CITE <EndNote><Cite><Author>Daly</Author><Year>1945</Year><RecNum>9</RecNum><DisplayText>(4)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516359386">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daly, D.</author></authors></contributors><titles><title>Central nervous system in acute disseminate lupus erythematosus</title><secondary-title>J Nerv Ment Dis</secondary-title></titles><periodical><full-title>J Nerv Ment Dis</full-title></periodical><pages>461-5</pages><volume>102</volume><edition>1945/11/01</edition><keywords><keyword>Humans</keyword><keyword>*Lupus Erythematosus, Systemic</keyword><keyword>*Nervous System</keyword><keyword>*LUPUS/erythematosus</keyword></keywords><dates><year>1945</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-3018 (Print)
0022-3018 (Linking)</isbn><accession-num>21004281</accession-num><urls><related-urls><url>;(4). His observations were astute, noting a high degree of heterogeneity in the neurological manifestations, and a prominent contribution of neurovascular disease. Over the following decades the effects of lupus on all levels of the nervous system has been recognized.The diversity of neurological disease in lupus stimulated calls for a classification system to facilitate its clinical and scientific study ADDIN EN.CITE <EndNote><Cite><Author>Kassan</Author><Year>1979</Year><RecNum>11</RecNum><DisplayText>(5)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516361016">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kassan, S. S.</author><author>Lockshin, M. D.</author></authors></contributors><titles><title>Central nervous system lupus erythematosus. The need for classification</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>1382-5</pages><volume>22</volume><number>12</number><edition>1979/12/01</edition><keywords><keyword>Autoantibodies/analysis</keyword><keyword>Central Nervous System Diseases/*classification/diagnosis/immunology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*classification/diagnosis/immunology</keyword></keywords><dates><year>1979</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0004-3591 (Print)
0004-3591 (Linking)</isbn><accession-num>518720</accession-num><urls><related-urls><url>;(5). In 1999 the American College of Rheumatology (ACR) developed criteria for case definitions for neurolupus ADDIN EN.CITE <EndNote><Cite><Year>1999</Year><RecNum>10</RecNum><DisplayText>(6)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516360563">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>599-608</pages><volume>42</volume><number>4</number><edition>1999/04/22</edition><keywords><keyword>Brain Diseases/*diagnosis/etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*diagnosis/psychology</keyword><keyword>Male</keyword><keyword>Mental Disorders/*diagnosis/etiology</keyword><keyword>Rheumatology/*standards</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>1999</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0004-3591 (Print)
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ADDIN EN.CITE.DATA (14). For example, the ACR criteria include terms such as headache and mood disorder which are highly prevalent in the general population and observed at similar frequency in healthy, matched controls, as well as patients with other chronic inflammatory diseases ADDIN EN.CITE <EndNote><Cite><Author>Ainiala</Author><Year>2001</Year><RecNum>99</RecNum><DisplayText>(15)</DisplayText><record><rec-number>99</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516887655">99</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ainiala, H.</author><author>Hietaharju, A.</author><author>Loukkola, J.</author><author>Peltola, J.</author><author>Korpela, M.</author><author>Metsanoja, R.</author><author>Auvinen, A.</author></authors></contributors><auth-address>Department of Neurology and Rehabilitation, Tampere University Hospital, Finland. jukkaps@koti.soon.fi</auth-address><titles><title>Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>419-23</pages><volume>45</volume><number>5</number><edition>2001/10/20</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Female</keyword><keyword>Finland/epidemiology</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Lupus Erythematosus, Systemic/classification/diagnosis/epidemiology</keyword><keyword>Lupus Vasculitis, Central Nervous System/classification/*diagnosis/epidemiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Odds Ratio</keyword><keyword>Reproducibility of Results</keyword><keyword>Rheumatology/*methods</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0004-3591 (Print)
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ADDIN EN.CITE.DATA (12). Exclusion of minor symptomatology leads to much improved sensitivity specificity of the criteria ADDIN EN.CITE <EndNote><Cite><Author>Ainiala</Author><Year>2001</Year><RecNum>99</RecNum><DisplayText>(15)</DisplayText><record><rec-number>99</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516887655">99</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ainiala, H.</author><author>Hietaharju, A.</author><author>Loukkola, J.</author><author>Peltola, J.</author><author>Korpela, M.</author><author>Metsanoja, R.</author><author>Auvinen, A.</author></authors></contributors><auth-address>Department of Neurology and Rehabilitation, Tampere University Hospital, Finland. jukkaps@koti.soon.fi</auth-address><titles><title>Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>419-23</pages><volume>45</volume><number>5</number><edition>2001/10/20</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Female</keyword><keyword>Finland/epidemiology</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Lupus Erythematosus, Systemic/classification/diagnosis/epidemiology</keyword><keyword>Lupus Vasculitis, Central Nervous System/classification/*diagnosis/epidemiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Odds Ratio</keyword><keyword>Reproducibility of Results</keyword><keyword>Rheumatology/*methods</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0004-3591 (Print)
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ADDIN EN.CITE.DATA (16). Prospective studies show that major neurological events develop in about 5% of patients with SLE, followed over 3 years ADDIN EN.CITE <EndNote><Cite><Author>Kampylafka</Author><Year>2013</Year><RecNum>186</RecNum><DisplayText>(17)</DisplayText><record><rec-number>186</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525447460">186</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kampylafka, E. I.</author><author>Alexopoulos, H.</author><author>Kosmidis, M. L.</author><author>Panagiotakos, D. B.</author><author>Vlachoyiannopoulos, P. G.</author><author>Dalakas, M. C.</author><author>Moutsopoulos, H. M.</author><author>Tzioufas, A. G.</author></authors></contributors><auth-address>Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.</auth-address><titles><title>Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: a 3-year prospective study of 370 patients</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e55843</pages><volume>8</volume><number>2</number><edition>2013/02/21</edition><keywords><keyword>Adult</keyword><keyword>Central Nervous System/*pathology/*physiopathology</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hospitalization/statistics & numerical data</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Lupus Erythematosus, Systemic/*epidemiology/pathology/physiopathology/therapy</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2013</year></dates><isbn>1932-6203 (Electronic)
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ADDIN EN.CITE.DATA (16)Much of the difficulty in classification stems from a comparative lack of understanding as to how neurological disease develops in people with lupus. It is notable that the ACR definitions focus largely on neurological syndromes, rather than pathophysiological mechanisms. This is in major contrast to renal lupus, where pathophysiological classification dictates treatment and prognosis (Figure 2) ADDIN EN.CITE <EndNote><Cite><Author>Weening</Author><Year>2004</Year><RecNum>19</RecNum><DisplayText>(20)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516365596">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weening, J. J.</author><author>D'Agati, V. D.</author><author>Schwartz, M. M.</author><author>Seshan, S. V.</author><author>Alpers, C. E.</author><author>Appel, G. B.</author><author>Balow, J. E.</author><author>Bruijn, J. A.</author><author>Cook, T.</author><author>Ferrario, F.</author><author>Fogo, A. B.</author><author>Ginzler, E. M.</author><author>Hebert, L.</author><author>Hill, G.</author><author>Hill, P.</author><author>Jennette, J. C.</author><author>Kong, N. C.</author><author>Lesavre, P.</author><author>Lockshin, M.</author><author>Looi, L. M.</author><author>Makino, H.</author><author>Moura, L. A.</author><author>Nagata, M.</author></authors></contributors><auth-address>Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands. j.j.weening@amc.uva.nl</auth-address><titles><title>The classification of glomerulonephritis in systemic lupus erythematosus revisited</title><secondary-title>J Am Soc Nephrol</secondary-title></titles><periodical><full-title>J Am Soc Nephrol</full-title></periodical><pages>241-50</pages><volume>15</volume><number>2</number><edition>2004/01/30</edition><keywords><keyword>Biopsy</keyword><keyword>Glomerulonephritis/*classification/etiology/*pathology</keyword><keyword>Humans</keyword><keyword>Kidney/pathology</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword></keywords><dates><year>2004</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1046-6673 (Print)
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ADDIN EN.CITE.DATA (24, 26) given the relatively high frequency of variants in the general population ADDIN EN.CITE <EndNote><Cite><Author>McGlasson</Author><Year>2017</Year><RecNum>132</RecNum><DisplayText>(27)</DisplayText><record><rec-number>132</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517414023">132</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McGlasson, S., Rannikmae, K., Bevan, S., Markus, H., Sudlow, C., Hunt, D.P.J</author></authors></contributors><titles><title>Rare variants of the 3’-5’ DNA exonuclease TREX1 in early onset small vessel stroke</title><secondary-title>Wellcome Open Research</secondary-title></titles><periodical><full-title>Wellcome Open Research</full-title></periodical><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>(27). CytokinesThere is dysregulation of multiple cytokine pathways in patients with SLE ADDIN EN.CITE <EndNote><Cite><Author>Lourenco</Author><Year>2009</Year><RecNum>129</RecNum><DisplayText>(28)</DisplayText><record><rec-number>129</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517403804">129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lourenco, E. V.</author><author>La Cava, A.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1670, USA.</auth-address><titles><title>Cytokines in systemic lupus erythematosus</title><secondary-title>Curr Mol Med</secondary-title></titles><periodical><full-title>Curr Mol Med</full-title></periodical><pages>242-54</pages><volume>9</volume><number>3</number><edition>2009/04/10</edition><keywords><keyword>Animals</keyword><keyword>Cytokines/*immunology</keyword><keyword>Dendritic Cells/immunology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*immunology/physiopathology</keyword><keyword>Lymphocyte Subsets/immunology</keyword><keyword>T-Lymphocytes, Helper-Inducer/immunology/physiology</keyword><keyword>Toll-Like Receptors/immunology</keyword></keywords><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1566-5240 (Print)
