CNS LUPUSCNS LUPUS

H. Michael Belmont, M.D.H. Michael Belmont, M.D.Director, Lupus ClinicDirector, Lupus Clinic

Bellevue HospitalBellevue HospitalChief Medical OfficerChief Medical Officer

Hospital for Joint DiseasesHospital for Joint DiseasesAssociate Professor of MedicineAssociate Professor of Medicine

New York University School of MedicineNew York University School of Medicine

OUTLINEOUTLINE

PATHOLOGYPATHOLOGY

ETIOLOGYETIOLOGY

IMAGING and DIAGNOSTIC TESTINGIMAGING and DIAGNOSTIC TESTING

CLINICAL SYNDROMESCLINICAL SYNDROMES

TREATMENTTREATMENT

RENAL versus CNS LUPUSRENAL versus CNS LUPUS

RENALRENAL CNS CNS

PathologyPathology WHO ClassificationWHO Classification DiverseDiverse NIH Activity & Chronicity IndexNIH Activity & Chronicity Index Poor correlation Poor correlation

with with clinical clinical syndromesyndrome

Poor correlation Poor correlation with with prognosis prognosis

EtiologyEtiology IC depositionIC deposition 5 distinct 5 distinct mechanismsmechanisms

DiagnosticsDiagnostics DNA, C3, C4, U/A, 24-hr urine CSF, anti-ribosomal P DNA, C3, C4, U/A, 24-hr urine CSF, anti-ribosomal P albumin, renal biopsy albumin, renal biopsy Imaging (CT, MRI)Imaging (CT, MRI)

Clinical Clinical Nephrotic – proteinuriaNephrotic – proteinuria 12 syndromes12 syndromes Nephritic – hematuria, HTN,Nephritic – hematuria, HTN, renal insufficiencyrenal insufficiency

Treatment Treatment Randomized controlled Randomized controlled EmpiricEmpiric clinical trials clinical trials AnecdotalAnecdotal

Open labelOpen label

PATHOLOGYPATHOLOGY

No specific pathological findings (normal)No specific pathological findings (normal)MicroinfarctionMicroinfarctionMicrothrombosesMicrothrombosesImmune complexes in the choroid plexusImmune complexes in the choroid plexusNeutrophilic vasculitisNeutrophilic vasculitisReversible leukoencephalopathyReversible leukoencephalopathyAdult cerebral distress syndrome ACDS Adult cerebral distress syndrome ACDS (cerebral capillary leak)(cerebral capillary leak)Medium artery thrombosisMedium artery thrombosisMicroangiopathy with eosinophilic microthrombiMicroangiopathy with eosinophilic microthrombi

Johnson and RichardsonJohnson and Richardson Medicine 1968 (N= 24)Medicine 1968 (N= 24)

Microinfarcts Microinfarcts 1717Perivascular microglia Perivascular microglia 1111MicrohemorrhagesMicrohemorrhages 66Vascular NecrosisVascular Necrosis 55Fibrin thrombiFibrin thrombi 33Perivascular infiltratesPerivascular infiltrates 33VasculitisVasculitis 3*3*

*”not prominent or generalized” *”not prominent or generalized”

Ellis and VerityEllis and VeritySeminars in Arthritis and Rheum 1979 (N = 57)Seminars in Arthritis and Rheum 1979 (N = 57)

VASCULOPATHYVASCULOPATHY 3737% (65%)% (65%)– Vascular HyalinizationVascular Hyalinization 3131– Perivascular inflammationPerivascular inflammation 1616– Endothelial proliferationEndothelial proliferation 1212– ThrombosisThrombosis 4 4– VasculitisVasculitis 4 4

MICROINFARCTSMICROINFARCTS 20 (38%)20 (38%)CVA (large infarcts)CVA (large infarcts) 5 (9%) 5 (9%)HEMORRHAGEHEMORRHAGE 24 (47%)24 (47%)– SAHSAH 1717– MicrohemorrhageMicrohemorrhage 1111– IntracerebralIntracerebral 2 2

INFECTIONINFECTION 16 (28%)16 (28%)TRANSVERSE MYELOPATHYTRANSVERSE MYELOPATHY 1 1

DevinskyDevinskyAnnals of Neurology 1988 (N = 50)Annals of Neurology 1988 (N = 50)

Autopsies 1968-84 NYHAutopsies 1968-84 NYH n = 8260n = 826050 Patients (SLE + autopsy)50 Patients (SLE + autopsy) 74% (37)74% (37) with clinical CNS lupus with clinical CNS lupus

