Pathology of Neuropsychiatric Systemic Lupus Erythematosus

  • Shunsei Hirohata


Small vessel non-inflammatory vasculopathy, microvessel occlusion, multifocal microinfarcts, microhaemorrhages and cortical atrophy were most frequently observed pathological changes in NPSLE. Although vasculitis in the brain is rather uncommon, it might be detected in about 10% of patients with NPSLE. It has been revealed that activation of complement appears to play an important role in the development of microvasculopathy in NPSLE. Autoantibodies, including anti-phospholipid antibodies, causing direct injury of endothelial cells would be involved in the deposition of complements. Since anti-NMDA receptor NR2 antibodies have been demonstrated to react with endothelial cells to induce the production of inflammatory cytokines, it is possible that these antibodies might also result in the microvascular changes in the brain. Recent studies have shed light on the roles of microglia in relation with type I interferons in the pathogenesis of NPSLE.


Pathology Microvasculopathy Vasculitis Autoantibodies Magnetic resonance imaging 


  1. 1.
    Gibson T, Myers AR. Nervous system involvement in systemic lupus erythematosus. Ann Rheum Dis. 1975;35:398–406.CrossRefPubMedGoogle Scholar
  2. 2.
    Harris EN, Hughes GR. Cerebral disease in systemic lupus erythematosus. Springer Semin Immunopathol. 1985;8:251–66.CrossRefPubMedGoogle Scholar
  3. 3.
    Govoni M, et al. The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J Autoimmun. 2016;4:41–72.CrossRefGoogle Scholar
  4. 4.
    Arinuma Y, et al. Brain magnetic resonance imaging in patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Lupus Sci Med. 2014;1:e000050.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ellis SG, Verity MA. Central venous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955-1977. Semin Arthritis Rheum. 1979;8:212–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Johnson RT, Richardson EP. The neurological manifestations of systemic lupus erythematosus: a clinical-pathological study of 24 cases and review of the literature. Medicine. 1968;47:337–69.CrossRefPubMedGoogle Scholar
  7. 7.
    Hanly JG, et al. Brain pathology in systemic lupus erythematosus. J Rheumatol. 1992;19:732–41.PubMedGoogle Scholar
  8. 8.
    Brooks WM, et al. The histopathologic associates of neurometabolite abnormalities in fatal neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2010;62:2055–63.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Ellison D, et al. Intramural platelet deposition in cerebral vasculopathy of systemic lupus erythematosus. J Clin Pathol. 1993;46:37–40.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cohen D, et al. Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology. 2017;55:77–86.CrossRefGoogle Scholar
  11. 11.
    Sibbitt WL, et al. Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum. 2010;40:32–52.CrossRefPubMedGoogle Scholar
  12. 12.
    Sibbitt WL, et al. Fluid attenuated inversion recovery (FLAIR) imaging in neuropsychiatric systemic lupus erythematosus. J Rheumatol. 2003;30:1983–9.PubMedGoogle Scholar
  13. 13.
    Jeong HW, et al. Brain MRI in neuropsychiatric lupus: associations with the 1999 ACR case definitions. Rheumatol Int. 2015;35:861–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Sibbitt WL, et al. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 1999;42:2026–38.CrossRefPubMedGoogle Scholar
  15. 15.
    Emmer BJ, et al. Selective involvement of the amygdala in systemic lupus erythematosus. PLoS Med. 2006;3:e499.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7:327–40.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hoeftberger R, et al. Update on neurological paraneoplastic syndromes. Curr Opin Oncol. 2015;27:489–95.CrossRefGoogle Scholar
  18. 18.
    Kozora E, et al. Magnetic resonance imaging abnormalities and cognitive deficits in systemic lupus erythematosus patients without overt central nervous system disease. Arthritis Rheum. 1998;41:41–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Appenzeller S, et al. Cerebral and corpus callosum atrophy in systemic lupus erythematosus. Arthritis Rheum. 2005;52:2783–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Appenzeller S, et al. Hippocampal atrophy in systemic lupus erythematosus. Ann Rheum Dis. 2006;65:1585–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Boey ML, et al. Thrombosis in SLE: striking association with the presence of circulating "lupus anticoagulant". Br Med J. 1983;287:1021–3.CrossRefGoogle Scholar