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ADDIN EN.CITE.DATA (35, 36). Type II interferons, interleukins (IL-2, IL-12, IL-18, IL-23) and TNF cytokine families are all dysregulated in lupus and their roles in brain disease are being evaluated ADDIN EN.CITE <EndNote><Cite><Author>Jeltsch-David</Author><Year>2014</Year><RecNum>5</RecNum><DisplayText>(37)</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1514930270">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jeltsch-David, H.</author><author>Muller, S.</author></authors></contributors><auth-address>Centre National de la Recherche Scientifique (CNRS), Immunopathologie et Chimie Therapeutique/Laboratory of Excellence Medalis, Institut de Biologie Moleculaire et Cellulaire, 15 rue Rene Descartes, 67000 Strasbourg, France.</auth-address><titles><title>Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers</title><secondary-title>Nat Rev Neurol</secondary-title></titles><periodical><full-title>Nat Rev Neurol</full-title></periodical><pages>579-96</pages><volume>10</volume><number>10</number><edition>2014/09/10</edition><keywords><keyword>Autoantibodies/*metabolism</keyword><keyword>Biomarkers/metabolism</keyword><keyword>Cytokines/*metabolism</keyword><keyword>Humans</keyword><keyword>Lupus Vasculitis, Central Nervous System/diagnosis/*immunology/therapy</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1759-4766 (Electronic)
1759-4758 (Linking)</isbn><accession-num>25201240</accession-num><urls><related-urls><url>;(37). Inflammatory cellsAlthough B cells and T cells undoubtedly play an important role in the pathogenesis of SLE, neuropathological analyses in individuals with lupus show little in the way of immune cell infiltration within the brain ADDIN EN.CITE <EndNote><Cite><Author>Scolding</Author><Year>2002</Year><RecNum>28</RecNum><DisplayText>(38)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516370706">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scolding, N. J.</author><author>Joseph, F. G.</author></authors></contributors><auth-address>University of Bristol, Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UK.</auth-address><titles><title>The neuropathology and pathogenesis of systemic lupus erythematosus</title><secondary-title>Neuropathol Appl Neurobiol</secondary-title></titles><periodical><full-title>Neuropathol Appl Neurobiol</full-title></periodical><pages>173-89</pages><volume>28</volume><number>3</number><edition>2002/06/13</edition><keywords><keyword>Autoantibodies/immunology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*etiology/immunology/*pathology/psychology</keyword><keyword>Mental Disorders/etiology</keyword><keyword>Nervous System/*pathology</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0305-1846 (Print)
0305-1846 (Linking)</isbn><accession-num>12060342</accession-num><urls><related-urls><url>;(38). This contrasts with other neuroinflammatory diseases such as multiple sclerosis where abundant B and T cells are found within inflammatory brain lesions ADDIN EN.CITE <EndNote><Cite><Author>Reich</Author><Year>2018</Year><RecNum>117</RecNum><DisplayText>(39)</DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517264089">117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reich, D. S.</author><author>Lucchinetti, C. F.</author><author>Calabresi, P. A.</author></authors></contributors><auth-address>From the Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda (D.S.R.), and the Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore (P.A.C.) - both in Maryland; and the Department of Neurology, Mayo Clinic, Rochester, MN (C.F.L.).</auth-address><titles><title>Multiple Sclerosis</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>169-180</pages><volume>378</volume><number>2</number><edition>2018/01/11</edition><keywords><keyword>Antibodies, Monoclonal/therapeutic use</keyword><keyword>Biomarkers</keyword><keyword>Brain/*pathology</keyword><keyword>Glatiramer Acetate/therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunologic Factors/*therapeutic use</keyword><keyword>Interferon-beta/therapeutic use</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>*Multiple Sclerosis/diagnostic imaging/drug therapy/etiology/pathology</keyword></keywords><dates><year>2018</year><pub-dates><date>Jan 11</date></pub-dates></dates><isbn>1533-4406 (Electronic)
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ADDIN EN.CITE.DATA (34, 40). These studies show how dysregulated cytokines can cause structural brain damage by manipulating the normal physiological processes of brain-resident immune cells. AntibodiesAntibodies are a major mediator of organ damage in SLE, and antibodies directed against multiple brain antigens are frequently produced ADDIN EN.CITE <EndNote><Cite><Author>Hanly</Author><Year>1994</Year><RecNum>133</RecNum><DisplayText>(41)</DisplayText><record><rec-number>133</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517414741">133</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hanly, J. G.</author><author>Fisk, J. D.</author><author>Eastwood, B.</author></authors></contributors><auth-address>Department of Medicine, Victoria General Hospital, Halifax, Nova Scotia, Canada.</auth-address><titles><title>Brain reactive autoantibodies and cognitive impairment in systemic lupus erythematosus</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>193-9</pages><volume>3</volume><number>3</number><edition>1994/06/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Autoantibodies/*blood</keyword><keyword>Brain/*immunology</keyword><keyword>Cognition Disorders/*etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*immunology</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Synaptosomes/immunology</keyword></keywords><dates><year>1994</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0961-2033 (Print)
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ADDIN EN.CITE.DATA (44), this syndrome is rarely seen in SLE, and the degree to which lower titres of such antibodies can cause neuropsychiatric dysfunction outside this clinical picture is unclear ADDIN EN.CITE <EndNote><Cite><Author>Lennox</Author><Year>2017</Year><RecNum>121</RecNum><DisplayText>(45)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517307517">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lennox, B. R.</author><author>Pollak, T.</author><author>Palmer-Cooper, E. C.</author><author>Scoriels, L.</author><author>Harrison, P. J.</author><author>Jones, P. B.</author><author>Lang, B.</author><author>Crowley, H.</author><author>Marks, J.</author><author>Vincent, A.</author></authors></contributors><auth-address>University of Oxford, Oxford OX3 7JX, Oxfordshire UK. Electronic address: Belinda.Lennox@psych.ox.ac.uk.
Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
Institute of Psychiatry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.</auth-address><titles><title>Serum neuronal cell-surface antibodies in first-episode psychosis-Authors' reply</title><secondary-title>Lancet Psychiatry</secondary-title></titles><periodical><full-title>Lancet Psychiatry</full-title></periodical><pages>187-188</pages><volume>4</volume><number>3</number><edition>2017/02/27</edition><dates><year>2017</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>2215-0374 (Electronic)
2215-0366 (Linking)</isbn><accession-num>28236947</accession-num><urls><related-urls><url>(17)30053-6</electronic-resource-num></record></Cite></EndNote>(45). Interestingly, more classic lupus-associated antibodies directed against nucleic acids, can also cross-react with NMDA-R epitopes and cause neurological dysfunction in rodent models ADDIN EN.CITE <EndNote><Cite><Author>DeGiorgio</Author><Year>2001</Year><RecNum>104</RecNum><DisplayText>(46)</DisplayText><record><rec-number>104</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516890247">104</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>DeGiorgio, L. A.</author><author>Konstantinov, K. N.</author><author>Lee, S. C.</author><author>Hardin, J. A.</author><author>Volpe, B. T.</author><author>Diamond, B.</author></authors></contributors><auth-address>Department of Neurology & Neuroscience, The Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York, USA.</auth-address><titles><title>A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus</title><secondary-title>Nat Med</secondary-title></titles><periodical><full-title>Nat Med</full-title></periodical><pages>1189-93</pages><volume>7</volume><number>11</number><edition>2001/11/02</edition><keywords><keyword>Animals</keyword><keyword>Antibodies, Antinuclear/cerebrospinal fluid/*immunology</keyword><keyword>Apoptosis</keyword><keyword>Cells, Cultured</keyword><keyword>Cross Reactions</keyword><keyword>Humans</keyword><keyword>In Vitro Techniques</keyword><keyword>Lupus Erythematosus, Systemic/*immunology/pathology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neurons/immunology/pathology</keyword><keyword>Receptors, N-Methyl-D-Aspartate/*immunology</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1078-8956 (Print)
1078-8956 (Linking)</isbn><accession-num>11689882</accession-num><urls><related-urls><url>;(46). In patients with SLE who have co-existing antiphospholipid syndrome there is a role for antiphospholipid antibodies in the mediation of thrombotic events including intracranial thromboembolism ADDIN EN.CITE <EndNote><Cite><Author>Ruiz-Irastorza</Author><Year>2010</Year><RecNum>135</RecNum><DisplayText>(47)</DisplayText><record><rec-number>135</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517415673">135</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ruiz-Irastorza, G.</author><author>Crowther, M.</author><author>Branch, W.</author><author>Khamashta, M. A.</author></authors></contributors><auth-address>Service of Internal Medicine, Hospital de Cruces-University of the Basque Country, Bizkaia, Spain. r.irastorza@</auth-address><titles><title>Antiphospholipid syndrome</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1498-509</pages><volume>376</volume><number>9751</number><edition>2010/09/09</edition><keywords><keyword>*Antiphospholipid Syndrome/complications/diagnosis/physiopathology/therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications, Hematologic/diagnosis/physiopathology/therapy</keyword><keyword>Thrombosis/etiology/therapy</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct 30</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>20822807</accession-num><urls><related-urls><url>(10)60709-X</electronic-resource-num></record></Cite></EndNote>(47). Therefore a broad spectrum of antibodies are implicated in the pathogenesis of neurolupus, though neurological expertise may be needed in their interpretation. Pathology and Imaging Brain biopsies are performed rarely in people with lupus. Consequently much of our understanding of the pathological basis of neurolupus comes from postmortem studies, which introduce a bias towards severe disease. The first dedicated studies identified prominent cerebral small vessel disease as a major neuropathological feature in most cases ADDIN EN.CITE <EndNote><Cite><Author>Johnson</Author><Year>1968</Year><RecNum>106</RecNum><DisplayText>(48)</DisplayText><record><rec-number>106</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516891779">106</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Johnson, R. T.</author><author>Richardson, E. P.</author></authors></contributors><titles><title>The neurological manifestations of systemic lupus erythematosus</title><secondary-title>Medicine (Baltimore)</secondary-title></titles><periodical><full-title>Medicine (Baltimore)</full-title></periodical><pages>337-69</pages><volume>47</volume><number>4</number><edition>1968/07/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adrenal Cortex Hormones/physiology</keyword><keyword>Adult</keyword><keyword>Autonomic Nervous System Diseases/etiology</keyword><keyword>Central Nervous System Diseases/*etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1968</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0025-7974 (Print)