CNS syndromes (n=37)CNS syndromes (n=37)– PsychoaffectivePsychoaffective 5 5– Neurological disordersNeurological disorders 1515– BothBoth 1717

CNS PathologyCNS Pathology 50% (25)50% (25)Embolic Brain InfarctsEmbolic Brain Infarcts 1010CNS InfectionCNS Infection 88Cardiac embolicCardiac embolic– Libman Sacks endocarditisLibman Sacks endocarditis 5 5– ValvulitisValvulitis 2 2– LA thrombosisLA thrombosis 2 2

TTPTTP 14 14 7(clinical),7(clinical), 7 7(pathological)(pathological)

Acute CNS VasculitisAcute CNS Vasculitis 00

HanlyHanlyJournal of Rheumatology 1992 (N = 7)Journal of Rheumatology 1992 (N = 7)

MicroinfarctsMicroinfarcts 55

Healed vasculitisHealed vasculitis 11

CMV InfectionCMV Infection 11

Meningeal lymphomaMeningeal lymphoma 11

Pathologic and Clinical Spectrum of Vasculopathy Pathologic and Clinical Spectrum of Vasculopathy in SLEin SLE

PathologyPathology PathogenesisPathogenesis Clinical PhenomenonClinical Phenomenon

CapillaritisCapillaritis Immune complex depositionImmune complex deposition Glomerulonephritis, pulmonary alveolarGlomerulonephritis, pulmonary alveolarVasculitisVasculitis Activation of complement,Activation of complement, hemorrhagehemorrhage

neutrophils, and endothelium neutrophils, and endothelium Cutaneous purpura, polyarteritis nodosa-Cutaneous purpura, polyarteritis nodosa-like like

Modeled by Arthus lesionModeled by Arthus lesion systemic and systemic and cerebral vasculitiscerebral vasculitis

Leukothrombosis Leukothrombosis Intravascular activation of complement, Widespread vascular injury, hypoxia, Intravascular activation of complement, Widespread vascular injury, hypoxia, acuteacute neutrophils, and vascular endothelium neutrophils, and vascular endothelium cerebral dysfunctioncerebral dysfunction, SIRS, SIRS Absence of local immune complexAbsence of local immune complex depositiondeposition Modeled by Shwartzman lesionModeled by Shwartzman lesion

ThrombosisThrombosis Antibodies to anionic phospholipid-protein Arterial and venous thrombosis, fetal wastage,Antibodies to anionic phospholipid-protein Arterial and venous thrombosis, fetal wastage,complexes interact with endothelial cells, thrombocytopenia, pulmonary complexes interact with endothelial cells, thrombocytopenia, pulmonary

hypertension, hypertension, platelets, or coagulation factorsplatelets, or coagulation factors CVACVA Modeled by APSModeled by APS Disseminated intravascular platelet Disseminated intravascular platelet TTPTTP aggregation, antibodies to ADAMTS-13aggregation, antibodies to ADAMTS-13

Atherosclerosis Atherosclerosis Activated endothelium, increasedActivated endothelium, increased MI, CVAMI, CVA endothelial cell adhesion molecules,endothelial cell adhesion molecules,

increased tissue factor, decreased increased tissue factor, decreased 27-hydroxylase27-hydroxylase

IMMUNE MEDIATED MECHANISMS OF IMMUNE MEDIATED MECHANISMS OF CNS LUPUSCNS LUPUS

InflammatoryInflammatoryFocal or Diffuse VasculitisFocal or Diffuse VasculitisDiffuse neutrophil mediated injury with Diffuse neutrophil mediated injury with

leukoaggregation/leukothrombosesleukoaggregation/leukothromboses

Antibody mediatedAntibody mediatedAPS - Ab mediated thrombosesAPS - Ab mediated thrombosesTTP - Ab to vWF cleaving protease/ADAMTSTTP - Ab to vWF cleaving protease/ADAMTSAnti-neuronal antibodyAnti-neuronal antibody

Cytokine neurotoxicityCytokine neurotoxicity

ETIOPATHOGENESIS of CNS LUPUSETIOPATHOGENESIS of CNS LUPUS

I. VasculopathyI. Vasculopathy InflammatoryInflammatory

Vasculitis Vasculitis (1)(1) – immune complex deposition – immune complex depositionShwartzman Phenomenon Shwartzman Phenomenon (2)(2) -- neutrophil mediated -- neutrophil mediated

injuryinjury NoninflammatoryNoninflammatory

Thrombotic Thrombotic (3)(3) – APS, TTP – APS, TTPArteriosclerosis Arteriosclerosis

II.II. Anti-neuronal antibody Anti-neuronal antibody (4)(4)anti-lymphocyte abs cross reacting with anti-neuronal anti-lymphocyte abs cross reacting with anti-neuronal anti-ribosomal P antibodyanti-ribosomal P antibodyanti-50kd neuronal filament antibodyanti-50kd neuronal filament antibodyanti-DNA cross reacting with NMDA glutamate receptoranti-DNA cross reacting with NMDA glutamate receptor

III.III. Cytokine Cytokine (5)(5)

Proposed Pathogenesis of CNS Proposed Pathogenesis of CNS LupusLupus

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

Neutrophil activation

Endothelial cell activation (priming)

Leukothrombosis

RestingEC

.

