CNS LUPUS

Report
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
RENAL versus CNS LUPUS
RENAL
CNS
Pathology
WHO Classification
NIH Activity & Chronicity Index
Diverse
Poor correlation with
clinical syndrome
Poor correlation with
prognosis
Etiology
IC deposition
5 distinct mechanisms
Diagnostics
DNA, C3, C4, U/A, 24-hr urine
albumin, renal biopsy
CSF, anti-ribosomal P
Imaging (CT, MRI)
Clinical
Nephrotic – proteinuria
Nephritic – hematuria, HTN,
renal insufficiency
12 syndromes
Treatment
Randomized controlled
clinical trials
Empiric
Anecdotal
Open label
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
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”
Ellis and Verity
Seminars in Arthritis and Rheum 1979 (N = 57)
VASCULOPATHY
–
–
–
–
–
Vascular Hyalinization
Perivascular inflammation
Endothelial proliferation
Thrombosis
Vasculitis
37% (65%)
31
16
12
4
4
MICROINFARCTS
CVA (large infarcts)
HEMORRHAGE
– SAH
– Microhemorrhage
– Intracerebral
INFECTION
TRANSVERSE MYELOPATHY
20 (38%)
5 (9%)
24 (47%)
17
11
2
16 (28%)
1
Devinsky
Annals of Neurology 1988 (N = 50)
Autopsies 1968-84 NYH
50 Patients (SLE + autopsy)
CNS syndromes (n=37)
– Psychoaffective
– Neurological disorders
– Both
CNS Pathology
Embolic Brain Infarcts
CNS Infection
Cardiac embolic
– Libman Sacks endocarditis
– Valvulitis
– LA thrombosis
TTP
Acute CNS Vasculitis
n = 8260
74% (37) with clinical CNS lupus
5
15
17
50% (25)
10
8
5
2
2
14 7(clinical), 7(pathological)
0
Hanly
Journal of Rheumatology 1992 (N = 7)
Microinfarcts
Healed vasculitis
CMV Infection
Meningeal lymphoma
5
1
1
1
Pathologic and Clinical Spectrum of Vasculopathy
in SLE
Pathology
Pathogenesis
Clinical Phenomenon
Capillaritis
Vasculitis
Immune complex deposition
Activation of complement,
neutrophils, and endothelium
Modeled by Arthus lesion
Glomerulonephritis, pulmonary alveolar
hemorrhage
Cutaneous purpura, polyarteritis nodosa-like
systemic and cerebral vasculitis
Leukothrombosis
Intravascular activation of complement,
neutrophils, and vascular endothelium
Absence of local immune complex
deposition
Modeled by Shwartzman lesion
Widespread vascular injury, hypoxia, acute
cerebral dysfunction, SIRS
Thrombosis
Antibodies to anionic phospholipid-protein
complexes interact with endothelial cells,
platelets, or coagulation factors
Modeled by APS
Disseminated intravascular platelet
aggregation, antibodies to ADAMTS-13
Arterial and venous thrombosis, fetal wastage,
thrombocytopenia, pulmonary hypertension,
CVA
Activated endothelium, increased
endothelial cell adhesion molecules,
increased tissue factor, decreased
27-hydroxylase
MI, CVA
Atherosclerosis
TTP
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
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)
Proposed Pathogenesis of CNS
Lupus
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
CR3
Resting PMN
Resting
EC
.. .....
.
ICAM-1
C5a
IC
.. . ...
.
.. . ... . .. .. . ...
.
... . .
Endothelial cell activation (priming)
IL-1ß
TNF
C1q
C5a
C5b-9
aEC
aPL
E-selectin
.. . ...
.
.. . ...
.
Leukothrombosis
Vaso-occlusive plug
.... ... .
.... ..
.. . ...
.
.. . ...
.