0025-7974 (Linking)</isbn><accession-num>5212395</accession-num><urls><related-urls><url>;(48). Importantly this is not a small vessel vasculitis, but rather a noninflammatory microangiopathy associated with microinfarction ADDIN EN.CITE <EndNote><Cite><Author>Johnson</Author><Year>1968</Year><RecNum>106</RecNum><DisplayText>(48)</DisplayText><record><rec-number>106</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516891779">106</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Johnson, R. T.</author><author>Richardson, E. P.</author></authors></contributors><titles><title>The neurological manifestations of systemic lupus erythematosus</title><secondary-title>Medicine (Baltimore)</secondary-title></titles><periodical><full-title>Medicine (Baltimore)</full-title></periodical><pages>337-69</pages><volume>47</volume><number>4</number><edition>1968/07/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adrenal Cortex Hormones/physiology</keyword><keyword>Adult</keyword><keyword>Autonomic Nervous System Diseases/etiology</keyword><keyword>Central Nervous System Diseases/*etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1968</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0025-7974 (Print)
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ADDIN EN.CITE.DATA (50, 51). Paired pathology-imaging studies show that these cerebral small vessel lesions seen on brain pathology correspond to “white matter hyperintensities” identifiable on magnetic resonance imaging (MRI) of the brainPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWJiaXR0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWJiaXR0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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Pn==
ADDIN EN.CITE.DATA (52). These MRI abnormalities are seen in the majority of people with lupus, even with mild neurological symptomatology (Figure 3A) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaXNlbWFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA (35) Clinical approach in neurolupusThe European League against Rheumatism (EULAR) recommendations for management of neurolupus emphasise the importance of careful evaluation of new neurological events in individuals with SLEPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXJ0c2lhczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA (53). It is important to remember that neurological symptoms may not be caused by lupus, and may simply represent highly prevalent neurological disease such as migraine or tension headache. Furthermore neurological symptoms may be caused directly or indirectly by drug therapiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (14, 54). As such investigation of these symptoms should involve a detailed history, careful examination and further investigation where indicated including MRI scan, CSF analysis and neurophysiologyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (54). Multidisciplinary discussion with a neurologist with an interest in neuroinflammatory disease and SLE can help. Recognised clinical syndromesThe recognized clinical neurological syndromes associated with lupus, are based loosely on the framework of the ACR criteria.StrokeThe earliest descriptions of lupus brain disease emphasized a prominent role for neurovascular disease ADDIN EN.CITE <EndNote><Cite><Author>Daly</Author><Year>1945</Year><RecNum>9</RecNum><DisplayText>(4)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516359386">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daly, D.</author></authors></contributors><titles><title>Central nervous system in acute disseminate lupus erythematosus</title><secondary-title>J Nerv Ment Dis</secondary-title></titles><periodical><full-title>J Nerv Ment Dis</full-title></periodical><pages>461-5</pages><volume>102</volume><edition>1945/11/01</edition><keywords><keyword>Humans</keyword><keyword>*Lupus Erythematosus, Systemic</keyword><keyword>*Nervous System</keyword><keyword>*LUPUS/erythematosus</keyword></keywords><dates><year>1945</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-3018 (Print)
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ADDIN EN.CITE.DATA (55-59). This observation of an increased stroke risk has been confirmed in large prospective registry-based studies ADDIN EN.CITE <EndNote><Cite><Author>Chiu</Author><Year>2012</Year><RecNum>22</RecNum><DisplayText>(57)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516365983">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiu, C. C.</author><author>Huang, C. C.</author><author>Chan, W. L.</author><author>Chung, C. M.</author><author>Huang, P. H.</author><author>Lin, S. J.</author><author>Chen, J. W.</author><author>Leu, H. B.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taiwan, ROC.</auth-address><titles><title>Increased risk of ischemic stroke in patients with systemic lupus erythematosus: a nationwide population-based study</title><secondary-title>Intern Med</secondary-title></titles><periodical><full-title>Intern Med</full-title></periodical><pages>17-21</pages><volume>51</volume><number>1</number><edition>2012/01/05</edition><keywords><keyword>Adult</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Comorbidity</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kaplan-Meier Estimate</keyword><keyword>Lupus Erythematosus, Systemic/*complications/epidemiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Stroke/epidemiology/*etiology</keyword><keyword>Taiwan/epidemiology</keyword></keywords><dates><year>2012</year></dates><isbn>1349-7235 (Electronic)
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ADDIN EN.CITE.DATA (58), but do not fully account for the excess of cases, implicating an additional inflammatory aetiology ADDIN EN.CITE <EndNote><Cite><Author>Wiseman</Author><Year>2014</Year><RecNum>26</RecNum><DisplayText>(60)</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516370044">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wiseman, S.</author><author>Marlborough, F.</author><author>Doubal, F.</author><author>Webb, D. J.</author><author>Wardlaw, J.</author></authors></contributors><auth-address>Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis</title><secondary-title>Cerebrovasc Dis</secondary-title></titles><periodical><full-title>Cerebrovasc Dis</full-title></periodical><pages>64-75</pages><volume>37</volume><number>1</number><edition>2014/01/10</edition><keywords><keyword>Biomarkers/*blood</keyword><keyword>*Blood Coagulation</keyword><keyword>Blood Proteins/*analysis</keyword><keyword>Brain Ischemia/*blood</keyword><keyword>Cell Adhesion Molecules/blood</keyword><keyword>Cytokines/*blood</keyword><keyword>Endothelium, Vascular/*physiopathology</keyword><keyword>*Fibrinolysis</keyword><keyword>Homocysteine/blood</keyword><keyword>Humans</keyword><keyword>Inflammation/*blood</keyword><keyword>Stroke/classification</keyword><keyword>Stroke, Lacunar/*blood</keyword></keywords><dates><year>2014</year></dates><isbn>1421-9786 (Electronic)
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ADDIN EN.CITE.DATA (61-63), highlighting the heterogeneity of underlying mechanisms which drive neurovascular disease in lupus. Small vessel diseaseCerebral small vessel disease (SVD) is a disorder of the brain’s perforating arterioles with typical MRI brain imaging features which include white matter hyperintensities (WMH, Figure 3a). Such appearances can occasionally cause diagnostic confusion with multiple sclerosis, although improved imaging should aid the distinction. Accelerated cerebral small vessel disease is a major cause of dementia in the general population, although the neurological significance of these findings in lupus remains to be determinedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaXNlbWFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA (18). It is likely that inflammatory mediators such as cytokines play a direct role ADDIN EN.CITE <EndNote><Cite><Author>Bailey</Author><Year>2012</Year><RecNum>161</RecNum><DisplayText>(65)</DisplayText><record><rec-number>161</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1520416435">161</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey, E. L.</author><author>Smith, C.</author><author>Sudlow, C. L.</author><author>Wardlaw, J. M.</author></authors></contributors><auth-address>Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.</auth-address><titles><title>Pathology of lacunar ischemic stroke in humans--a systematic review</title><secondary-title>Brain Pathol</secondary-title></titles><periodical><full-title>Brain Pathol</full-title></periodical><pages>583-91</pages><volume>22</volume><number>5</number><edition>2012/02/15</edition><keywords><keyword>Brain Ischemia/*complications</keyword><keyword>Databases, Factual/statistics & numerical data</keyword><keyword>Humans</keyword><keyword>Stroke, Lacunar/*etiology/*pathology</keyword><keyword>Terminology as Topic</keyword></keywords><dates><year>2012</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1750-3639 (Electronic)
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ADDIN EN.CITE.DATA (68) or posterior reversible encephalopathy syndrome ADDIN EN.CITE <EndNote><Cite><Author>Shaharir</Author><Year>2013</Year><RecNum>86</RecNum><DisplayText>(69)</DisplayText><record><rec-number>86</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516800871">86</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shaharir, S. S.</author><author>Remli, R.</author><author>Marwan, A. A.</author><author>Said, M. S.</author><author>Kong, N. C.</author></authors></contributors><auth-address>Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre, Malaysia. sazliyana@</auth-address><titles><title>Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: pooled analysis of the literature reviews and report of six new cases</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>492-6</pages><volume>22</volume><number>5</number><edition>2013/02/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Posterior Leukoencephalopathy Syndrome/*complications</keyword><keyword>Retrospective Studies</keyword><keyword>Young Adult</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1477-0962 (Electronic)
