Systemic Lupus Erythematosus

and Neuropsychiatric Disease

Barbara E. Ostrov, M.D.

Professor of Pediatrics and Medicine
Pediatric Rheumatology and Rheumatology
Penn State Hershey
 Case 1
 40 yo African-American F diagnosed with SLE x
6 mos - 2006
 SLE features leading to dx:
 polyarthritis, +ANA, +anti-DNA, rash, fatigue,
cytopenia
 2007 presented with fever, muscle pain,
malaise, overwhelming depressive sx for 2 wks
 WBC 3000, Hb 11.0; ESR 90
 urinalysis 2+protein, 1+ RBC
 seems very withdrawn
 dialysis required; depressive sx progress
 Case 2
 15 yo Hispanic F with no past hx presents to
ED in 2006 for 2nd time in the past month
 6 weeks of recurrent fevers, HA, fatigue
 on exam, temp 39.0; BP 145/85; HR 100
 obviously in pain with photophobia from HA
 no rash
 tender joints on exam
 no edema

 Labs:
 WBC 2500; Hemoglobin 7.5 platelets 140,000
 ESR 80 mm/h
 vision deteriorates; HA continues
 Case 3
 36 yo white F with SLE x 20 yrs
 historical SLE features:
 chorea, arthritis, WBC 2.0-3.0, low
platelets; adrenal insufficiency, + ACL Ab
 age 31, after 2 miscarriages, delivered 30 wk
baby
 peri-partum: SLE flare with rash, arthritis, low
platelets
 6-9 months post-partum: notes gradual
memory difficulties
 short term memory, work with #s, sequencing
tasks
Case 4
 30 yo Asian F with SLE x 15 yrs
 historical SLE features:
 rash, arthritis, cytopenias: WBC 2.5-4.5,
Hb 10-11, platelets 150,000
 AVN both hips, + DNA Ab, ESR 30-50
 presents in 2001 with fever, severe
malaise, muscle and joint pain, HA,
tingling feet
 WBC 2,000, Hb 10.0, ESR 80,creatinine 0.7
 rapidly progressive weakness of legs over
2 days in ICU
Objectives
 review the epidemiology of SLE
 discuss the criteria of SLE
 discuss organ system involvement
and tailored treatment of SLE
 focus on the various neurologic
features of SLE
 discuss morbidity/mortality of SLE
Incidence
 5% of pts in US pediatric rheum practices
 10% of US adult rheum practices
 Incidence:
 2-8/100,000/yr in adults
 0.3-0.9/100,000/yr in children
 5,000-10,000 prevalence in US children
 ~ 100,000-200,000 adults

 varies with ethnic groups

 up to 3 fold > in other ethnic groups:
 African American, Hispanic, Asian
Demographics
 Adult onset 80% cases
 Childhood onset SLE 20% of all cases
 < 5% with onset prior to age 10
 F:M ratio = 9:1 in teens/adults
 5:1 in children
 Twin studies:
 24% concordance in monozygotic twins
 2% in dizygotic twins
 HLA-DR2 and DR3
 increases RR 2-3 x in Caucasians
Etiology/ Pathogenesis
 Etiologic factors include:
 Immune dysregulation:
 hypergammaglobulinemia
 complement deficiency (C2, C4, C5)
 autoantibody production
 cytokine activitation
 inability to clear immune complexes
 organ and tissue deposition
 T cell lymphocytopenia
 defect in switch from T helper 0
to T helper 2 cells
 thus promoting B cell activation.
 Etiology/ Pathogenesis
 Hormones
 relative  androgens  estrogens
 Exacerbated by pregnancy in some
 Environmental factors:
 UV light
 Viral infection (?EBV, ?CMV)
 Drugs
 Hydralazine, isoniazid, minocycline,
anticonvulsants
1997 ACR Criteria
 Malar rash  + ANA
 Discoid rash  + Immunoserology
 Photosensitivity  dsDNA Antibodies

 Oral/nasal ulcers  Anti-Smith Antibodies

 Antiphospholipid Ab’s
 Serositis
 Nephritis
 Non-erosive arthritis
 Cytopenias
 Neuropsychiatric

