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OUTLINE

CNS LUPUS H. Michael Belmont, M.D. Director, Lupus Clinic Bellevue Hospital Chief Medical Officer Hospital for Joint Diseases Associate Professor of Medicine New York University School of Medicine. OUTLINE. PATHOLOGY ETIOLOGY IMAGING and DIAGNOSTIC TESTING CLINICAL SYNDROMES TREATMENT.

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OUTLINE

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  1. CNS LUPUSH. Michael Belmont, M.D.Director, Lupus ClinicBellevue HospitalChief Medical OfficerHospital for Joint DiseasesAssociate Professor of MedicineNew York University School of Medicine

  2. OUTLINE • PATHOLOGY • ETIOLOGY • IMAGING and DIAGNOSTIC TESTING • CLINICAL SYNDROMES • TREATMENT

  3. RENAL versus CNS LUPUS RENAL CNS • PathologyWHO Classification Diverse NIH Activity & Chronicity IndexPoor correlation with clinical syndrome Poor correlation with prognosis • EtiologyIC deposition 5 distinct mechanisms • DiagnosticsDNA, C3, C4, U/A, 24-hr urine CSF, anti-ribosomal P albumin, renal biopsy Imaging (CT, MRI) • Clinical Nephrotic – proteinuria12 syndromes Nephritic – hematuria, HTN, renal insufficiency • Treatment Randomized controlled Empiric clinical trials Anecdotal Open label

  4. PATHOLOGY • No specific pathological findings (normal) • Microinfarction • Microthromboses • Immune complexes in the choroid plexus • Neutrophilic vasculitis • Reversible leukoencephalopathy • Adult cerebral distress syndrome ACDS (cerebral capillary leak) • Medium artery thrombosis • Microangiopathy with eosinophilic microthrombi

  5. Johnson and RichardsonMedicine 1968 (N= 24) • Microinfarcts 17 • Perivascular microglia 11 • Microhemorrhages 6 • Vascular Necrosis 5 • Fibrin thrombi 3 • Perivascular infiltrates 3 • Vasculitis 3* *”not prominent or generalized”

  6. Ellis and VeritySeminars in Arthritis and Rheum 1979 (N = 57) • VASCULOPATHY 37% (65%) • Vascular Hyalinization 31 • Perivascular inflammation 16 • Endothelial proliferation 12 • Thrombosis 4 • Vasculitis 4 • MICROINFARCTS 20 (38%) • CVA (large infarcts) 5 (9%) • HEMORRHAGE 24 (47%) • SAH 17 • Microhemorrhage 11 • Intracerebral 2 • INFECTION 16 (28%) • TRANSVERSE MYELOPATHY 1

  7. DevinskyAnnals of Neurology 1988 (N = 50) • Autopsies 1968-84 NYH n = 8260 • 50 Patients (SLE + autopsy) 74% (37) with clinical CNS lupus • CNS syndromes (n=37) • Psychoaffective 5 • Neurological disorders 15 • Both 17 • CNS Pathology 50% (25) • Embolic Brain Infarcts 10 • CNS Infection 8 • Cardiac embolic • Libman Sacks endocarditis 5 • Valvulitis 2 • LA thrombosis 2 • TTP 14 7(clinical), 7(pathological) • Acute CNS Vasculitis 0

  8. HanlyJournal of Rheumatology 1992 (N = 7) • Microinfarcts 5 • Healed vasculitis 1 • CMV Infection 1 • Meningeal lymphoma 1

  9. Pathologic and Clinical Spectrum of Vasculopathy in SLE PathologyPathogenesisClinical Phenomenon Capillaritis Immune complex deposition Glomerulonephritis, pulmonary alveolar Vasculitis Activation of complement, hemorrhage neutrophils, and endothelium Cutaneous purpura, polyarteritis nodosa-like Modeled by Arthus lesion systemic and cerebral vasculitis Leukothrombosis Intravascular activation of complement, Widespread vascular injury, hypoxia, acute neutrophils, and vascular endothelium cerebral dysfunction, SIRS Absence of local immune complex deposition Modeled by Shwartzman lesion Thrombosis Antibodies to anionic phospholipid-protein Arterial and venous thrombosis, fetal wastage, complexes interact with endothelial cells, thrombocytopenia, pulmonary hypertension, platelets, or coagulation factors CVA Modeled by APS Disseminated intravascular platelet TTP aggregation, antibodies to ADAMTS-13 Atherosclerosis Activated endothelium, increased MI, CVA endothelial cell adhesion molecules, increased tissue factor, decreased 27-hydroxylase