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ADDIN EN.CITE.DATA (70). Seizures should carefully evaluated with a neurologist for underlying cause and use of anticonvulsant agents discussed in those at high risk of seizure recurrence. If anticonvulsant medication is used, particular attention may need to be paid to issues such as drug interactions and teratogenicity.MyelopathySpinal cord disease is an uncommon but serious neurological complication in people with lupus. Over the past decade, the identification of pathogenic antibodies against glial antigens such as the aquaporin-4 water channel has demonstrated that “lupus myelitis” can, in part, be explained by concomitant neuromyelitis optica spectrum disorder (NMOSD)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaXR0b2NrPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA (71). These autoantibodies, together with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, should be tested in spinal cord presentations, especially in the context of “longitudinally extensive transverse myelitis” where inflammation extends over at least 3 vertebral segments ADDIN EN.CITE <EndNote><Cite><Author>Sellner</Author><Year>2010</Year><RecNum>142</RecNum><DisplayText>(72)</DisplayText><record><rec-number>142</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517422720">142</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sellner, J.</author><author>Boggild, M.</author><author>Clanet, M.</author><author>Hintzen, R. Q.</author><author>Illes, Z.</author><author>Montalban, X.</author><author>Du Pasquier, R. A.</author><author>Polman, C. H.</author><author>Sorensen, P. S.</author><author>Hemmer, B.</author></authors></contributors><auth-address>Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Germany. sellner@lrz.tum.de</auth-address><titles><title>EFNS guidelines on diagnosis and management of neuromyelitis optica</title><secondary-title>Eur J Neurol</secondary-title></titles><periodical><full-title>Eur J Neurol</full-title></periodical><pages>1019-32</pages><volume>17</volume><number>8</number><edition>2010/06/10</edition><keywords><keyword>Electrodiagnosis</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Methylprednisolone/therapeutic use</keyword><keyword>Neuromyelitis Optica/*diagnosis/*therapy</keyword><keyword>Neuroprotective Agents/therapeutic use</keyword><keyword>Plasma Exchange</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1468-1331 (Electronic)
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ADDIN EN.CITE.DATA (76), with diverse treatment options ADDIN EN.CITE <EndNote><Cite><Author>Kovacs</Author><Year>2000</Year><RecNum>34</RecNum><DisplayText>(77)</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516406262">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacs, B.</author><author>Lafferty, T. L.</author><author>Brent, L. H.</author><author>DeHoratius, R. J.</author></authors></contributors><auth-address>Department of Medicine, Albert Einstein Medical Center, Philadelphia 19141, USA.</auth-address><titles><title>Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Ann Rheum Dis</full-title></periodical><pages>120-4</pages><volume>59</volume><number>2</number><edition>2000/02/09</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Glucocorticoids/therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/therapeutic use</keyword><keyword>Lupus Erythematosus, Systemic/*complications/drug therapy</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Methylprednisolone/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Myelitis, Transverse/diagnosis/drug therapy/*etiology</keyword><keyword>Prognosis</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2000</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0003-4967 (Print)
0003-4967 (Linking)</isbn><accession-num>10666167</accession-num><urls><related-urls><url>;(77), requiring careful evaluation. MeningitisMeningitis, as described in the ACR case definitions, specifically refers to an autoimmune aseptic meningitis. This can occurs in lupus patients in isolation, but can also accompany other events such transverse myelitis ADDIN EN.CITE <EndNote><Cite><Author>Baizabal-Carvallo</Author><Year>2009</Year><RecNum>48</RecNum><DisplayText>(78)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516410930">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baizabal-Carvallo, J. F.</author><author>Delgadillo-Marquez, G.</author><author>Estanol, B.</author><author>Garcia-Ramos, G.</author></authors></contributors><auth-address>Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico. baicarjf@</auth-address><titles><title>Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus</title><secondary-title>Eur Neurol</secondary-title></titles><periodical><full-title>Eur Neurol</full-title></periodical><pages>143-8</pages><volume>61</volume><number>3</number><edition>2008/12/19</edition><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Meningitis/*complications/epidemiology</keyword><keyword>Meningitis, Aseptic/complications/epidemiology</keyword><keyword>Meningitis, Bacterial/complications/epidemiology</keyword><keyword>Meningitis, Cryptococcal/complications/epidemiology</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2009</year></dates><isbn>1421-9913 (Electronic)
0014-3022 (Linking)</isbn><accession-num>19092250</accession-num><urls><related-urls><url>;(78). It is rare. Given that many individuals with lupus are immunosuppressed, a critical differential diagnosis is one of an infectious meningitis caused by typical or opportunistic pathogens. A broad spectrum of pathogens including Cryptococcus neoformans and Listeria monocytogenes can cause meningitis in lupus patients and microbiological advice should be sought ADDIN EN.CITE <EndNote><Cite><Author>Baizabal-Carvallo</Author><Year>2009</Year><RecNum>48</RecNum><DisplayText>(78)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516410930">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baizabal-Carvallo, J. F.</author><author>Delgadillo-Marquez, G.</author><author>Estanol, B.</author><author>Garcia-Ramos, G.</author></authors></contributors><auth-address>Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico. baicarjf@</auth-address><titles><title>Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus</title><secondary-title>Eur Neurol</secondary-title></titles><periodical><full-title>Eur Neurol</full-title></periodical><pages>143-8</pages><volume>61</volume><number>3</number><edition>2008/12/19</edition><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Meningitis/*complications/epidemiology</keyword><keyword>Meningitis, Aseptic/complications/epidemiology</keyword><keyword>Meningitis, Bacterial/complications/epidemiology</keyword><keyword>Meningitis, Cryptococcal/complications/epidemiology</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2009</year></dates><isbn>1421-9913 (Electronic)
0014-3022 (Linking)</isbn><accession-num>19092250</accession-num><urls><related-urls><url>;(78). The clinical presentation of opportunistic organisms may vary, for example fungal meningitis or listeriosis may present with raised intracranial pressure and cranial neuropathies rather than meningism and fever ADDIN EN.CITE <EndNote><Cite><Author>Baizabal-Carvallo</Author><Year>2009</Year><RecNum>48</RecNum><DisplayText>(78)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516410930">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baizabal-Carvallo, J. F.</author><author>Delgadillo-Marquez, G.</author><author>Estanol, B.</author><author>Garcia-Ramos, G.</author></authors></contributors><auth-address>Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico. baicarjf@</auth-address><titles><title>Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus</title><secondary-title>Eur Neurol</secondary-title></titles><periodical><full-title>Eur Neurol</full-title></periodical><pages>143-8</pages><volume>61</volume><number>3</number><edition>2008/12/19</edition><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Meningitis/*complications/epidemiology</keyword><keyword>Meningitis, Aseptic/complications/epidemiology</keyword><keyword>Meningitis, Bacterial/complications/epidemiology</keyword><keyword>Meningitis, Cryptococcal/complications/epidemiology</keyword><keyword>Prevalence</keyword><keyword>Risk Factors</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2009</year></dates><isbn>1421-9913 (Electronic)
0014-3022 (Linking)</isbn><accession-num>19092250</accession-num><urls><related-urls><url>;(78). Aseptic meningitis has also been described as a consequence of drugs used to treat lupus, including NSAIDs ADDIN EN.CITE <EndNote><Cite><Author>Faurie</Author><Year>2010</Year><RecNum>145</RecNum><DisplayText>(79)</DisplayText><record><rec-number>145</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517423732">145</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Faurie, P.</author><author>Perard, L.</author><author>Hot, A.</author><author>Desmurs-Clavel, H.</author><author>Fassier, T.</author><author>Boibieux, A.</author><author>Ninet, J.</author></authors></contributors><auth-address>Service de medecine interne, hopital Edouard-Herriot, 69003 Lyon, France.</auth-address><titles><title>[Recurrent aseptic meningitis secondary to nonsteroidal anti-inflammatory drugs in a patient with lupus]</title><secondary-title>Rev Med Interne</secondary-title></titles><periodical><full-title>Rev Med Interne</full-title></periodical><pages>e1-3</pages><volume>31</volume><number>10</number><edition>2010/06/15</edition><keywords><keyword>Adult</keyword><keyword>Anti-Inflammatory Agents, Non-Steroidal/*adverse effects</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Ibuprofen/*adverse effects</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Meningitis, Aseptic/*chemically induced</keyword><keyword>Recurrence</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><orig-pub>Meningite aseptique recidivante due aux anti-inflammatoires non steroidiens chez une patiente lupique.</orig-pub><isbn>1768-3122 (Electronic)
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ADDIN EN.CITE.DATA (81, 82). Myoclonus has also been described ADDIN EN.CITE <EndNote><Cite><Author>Joseph</Author><Year>2007</Year><RecNum>43</RecNum><DisplayText>(83)</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516409152">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joseph, F. G.</author><author>Lammie, G. A.</author><author>Scolding, N. J.</author></authors></contributors><auth-address>Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.</auth-address><titles><title>CNS lupus: a study of 41 patients</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title></periodical><pages>644-54</pages><volume>69</volume><number>7</number><edition>2007/08/19</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Vasculitis, Central Nervous</keyword><keyword>System/diagnosis/*epidemiology/physiopathology/*psychology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug 14</date></pub-dates></dates><isbn>1526-632X (Electronic)
0028-3878 (Linking)</isbn><accession-num>17698785</accession-num><urls><related-urls><url>;(83). The aetiology of these movement disorders is poorly understood and neuroimaging studies do not usually identify evidence of a localizing lesion ADDIN EN.CITE <EndNote><Cite><Author>Baizabal-Carvallo</Author><Year>2013</Year><RecNum>146</RecNum><DisplayText>(84)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517424472">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baizabal-Carvallo, J. F.</author><author>Bonnet, C.</author><author>Jankovic, J.</author></authors></contributors><auth-address>Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, The Smith Tower, Suite 1801, 6550 Fannin, Houston, TX, 77030, USA, baizabaljf@.</auth-address><titles><title>Movement disorders in systemic lupus erythematosus and the antiphospholipid syndrome</title><secondary-title>J Neural Transm (Vienna)</secondary-title></titles><periodical><full-title>J Neural Transm (Vienna)</full-title></periodical><pages>1579-89</pages><volume>120</volume><number>11</number><edition>2013/04/13</edition><keywords><keyword>Antiphospholipid Syndrome/*complications/diagnosis</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications/diagnosis</keyword><keyword>Movement Disorders/*etiology</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1435-1463 (Electronic)
