Diagnostic approach to the neuropsychiatric manifestations of systemic lupus erythematosus
- Peter H Schur, MD
Peter H Schur, MD
- Editor-in-Chief — Rheumatology
- Section Editor — Basic Science
- Professor of Medicine
- Harvard Medical School
- Section Editors
- Michael J Aminoff, MD, DSc
Michael J Aminoff, MD, DSc
- Editor-in-Chief — Neurology
- Section Editor — Medical Neurology
- Professor of Neurology
- University of California, San Francisco School of Medicine
- Jonathan M Silver, MD
Jonathan M Silver, MD
- Section Editor — Mental and Medical Disorders
- Clinical Professor of Psychiatry
- New York University School of Medicine
Systemic lupus erythematosus (SLE) may involve the nervous system and present with a number of different neurologic and psychiatric syndromes (table 1). These neuropsychiatric manifestations may mimic symptoms due to intercurrent illness, medication use, and functional disturbances (table 2). The term lupus cerebritis refers to the neuropsychiatric manifestations of lupus that appear to have an organic rather than psychiatric basis, rather than a specific pathophysiologic mechanism.
Although it would be desirable to have diagnostic tests that establish a specific diagnosis of neuropsychiatric lupus, such tests do not exist. Thus, the approach to patients with neuropsychiatric symptoms consists of studies that establish the diagnosis of SLE, distinguish between organic and functional etiologies, and exclude symptoms not due to SLE. A typical workup for the patient with acutely altered behavior and mental status is outlined in Table 3 (table 3).
Diagnostic testing, and the interpretation of such testing, in patients suspected of having neuropsychiatric manifestations of SLE are reviewed here. Details of the clinical neurologic and psychiatric manifestations of SLE are presented separately. (See "Neurologic manifestations of systemic lupus erythematosus" and "Neuropsychiatric manifestations of systemic lupus erythematosus".)
Serologic tests are typically used to help establish the diagnosis of SLE. The antinuclear antibody (ANA) titer is positive in virtually all patients with this disorder. However, the presence of ANA is not a very specific finding, and many non-SLE patients have symptoms such as headache or fatigue with only a weakly positive ANA. Serum levels of anti-DNA and anti-Sm antibodies and low levels of complement are useful in this setting to corroborate the diagnosis of SLE. (See "Diagnosis and differential diagnosis of systemic lupus erythematosus in adults".)
In the patient with established SLE, an association between neuropsychiatric symptoms and specific antibodies has been demonstrated (by some) in a few circumstances [1-3]:To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Greenwood DL, Gitlits VM, Alderuccio F, et al. Autoantibodies in neuropsychiatric lupus. Autoimmunity 2002; 35:79.
- Senécal JL, Raymond Y. The pathogenesis of neuropsychiatric manifestations in systemic lupus erythematosus: a disease in search of autoantibodies, or autoantibodies in search of a disease? J Rheumatol 2004; 31:2093.
- Zandman-Goddard G, Chapman J, Shoenfeld Y. Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin Arthritis Rheum 2007; 36:297.
- West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 1995; 99:153.
- Asherson RA, Mercey D, Phillips G, et al. Recurrent stroke and multi-infarct dementia in systemic lupus erythematosus: association with antiphospholipid antibodies. Ann Rheum Dis 1987; 46:605.
- Boumpas DT, Austin HA 3rd, Fessler BJ, et al. Systemic lupus erythematosus: emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann Intern Med 1995; 122:940.
- Toubi E, Khamashta MA, Panarra A, Hughes GR. Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med 1995; 99:397.
- Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003; 30:985.
- Bonfa E, Golombek SJ, Kaufman LD, et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 1987; 317:265.
- Nojima Y, Minota S, Yamada A, et al. Correlation of antibodies to ribosomal P protein with psychosis in patients with systemic lupus erythematosus. Ann Rheum Dis 1992; 51:1053.
- van Dam A, Nossent H, de Jong J, et al. Diagnostic value of antibodies against ribosomal phosphoproteins. A cross sectional and longitudinal study. J Rheumatol 1991; 18:1026.
- Gerli R, Caponi L, Tincani A, et al. Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients. Rheumatology (Oxford) 2002; 41:1357.
- Karassa FB, Afeltra A, Ambrozic A, et al. Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis. Arthritis Rheum 2006; 54:312.
- West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am 1994; 20:129.
- Denburg SD, Behmann SA, Carbotte RM, Denburg JA. Lymphocyte antigens in neuropsychiatric systemic lupus erythematosus. Relationship of lymphocyte antibody specificities to clinical disease. Arthritis Rheum 1994; 37:369.