  22. 22.
    Harris EN, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Harris EN, et al. Cerebral infarction in systemic lupus: association with anticardiolipin antibodies. Clin Exp Rheumatol. 1984;1:47–51.Google Scholar
  24. 24.
    Harris EN, et al. Cross-reactivity of antiphospholipid antibodies. J Clin Lab Immunol. 1985;16:1–6.PubMedGoogle Scholar
  25. 25.
    Carreras LO, Vermelyn JG. "Lupus" anticoagulant and thrombosis-possible role of 1inhibition of prostacyclin formation. Thromb Haemost. 1982;48:38–40.PubMedGoogle Scholar
  26. 26.
    Arinuma Y, et al. Histopathological analysis of cerebral hemorrhage in systemic lupus erythematosus complicated with antiphospholipid syndrome. Mod Rheumatol. 2011;21:509–13.CrossRefPubMedGoogle Scholar
  27. 27.
    Wallace DJ, Metzger AL. Systemic lupus erythematosus and the nervous system. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 4th ed. Philadelphia: Lea & Febiger; 1993. p. 370–85.Google Scholar
  28. 28.
    Jennekens FGI, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Pathogenetic mechanisms of clinical syndromes: a literature investigation. Rheumatology. 2002;41:619–30.CrossRefPubMedGoogle Scholar
  29. 29.
    Belmont HM, et al. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium. Arthritis Rheum. 1996;39:9–22.CrossRefPubMedGoogle Scholar
  30. 30.
    Cohen D, et al. Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J Pathol. 2011;225:502–11.CrossRefPubMedGoogle Scholar
  31. 31.
    Chua JS, et al. Complement factor C4d is a common denominator in thrombotic microangiopathy. J Am Soc Nephrol. 2015;26:2239–47.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Muscal E, Brey RL. Neurological manifestations of systemic lupus erythematosus in children and adults. Neurol Clin. 2010;28:61–73.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Salmon JE, et al. Complement activation as a mediator of antiphospholipid antibody inducedpregnancy loss and thrombosis. Ann Rheum Dis. 2002;61(Suppl 2):ii46–50.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87.CrossRefPubMedGoogle Scholar
  35. 35.
    Abe G, et al. Brain MRI in patients with acute confusional state of diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Mod Rheumatol. 2017;27:278–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Tono T, et al. Transverse myelitis extended to disseminated encephalitis in systemic lupus erythematosus: histological evidence for vasculitis. Mod Rheumatol. 2016;26:958–62.PubMedGoogle Scholar
  37. 37.
    Hirohata S, Hayakawa K. Enhanced interleukin-6 messenger RNA expression by neuronal cells in a patient with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 1999;42:2729–30.CrossRefPubMedGoogle Scholar
  38. 38.
    Abbott NJ, et al. The blood-brain barrier in systemic lupus erythematosus. Lupus. 2003;12:908–15.CrossRefPubMedGoogle Scholar
  39. 39.
    Hirohata S, et al. Blood-brain barrier damages and intrathecal synthesis of anti-N-methyl-D-aspartate receptor NR2 antibodies in diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Arthritis Res Ther. 2014;16:R77.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hirohata S, et al. Association of cerebrospinal fluid anti-Sm antibodies with acute confusional state in systemic lupus erythematosus. Arthritis Res Ther. 2014;16:450.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kent DL, et al. The clinical efficacy of magnetic resonance imaging in neuroimaging. Ann Intern Med. 1994;120:856–71.CrossRefPubMedGoogle Scholar
  42. 42.
    Brey RL. Antiphospholipid antibodies in young adults with stroke. J Thromb Thrombolysis. 2005;20:105–12.CrossRefPubMedGoogle Scholar
  43. 43.
    Hanly JG, et al. A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus. Arthritis Rheum. 1999;42:728–34.CrossRefPubMedGoogle Scholar
  44. 44.