....

. .. ....

. .....

.. .....

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ICAM-1CR3C5aIC

Resting PMN

IL-1ßTNFC1qC5aC5b-9aECaPL

E-selectin...

.. .. ...

.. .. .. .. ..

.

....

. .. ..

..

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. ....

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. ... ...

. .....

.. .. .. .

... .Vaso-occlusive plug

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Endothelial Cell Adhesion Molecule ExpressionEndothelial Cell Adhesion Molecule Expressionin Active versus Inactive SLEin Active versus Inactive SLE

0

0.5

1

1.5

2

2.5

ELAM-1 VCAM-1 ICAM-1

control (n=16) inactive SLE (n= 5) active SLE (n=11)

*P <0.01 active vs. control**P <0.025 active vs. inactive

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Belmont, Buyon, Giorno, Abramson: Arthritis Rheum, 1994

Acute Reversible Hypoxemia in Systemic Acute Reversible Hypoxemia in Systemic Lupus ErythematosusLupus Erythematosus

Annals of Internal Medicine 1991; 114-941-947Annals of Internal Medicine 1991; 114-941-947

Steven B. Abramson, MD; Jeffrey Dobro, MD; Mark A. Eberle, MD; Marc Benton, Steven B. Abramson, MD; Jeffrey Dobro, MD; Mark A. Eberle, MD; Marc Benton, MD; Joan Reibman, MD; Hadassah Epstein; David M. Rapoport, MD;MD; Joan Reibman, MD; Hadassah Epstein; David M. Rapoport, MD;

H. Michael Belmont, MD; and Roberta M. Goldring, MDH. Michael Belmont, MD; and Roberta M. Goldring, MD

SLE flare with reversible SLE flare with reversible hypoxemiahypoxemia

MRI showing gray matter lesions the L posterior brain

REVERSIBLE REVERSIBLE LEUKOENCEPHALOPATHYLEUKOENCEPHALOPATHY

IMAGING AND DIAGNOSTIC STUDIESIMAGING AND DIAGNOSTIC STUDIES

CTCTMRIMRISPECTSPECTPETPETANGIOGRAPHYANGIOGRAPHYCSF studiesCSF studiesEEGEEGNeuropsychological testingNeuropsychological testingSerological (autoantibodies)Serological (autoantibodies)

IMAGINGIMAGINGCTCTMRIMRISPECTSPECTPETPETMRAMRACT angiogramCT angiogramConventional angiogramsConventional angiogramsCSF analysesCSF analyses– CellsCells– ProteinProtein– Oligoclonal bandsOligoclonal bands– IgG/albumin indexIgG/albumin index– CytokinesCytokines

EEGEEGNeuropsychological testingNeuropsychological testingAnti-neuronal antibodies (e.g. ribosomal-P, Anti-neuronal antibodies (e.g. ribosomal-P, neurofilimant, NR2 NMDA glutamate receptor)neurofilimant, NR2 NMDA glutamate receptor)

ImagingImagingNo pathognomonic findingNo pathognomonic findingMRI and CT can both exclude brain absecess, MRI and CT can both exclude brain absecess, intracerebral hemorrhage, gross cerebral edema and intracerebral hemorrhage, gross cerebral edema and CVACVAMRI superior to CT in detecting acute CNS injury MRI superior to CT in detecting acute CNS injury including transverse myelitis, new infarct or disruption of including transverse myelitis, new infarct or disruption of the blood brain barrierthe blood brain barrierNormal MRI doesn’t exclude CNS lupus and punctate Normal MRI doesn’t exclude CNS lupus and punctate lesions, especially on T2 weighted images, not specificlesions, especially on T2 weighted images, not specificMRA, angiography and CT angiogram typically incapably MRA, angiography and CT angiogram typically incapably of resolution to demonstrate small vessel vasculopathyof resolution to demonstrate small vessel vasculopathySPECT and PET lack specificity and not reliableSPECT and PET lack specificity and not reliableEEG useful for identifying seizure, encephalopathy or EEG useful for identifying seizure, encephalopathy or brain deathbrain death