  10. IMMUNE MEDIATED MECHANISMS OF CNS LUPUS Inflammatory Focal or Diffuse Vasculitis Diffuse neutrophil mediated injury with leukoaggregation/leukothromboses Antibody mediated APS - Ab mediated thromboses TTP - Ab to vWF cleaving protease/ADAMTS Anti-neuronal antibody Cytokine neurotoxicity

  11. ETIOPATHOGENESIS of CNS LUPUS I. Vasculopathy Inflammatory Vasculitis (1) – immune complex deposition Shwartzman Phenomenon (2) -- neutrophil mediated injury Noninflammatory Thrombotic (3) – APS, TTP Arteriosclerosis II. Anti-neuronal antibody (4) anti-lymphocyte abs cross reacting with anti-neuronal anti-ribosomal P antibody anti-50kd neuronal filament antibody anti-DNA cross reacting with NMDA glutamate receptor III. Cytokine (5)

  12. Proposed Pathogenesis of CNS Lupus

  13. Evidence for Acute Cerebral Distress Syndrome (cerebral capillary leak) in SLE Increased C3a, C5a Increased neutrophil CD11b/CD18 (beta 2 integrin, CR3) Increased endothelial cell adhesion molecules Reversible hypoxemia (forme fruste of ARDS) Histologic evidence of leukoaggregates (CNS, mesentery) Reversible posterior leukoencephalopathy

  14. Neutrophil activation CR3 . . . ICAM-1 . . . . . . . . . . . . . . . . . . C5a IC . . . . . . . . . . . . . . . . Resting PMN . . . . . . . . . . . . . . . . . . . . . . . . . . . Resting EC Endothelial cell activation (priming) IL-1ß TNF C1q C5a C5b-9 aEC aPL . . . . . . E-selectin . Leukothrombosis . . . . . . . . . . . . . . . Vaso-occlusive plug . . . . . . . . . . . . . . . . . . . . . . . . . . .

  15. Endothelial Cell Adhesion Molecule Expressionin Active versus Inactive SLE *P <0.01 active vs. control **P <0.025 active vs. inactive * * ** Immunohistochemical score * T Belmont, Buyon, Giorno, Abramson: Arthritis Rheum, 1994

  16. Acute Reversible Hypoxemia in Systemic Lupus ErythematosusAnnals of Internal Medicine 1991; 114-941-947Steven B. Abramson, MD; Jeffrey Dobro, MD; Mark A. Eberle, MD; Marc Benton, MD; Joan Reibman, MD; Hadassah Epstein; David M. Rapoport, MD;H. Michael Belmont, MD; and Roberta M. Goldring, MD

  17. SLE flare with reversible hypoxemia

  18. MRI showing gray matter lesions the L posterior brain

  19. REVERSIBLE LEUKOENCEPHALOPATHY

  20. IMAGING AND DIAGNOSTIC STUDIES CT MRI SPECT PET ANGIOGRAPHY CSF studies EEG Neuropsychological testing Serological (autoantibodies)

  21. IMAGING • CT • MRI • SPECT • PET • MRA • CT angiogram • Conventional angiograms • CSF analyses • Cells • Protein • Oligoclonal bands • IgG/albumin index • Cytokines • EEG • Neuropsychological testing • Anti-neuronal antibodies (e.g. ribosomal-P, neurofilimant, NR2 NMDA glutamate receptor)

  22. Imaging • No pathognomonic finding • MRI and CT can both exclude brain absecess, intracerebral hemorrhage, gross cerebral edema and CVA • MRI superior to CT in detecting acute CNS injury including transverse myelitis, new infarct or disruption of the blood brain barrier • Normal MRI doesn’t exclude CNS lupus and punctate lesions, especially on T2 weighted images, not specific • MRA, angiography and CT angiogram typically incapably of resolution to demonstrate small vessel vasculopathy • SPECT and PET lack specificity and not reliable • EEG useful for identifying seizure, encephalopathy or brain death

  23. Diagnostic Testing • LP most useful to exclude infection, hemorrhage or confirm organic rather than functional process • NP testing most useful to distinguish functional from organic etiology of psychiatric syndromes • Anti-ribosomal P antibodies useful in patients with psychosis • Antiphospholipid antibodies useful in CVA, seizures and focal neurological defects

