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1 SLE and CNS Lupus Naoko Ohya, M.D. Department of Rheumatology, Yokohama Seibu Hospital, St. Marianna University School of Medicine NICHIDOKU-IHO Vol. 53 No (2008) Summary Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease with a broad range of clinical features, and entails neuropsychiatric complications associated with increased morbidity and mortality. Although a variety of diffuse and focal neuropsychiatric symptoms are seen in patients with SLE, it is difficult to differentiate CNS lupus from secondary CNS complications caused by nephritis, hypertension, infection, or medication. In particular, exclusion of steroid psychosis poses difficulty. Abnormal findings in EEG, images like MRI or SPECT, or cerebrospinal fluid (CSF) examination are not specific to CNS lupus. Neuroimaging techniques maximize usefulness of immunological examinations when both are combined. Early diagnosis and treatment assist in mitigating the mortality and morbidity associated with CNS lupus. systemic lupus erythematosus SLE CNS SLECNS ,000 SLE SLE SLE T B SLE 38 DNA Sm
2 4 SLE SS-A RNP the American Collage of Rheumatology ACR 1 SLE 1 SLE SLE PSL mg/Kg/ PSL mg/Kg/ CNS PSL mg/Kg/ 0.5 1g/ 3 SLE CY AZA CyA MMF SLE CNS SLE CNS SLE CNS neuropsychiatric SLE NPSLE SLE SLE
3 10 35 SLE SLE CNS SLE SLE SLE 1999 ACR SLE 19 2 CNS 4 CNS SLE 20 SLE 7 8 SLE SLE antiphospholipid syndrome APS APS APS SLE
4 SLE CNS SLE ACR CNS 80 CNS SLE PSL 40mg/ 85 PSL 40mg/ MRI CNS Hirohata CNS 14 SLE SLE ds-dna Sm SLE SLE DNA CNS SLE CNS Sm P Sm SLE SLE APS MRI MRI MRI 19 SLElupus anticoagulant LACanticardiolipin antibodies acl 2-GPI LAC LAC GPI 20 SLE
5 CNS CNS kDa SLE SLE 22 DNA NR2 NR2 CNS 23 SLE Q IgG index IL-6 IL-8 IFN IgG idex Hirohata 25 CNS CNS SLE IL-6 IL-6 3 CNS glial fibrillary acidic protein GFAP neurofilament triplet protein NFL NFL IL-6 IL-8 origoclonal immunoglobulins GFAP NFLMRI IFN- SLE SLE CNS 80 CNS SLE 60 CT MRI SPECT PET CT CT MRI SPECT MRI CT MRI CNS MRI MRI SLE CNS MRI CNS SLE 9 40 SLE SLE 26 SLE CNS 16 MRI 4 4 focal lesion 2 atrophy 4 focal lesion atrophy2 1 MRI focal lesion Atrophy 2 1
6 CYfocal lesion atrophy 4 3 diffuse 2 akinetic mutism astrocytosis focal lesion p < 0.05 SLE SPECT MRI SLE 2 cm focal lesion MRI SLE 1996 reversible posterior leukoencephalopathy syndrome RPLS Hinchey RPLS RPLS blood brain barrier BBB 28 MRI CNS
7 diffuse type CNS 29 SPECT Sibbit SPECT SPECT MRI SPECT SPECT Kodama 31 SLE20 SPECT 15 SPECT 9 4 SPECT subclinical PET positoron emission tomography SPECT CNS PET 100 MRI 50 MRI PET PET CNS 32 CNS CNS CNS 3 33 CNS PSL 60mg/ 1g/ 3 IgG index IL-6 SLE CY AZA AZA CY IVCY IVCY CNS Barile 36 CNS IVCY IVCY CY A B C D
8 ST CNS SPECT CNS 37 CD20 CNS SLE 38 DNA SLE mm/hr2,400/ L Hb 12.8/ dl PLT 6.2 / L ANA 2,560 CH50 < 10U/mL C3 14mg/dL C4 1mg/dLC1q > 20 g/ml IgG 3,368mg/dL IgA 207mg/dL IgM 303mg/dL ds-dna 640IU/mL RNP 2 Sm 2 SS-A MPO-ANCA LA acl PSL 30mg/ 50mg/ 81mg/dL IgG Index 0.3 MRI 2 FLAIR MCA DWIADC map MRA 3 MCA CNS PSL 60mg/ 3 2 MRI SLE CNS 34 DNA SLE PSL 15mg/ mm/hr 1,900/ L RBC 409 / L PLT 6.9 / L
9 FLAIR MCA DWI ADC map 1 MCA M2 1 M2
10 T2 FLAIR DWIADC map T1 T bil 0.7mg/dL AST 606IU/L ALT 520IU/L LDH 911IU/L ALP 183IU/L GTP 689IU/L M2 ANA 320 CH50 < 10U/mL C3 30mg/dL C4 1mg/dL C1q 5.6 g/ml IgG 2,460mg/dL IgA 566mg/dL IgM 136mg/dL ds- DNA 45.5IU/mL RNP Sm SS-A MPO-ANCA LAC acl 10/ mg/dL IgG Index 0.5 MRI 4 T2 FLAIR T1 DWIADC map CNS PSL 50mg/ 1mg/Kg 2 MRI AZA AZA 300mg PSL 10mg/ SLE MRI 80 CH5017.8U/mL C3 82mg/dL C4 12mg/dL IC Ciq 4.4 g/ml ds-dna 10.0IU/mL 9/3 100IgG Index 0.61 MRI 20mg/ 80 CH50 < 10U/mL C3 60mg/dL C4 5mg/dL IC Ciq 4.4 g/ml ds-dna 56.0IU/mL MRI 5 FLAIR T2 DWI ADC map SLE AZA SLE SLE AZA SLE
11 FLAIRDWI T2 ADC map MRI Raynaud DNA 169U/mL SLE C3 14 C4 3 CH acl LAC PSL 50mg/ 1 IgG IgG index 0.8 MRI CNS CY CY 2 3
