Central nervous system involvement in systemic lupus erythematosus: cerebral imaging and serological profile in patients with and without overt neuropsychiatric manifestations

Abstract

The aim of this study was to evaluate morphological and functional abnormalities by cerebral imaging in a series of systemic lupus erythematosus (SLE) patients with and without overt central nervous system (CNS) manifestations, and to detect possible relationships with clinical parameters and a large panel of autoantibodies, including those reactive against neurotypic and gliotypic antigens. 68 patients with SLE were investigated in a cross-sectional study which included clinical evaluation of symptoms, cerebral magnetic resonance imaging (MRI) and brain single photon emission tomography (SPECT) analysis, electroencephalography (EEG), and serological tests for antibodies directed against nuclear, cytoplasmic neuronal and glial cell-related antigens.

The results of this study showed: (1) a significant positive association of (a) anti-glial fibrillary acidic protein (GFAP) serum antibodies with neuropsychiatric (NP) manifestations and (b) antiserin proteinase 3 (anti-PR3/c-ANCA) serum antibodies with pathological cerebral SPECT; (2) the presence of significantly higher values of (a) SLICC organ damage index in patients with abnormal MRI and (b) SLAM activity index in patients with abnormal SPECT; and (3) the association of (a) abnormal MRI with nonactive NP manifestations and (b) combined abnormality of brain SPECT and MRI with the occurrence of overall overt NP manifestations and with those of the organic/major type.

Neuropsychiatric manifestations, namely those of the organic/major type, appeared to be significantly associated to the presence of a serum antibody against GFAP, a gliotypic antigen. There was also evidence of an association between SPECT abnormality and the presence of anti-PR3 (c-ANCA). Furthermore, brain imaging by MRI and SPECT applied to SLE patients appears to express CNS involvement significantly related to specific categories of NP manifestations. The abnormalities detected by the two tests seem to be preferentially associated with different activity phases of the NP disorder or of the lupus disease.

Keywords

systemic lupus erythematosus central nervous system autoantibodies MRI SPECT

Get full access to this article

View all access options for this article.

References

Kassan SS , Lockshin MD . Central nervous system lupus erythematosus: the need for classification . Arthritis Rheum 1979; 22: 1382-1385 .

Bruyn GA . Controversies in lupus: nervous system involvement . Ann Rheum Dis 1995; 54: 159-167 .

Jacobs L , Kinkel PR , Costello PB et al. Central nervous system lupus erythematosus: the value of magnetic resonance imaging . J Rheumatol 1988; 15: 601-606 .

Sibbitt WLJ , Sibbitt RR , Griffey RH et al. Magnetic resonance and computed tomographic imaging in the evaluation of acute neuropsychiatric disease in systemic lupus erythematosus . Ann Rheum Dis 1989; 48: 1014-1022 .

Bell CL , Partington C , Robbins M et al. Magnetic resonance imaging of central nervous system lesions in patients with lupus erythematosus. Correlation with clinical remission and antineurofilament and anticardiolipin antibody titers . Arthritis Rheum 1991; 34: 432-441 .

Stimmler MM , Coletti PM , Quismorio FPJ . Magnetic resonance imaging of the brain in neuropsychiatric systemic lupus erythematosus . Semin Arthritis Rheum 1993; 22: 335-349 .

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: 615-618 .

Jarek MJ , West SG , Baker MR , Rak KM . Magnetic resonance imaging in systemic lupus erythematosus patients without a history of neuropyschiatric lupus erythematosus . Arthritis Rheum 1994; 37: 1609-1613 .

Ishikawa O , Ohnishi K , Miyachi Y , Ishizaka H . Cerebral lesions in systemic lupus erithematosus detected by magnetic resonance imaging. Relationship to anticardiolipin antibody . J Rheumatol 1994; 21: 87-90 .

10.

Gonzalez-Crespo MR , Blanco FJ , Ramos A et al. Magnetic resonance imaging of the brain in systemic lupus erythematosus . Br J Rheumatol 1995; 34: 1055-1060 .

11.

Kozora E , Thompson LL , West SG , Kotzin BL . Analysis of cognitive and psychological deficits in systemic lupus erythematosus patients without overt central nervous system disease . Arthritis Rheum 1996; 39: 2035-2045 .

12.

Nossent JC , Hovestadt A , Schonfeld DH , Swaak AJ . Single-photonemission computed tomography of the brain in the evaluation of cerebral lupus . Arthritis Rheum 1991; 34: 1397-1403 .