  24. CLINICAL ASPECTS THE AMERICAN COLLEGE OF RHEUMATOLOGY NOMENCLATURE AND CASE DEFINITIONS FOR NEUROPSYCHIATRIC LUPUS SYNDROMES Neuropsychiatric syndromes observed in systemic lupus erythematosus Central nervous system Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and benign intracranial hypertension) Movement disorder (chorea) Myelopathy Seizure disorders Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis ARTHRITIS & RHEUMATISM Vol. 42, No. 4, April 1999, pp 599-608 1999 American College of Rheumatology

  25. Prevalence of 12 NP Clinical Syndromes in CNS lupus (N=300) • Headache 24% • CVA 18% • Mood disorder 17% • Cognitive dysfunction 11% • Psychosis 8% • Seizure disorder 8% • Anxiety Disorder 7% • Aseptic meningitis 4% • Acute confusional state 4% • Transverse myelopathy 1% • Movement disorder 1% • Demyelinating syndrome 1% Sanna G, et al Journal of Rheumatology 2003:30;985-992

  26. Peripheral Nervous System • Acute inflammatory demyelinating polyradiculopathy (Guillain-Barre Syndrome) • Autonomic disorder • Mononeuropathy, single or multiplex • Myasthenia gravis • Cranial Neuropathy • Plexopathy • Polyneuropathy

  27. HEADACHE Tension Vascular/Migraine Common, Complex, Ocular, Vertebral- Basilar SLE immune mediated inflammatory mechanism (aseptic meningitis, pseudotumor cerebri, etc.)

  28. SEIZURE Diffuse cerebral injury Diffuse APS Diffuse vasculitis Diffuse leukoaggregation/ACDS/PMN mediated Anti-neuronal antibody Cytokines Focal Focal APS

  29. ACUTE CONFUSIONAL SYNDROME (DELIRIUM,OMS) Diffuse cerebral injury Diffuse APS Diffuse vasculitis Diffuse leukoaggregation/ACDS/PMN mediated Anti-neuronal antibody Cytokines

  30. CEREBRAL VASCULAR ACCIDENT Atherogenesis and thrombogenesis HTN, DM, cigarettes, cholesterol, sedentary, LDL, homocysteine Steroids Immune complex injury APS Larger vessel vasculitis (RARE)

  31. ASEPTIC MENINGITIS Viral NSAIDS - Ibuprofen SLE - Immune mediated inflammatory disorder (IMID) (e.g. meningeal vasculopathy)

  32. PSYCHIATRIC DISORDERS PSYCHOSES ORGANIC AFFECTIVE (MOOD) DISORDER ANXIETY DISORDER SLE Immune mediated inflammatory disorder (IMID)

  33. TRANSVERSE MYELITIS Spinal artery - APS - Vasculitis - Leukoaggregation/neutrophil mediated

  34. MOVEMENT DISORDERDEMYELINATING SYNDROMECOGNITIVE DYSFUNCTION

  35. TREATMENT Order of Operations SLE vs. Non-SLE mechanism - HTN (cerebral vasospasm) - Infectious viral, bacterial, TB, fungal, etc. - Toxic metabolic Drug, electrolyte, uremia, etc. - Functional

  36. SLE: DISTINGUISH INFLAMMATORY FROM THROMBOTIC THROMBOTIC - APS vs. TTP vs. atherogenesis - Anticoagulation - Plasmapheresis - Statins - Anti-platelet (e.g. aspirin, plavix) - CAPS Heparin, steroids, cyclophosphamide plasmapheresis, IVGG

  37. TREATMENTS I. SYMPTOMATIC Antianxiety drug Antipsychotic drug Antiepilepsy drug Antidepressive drug (TCA, SSRI, dual inhibitor) 2. IMMUNOMODULATORY Steroids Cyclophosphamide Other cytotoxics Plasmapheresis IVGG Bromocriptine Stem cell transplant 3. ANTICOAGULATION Heparin Coumadin LMWH Thrombolytic Plavix

  38. STEROIDS- CYCLOPHOSPHAMIDE- AZATHIOPRINE- MTX- MYCOPHENOLATE MOFETIL- PLASMAPHERESIS- IVGG- BROMOCRIPTINE- BMT/SCT with autologous peripheral blood stem cells or HLA-identical cells

  39. SUMMARY • DIVERSE ETIOLOGY and PATHOLOGY • DIVERSE CLINICAL SYNDROMES • EXCLUDE NON-SLE, NONIMMUNE MEDIATED PROCESS • DISTINGUISH INFLAMMATORY versus THROMBOTIC MECHANISMS • ANTICOAGULATION versus INFLAMMATORY/IMMUNOMODULATORY THERAPY

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