12 acrocyanosis CY 1 SLE CNS CNS 1 Hochberg MC: Updating the American Collage of Rheumatology revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum. : 1725, Gladman DD, Urowitz MB: Prognosis, mortality, and morbidity in systemic lupus erythematosus. (In) Wallace DJ, Hahn BH (eds): Dubois Lupus Eryhthematosus, 6th ed. 1255, 2002, Lippincott Williams & Wilkins, Philadelphia 3 Appenzeller S, Cendes F, Costallat LT: Epileptic seizures in systemic lupus erythematosus: Neurology : , ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature: The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndrom. Arthritis Rheum. : , Wong KL, Woo EK, Yu YL, et al: Neurological manifestations of systemic lupus erythematosus: a prospective study. Q J Med : , Hanly JG, McCurdy G, Fougere L, et al: Neuropsychiatric events in systemic lupus erythematosus: attribution and clinical significance. J Rheumatol : , Futrell N, Millikan C: Frequency, etiology, and prevention of stroke in patients with systemic lupus erythematosus. Stroke: : , Mikdashi J, Handwerger B, Langenberg P, et al: Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus. Stroke. : , Kovacs B, Lafferty TL, Brent LH, et al: Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis: : , Mok CC, Lau CS, Chan EY, et al: Acute transverse myelopathy in systemic lupus erythematosus: clinical presentation, treatment, and outcome. J Rheumatol : , Carbotte RM, Denburg SD, Denburg JA, et al: Cognitive dysfunction in systemic lupus erythematosus is independent of active disease. J Rheumatol : , Denburg SD, Denburg JA, Carbotte RM et al: Cognitive deficits in systemic lupus erythematosus. Rheum Dis Clin North Am : , Hirohata S, Iwamoto S, Miyamoto T, et al: A patient with systemic lupus erythematosus presenting both central nervous system lupus and steroid induced psychosis. J Rheumatol : , Isshi K, Hirohata S: Association of anti-ribosomal P protein antibodies with neuropsychiatric system lupus erythematosus. Arthritis Rheum : , Isshi K, Hirohata S: Differential roles of the anti-ribosomal P antibody and antineuronal antibody in the pathologenesis of central nervous system involvement in systemic lupus erythematosus. Arthritis Rheum : , Herranz MT, Rivier G, Khamashta MA, et al : Association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus. Arthritis Rheum : , Appenzeller S, Cendes F, Costallat LT: Epileptic seizures in systemic lupus erythematosus. Neurology. : , Lampropoulos CE, Koutroumanidis M, Reynolds PP, et al: Electroencephalography in the assessment of neuropsychiatric manifestations in antiphospholipid syndrome and systemic lupus erythematosus. Arthritis Rheum : , Avcin T, Benseler SM, Tyrrell PN, et al: A followup study of antiphospholipid antibodies and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus. Arthritis Rheum : 206-
13 213, Bluestein HG, Williams GW, Steinberg AD: Cerebrospinal fluid antibodies to neuronal cells: association with neuropsychiatric manifestations of systemic lupus erythematosus. Am J Med : , 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 : , DeGiorgio LA, Konstantinov KN, Lee SC, et al: A subset of lupus anti-dna antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med: : , Katsumata Y, Harigai M, Kawaguchi Y, et al: Diagnostic reliability of cerebral spinal fluid tests for acute confusional state (delirium) in patients with systemic lupus erythematosus: interleukin 6 (IL-6), IL-8, interferonalpha, IgG index, and Q-albumin. J Rheumatol : , 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: : , Appenzeller S, Rondina JM, Li LM, et al: Cerebral and corpus callosum atrophy in systemic lupus erythematosus. Arthritis Rheum : , Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med : , Reversible posterior leukoencephalopathy syndrome (RPLS) Ishimori ML, Pressman BD, Wallace DJ, et al: Posterior reversible encephalopathy syndrome: another manifestation of CNS SLE? Lupus : , Sibbitt WL Jr, Sibbitt RR,Brooks WM: Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum : , Kodama K, Okada S, Hino T, et al: Single photon emission computed tomography in systemic lupus erythematosus with phychiatric symptoms. J Neurol Neurosurg Psychiatry : , 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 : , CNS Neuwelt CM, Lacks S, Kaye BR, et al: Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med : 32-41, Boumpas DT, Yamada H, Patronas NJ, et al: Pulse cyclophosphamide for severe neuropsychiatric lupus. Q J Med Dec : , Barile-Fabris L, Ariza-Andraca R, Olguín-Ortega L, et al: Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis: : , CNS Saito K, Nawata M, Nakayamada S, et al: Successful treatment with anti-cd20 monoclonal antibody (rituximab) of life-threatening refractory systemic lupus erythematosus with renal and central nervous system involvement. Lupus : , Tokunaga M, Saito K, Kawabata D, et al: Efficary of rituximab (anti-cd20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis : , 2007
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