13.

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: 1253-1262 .

14.

Lin WY , Wang SJ , Yen TC , Lan JL . Technetium-99m-HMPAO brain SPECT in systemic lupus erythematosus with CNS involvement . J Nucl Med 1997; 38: 1112-1115 .

15.

Sabbadini MG , Manfredi AA , Bozzolo E et al. Central nervous system involvement in systemic lupus erythematosus patients without overt neuropsychiatric manifestations . Lupus 1999; 8: 11-19 .

16.

Nomura K , Yamano S , Ikeda Y et al. Asymptomatic cerebrovascular lesions detected by magnetic resonance imaging in patients with systemic lupus erythematosus lacking a history of neuropsychiatric events . Intern Med 1999; 38: 785-795 .

17.

Reiff A , Miller J , Shaham B et al. Childhood central nervous system lupus; longitudinal assessment using single photon emission computed tomography . J Rheumatol 1997; 24: 2461-2465 .

18.

Russo R , Gilday D , Laxer RM et al. Single photon emission computed tomography scanning in childhood systemic lupus erythematosus . J Rheumatol 1998; 25: 576-582 .

19.

Falcini F , De Cristofaro MTR , Ermini M et al. Regional cerebral blood flow in juvenile systemic lupus erythematosus: a prospective SPECT study . J Rheumatol 1998; 25: 583-638 .

20.

Ellis SG , Verity MA . Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955-1977 . Semin Arthritis Rheum 1979; 8: 212-221 .

21.

Harbeck RJ , Hoffman AA , Hoffman SA , Shucard DW . Cerebrospinal fluid and the choroid plexus during acute immune complex disease . Clin Immunol Immunopathol 1979; 13: 413-425 .

22.

Kurki P , Helve T , Dahl D , Virtanen I . Neurofilament antibodies in systemic lupus erythematosus . J Rheumatol 1986; 13: 69-73 .

23.

Denburg SD , Carbotte RM , Long AA , Denburg JA . Neuropsychological correlates of serum lymphocytotoxic antibodies in systemic lupus erythematosus . Brain Behav Immun 1988; 2: 222-234 .

24.

Alcocer-Varela J , Aleman-Hoey D , Alarcon-Segovia D . Interleukin-1 and interleukin-6 activities are increased in the cerebrospinal fluid of patients with CNS lupus erythematosus and correlate with local late T-cell activation markers . Lupus 1992; 1: 111-117 .

25.

Asherson RA , Khamashta MA , Gil A et al. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus like disease, and the primary antiphospholipid syndrome . Am J Med 1989; 86: 391-399 .

26.

Fields RA , Sibbitt WL , Toubbeh H , Bankhurst AD . Neuropsychiatric lupus erythematosus, cerebral infarctions, and anticardiolipin antibodies . Ann Rheum Dis 1990; 49: 114-117 .

27.

Denburg JA , Denburg SD . Nervous system lupus: pathogenesis and rationale for therapy . Scand J Rheumatol 1995; 12: 263-273 .

28.

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: 369-375 .

29.

Hanly JG , Rajaraman S , Behmann S , Denburg JA . A novel neuronal antigen identified by sera from patients with systemic lupus erythematosus . Arthritis Rheum 1988; 31: 1492-1499 .

30.

Moore P , Vo T , Carlock L . Identification and cloning of a brain autoantigen in neuro-behavioral SLE . J Neuroimmunol 1998; 82: 116-125 .

31.

Schneebaum AB , Singleton JD , West SG et al. Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus . Am J Med 1991; 90: 54-62 .

32.

Nojima Y , Minota S , Yamada A et al. Correlation of autoantibodies to ribosomal P protein with psychosis in patients with systemic lupus erythematosus . Ann Rheum Dis 1992; 51: 1053-1055 .

33.

Teh LS , Hay EM , Amos N et al. Anti-P antibodies are associated with psychiatric and focal cerebral disorders in patients with systemic lupus erythematosus . Br J Rheumatol 1993; 32: 287-290 .

34.

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: 153-163 .

35.

Arnett FC , Reveille JD , Moutsopoulos HM et al. Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations . Arthritis Rheum 1996; 39: 1833-1839 .

36.