0300-9564 (Linking)</isbn><accession-num>23580159</accession-num><urls><related-urls><url>;(84). Both ischaemic and antibody-mediated causes have been postulated, though not convincingly demonstrated. Demyelinating syndromeAn association between lupus and multiple sclerosis-like brain changes has been suggested, and sometimes termed “lupoid sclerosis” ADDIN EN.CITE <EndNote><Cite><Author>Keiserman</Author><Year>2010</Year><RecNum>36</RecNum><DisplayText>(85)</DisplayText><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516407882">36</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Keiserman, B.</author><author>da Silva, L. F.</author><author>Keiserman, M. W.</author><author>von Muhlen, C. A.</author><author>Staub, H. L.</author></authors></contributors><auth-address>Department of Rheumatology, Sao Lucas Hospital, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga 6690/220, Porto Alegre, Brazil. briele.K@</auth-address><titles><title>Lupoid sclerosis</title><secondary-title>Rheumatol Int</secondary-title></titles><periodical><full-title>Rheumatol Int</full-title></periodical><pages>431-4</pages><volume>30</volume><number>4</number><edition>2009/10/15</edition><keywords><keyword>Antibodies, Antinuclear/blood/*immunology</keyword><keyword>Antibodies, Antiphospholipid/blood/*immunology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*immunology/pathology</keyword><keyword>Multiple Sclerosis/complications/*immunology/pathology</keyword><keyword>PubMed</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1437-160X (Electronic)
0172-8172 (Linking)</isbn><accession-num>19826821</accession-num><urls><related-urls><url>;(85). However, many such studies pre-date high quality MRI brain imaging which has greatly facilitated accurate diagnosis of multiple sclerosis (MS). Much of this confusion stems from the superficial similarities between the presence of small white matter lesions on the MRI brain scans of patients with both MS and lupus. Advances in our understanding of the pathogenesis of multiple sclerosis in the past decades highlight that these lesions are distinct from those observed in lupus ADDIN EN.CITE <EndNote><Cite><Author>Frohman</Author><Year>2006</Year><RecNum>170</RecNum><DisplayText>(86)</DisplayText><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525422228">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Frohman, E. M.</author><author>Racke, M. K.</author><author>Raine, C. S.</author></authors></contributors><auth-address>Department of Neurology and Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. elliot.frohman@utsouthwestern.edu</auth-address><titles><title>Multiple sclerosis--the plaque and its pathogenesis</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>942-55</pages><volume>354</volume><number>9</number><edition>2006/03/03</edition><keywords><keyword>Animals</keyword><keyword>Axons/pathology/physiology/ultrastructure</keyword><keyword>B-Lymphocytes/physiology</keyword><keyword>Brain/pathology</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Interleukins/physiology</keyword><keyword>Multiple Sclerosis/drug therapy/etiology/immunology/*pathology</keyword><keyword>Myelin Sheath/*pathology/ultrastructure</keyword><keyword>T-Lymphocytes/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Mar 2</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>16510748</accession-num><urls><related-urls><url>;(86). Lesions in multiple sclerosis can usually be distinguished from those of lupus with MRI brain imaging. For example, lesions in lupus rarely enhance and correlate at a pathological level with small vessel injuryPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWJiaXR0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA (88), and a more plausible explanation is that, as is often seen autoimmunity, the two diseases coexist in a single individual ADDIN EN.CITE <EndNote><Cite><Author>Jacome Sanchez</Author><Year>2018</Year><RecNum>172</RecNum><DisplayText>(89)</DisplayText><record><rec-number>172</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525422565">172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jacome Sanchez, E. C.</author><author>Garcia Castillo, M. A.</author><author>Gonzalez, V. P.</author><author>Guillen Lopez, F.</author><author>Correa Diaz, E. P.</author></authors></contributors><auth-address>Department of Neurology, Hospital Carlos Andrade Marin, Ecuador.
Department of Neurology, Hospital Jose Carrasco de Cuenca, Popayan y Pacto Andino, Ecuador.
Department of Neurology, Hospital Carlos Andrade Marin, Ecuador.279227
Universidad Central del Ecuador, Ecuador.</auth-address><titles><title>Coexistence of systemic lupus erythematosus and multiple sclerosis. A case report and literature review</title><secondary-title>Mult Scler J Exp Transl Clin</secondary-title></titles><periodical><full-title>Mult Scler J Exp Transl Clin</full-title></periodical><pages>2055217318768330</pages><volume>4</volume><number>2</number><edition>2018/04/18</edition><keywords><keyword>Ecuador</keyword><keyword>Multiple sclerosis</keyword><keyword>systemic lupus erythematosus</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr-Jun</date></pub-dates></dates><isbn>2055-2173 (Print)
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ADDIN EN.CITE.DATA (90), but there is no convincing evidence that this incidence is higher than that seen in the general population ADDIN EN.CITE <EndNote><Cite><Author>Davey</Author><Year>2008</Year><RecNum>37</RecNum><DisplayText>(91)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516408157">37</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Davey, R.</author><author>Bamford, J.</author><author>Emery, P.</author></authors></contributors><auth-address>Department of Neurology, Mid-Yorkshire NHS Trust, UK. daveyrichard@.uk</auth-address><titles><title>The ACR classification criteria for headache disorders in SLE fail to classify certain prevalent headache types</title><secondary-title>Cephalalgia</secondary-title></titles><periodical><full-title>Cephalalgia</full-title></periodical><pages>296-9</pages><volume>28</volume><number>3</number><edition>2008/02/08</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Female</keyword><keyword>Headache Disorders/*classification/complications</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*classification/complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Rheumatology/*standards</keyword><keyword>Societies, Medical/*standards</keyword><keyword>United States</keyword></keywords><dates><year>2008</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1468-2982 (Electronic)
0333-1024 (Linking)</isbn><accession-num>18254898</accession-num><urls><related-urls><url>;(91). Thus the entity of “lupus headache” is controversial ADDIN EN.CITE <EndNote><Cite><Author>Mitsikostas</Author><Year>2014</Year><RecNum>39</RecNum><DisplayText>(92)</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516408512">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitsikostas, D. D.</author><author>Katsiari, C.</author><author>Sfikakis, P. P.</author></authors></contributors><auth-address>Athens Naval Hospital, Athens, Greece.</auth-address><titles><title>Lupus headache may not exist: comment on the article by Hanly et Al</title><secondary-title>Arthritis Rheumatol</secondary-title></titles><periodical><full-title>Arthritis Rheumatol</full-title></periodical><pages>1058</pages><volume>66</volume><number>4</number><edition>2014/04/24</edition><keywords><keyword>Autoantibodies/*blood</keyword><keyword>Female</keyword><keyword>Headache/*epidemiology/*immunology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*epidemiology/*immunology</keyword><keyword>Male</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2326-5205 (Electronic)
2326-5191 (Linking)</isbn><accession-num>24757160</accession-num><urls><related-urls><url>;(92). Headache in individuals with lupus should be approached in the same way as in the general population, noting the broader differential diagnosis of any new acute headache to include a higher risk of infectious and neurovascular aetiologies ADDIN EN.CITE <EndNote><Cite><Author>Mimori</Author><Year>2000</Year><RecNum>139</RecNum><DisplayText>(62)</DisplayText><record><rec-number>139</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517417929">139</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mimori, A.</author><author>Suzuki, T.</author><author>Hashimoto, M.</author><author>Nara, H.</author><author>Yoshio, T.</author><author>Masuyama, J. I.</author><author>Okazaki, H.</author><author>Hirata, D.</author><author>Kano, S.</author><author>Minota, S.</author></authors></contributors><auth-address>Division of Rheumatology and Clinical Immunology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi, Japan.</auth-address><titles><title>Subarachnoid hemorrhage and systemic lupus erythematosus</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>521-6</pages><volume>9</volume><number>7</number><edition>2000/10/18</edition><keywords><keyword>Adult</keyword><keyword>Age of Onset</keyword><keyword>Aneurysm, Ruptured/diagnosis/surgery</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Intracranial Aneurysm/diagnosis/surgery</keyword><keyword>Japan/epidemiology</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Middle Aged</keyword><keyword>Retrospective Studies</keyword><keyword>Subarachnoid Hemorrhage/epidemiology/*etiology/mortality</keyword></keywords><dates><year>2000</year></dates><isbn>0961-2033 (Print)
0961-2033 (Linking)</isbn><accession-num>11035418</accession-num><urls><related-urls><url>;(62). Psychiatric disease The term “lupus psychosis” has been used to describe single or repeated episodes of thought disorders such as hallucinations and delusions occurring in people with SLE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbnplbGxlcjwvQXV0aG9yPjxZZWFyPjIwMDg8L1ll
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ADDIN EN.CITE.DATA (45, 95). Individuals with lupus are exposed to a number of biological substances which can cause psychosis, in particular corticosteroids and circulating antibodies directed against the NMDA-R ADDIN EN.CITE <EndNote><Cite><Author>Lennox</Author><Year>2017</Year><RecNum>121</RecNum><DisplayText>(45)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517307517">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lennox, B. R.</author><author>Pollak, T.</author><author>Palmer-Cooper, E. C.</author><author>Scoriels, L.</author><author>Harrison, P. J.</author><author>Jones, P. B.</author><author>Lang, B.</author><author>Crowley, H.</author><author>Marks, J.</author><author>Vincent, A.</author></authors></contributors><auth-address>University of Oxford, Oxford OX3 7JX, Oxfordshire UK. Electronic address: Belinda.Lennox@psych.ox.ac.uk.
Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
Institute of Psychiatry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.</auth-address><titles><title>Serum neuronal cell-surface antibodies in first-episode psychosis-Authors' reply</title><secondary-title>Lancet Psychiatry</secondary-title></titles><periodical><full-title>Lancet Psychiatry</full-title></periodical><pages>187-188</pages><volume>4</volume><number>3</number><edition>2017/02/27</edition><dates><year>2017</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>2215-0374 (Electronic)
2215-0366 (Linking)</isbn><accession-num>28236947</accession-num><urls><related-urls><url>(17)30053-6</electronic-resource-num></record></Cite></EndNote>(45). An association has also been identified between psychosis in lupus and anti-ribosomal-P antibodies ADDIN EN.CITE <EndNote><Cite><Author>Bonfa</Author><Year>1987</Year><RecNum>165</RecNum><DisplayText>(96)</DisplayText><record><rec-number>165</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525216084">165</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bonfa, E.</author><author>Golombek, S. J.</author><author>Kaufman, L. D.</author><author>Skelly, S.</author><author>Weissbach, H.</author><author>Brot, N.</author><author>Elkon, K. B.</author></authors></contributors><titles><title>Association between lupus psychosis and anti-ribosomal P protein antibodies</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>265-71</pages><volume>317</volume><number>5</number><edition>1987/07/30</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Antibodies, Antinuclear/analysis</keyword><keyword>Autoantibodies/*analysis</keyword><keyword>DNA/immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications/immunology</keyword><keyword>Male</keyword><keyword>Neurocognitive Disorders/etiology/*immunology</keyword><keyword>Phosphoproteins/*immunology</keyword><keyword>Radioimmunoassay</keyword><keyword>Ribosomal Proteins/*immunology</keyword></keywords><dates><year>1987</year><pub-dates><date>Jul 30</date></pub-dates></dates><isbn>0028-4793 (Print)
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ADDIN EN.CITE.DATA (97). However, while antibodies directed against dsDNA, NMDA and ribosomal-P may exhibit some neurotoxic effects in adoptive transfer experiments, their role in mediating psychiatric symptomatology and other brain symptoms in humans is not clearPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJhc3NhPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48
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ADDIN EN.CITE.DATA (98). A proportion of psychotic events in lupus are temporally related to corticosteroid use, although such observations are likely to be confounded by increases in systemic disease activity which might precede increased steroid dosePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaXNoaW11cmE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy
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ADDIN EN.CITE.DATA (99-101). Differentiation of steroid-induced psychosis from lupus-associated psychosis is particularly challenging ADDIN EN.CITE <EndNote><Cite><Author>Bhangle</Author><Year>2013</Year><RecNum>52</RecNum><DisplayText>(100)</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516456493">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhangle, S. D.</author><author>Kramer, N.</author><author>Rosenstein, E. D.</author></authors></contributors><auth-address>Division of Rheumatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.</auth-address><titles><title>Corticosteroid-induced neuropsychiatric disorders: review and contrast with neuropsychiatric lupus</title><secondary-title>Rheumatol Int</secondary-title></titles><periodical><full-title>Rheumatol Int</full-title></periodical><pages>1923-32</pages><volume>33</volume><number>8</number><edition>2013/04/17</edition><keywords><keyword>Adrenal Cortex Hormones/*adverse effects/therapeutic use</keyword><keyword>Diagnosis, Differential</keyword><keyword>Humans</keyword><keyword>Lupus Vasculitis, Central Nervous System/*diagnosis/drug therapy</keyword><keyword>Mental Disorders/*chemically induced/*diagnosis</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1437-160X (Electronic)
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ADDIN EN.CITE.DATA (108, 109), though true dementia is not common ADDIN EN.CITE <EndNote><Cite><Author>Hanly</Author><Year>2011</Year><RecNum>55</RecNum><DisplayText>(110)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516726630">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hanly, J. G.</author><author>Fisk, J. D.</author></authors></contributors><titles><title>Diagnosis of cognitive impairment in adult and pediatric SLE</title><secondary-title>Nat Rev Rheumatol</secondary-title></titles><periodical><full-title>Nat Rev Rheumatol</full-title></periodical><pages>564-5</pages><volume>7</volume><number>10</number><edition>2011/08/25</edition><keywords><keyword>Adult</keyword><keyword>Child</keyword><keyword>Cognition Disorders/*diagnosis/etiology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*psychology</keyword><keyword>Neuropsychological Tests</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug 23</date></pub-dates></dates><isbn>1759-4804 (Electronic)
1759-4790 (Linking)</isbn><accession-num>21862982</accession-num><urls><related-urls><url>;(110). There is no clear association with lupus activity ADDIN EN.CITE <EndNote><Cite><Author>Glanz</Author><Year>1997</Year><RecNum>59</RecNum><DisplayText>(111)</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516749976">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Glanz, B. I.</author><author>Slonim, D.</author><author>Urowitz, M. B.</author><author>Gladman, D. D.</author><author>Gough, J.</author><author>MacKinnon, A.</author></authors></contributors><auth-address>Department of Psychology, Wellesley Hospital, Toronto, Ontario, Canada.</auth-address><titles><title>Pattern of neuropsychologic dysfunction in inactive systemic lupus erythematosus</title><secondary-title>Neuropsychiatry Neuropsychol Behav Neurol</secondary-title></titles><periodical><full-title>Neuropsychiatry Neuropsychol Behav Neurol</full-title></periodical><pages>232-8</pages><volume>10</volume><number>4</number><edition>1997/11/14</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Anti-Inflammatory Agents/administration & dosage/adverse effects</keyword><keyword>Atrophy/chemically induced</keyword><keyword>Brain/drug effects/*physiopathology</keyword><keyword>Cognition Disorders/*complications/diagnosis/etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications/drug therapy/*physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuropsychological Tests</keyword><keyword>Prednisone/administration & dosage/adverse effects</keyword></keywords><dates><year>1997</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0894-878X (Print)
0894-878X (Linking)</isbn><accession-num>9359119</accession-num><urls><related-urls><url>;(111). Screening tools are of use to identify cognitive dysfunction in the clinic and should prompt more detailed neuropsychological testing if abnormal ADDIN EN.CITE <EndNote><Cite><Author>Kozora</Author><Year>2004</Year><RecNum>56</RecNum><DisplayText>(112)</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516727846">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kozora, E.</author><author>Ellison, M. C.</author><author>West, S.</author></authors></contributors><auth-address>National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado, USA. kozorae@</auth-address><titles><title>Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>810-8</pages><volume>51</volume><number>5</number><edition>2004/10/13</edition><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Vasculitis, Central Nervous System/*diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuropsychological Tests/*standards</keyword><keyword>Reproducibility of Results</keyword><keyword>Rheumatology/standards</keyword><keyword>Societies, Medical</keyword><keyword>United States</keyword></keywords><dates><year>2004</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>0004-3591 (Print)
0004-3591 (Linking)</isbn><accession-num>15478145</accession-num><urls><related-urls><url>;(112). However cognitive changes can be transient and their substrate poorly defined. While some correlation with MRI abnormalities has been identified, this is not a robust association ADDIN EN.CITE <EndNote><Cite><Author>Ainiala</Author><Year>2005</Year><RecNum>92</RecNum><DisplayText>(113)</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516803098">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ainiala, H.</author><author>Dastidar, P.</author><author>Loukkola, J.</author><author>Lehtimaki, T.</author><author>Korpela, M.</author><author>Peltola, J.</author><author>Hietaharju, A.</author></authors></contributors><auth-address>Department of Neurology, Tampere University Hospital, Tampere, Finland. jukkaps@koti.soon.fi</auth-address><titles><title>Cerebral MRI abnormalities and their association with neuropsychiatric manifestations in SLE: a population-based study</title><secondary-title>Scand J Rheumatol</secondary-title></titles><periodical><full-title>Scand J Rheumatol</full-title></periodical><pages>376-82</pages><volume>34</volume><number>5</number><edition>2005/10/20</edition><keywords><keyword>Adult</keyword><keyword>Atrophy</keyword><keyword>Brain/*pathology</keyword><keyword>Cognition Disorders/etiology/*pathology</keyword><keyword>Epilepsy/etiology/pathology</keyword><keyword>Female</keyword><keyword>Glucocorticoids/therapeutic use</keyword><keyword>Humans</keyword><keyword>Lupus Vasculitis, Central Nervous System/complications/drug therapy/*pathology</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2005</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><isbn>0300-9742 (Print)
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ADDIN EN.CITE.DATA (35). Evaluation of cognitive symptoms in people with lupus requires careful clinical evaluation, paying attention to addition factors such as depression and medication which can contribute to cognitive dysfunction. Neither corticosteroids ADDIN EN.CITE <EndNote><Cite><Author>Denburg</Author><Year>1994</Year><RecNum>60</RecNum><DisplayText>(114)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516751178">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Denburg, S. D.</author><author>Carbotte, R. M.</author><author>Denburg, J. A.</author></authors></contributors><auth-address>Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.</auth-address><titles><title>Corticosteroids and neuropsychological functioning in patients with systemic lupus erythematosus</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>1311-20</pages><volume>37</volume><number>9</number><edition>1994/09/01</edition><keywords><keyword>Adrenal Cortex Hormones/adverse effects/*therapeutic use</keyword><keyword>Adult</keyword><keyword>Affect/*drug effects</keyword><keyword>Cognition/*drug effects</keyword><keyword>Double-Blind Method</keyword><keyword>Drug Administration Schedule</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*drug therapy/*physiopathology/psychology</keyword><keyword>Nervous System/*physiopathology</keyword><keyword>Neuropsychological Tests</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0004-3591 (Print)