- Hanson VG, Horowitz M, Rosenbluth D, et al. Systemic lupus erythematosus patients with central nervous system involvement show autoantibodies to a 50-kD neuronal membrane protein. J Exp Med 1992; 176:565.
- Omdal R, Brokstad K, Waterloo K, et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol 2005; 12:392.
- Husebye ES, Sthoeger ZM, Dayan M, et al. Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann Rheum Dis 2005; 64:1210.
- Lapteva L, Nowak M, Yarboro CH, et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum 2006; 54:2505.
- Harrison MJ, Ravdin LD, Lockshin MD. Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum 2006; 54:2515.
- Hanly JG, Robichaud J, Fisk JD. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol 2006; 33:1553.
- Steup-Beekman G, Steens S, van Buchem M, Huizinga T. Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 2007; 16:329.
- Kimura A, Kanoh Y, Sakurai T, et al. Antibodies in patients with neuropsychiatric systemic lupus erythematosus. Neurology 2010; 74:1372.
- Galeazzi M, Annunziata P, Sebastiani GD, et al. Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. European Concerted Action on the Immunogenetics of SLE. J Rheumatol 2000; 27:135.
- Williams RC Jr, Sugiura K, Tan EM. Antibodies to microtubule-associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2004; 50:1239.
- Lefranc D, Launay D, Dubucquoi S, et al. Characterization of discriminant human brain antigenic targets in neuropsychiatric systemic lupus erythematosus using an immunoproteomic approach. Arthritis Rheum 2007; 56:3420.
- Kozora E, Ellison MC, West S. Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus. Arthritis Rheum 2004; 51:810.
- Carbotte RM, Denburg SD, Denburg JA. Prevalence of cognitive impairment in systemic lupus erythematosus. J Nerv Ment Dis 1986; 174:357.
- Rogers MP, Waterhouse E, Nagel JS, et al. I-123 iofetamine SPECT scan in systemic lupus erythematosus patients with cognitive and other minor neuropsychiatric symptoms: a pilot study. Lupus 1992; 1:215.
- Holliday SL, Navarrete MG, Hermosillo-Romo D, et al. Validating a computerized neuropsychological test battery for mixed ethnic lupus patients. Lupus 2003; 12:697.
- Hirohata S, Miyamoto T. Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum 1990; 33:644.
- McLean BN, Miller D, Thompson EJ. Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Behçet's disease involving the nervous system. J Neurol Neurosurg Psychiatry 1995; 58:548.
- Okamoto H, Katsumata Y, Nishimura K, Kamatani N. Interferon-inducible protein 10/CXCL10 is increased in the cerebrospinal fluid of patients with central nervous system lupus. Arthritis Rheum 2004; 50:3731.
- George-Chandy A, Trysberg E, Eriksson K. Raised intrathecal levels of APRIL and BAFF in patients with systemic lupus erythematosus: relationship to neuropsychiatric symptoms. Arthritis Res Ther 2008; 10:R97.
- Trysberg E, Nylen K, Rosengren LE, Tarkowski A. Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum 2003; 48:2881.
- Khoshbin S, Levine L, Milrod L, et al. Cortical evoked potential mapping in complex partial seizures (abstract). Neurology 1984; 34:S219.
- Ritchlin CT, Chabot RJ, Alper K, et al. Quantitative electroencephalography. A new approach to the diagnosis of cerebral dysfunction in systemic lupus erythematosus. Arthritis Rheum 1992; 35:1330.
- Sibbitt WL Jr, Sibbitt RR, Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1999; 42:2026.
- Jarek MJ, West SG, Baker MR, Rak KM. Magnetic resonance imaging in systemic lupus erythematosus patients without a history of neuropsychiatric lupus erythematosus. Arthritis Rheum 1994; 37:1609.
- Stimmler MM, Coletti PM, Quismorio FP Jr. Magnetic resonance imaging of the brain in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum 1993; 22:335.
- Scott TF, Hess D, Brillman J. Antiphospholipid antibody syndrome mimicking multiple sclerosis clinically and by magnetic resonance imaging. Arch Intern Med 1994; 154:917.
- Kozora E, West SG, Kotzin BL, et al. Magnetic resonance imaging abnormalities and cognitive deficits in systemic lupus erythematosus patients without overt central nervous system disease. Arthritis Rheum 1998; 41:41.
- Taccari E, Sili Scavalli A, Spadaro A, et al. Magnetic resonance imaging (MRI) of the brain in SLE: ECLAM and SLEDAI correlations. Clin Exp Rheumatol 1994; 12:23.