Watanabe T , Sato T , Uchiumi T , Arakawa M . Neuropsychiatric manifestations in patients with systemic lupus erythematosus: diagnostic and predictive value of longitudinal examination of antiribosomal P antibody . Lupus 1996; 5: 178-183 .

37.

Stafford HA , Chen AE , Anderson CJ et al. Anti-ribosomal and ‘Ppeptide’-specific autoantibodies bind to T lymphocytes . Clin Exp Immunol 1997; 109: 12-19 .

38.

How A , Dent PB , Liao SK , Denburg JA . Antineuronal antibodies in neuropsychiatric systemic lupus erythematosus . Arthritis Rheum 1985; 28: 789-795 .

39.

Bluestein HG , Woods VLJ . Antineuronal antibodies in systemic lupus erythematosus . Arthritis Rheum 1982; 25: 773-778 .

40.

Williams GW , Bluestein HG , Steinberg AD . Brain-reactive lymphocytotoxic antibody in the cerebrospinal fluid of patients with systemic lupus erythematosus: correlation with central nervous system involvement . Clin Immunol Immunopathol 1981; 18: 126-132 .

41.

Long AA , Denburg SD , Carbotte RM et al. Serum lymphocytotoxic antibodies and neurocognitive function in systemic lupus erythematosus . Ann Rheum Dis 1990; 49: 249-253 .

42.

Robbins ML , Kornguth SE , Bell CL et al. Antineurofilament antibody evaluation in neuropsychiatric systemic lupus erythematosus. Combination with anticardiolipin antibody assay and magnetic resonance imaging . Arthritis Rheum 1988; 31: 623-631 .

43.

Cullum N , Coleman J , Casson I , McLean W . Antibodies to tubulin and microtubule-associated proteins. A study in diabetes mellitus, systemic lupus erythematosus and rheumatoid arthritis . Mol Chem Neuropathol 1991; 15: 159-172 .

44.

Manco-Johnson M , Nuss R . Lupus anticoagulant in children with thrombosis . Am J Hematol 1995; 48: 240-243 .

45.

Hess DC . Cerebral lupus vasculopathy. Mechanisms and clinical relevance . Ann NY Acad Sci 1997; 823: 154-168 .

46.

Tan EM , Cohen AS , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1272 .

47.

Liang M , Socher S , Larson M , Schur P . Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus . Arthritis Rheum 1989; 32: 1107-1118 .

48.

Gladman D , Ginzler E , Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus . Arthritis Rheum 1996; 39: 363-369 .

49.

Folstein MF , Folstein SF , McHugh PR . ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res 1975; 12: 189-198 .

50.

Schur PH . Clinical features of SLE In: Kelley WN , Harris ED , Ruddy S , Sledge CB , (eds). Textbook of Rheumatology, 4th edn, vol. 2. Saunders: Philadelphia 1993, pp 1017-1042.

51.

Denburg JA , Carbotte RM , Denburg SD . Neuronal antibodies and cognitive function in systemic lupus erythematosus . Neurology 1987; 37: 464-467 .

52.

Carbotte RM , Denburg SD , Denburg JA . Prevalence of cognitive impairment in systemic lupus erythematosus . J Nerv Ment Dis 1986; 174: 357-364 .

53.

Terryberry J , Sutjita M , Shoenfeld Y et al. Myelin and microbespecific antibodies in Guillain-Barreé syndrome . J Clin Lab Anal 1995; 9: 308-319 .

54.

Terryberry J , Thor G , Peter J . Autoantibodies in neurodegeneration: frequencies and intrathecal analysis . Neurobiol Aging 1998; 19: 205-216 .

55.

Colamussi P , Giganti M , Cittanti C et al. Brain single-photon emission tomography with 99mTc-HMPAO in neuropsychiatric systemic lupus erythematosus: relations with EEG and MRI findings and clinical manifestations . Eur J Nucl Med 1995; 22: 17-24 .

56.

Nease JR , Owens D , Sox JH . Threshold analysis using diagnostic tests with multiple results . Med Decis Making 1989; 9: 91-103 .

57.

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: 159-165 .

58.

Chinn RJ , Wilkinson ID , Hall-Craggs MA et al. Magnetic resonance imaging of the brain and cerebral proton spectroscopy in patients with systemic lupus erythematosus . Arthritis Rheum 1997; 40: 36-46 .

59.

Emmi L , Bramati M , De Cristofaro MT et al. MRI and SPECT investigations of the CNS in SLE patients . Clin Exp Rheumatol 1993; 11: 13-20 .