0004-3591 (Linking)</isbn><accession-num>7945494</accession-num><urls><related-urls><url>;(114) nor NMDA-R antagonists ADDIN EN.CITE <EndNote><Cite><Author>Petri</Author><Year>2011</Year><RecNum>61</RecNum><DisplayText>(115)</DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516751236">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petri, M.</author><author>Naqibuddin, M.</author><author>Sampedro, M.</author><author>Omdal, R.</author><author>Carson, K. A.</author></authors></contributors><auth-address>Johns Hopkins University, Baltimore, MD 21205, USA. mpetri@jhmi.edu</auth-address><titles><title>Memantine in systemic lupus erythematosus: a randomized, double-blind placebo-controlled trial</title><secondary-title>Semin Arthritis Rheum</secondary-title></titles><periodical><full-title>Semin Arthritis Rheum</full-title></periodical><pages>194-202</pages><volume>41</volume><number>2</number><edition>2011/04/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cognition Disorders/*drug therapy/etiology</keyword><keyword>Double-Blind Method</keyword><keyword>Excitatory Amino Acid Antagonists/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*drug therapy</keyword><keyword>Male</keyword><keyword>Memantine/*therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Neuropsychological Tests</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1532-866X (Electronic)
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ADDIN EN.CITE.DATA (116). Rare entitiesThe posterior reversible encephalopathy syndrome (PRES) is a clinic-radiological syndrome of headache, seizures and encephalopathy associated with white matter changes which occurs mainly towards the posterior regions of the brain ADDIN EN.CITE <EndNote><Cite><Author>Baizabal-Carvallo</Author><Year>2009</Year><RecNum>47</RecNum><DisplayText>(117)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516410922">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baizabal-Carvallo, J. F.</author><author>Barragan-Campos, H. M.</author><author>Padilla-Aranda, H. J.</author><author>Alonso-Juarez, M.</author><author>Estanol, B.</author><author>Cantu-Brito, C.</author><author>Garcia-Ramos, G.</author></authors></contributors><auth-address>Department of Neurology and Psychiatry, Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran, Mexico City, Mexico. baicarjf@</auth-address><titles><title>Posterior reversible encephalopathy syndrome as a complication of acute lupus activity</title><secondary-title>Clin Neurol Neurosurg</secondary-title></titles><periodical><full-title>Clin Neurol Neurosurg</full-title></periodical><pages>359-63</pages><volume>111</volume><number>4</number><edition>2009/01/09</edition><keywords><keyword>Adult</keyword><keyword>Brain Diseases, Metabolic/epidemiology/*etiology/*pathology/physiopathology</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/epidemiology/*etiology</keyword><keyword>Lupus Erythematosus, Systemic/*complications/pathology</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Renal Insufficiency/epidemiology/*etiology</keyword><keyword>Young Adult</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>1872-6968 (Electronic)
0303-8467 (Linking)</isbn><accession-num>19128872</accession-num><urls><related-urls><url>;(117). Despite its name, the neurological damage caused by PRES is not necessarily reversible and can occur throughout the brain. A number of cases of PRES in people with SLE have been reported ADDIN EN.CITE <EndNote><Cite><Author>Shaharir</Author><Year>2013</Year><RecNum>86</RecNum><DisplayText>(69)</DisplayText><record><rec-number>86</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516800871">86</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shaharir, S. S.</author><author>Remli, R.</author><author>Marwan, A. A.</author><author>Said, M. S.</author><author>Kong, N. C.</author></authors></contributors><auth-address>Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre, Malaysia. sazliyana@</auth-address><titles><title>Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: pooled analysis of the literature reviews and report of six new cases</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>492-6</pages><volume>22</volume><number>5</number><edition>2013/02/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Posterior Leukoencephalopathy Syndrome/*complications</keyword><keyword>Retrospective Studies</keyword><keyword>Young Adult</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1477-0962 (Electronic)
0961-2033 (Linking)</isbn><accession-num>23435619</accession-num><urls><related-urls><url>;(69), but this syndrome can be confounded by associations with immunosuppressive medications and uncontrolled hypertension, and therefore the precise aetiological factors are not fully understood ADDIN EN.CITE <EndNote><Cite><Author>Shaharir</Author><Year>2013</Year><RecNum>86</RecNum><DisplayText>(69)</DisplayText><record><rec-number>86</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516800871">86</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shaharir, S. S.</author><author>Remli, R.</author><author>Marwan, A. A.</author><author>Said, M. S.</author><author>Kong, N. C.</author></authors></contributors><auth-address>Department of Internal Medicine, Universiti Kebangsaan Malaysia Medical Centre, Malaysia. sazliyana@</auth-address><titles><title>Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: pooled analysis of the literature reviews and report of six new cases</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>492-6</pages><volume>22</volume><number>5</number><edition>2013/02/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Posterior Leukoencephalopathy Syndrome/*complications</keyword><keyword>Retrospective Studies</keyword><keyword>Young Adult</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1477-0962 (Electronic)
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GbG9yaWNhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA (123, 124). Prospective studies, based on electrophysiological studies rather than symptoms, suggest that the commonest electrophysiological pattern is that of a sensorimotor axonal neuropathy ADDIN EN.CITE <EndNote><Cite><Author>Omdal</Author><Year>2001</Year><RecNum>73</RecNum><DisplayText>(122)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516792506">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Omdal, R.</author><author>Loseth, S.</author><author>Torbergsen, T.</author><author>Koldingsnes, W.</author><author>Husby, G.</author><author>Mellgren, S. I.</author></authors></contributors><auth-address>Department of Clinical Medicine/Neurology, University Hospital of Tromso, Oslo, Norway. romdal@online.no</auth-address><titles><title>Peripheral neuropathy in systemic lupus erythematosus--a longitudinal study</title><secondary-title>Acta Neurol Scand</secondary-title></titles><periodical><full-title>Acta Neurol Scand</full-title></periodical><pages>386-91</pages><volume>103</volume><number>6</number><edition>2001/06/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Analysis of Variance</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Male</keyword><keyword>Median Nerve/physiopathology</keyword><keyword>Middle Aged</keyword><keyword>Neural Conduction/physiology</keyword><keyword>Neurons, Afferent/physiology</keyword><keyword>Polyneuropathies/diagnosis/*etiology/physiopathology</keyword><keyword>Radial Nerve/physiopathology</keyword><keyword>Sural Nerve/physiopathology</keyword><keyword>Ulnar Nerve/physiopathology</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0001-6314 (Print)
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ADDIN EN.CITE.DATA (125). Identification of inflammatory demyelination on nerve conduction studies should provoke examination of the CSF and a search for paraproteinaemic comorbidities ADDIN EN.CITE <EndNote><Cite><Author>Vina</Author><Year>2005</Year><RecNum>74</RecNum><DisplayText>(126)</DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516792797">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vina, E. R.</author><author>Fang, A. J.</author><author>Wallace, D. J.</author><author>Weisman, M. H.</author></authors></contributors><auth-address>Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.</auth-address><titles><title>Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: prognosis and outcome</title><secondary-title>Semin Arthritis Rheum</secondary-title></titles><periodical><full-title>Semin Arthritis Rheum</full-title></periodical><pages>175-84</pages><volume>35</volume><number>3</number><edition>2005/12/06</edition><keywords><keyword>Adult</keyword><keyword>Biopsy</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Immunoglobulins, Intravenous/therapeutic use</keyword><keyword>Immunologic Factors/therapeutic use</keyword><keyword>Lupus Erythematosus, Systemic/*complications</keyword><keyword>Median Nerve/pathology</keyword><keyword>Middle Aged</keyword><keyword>Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/*complications/drug</keyword><keyword>therapy/pathology</keyword><keyword>Prognosis</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2005</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0049-0172 (Print)
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ADDIN EN.CITE.DATA (72, 133). Cranial neuropathies affecting all cranial nerves have been reported in lupusPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZW5ldmF5PC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA (137, 138). Functional diseaseFunctional symptoms are real but are not caused by underlying neurological disease. Functional neurological disease is a common cause of neurological symptoms, in both general medicine and neurology clinics, and can therefore frequently co-exist with inflammatory diseases such as lupus ADDIN EN.CITE <EndNote><Cite><Author>Stone</Author><Year>2009</Year><RecNum>124</RecNum><DisplayText>(139)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517314237">124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stone, J.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. Jon.Stone@ed.ac.uk</auth-address><titles><title>The bare essentials: Functional symptoms in neurology</title><secondary-title>Pract Neurol</secondary-title></titles><periodical><full-title>Pract Neurol</full-title></periodical><pages>179-89</pages><volume>9</volume><number>3</number><edition>2009/05/19</edition><keywords><keyword>Dissociative Disorders/diagnosis</keyword><keyword>Humans</keyword><keyword>Mental Disorders/*diagnosis</keyword><keyword>Nervous System Diseases/*diagnosis</keyword><keyword>Neurology/*methods</keyword><keyword>Terminology as Topic</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1474-7766 (Electronic)
1474-7758 (Linking)</isbn><accession-num>19448064</accession-num><urls><related-urls><url>;(139). Incorrectly attributing functional symptoms to an inflammatory cause can lead to an inappropriate escalation in immunotherapy or unnecessary investigation. A specialist neurological opinion can help identify positive findings of functional neurological disease. The incidence of functional symptomatology in lupus and other inflammatory diseases is unknown and merits further study ADDIN EN.CITE <EndNote><Cite><Author>Stone</Author><Year>2009</Year><RecNum>124</RecNum><DisplayText>(139)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517314237">124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stone, J.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. Jon.Stone@ed.ac.uk</auth-address><titles><title>The bare essentials: Functional symptoms in neurology</title><secondary-title>Pract Neurol</secondary-title></titles><periodical><full-title>Pract Neurol</full-title></periodical><pages>179-89</pages><volume>9</volume><number>3</number><edition>2009/05/19</edition><keywords><keyword>Dissociative Disorders/diagnosis</keyword><keyword>Humans</keyword><keyword>Mental Disorders/*diagnosis</keyword><keyword>Nervous System Diseases/*diagnosis</keyword><keyword>Neurology/*methods</keyword><keyword>Terminology as Topic</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1474-7766 (Electronic)