Diagnostic TestingDiagnostic Testing

LP most useful to exclude infection, hemorrhage LP most useful to exclude infection, hemorrhage or confirm organic rather than functional or confirm organic rather than functional processprocess

NP testing most useful to distinguish functional NP testing most useful to distinguish functional from organic etiology of psychiatric syndromesfrom organic etiology of psychiatric syndromes

Anti-ribosomal P antibodies useful in patients Anti-ribosomal P antibodies useful in patients with psychosiswith psychosis

Antiphospholipid antibodies useful in CVA, Antiphospholipid antibodies useful in CVA, seizures and focal neurological defectsseizures and focal neurological defects

CLINICAL ASPECTSCLINICAL ASPECTSTHE AMERICAN COLLEGE OF RHEUMATOLOGY NOMENCLATURE AND THE AMERICAN COLLEGE OF RHEUMATOLOGY NOMENCLATURE AND

CASE DEFINITIONS FOR NEUROPSYCHIATRIC LUPUS SYNDROMESCASE DEFINITIONS FOR NEUROPSYCHIATRIC LUPUS SYNDROMES

Neuropsychiatric syndromes observed in systemic lupus erythematosusNeuropsychiatric syndromes observed in systemic lupus erythematosus

Central nervous systemCentral nervous system

Aseptic meningitisAseptic meningitis

Cerebrovascular diseaseCerebrovascular disease

Demyelinating syndromeDemyelinating syndrome

Headache (including migraine and benign intracranial hypertension)Headache (including migraine and benign intracranial hypertension)

Movement disorder (chorea)Movement disorder (chorea)

MyelopathyMyelopathy

Seizure disordersSeizure disorders

Acute confusional stateAcute confusional state

Anxiety disorderAnxiety disorder

Cognitive dysfunctionCognitive dysfunction

Mood disorderMood disorder

PsychosisPsychosis ARTHRITIS & RHEUMATISMARTHRITIS & RHEUMATISM

Vol. 42, No. 4, April 1999, pp 599-608Vol. 42, No. 4, April 1999, pp 599-608

1999 American College of Rheumatology1999 American College of Rheumatology

Prevalence of 12 NP Clinical Prevalence of 12 NP Clinical Syndromes in CNS lupus (N=300)Syndromes in CNS lupus (N=300)HeadacheHeadache 24%24%CVACVA 18%18%Mood disorderMood disorder 17%17%Cognitive dysfunction Cognitive dysfunction 11%11%PsychosisPsychosis 8% 8%Seizure disorderSeizure disorder 8% 8%Anxiety DisorderAnxiety Disorder 7% 7%Aseptic meningitisAseptic meningitis 4% 4%Acute confusional stateAcute confusional state 4% 4%Transverse myelopathyTransverse myelopathy 1% 1%Movement disorderMovement disorder 1% 1%Demyelinating syndromeDemyelinating syndrome 1% 1%

Sanna G, et al Journal of Rheumatology 2003:30;985-992Sanna G, et al Journal of Rheumatology 2003:30;985-992

Peripheral Nervous SystemPeripheral Nervous System

Acute inflammatory demyelinating Acute inflammatory demyelinating polyradiculopathy (Guillain-Barre Syndrome)polyradiculopathy (Guillain-Barre Syndrome)

Autonomic disorderAutonomic disorder

Mononeuropathy, single or multiplexMononeuropathy, single or multiplex

Myasthenia gravisMyasthenia gravis

Cranial NeuropathyCranial Neuropathy

PlexopathyPlexopathy

PolyneuropathyPolyneuropathy

HEADACHEHEADACHE TensionTension

Vascular/MigraineVascular/Migraine Common, Complex, Ocular, Common, Complex, Ocular,

Vertebral-Vertebral- BasilarBasilar

SLE immune mediated inflammatory SLE immune mediated inflammatory mechanismmechanism (aseptic meningitis, pseudotumor (aseptic meningitis, pseudotumor

cerebri, etc.) cerebri, etc.)

