CENTRAL NERVOUS SYSTEM INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS: MAGNETIC RESONANCE IMAGING AND C

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CENTRAL NERVOUS SYSTEM INVOLVEMENT IN SYSTEMIC
LUPUS ERYTHEMATOSUS MAGNETIC RESONANCE IMAGING
AND CEREBROSPINAL FLUID ANALYSIS

• Simone Appenzeller
• State University of Campinas-UNICAMP, Campinas,
  Brazil

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Introduction

• Central nervous system (CNS) manifestations occur
  in up to 70 of SLE patients, depending on
  criteria applied for diagnosis
• Symptoms are diverse
• Secondary causes must be excluded
• Hypertension
• Infections
• Metabolic abnormalities
• Drug toxicity

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Introduction

• Pathogenesis
• Autoantibodies and cytokine mediated neuronal
  dysfunction
• Intracranial angiopathy
• Coagulopathy

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Introduction

• Magnetic resonance imaging is considered gold
  standard for diagnosis of anatomic brain
  abnormalities
• Findings are diverse
• Cerebral atrophy
• White matter lesions
• Poor clinical correlations

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Introduction
Neuroimage. 200734(2)694-701
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Objective

• To evaluate cerebrospinal fluid (CSF) and MRI
  findings in SLE with active and inactive CNS
  involvement

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Inclusion criteria

• 30 SLE with CNS manifestations (ACR, 1999)
• Active
• Inactive
• Drug free state or stable low doses of
  immunosuppressive therapy for at least 6 months
  (10 mg of prednisone or equivalent, 100 mg/day
  azathioprine)
• Controls with similar age and gender distribution
• No chronic disease
• CSF mielography CT

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Exclusion criteria

• Not able to undergo MRI exams
• Claustrophobia, pacemaker and prosthetic valves
• Previous clinical conditions that could influence
  cerebral atrophy
• history of stroke
• epilepsy
• arterial hypertension
• diabetes mellitus
• alcohol and drug abuse
• renal insufficiency
• and malignancy
• Patients who fulfilled the ACR criteria for
  Sjogren syndrome

10 patients excluded
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CSF

• CSF (10 mL) samples
• CSF leukocyte count
• IgG synthesis and
• oligoclonal IgG bands
• Paired samples of serum and CSF were stored at -
  80º C
• All measures were made at a single occasion in
  order to minimize the intra assay variability
• IgG and albumin
• measured by nephelometry (BNII Dade Behring,
  Marburg, Germany), and
• Blood-brain barrier function CSF albumin/serum
  albumin
• Intrathecal synthesis Link Indexes (LI)
• CSF IgG/CSF albumin/serum albumin
• Oligoclonal IgG bands
• identified by isoelectrofocusing

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CSF

• The IL12, IFNg, TNFa, and IL10
• quantified using commercial kits from Biosource
  International, Nivelles, Belgium
• Intratecal synthesis serum albumin/CSF
  albuminCSF Il12/serum Il12

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MRI

• 2.0 Tesla system (Elscint, PrestigeR).
• All exams covered the whole brain using 6.0 mm
  slice thick and 1.2 mm inter-slice gap.

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White matter lesions

• Number and localizations
• visually at a work station
• The proton-density and T2 -weighted images were
  scored according to the following items
• number of frontal, parietal, temporal, occipital,
  infratentorial, basal ganglia (including internal
  capsule) lesions
• number of periventricular, callosal/subcallosal,
  number of juxta cortical (contiguous with the
  cortex) lesions
• number of lesions gt 6mm

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Atrophy

• Cerebral volumes were determined in T1sagittal
  images with semi-automatic segmentation.
• Software Neuroline
• Cerebral volumes were corrected for intracranial
  volume
• Results were compared to healthy controls with
  similar age and gender.

Watson C, et al. Archives of Neurology, 1997.
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Arthritis and Rheum, 2005
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Statistics

• Demographic data were compared with chi-square
  test.
• Cerebral volumes were compared using two sample
  t-test.
• Statistics
• Non-parametric analysis of variance
• Kruskal-Wallis test
• Spearman Rank test
• A p value smaller than 0.05 was considered to be
  significant.