- Ishikawa O, Ohnishi K, Miyachi Y, Ishizaka H. Cerebral lesions in systemic lupus erythematosus detected by magnetic resonance imaging. Relationship to anticardiolipin antibody. J Rheumatol 1994; 21:87.
- Sibbitt WL Jr, Brooks WM, Haseler LJ, et al. Spin-spin relaxation of brain tissues in systemic lupus erythematosus. A method for increasing the sensitivity of magnetic resonance imaging for neuropsychiatric lupus. Arthritis Rheum 1995; 38:810.
- McCune WJ, MacGuire A, Aisen A, Gebarski S. Identification of brain lesions in neuropsychiatric systemic lupus erythematosus by magnetic resonance scanning. Arthritis Rheum 1988; 31:159.
- Jacobs L, Kinkel PR, Costello PB, et al. Central nervous system lupus erythematosus: the value of magnetic resonance imaging. J Rheumatol 1988; 15:601.
- Cauli A, Montaldo C, Peltz MT, et al. Abnormalities of magnetic resonance imaging of the central nervous system in patients with systemic lupus erythematosus correlate with disease severity. Clin Rheumatol 1994; 13:615.
- Appenzeller S, Rondina JM, Li LM, et al. Cerebral and corpus callosum atrophy in systemic lupus erythematosus. Arthritis Rheum 2005; 52:2783.
- Shapira-Lichter I, Vakil E, Litinsky I, et al. Learning and memory-related brain activity dynamics are altered in systemic lupus erythematosus: a functional magnetic resonance imaging study. Lupus 2013; 22:562.
- Zivadinov R, Shucard JL, Hussein S, et al. Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement. Lupus 2013; 22:675.
- Zimny A, Szmyrka-Kaczmarek M, Szewczyk P, et al. In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging. Lupus 2014; 23:10.
- Rubbert A, Marienhagen J, Pirner K, et al. Single-photon-emission computed tomography analysis of cerebral blood flow in the evaluation of central nervous system involvement in patients with systemic lupus erythematosus. Arthritis Rheum 1993; 36:1253.
- Driver CB, Wallace DJ, Lee JC, et al. Clinical validation of the watershed sign as a marker for neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2008; 59:332.
- Emmi L, Bramati M, De Cristofaro MT, et al. MRI and SPECT investigations of the CNS in SLE patients. Clin Exp Rheumatol 1993; 11:13.
- Nossent JC, Hovestadt A, Schönfeld DH, Swaak AJ. Single-photon-emission computed tomography of the brain in the evaluation of cerebral lupus. Arthritis Rheum 1991; 34:1397.
- Waterloo K, Omdal R, Sjöholm H, et al. Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow. J Neurol 2001; 248:595.
- Govoni M, Castellino G, Padovan M, et al. Recent advances and future perspective in neuroimaging in neuropsychiatric systemic lupus erythematosus. Lupus 2004; 13:149.
- Harris KG, Yuh WT. Intracranial vasculitis. Neuroimaging Clin N Am 1994; 4:773.
- Griffey RH, Brown MS, Bankhurst AD, et al. Depletion of high-energy phosphates in the central nervous system of patients with systemic lupus erythematosus, as determined by phosphorus-31 nuclear magnetic resonance spectroscopy. Arthritis Rheum 1990; 33:827.
- Sibbitt WL Jr, Haseler LJ, Griffey RH, et al. Analysis of cerebral structural changes in systemic lupus erythematosus by proton MR spectroscopy. AJNR Am J Neuroradiol 1994; 15:923.
- Axford JS, Howe FA, Heron C, Griffiths JR. Sensitivity of quantitative (1)H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus. Ann Rheum Dis 2001; 60:106.
- Pinching AJ, Travers RL, Hughes GR, et al. Oxygen-15 brain scanning for detection of cerebral involvement in systemic lupus erythematosus. Lancet 1978; 1:898.
- Weiner SM, Otte A, Schumacher M, et al. Diagnosis and monitoring of central nervous system involvement in systemic lupus erythematosus: value of F-18 fluorodeoxyglucose PET. Ann Rheum Dis 2000; 59:377.
- Steens SC, Admiraal-Behloul F, Bosma GP, et al. Selective gray matter damage in neuropsychiatric lupus. Arthritis Rheum 2004; 50:2877.
- Steens SC, Bosma GP, Steup-Beekman GM, et al. Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus. Arthritis Res Ther 2006; 8:R38.
- Kumral E, Evyapan D, Keser G, et al. Detection of microembolic signals in patients with neuropsychiatric lupus erythematosus. Eur Neurol 2002; 47:131.