SEIZURESEIZURE

Diffuse cerebral injuryDiffuse cerebral injury Diffuse APSDiffuse APS Diffuse vasculitisDiffuse vasculitis

Diffuse leukoaggregation/ACDS/PMN Diffuse leukoaggregation/ACDS/PMN mediatedmediated

Anti-neuronal antibodyAnti-neuronal antibodyCytokinesCytokines

FocalFocalFocal APSFocal APS

ACUTE CONFUSIONAL ACUTE CONFUSIONAL SYNDROME (DELIRIUM,OMS)SYNDROME (DELIRIUM,OMS)

Diffuse cerebral injuryDiffuse cerebral injury

Diffuse APSDiffuse APS Diffuse vasculitisDiffuse vasculitis

Diffuse leukoaggregation/ACDS/PMN Diffuse leukoaggregation/ACDS/PMN mediatedmediated

Anti-neuronal antibodyAnti-neuronal antibodyCytokines Cytokines

CEREBRAL VASCULAR CEREBRAL VASCULAR ACCIDENTACCIDENT

Atherogenesis and thrombogenesis Atherogenesis and thrombogenesis HTN, DM, cigarettes, cholesterol, HTN, DM, cigarettes, cholesterol, sedentary, LDL, homocysteinesedentary, LDL, homocysteine

SteroidsSteroidsImmune complex injuryImmune complex injury

APSAPS

Larger vessel vasculitis (RARE) Larger vessel vasculitis (RARE)

ASEPTIC MENINGITISASEPTIC MENINGITIS

ViralViral

NSAIDSNSAIDS- Ibuprofen - Ibuprofen

SLE - Immune mediated inflammatorySLE - Immune mediated inflammatory disorder (IMID) (e.g. meningeal disorder (IMID) (e.g. meningeal

vasculopathy) vasculopathy)

PSYCHIATRIC DISORDERSPSYCHIATRIC DISORDERS

PSYCHOSESPSYCHOSESORGANIC AFFECTIVE (MOOD) ORGANIC AFFECTIVE (MOOD) DISORDERDISORDERANXIETY DISORDERANXIETY DISORDER

SLE Immune mediated inflammatorySLE Immune mediated inflammatory disorder (IMID) disorder (IMID)

TRANSVERSE MYELITISTRANSVERSE MYELITIS

Spinal arterySpinal artery

- APS- APS

- Vasculitis- Vasculitis

- Leukoaggregation/neutrophil mediated- Leukoaggregation/neutrophil mediated

MOVEMENT DISORDERMOVEMENT DISORDERDEMYELINATING SYNDROMEDEMYELINATING SYNDROME

COGNITIVE DYSFUNCTIONCOGNITIVE DYSFUNCTION

TREATMENTTREATMENT

Order of OperationsOrder of Operations

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

SLE: DISTINGUISH SLE: DISTINGUISH INFLAMMATORY FROM INFLAMMATORY FROM

THROMBOTICTHROMBOTIC

THROMBOTICTHROMBOTIC- APS vs. TTP vs. atherogenesis- APS vs. TTP vs. atherogenesis- Anticoagulation- Anticoagulation- Plasmapheresis- Plasmapheresis- Statins- Statins- Anti-platelet (e.g. aspirin, plavix)- Anti-platelet (e.g. aspirin, plavix)- CAPS- CAPS Heparin, steroids, cyclophosphamide Heparin, steroids, cyclophosphamide

plasmapheresis, IVGG plasmapheresis, IVGG

TREATMENTSTREATMENTS I.I. SYMPTOMATICSYMPTOMATIC

Antianxiety drugAntianxiety drugAntipsychotic drugAntipsychotic drugAntiepilepsy drugAntiepilepsy drugAntidepressive drug (TCA, SSRI, dual inhibitor)Antidepressive drug (TCA, SSRI, dual inhibitor)

2. IMMUNOMODULATORY 2. IMMUNOMODULATORY SteroidsSteroidsCyclophosphamideCyclophosphamideOther cytotoxicsOther cytotoxicsPlasmapheresisPlasmapheresisIVGGIVGGBromocriptineBromocriptineStem cell transplantStem cell transplant

3.3. ANTICOAGULATIONANTICOAGULATIONHeparin Heparin CoumadinCoumadinLMWHLMWHThrombolyticThrombolyticPlavixPlavix

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

SUMMARYSUMMARY

DIVERSE ETIOLOGY and PATHOLOGYDIVERSE ETIOLOGY and PATHOLOGY

DIVERSE CLINICAL SYNDROMESDIVERSE CLINICAL SYNDROMES

EXCLUDE NON-SLE, NONIMMUNE MEDIATED EXCLUDE NON-SLE, NONIMMUNE MEDIATED PROCESSPROCESS

DISTINGUISH INFLAMMATORY versus THROMBOTIC DISTINGUISH INFLAMMATORY versus THROMBOTIC MECHANISMSMECHANISMS

ANTICOAGULATION versus ANTICOAGULATION versus INFLAMMATORY/IMMUNOMODULATORY THERAPYINFLAMMATORY/IMMUNOMODULATORY THERAPY