1474-7758 (Linking)</isbn><accession-num>19448064</accession-num><urls><related-urls><url>;(139). Treatment of neurolupusWhile efforts have been made to guide best practice in the diagnosis and management of neurolupus, there is only a weak evidence base on which to develop such recommendationsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXJ0c2lhczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA (30). For example, activation of the type I interferon response is an important determinant of organ-specific disease and is implicated in aspects of brain disease. Similarly, B-cell pathways play an important role in neurological syndromes caused by pathogenic autoantibodies. Thus, with the advent of more accurate biomarkers to identify aberrant immunological pathways, heterogeneous populations could be divided into those who are predicted to respond to targeted therapies, acting as a basis for rational trial design (Figure 4) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0dsYXNzb248L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA (29). If this approach is to provide a logical framework for developing therapies, then we need to incorporate such a molecular understanding into clinical classification. At present, the classification system for neurological disease in lupus is largely based on neurological syndromes and does not incorporate a pathophysiological understanding of the disease (Figure 2). The need to move from a syndromic toward a mechanistic classification is perhaps best exemplified by spinal cord disease in lupus (Figure 2C). The 1999 ACR case definitions refer to a broad syndrome of “lupus myelopathy”. However, as our understanding of the pathogenesis of spinal cord disease in lupus has advanced, together with the discovery of strong biomarkers and improved imaging, it is clear that A single syndrome such as ““lupus myelopathy” can be caused by at least three different pathophysiological processes. These include (e.g. aAntibodies against aquaporin-4, antibody-independent inflammation and spinal vascular disease). It is likely that each of these different mechanisms may require a different therapeutic approach. Furthermore some syndromes, such as “lupus headache”, may not exist at all. As such the classification system used in neurolupus requires substantial revision, reflecting the transition to a molecular understanding of disease (Figure 2). A critical step in the future success of neurolupus clinical trials will be improving the quantification of neurological outcomes. There is a particular need to develop validated imaging and laboratory biomarkers of neurological disease in lupus which can supplement complex clinical assessment. MRI brain scans are invariably abnormal in lupus, and change over time. As such, imaging biomarkers may play a role as our ability to quantify macrostructural and microstructural damage (Figure 3). Serum and CSF biomarkers of “brain damage”, such as ultrasensitive detection of neurofilament protein, have been developed as a surrogate marker for clinical trials in neuroinflammatory and neurodegenerative diseasesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb2huc29uPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA (146). Thus the rapid progress in our understanding of both pathophysiology and biomarkers of neurolupus is providing a much-needed roadmap to advance the field.SummaryNeurological disease is an area of major unmet need for people with lupus, providing a complex conceptual and practical challenge. An improved molecular understanding of how lupus can damage the brain and nervous system is providing opportunities to pursue stratified medicine approaches. Advancing the field will require our tools for classifying and measuring neurological disease in lupus to be reevaluated. Conflicts of InterestNoneAcknowledgementsDH is supported by the Medical Research Foundation Emerging Leaders Prize. DH and SM are supported by the Wellcome Trust WT101153MA. Research by SW has been supported by Lupus UK. SM is supported by the Anne Rowling ClinicSyndromeImplicated mechanisms and potential therapeutic targetsCNSLarge and small vessel diseaseLarge vessel atheromatous diseasePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Vcm93aXR6PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA (18)Antiphospholipid antibodies ADDIN EN.CITE <EndNote><Cite><Author>Ruiz-Irastorza</Author><Year>2010</Year><RecNum>135</RecNum><DisplayText>(47)</DisplayText><record><rec-number>135</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1517415673">135</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ruiz-Irastorza, G.</author><author>Crowther, M.</author><author>Branch, W.</author><author>Khamashta, M. A.</author></authors></contributors><auth-address>Service of Internal Medicine, Hospital de Cruces-University of the Basque Country, Bizkaia, Spain. r.irastorza@</auth-address><titles><title>Antiphospholipid syndrome</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1498-509</pages><volume>376</volume><number>9751</number><edition>2010/09/09</edition><keywords><keyword>*Antiphospholipid Syndrome/complications/diagnosis/physiopathology/therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications, Hematologic/diagnosis/physiopathology/therapy</keyword><keyword>Thrombosis/etiology/therapy</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct 30</date></pub-dates></dates><isbn>1474-547X (Electronic)
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0300-9564 (Linking)</isbn><accession-num>23580159</accession-num><urls><related-urls><url>;(84)Demyelinating syndromeNot clearly associated with SLE ADDIN EN.CITE <EndNote><Cite><Author>Jacome Sanchez</Author><Year>2018</Year><RecNum>172</RecNum><DisplayText>(89)</DisplayText><record><rec-number>172</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525422565">172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jacome Sanchez, E. C.</author><author>Garcia Castillo, M. A.</author><author>Gonzalez, V. P.</author><author>Guillen Lopez, F.</author><author>Correa Diaz, E. P.</author></authors></contributors><auth-address>Department of Neurology, Hospital Carlos Andrade Marin, Ecuador.
Department of Neurology, Hospital Jose Carrasco de Cuenca, Popayan y Pacto Andino, Ecuador.
Department of Neurology, Hospital Carlos Andrade Marin, Ecuador.279227
Universidad Central del Ecuador, Ecuador.</auth-address><titles><title>Coexistence of systemic lupus erythematosus and multiple sclerosis. A case report and literature review</title><secondary-title>Mult Scler J Exp Transl Clin</secondary-title></titles><periodical><full-title>Mult Scler J Exp Transl Clin</full-title></periodical><pages>2055217318768330</pages><volume>4</volume><number>2</number><edition>2018/04/18</edition><keywords><keyword>Ecuador</keyword><keyword>Multiple sclerosis</keyword><keyword>systemic lupus erythematosus</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr-Jun</date></pub-dates></dates><isbn>2055-2173 (Print)
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ADDIN EN.CITE.DATA (90)Psychiatric diseaseCytokine dysregulation ADDIN EN.CITE <EndNote><Cite><Author>Leighton</Author><Year>2018</Year><RecNum>54</RecNum><DisplayText>(107)</DisplayText><record><rec-number>54</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1516463164">54</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leighton, S. P.</author><author>Nerurkar, L.</author><author>Krishnadas, R.</author><author>Johnman, C.</author><author>Graham, G. J.</author><author>Cavanagh, J.</author></authors></contributors><auth-address>Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.</auth-address><titles><title>Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis</title><secondary-title>Mol Psychiatry</secondary-title></titles><periodical><full-title>Mol Psychiatry</full-title></periodical><pages>48-58</pages><volume>23</volume><number>1</number><edition>2017/11/15</edition><dates><year>2018</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1476-5578 (Electronic)
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ADDIN EN.CITE.DATA (132, 150)Myasthenia GravisAntibody-mediated (Anti-ACHr, Anti-MuSK) ADDIN EN.CITE <EndNote><Cite><Author>Nacu</Author><Year>2015</Year><RecNum>185</RecNum><DisplayText>(151)</DisplayText><record><rec-number>185</rec-number><foreign-keys><key app="EN" db-id="vdrzf9vpo2z9f2e5vf7xfsw6555zx99zt9w9" timestamp="1525445467">185</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nacu, A.</author><author>Andersen, J. B.</author><author>Lisnic, V.</author><author>Owe, J. F.</author><author>Gilhus, N. E.</author></authors></contributors><auth-address>a Department of Neurology , Haukeland University Hospital , Bergen , Norway .</auth-address><titles><title>Complicating autoimmune diseases in myasthenia gravis: a review</title><secondary-title>Autoimmunity</secondary-title></titles><periodical><full-title>Autoimmunity</full-title></periodical><pages>362-8</pages><volume>48</volume><number>6</number><edition>2015/04/29</edition><keywords><keyword>Animals</keyword><keyword>Autoantibodies/immunology</keyword><keyword>Autoantigens/immunology</keyword><keyword>Autoimmune Diseases/*complications</keyword><keyword>Autoimmunity</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>LDL-Receptor Related Proteins/immunology</keyword><keyword>Myasthenia Gravis/*complications/diagnosis/genetics/*immunology</keyword><keyword>Receptor Protein-Tyrosine Kinases/immunology</keyword><keyword>Receptors, Cholinergic/immunology</keyword><keyword>Receptors, Nicotinic/immunology</keyword><keyword>Thymoma/complications</keyword><keyword>Autoimmune disease</keyword><keyword>comorbidity</keyword><keyword>myasthenia gravis</keyword></keywords><dates><year>2015</year></dates><isbn>1607-842X (Electronic)
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ADDIN EN.CITE.DATA (75, 77). Each of these causes may benefit from differing approaches. As such, what was previously considered a single disease entity, is cause by differing pathogenic mechanisms, with implications for treatment and clinical trial design. Figure 3. MRI imaging in lupus brain disease. (A,B) Fluid-attenuated inversion recovery MRI scan of a representative individual with lupus, showing accelerated cerebral small vessel disease, highlighted red arrows (C,D) Advanced MRI techniques such as diffusion tensor imaging and tractography can allow identification of individual white matter tracts and measures such as mean diffusivity can identify microstructural disease. Tractography images of lupus patient shown, each line represents individual white matter tract. Credit: Mark Bastin, Joanna Wardlaw, Stewart Wiseman.Figure 4. Neurolupus: Towards molecular stratificationBrain disease in lupus is clinically heterogeneous (left), but may be driven by certain pathways, allowing stratification of individual populations (e.g. type I interferon pathway, pathogenic autoantibodies). Improvements in biomarkers will allow identification of such patients such that they can undergo clinical trials targeted at the specific pathway. Central to the success of such pathways are the development of brain biomarkers (e.g. MRI scans, markers of brain damage) to supplement clinical assessment. References ADDIN EN.REFLIST 1.Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-21.2.M K. Lupus Erythematosus1875.3.Osler W. On the visceral complications of erythema exudativum multiforme. Am J Med Sci. 1895(110):629-46.4.Daly D. Central nervous system in acute disseminate lupus erythematosus. J Nerv Ment Dis. 1945;102:461-5.5.Kassan SS, Lockshin MD. Central nervous system lupus erythematosus. 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