    Mikdashi J, Handwerger B. Predictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology. 2004;43:1555–60.CrossRefPubMedGoogle Scholar
  45. 45.
    McLaurin EY, et al. Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology. 2005;64:297–303.CrossRefPubMedGoogle Scholar
  46. 46.
    Menon S, et al. A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus. Arthritis Rheum. 1999;42:735–41.CrossRefPubMedGoogle Scholar
  47. 47.
    Steens SC, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lapteva L, et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2505–14.CrossRefPubMedGoogle Scholar
  49. 49.
    Omdal R, et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol. 2005;12:392–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Arinuma Y, et al. Association of cerebrospinal fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2008;58:1130–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Lauvsnes MB, et al. Association of hippocampal atrophy with cerebrospinal fluid antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor in patients with systemic lupus erythematosus and patients with primary Sjøgren’s syndrome. Arthritis Rheumatol. 2014;66:3387–94.CrossRefPubMedGoogle Scholar
  52. 52.
    Yoshio T, et al. IgG anti-NR2 glutamate receptor autoantibodies from patients with systemic lupus erythematosus activate endothelial cells. Arthritis Rheum. 2013;65:457–63.CrossRefPubMedGoogle Scholar
  53. 53.
    ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599–608.CrossRefGoogle Scholar
  54. 54.
    Cervera R, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine. 2003;82:299–308.CrossRefPubMedGoogle Scholar
  55. 55.
    Toubi E, et al. Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med. 1995;99:397–401.CrossRefPubMedGoogle Scholar
  56. 56.
    Kimura M, et al. Reversible focal neurological deficits in systemic lupus erythematosus: report of 2 cases and review of the literature. J Neurol Sci. 2008;272:71–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Sanna G, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol. 2003;30:985–92.PubMedGoogle Scholar
  58. 58.
    Andrade RM, et al., LUMINA Study Group. Seizures in patients with systemic lupus erythematosus: data from LUMINA, a multiethnic cohort (LUMINA LIV). Ann Rheum Dis. 2008; 67:829–34.Google Scholar
  59. 59.
    Appenzeller S, et al. Epileptic seizures in systemic lupus erythematosus. Neurology. 2004;63:1808–12.CrossRefPubMedGoogle Scholar
  60. 60.
    Bluestein HG, et al. Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med. 1981;70:240–6.CrossRefPubMedGoogle Scholar
  61. 61.
    Birnbaum J, et al. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum. 2009;60:3378–87.CrossRefPubMedGoogle Scholar
  62. 62.
    Taniguchi M, et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res Mol Brain Res. 2000;78:131–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Oomatia A, et al. Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty-five-year study period. Arthritis Rheumatol. 2014;66:1000–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Bialas AR, et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature. 2017;546:539–43.PubMedGoogle Scholar
  65. 65.
    Wang J, et al. Microglia activation induced by serum of SLE patients. J Neuroimmunol. 2017;310:135–42.CrossRefPubMedGoogle Scholar
  66. 66.
    Shintaku M, Matsumoto R. Disseminated perivenous necrotizing encephalomyelitis in systemic lupus erythematosus: report of an autopsy case. Acta Neuropathol. 1998;95:313–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Mizutani T, et al. A case of demyelinating encephalomyelitis with some resemblance to collagen disease. J Neurol. 1977;217(1):43–52.CrossRefPubMedGoogle Scholar
  68. 68.
    Matsumoto R, et al. Systemic lupus erythematosus with multiple perivascular spongy changes in the cerebral deep structures, midbrain and cerebellar white matter: a case report. J Neurol Sci. 1997;145:147–53.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Shunsei Hirohata
    • 1
    • 2
  1. 1.Department of RheumatologyNobuhara HospitalTatsunoJapan
  2. 2.Department of Rheumatology & Infectious DiseasesKitasato University School of MedicineSagamiharaJapan

Personalised recommendations