60.

Brooks WM , Sabet A , Sibbitt WLJ et al. Neurochemistry of brain lesions determined by spectroscopy imaging in systemic lupus erythematosus . J Rheumatol 1997; 24: 2323-2329 .

61.

Colamussi P , Trotta F , Ricci R et al. Brain perfusion SPET and proton magnetic resonance spectroscopy in the evaluation of two systemic lupus erythematosus patients with mild neuropsychiatric manifestations . Nucl Med Commun 1997; 18: 269-273 .

62.

Villareal G , Drenkard C , Villa A et al. Prevalence of 13 autoantibodies and of 16/6 and related pathogenic idiotypes in 465 patients with systemic lupus erythematosus and their relationship with disease activity . Lupus 1997; 6: 425-435 .

63.

Hentati B , Ternynck T , Avrameas S , Payelle-Brogard B. Comparison of natural autoantibodies to autoantibodies arising during lupus in (NZB6 NZW) F1 mice . J Autoimmun 1991; 4: 341-356 .

64.

Levy-Soussan P , Berneman A , Poirier M et al. Differences in the natural autoantibody patterns of patients with schizophrenia and normal individuals . J Psychiatry Neurosci 1996; 21: 89-95 .

65.

Dighiero G , Lymberi P , Monot C , Abuaf N . Sera with high levels of anti-smooth muscle and anti-mitochondrial antibodies frequently bind to cytoskeleton proteins . Clin Exp Immunol 1990; 82: 52-56 .

66.

Adyel F , Hentati B , Boulila A et al. Characterization of autoantibody activities in sera anti-DNA antibody and circulating immune complexes from 12 systemic lupus erythematosus patients . J Clin Lab Anal 1996; 10: 451-457 .

67.

Gilbert D , Brard F , Margaritte C et al. An idiotype D23-bearing polyspecific murine anti-DNA monoclonal antibody forms glomerular immune deposits. Pathogenic role of natural autoantibodies? Mol Immunol 1995; 32: 477-486 .

68.

Jozwiak W , Koscielak J . Lactosylsphingosine-reactive antibody and CEA in patients with colorectal cancer . Eur J Cancer Clin Oncol 1982; 18: 617-621 .

69.

Martinez X , Tintore M , Montalban J et al. Antibodies against gangliosides in patients with SLE and neurological manifestations . Lupus 1992; 1: 299-302 .

70.

Sindern E , Stark E , Haas J , Steck AJ . Serum antibodies to GMl and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy . Acta Neurol Scand 1991; 83: 399-402 .

71.

Kaise S , Yasuda T , Kasukawa R et al. Antiglycolipid antibodies in normal and pathologic human sera and synovial fluids . Vox Sang 1985; 49: 292-300 .

72.

Chen Y , Wu F , Hou L et al. Antiganglioside antibodies in cerebro spinal fluid of children with neuropsychiatric lupus erythematosus . Chin Med J 1997; 110: 594-597 .

73.

Compston D , Scolding N . Immune-mediated oligodendrocyte injury . Ann NY Acad Sci 1991; 633: 196-204 .

74.

Sun K , Liu W , Tsai C et al. Inhibition of astrocyte proliferation and binding to brain tissue of anticardiolipin antibodies purified from lupus serum . Ann Rheum Dis 1992; 51: 707-712 .

75.

Uvestad E , Williams K , Matre R et al. Fc receptors for IgG on cultured human microglia mediated cytotoxicity and phagocytosis of antibodycoated targets . J Neuropathol Exp Neurol 1994; 53: 27-36 .

76.

McLean B , Miller D , Thompson E . Oligoclonal banding of IgG in CSF blood-brain barrier function and MRI findings in patients with sarcoidosis systemic lupus, erythematosus and Bechet's disease involving the nervous system . J Neurol Neurosurg Psychiatry 1995; 58: 548-554 .

77.

Ishida K , Kaneko K , Kubota T et al. Identification and characterization of an anti-glial acidic fibrillary protein antibody with a uniquespecificity in a demented patient with an autoimmune disorder . J Neurol Sci 1997; 151: 41-48 .

78.

Singh V , Warren R , Averett R , Ghaziuddin M . Circulating autoantibodies to neuronal and glial filament proteins in autism . Pediatr Neurol 1997; 17: 88-90 .