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Demographic data

• Patients
• Mean age of 30.2 (SD9.2 range 19-45)
• Mean disease duration 64.5 months (range 1-372
  months, SD48.50)
• Controls
• Mean age of 31.8 years
• Range 20 to 55 years (SD10.2 )

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Results

• Active SLE disease was observed in 20 patients
  with mean SLEDAI score of 14.0 (range 9-20
  SD5.9).
• Active CNS disease at the time of MRI scan was
  observed in 12 of 30 patients with history of CNS
  involvement.
• Mean SLICC/ACR-DI scores at study entry were 2.3
  (range 0-5 SD1.8).

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Results

• CNS manifestations
• Headache 15
• Cognitive impairment 20
• Mood disorder 10
• Acute confusional state 4
• Anxiety 5
• Psychosis 3
• Mielopathy 2
• Aseptic meningitis 2

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MRI findings

• SLE patients
• Atrophy 5 (25)
• Hyperintense white matter lesions 12 (60)
• Demyelinating lesions 3 (15)
• Controls all normal MRIs

No correlation to clinical findings
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MRI findings
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Cerebral Volume
P0,002
SLE
Controls
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Cerebral Volume
Pgt0,05
Plt0,001
SLE w/inactive CNS
SLE w/ active CNS
Controls
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Serum findings
Plt0.001
Plt0.001
controls
SLE
controls
SLE
P0.03
Pgt0.05
controls
SLE
controls
SLE
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Associations

• INFg, TNF a and Il12 associated with disease
  activity

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CSF findings in SLE

• Mild pleocytosis 8 (66)
• Intrathecal production of IgG 2 (10)
• Brain-barrier rupture 4 (20)
• All SLE patients with new onset of neurological
  symptoms had pleocytosis, and intrathecal or
  brain barrier rupture.
• Oligoclonal IgG bands -
• HTLV 1 -

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CSF findings
Plt0.001
Plt0.001
controls
SLE
controls
SLE
P0.02
P0.028
controls
controls
SLE
SLE
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CSF findings

• Active CNS manifestations had higher IL12, IFNg,
  TNFa, and IL10
• Intrathecal synthesis 5/12 patients with active
  CNS manifestations
• Inactive CNS manifestations had higher levels of
  TNFa and IFNg than controls
• No correlation to specific CNS manifestations

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Associations

• In SLE patients, total lesion count was
  associated with inactive CNS manifestations and
  SLICC/ACR-DI scores.
• No correlation of CSF findings with white matter
  lesions was observed.
• Cortical volume reduction was associated with
  IFNg (r0.5 p0.01).
• TNF a associated with leucocytes counts in CSF

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Discussion

• B cell proliferation, differentiation and
  antibody production is coordinated by the helper
  T cells and the cytokines they produce
• Other cells within and outside the immune system
  also produces this cytokines
• We quantified both pro and anti-inflammatory
  cytokines independent of their source

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Discussion

• Il12
• Early phase of inflammatory response
• Secreted by monocytes
• No correlation to lesions (contrary to MS)
• IFNg
• Potent proinflammatory response
• Ability to induce the production of other
  proinflammatory cytokines
• Role in atrophy?

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Discussion

• TNF a
• Induces endothelial adhesion molecules
• Recruitment of leukocytes to CNS
• Myelinotoxic in MS
• Correlation to MRS findings?
• NAA/Cr ratios abnormalities
• Il10
• Inhibits synthesis of Th1 cytokines
• MS lower disability and lower lesion load

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Conclusions

• MRI abnormalities are frequently observed in SLE
  patients and are associated with past CNS
  manifestations and cumulative damage.
• Although we observed immunologic abnormalities in
  CSF of SLE patients, only IFNg correlated with
  MRI abnormalities.

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Acknowledgments

• Heloisa Ruocco, MD, PhD
• Carlos Oliveira Brandao, PhD
• Leonilda M.B. Santos, PhD
• Lilian TL Costallat, MD, PhD
• Fernando Cendes, MD, PhD