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CNS LUPUS H. Michael Belmont, M. D

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1 CNS LUPUS H. Michael Belmont, M. D
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

2 OUTLINE PATHOLOGY ETIOLOGY IMAGING and DIAGNOSTIC TESTING
CLINICAL SYNDROMES TREATMENT

3 RENAL versus CNS LUPUS Pathology WHO Classification Diverse
RENAL CNS Pathology WHO Classification Diverse NIH Activity & Chronicity Index Poor correlation with clinical syndrome Poor correlation with prognosis Etiology IC deposition distinct mechanisms Diagnostics DNA, C3, C4, U/A, 24-hr urine CSF, anti-ribosomal P albumin, renal biopsy Imaging (CT, MRI) Clinical Nephrotic – proteinuria 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 Richardson Medicine 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 Verity Seminars in Arthritis and Rheum 1979 (N = 57)
VASCULOPATHY 37% (65%) Vascular Hyalinization 31 Perivascular inflammation 16 Endothelial proliferation 12 Thrombosis 4 Vasculitis MICROINFARCTS (38%) CVA (large infarcts) (9%) HEMORRHAGE (47%) SAH 17 Microhemorrhage 11 Intracerebral 2 INFECTION (28%) TRANSVERSE MYELOPATHY 1

7 Devinsky Annals of Neurology 1988 (N = 50)
Autopsies 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 Cardiac embolic Libman Sacks endocarditis 5 Valvulitis LA thrombosis TTP (clinical), 7(pathological) Acute CNS Vasculitis 0

8 Hanly Journal 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
Pathology Pathogenesis Clinical 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 Endothelial cell activation (priming)
Leukothrombosis Resting EC . ICAM-1 CR3 C5a IC Resting PMN IL-1ß TNF C1q C5b-9 aEC aPL E-selectin Vaso-occlusive plug

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18 Endothelial Cell Adhesion Molecule Expression in 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

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20 Acute Reversible Hypoxemia in Systemic Lupus Erythematosus Annals of Internal Medicine 1991; Steven 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

21 SLE flare with reversible hypoxemia

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23 MRI showing gray matter lesions the L posterior brain

24 REVERSIBLE LEUKOENCEPHALOPATHY

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

26 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)

27 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

28 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

29 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 1999 American College of Rheumatology

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

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

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

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

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

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

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

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

39 TRANSVERSE MYELITIS Spinal artery - APS - Vasculitis
- Leukoaggregation/neutrophil mediated

40 MOVEMENT DISORDER DEMYELINATING SYNDROME COGNITIVE DYSFUNCTION

41 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

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

43 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

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

45 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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