Endothelial Cell Adhesion Molecule Expression
in Active versus Inactive SLE
Immunohistochemical score
control (n=16)
2.5
2
inactive SLE (n= 5)
active SLE (n=11)
*P <0.01 active vs. control
**P <0.025 active vs. inactive
1.5
*
**
*
1
0.5
*
T
0
ELAM-1
VCAM-1
Belmont, Buyon, Giorno, Abramson: Arthritis Rheum, 1994
ICAM-1
Acute Reversible Hypoxemia in Systemic
Lupus Erythematosus
Annals of Internal Medicine 1991; 114-941-947
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
SLE flare with reversible
hypoxemia
MRI showing gray matter lesions the L posterior brain
REVERSIBLE
LEUKOENCEPHALOPATHY
IMAGING AND DIAGNOSTIC STUDIES
CT
MRI
SPECT
PET
ANGIOGRAPHY
CSF studies
EEG
Neuropsychological testing
Serological (autoantibodies)
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)
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
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
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
Prevalence of 12 NP Clinical
Syndromes in CNS lupus (N=300)
Headache
CVA
Mood disorder
Cognitive dysfunction
Psychosis
Seizure disorder
Anxiety Disorder
Aseptic meningitis
Acute confusional state
Transverse myelopathy
Movement disorder
Demyelinating syndrome
24%
18%
17%
11%
8%
8%
7%
4%
4%
1%
1%
1%
Sanna G, et al Journal of Rheumatology 2003:30;985-992
Peripheral Nervous System
Acute inflammatory demyelinating
polyradiculopathy (Guillain-Barre Syndrome)
Autonomic disorder
Mononeuropathy, single or multiplex
Myasthenia gravis
Cranial Neuropathy
Plexopathy
Polyneuropathy
HEADACHE
Tension
Vascular/Migraine
Common, Complex, Ocular,
Vertebral- Basilar
SLE immune mediated inflammatory
mechanism
(aseptic meningitis, pseudotumor
cerebri, etc.)
SEIZURE
Diffuse cerebral injury
Diffuse APS
Diffuse vasculitis
Diffuse leukoaggregation/ACDS/PMN
mediated
Anti-neuronal antibody
Cytokines
Focal
Focal APS
ACUTE CONFUSIONAL
SYNDROME (DELIRIUM,OMS)
Diffuse cerebral injury
Diffuse APS
Diffuse vasculitis
Diffuse leukoaggregation/ACDS/PMN
mediated
Anti-neuronal antibody
Cytokines
CEREBRAL VASCULAR
ACCIDENT
Atherogenesis and thrombogenesis
HTN, DM, cigarettes, cholesterol,
sedentary, LDL, homocysteine
Steroids
Immune complex injury
APS
Larger vessel vasculitis (RARE)
ASEPTIC MENINGITIS
Viral
NSAIDS
- Ibuprofen
SLE - Immune mediated inflammatory
disorder (IMID) (e.g. meningeal
vasculopathy)
PSYCHIATRIC DISORDERS
PSYCHOSES
ORGANIC AFFECTIVE (MOOD)
DISORDER
ANXIETY DISORDER
SLE Immune mediated inflammatory
disorder (IMID)
TRANSVERSE MYELITIS
Spinal artery
- APS
- Vasculitis
- Leukoaggregation/neutrophil mediated
MOVEMENT DISORDER
DEMYELINATING SYNDROME
COGNITIVE DYSFUNCTION
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
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
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
-
STEROIDS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
MTX
MYCOPHENOLATE MOFETIL
PLASMAPHERESIS
IVGG
BROMOCRIPTINE
BMT/SCT with autologous peripheral blood
stem cells or HLA-identical cells
SUMMARY
DIVERSE ETIOLOGY and PATHOLOGY
DIVERSE CLINICAL SYNDROMES
EXCLUDE NON-SLE, NONIMMUNE MEDIATED
PROCESS
DISTINGUISH INFLAMMATORY versus THROMBOTIC
MECHANISMS
ANTICOAGULATION versus
INFLAMMATORY/IMMUNOMODULATORY THERAPY

similar documents