Aim: more homogeneous population in research

4/11 criteria: 88% Sensitivity/Specificity
 Cutaneous
 Malar
 “butterfly” rash
 ½ to 1/3 at onset
 symmetric
 SPARES nasolabial fold
 no scarring
 Discoid
 face, helix, scalp
 Often asymmetric
 demarcated papular
lesions
 Scarring, alopecia
 More severe in dark
skinned people
 Photosensitivity
Treatment for Skin
 Sun block
 70% are photosensitive
 at least 45 SPF
 antimalarial agents
 NON immune suppressing
 hydroxychloroquine >> chloroquine >>> quinacrine
 ~70% response rate
 monitor annual eye exams
 occasionally:
 dapsone, steroids, azathioprine, rituximab
 Oral and Nasal Ulcerations
 Classically, PAINLESS
ulcerations
 occur on the HARD
palate
 buccal = non-specific
 In the nose they
occur on the septum
 asx septal
perforation can occur
 Serositis/ Cardio-pulmonary
 Pericarditis is most  Pleural effusions (~30%)
common cardiac in children
complication (30%)  2º pleural inflammation or
 May be subclinical pneumonitis
 Sx: precordial chest  or to nephrotic syndrome
pain,  by laying down,   Usually bilateral and
by sitting up and forward small w/o respiratory
 Constriction, tamponade compromise
rare  Pulmonary hemorrhage -
rare
 life threatening
complication
Serositis Treatment
 Rule out infection
 serosal fluid analysis for infection, ANA
 + ANA MAY suggest lupus etiology

 Rule out other causes of chest pain or

effusions: MI, PE, coaguloapthy, GI cause
 NSAID can help pain
 steroids low to moderate dose
 1-2 mg/k/d
 max ~ 40-60mg a day
 usually do not need very hi doses
Nephritis
 Clinically active in 50-75% of pts
 Likely to some degree in ALL with SLE
 Bx, EM shows some change on all

 Presentation (in order of frequency):

 Microscopic hematuria
 Proteinuria
 Lowered GFR
 Worst prognosis:
 poorly controlled HTN  creatinine
 Class IV, nephrotic syndrome
 males, AA, ? Hispanic races
 Renal disease usually w/in 2 yrs of onset
WHO Classification
 Class I  Normal
 Class IIA  Minimal change
 Class IIB  Mesangial proliferation
 Class III  Focal/segmental proliferation
 Class IV  Diffuse proliferative
 Class V  Membranous
 Class VI  Glomerulosclerosis

DPGN membranous
Treatment Renal Disease
 Crucial to control BP
 poor control predicts ESRD
 mild class II to III
 azathioprine, mycophenolate and possibly
cyclophosphamide
 class IV
 pulse cyclophosphamide
 mycophenolate
 2-3 years maintenance
 Future roles for anti-B cell therapies
(rituximab), other biologics
Arthritis
 Non-erosive, Painful or painless
 Jacoud arthropathy
 reversible subluxation due to tenosynovitis
 Symmetric small and large joint involvement
Treatment of Arthritis
 Most pts respond to common regimen:
 NSAIDs
 anti-malarials
 low dose prednisone < 10 mg a day
 beneficial in > 75% of pts

 uncommon need for higher doses

 For those who fail:
 methotrexate, leflunomide
 consider anti-TNF agents (??drug induced LE)
 consider rituximab
Cytopenias
 Rule out other causes:
 medication induced, sepsis, TTP
 All cell lines can be affected
 Hemolytic Anemia - Coomb’s positive
 Thrombocytopenia < 100,000
 Leukopenia
 Lymphopenia (<1500 cells/mm3)

 Treatment:
 steroids: 1-2 mg/kg/d prednisone; ? pulse
 IVIG
 rituximab
 consider TTP, urgent plasmapheresis
Positive ANA
 IFA
 Usually peripheral or homogenous pattern
 patterns have poor specificity for SLE
 > 98% of pts with SLE
 NOT sufficient for diagnosis
 NOT predictive of severity
 NO correlation with disease activity for most
 MORE common in healthy people
 due to meds, viral infections, normal variation
 5% of general peds population

 20% adult population

 Positive ANA
 HMC Lab uses Laser Bead technology
 in Power Chart, ANA “positive” means:
 > 1 of these found:
 anti-DS-DNA, anti-Smith, anti-RNP, anti-SCL-70, anti-
JO-1, anti-histone, centromere, anti-SS-A, anti-SS-B
 results 100-200 often false +

 for some dx, expect + ANA but - other

serology  Athena unreliable
 order “SEND OUT” for ANA by IFA or repeat
any serology by ordering “SEND OUT”
 NOTE: ANA “screen” reported with no
titer clue that a lab is using this method
 Immunoserologies
 Anti-Double-Stranded DNA Antibodies
 Present in ~ 60% patients with active SLE
 Very specific
 Fluctuates with disease activity
 may be predictive of nephritis
 Anti-Smith Antibodies
 Present in 25-30% of SLE
 Very specific
 does not fluctuate with disease activity
 Higher frequency in black females
Antiphospholipid Antibodies

 Antibodies which bind to negatively

charged phospholipids
 Anticardiolipin IgG, IgM
 Anti -2 Glycoprotein-1 IgG, IgM
 Lupus anticoagulant, Prolonged PTT
 DRVVT, Platelet neutralization procedure
 Historical interest:
 False positive RPR test
 uses a cardiolipin-cholesterol-phosphatidylcholine
antigen which can give false results
Antiphospholipid Syndrome

 Presentations:
 Recurrent fetal loss; 2nd, 3rd >1st trimester
 Arterial thrombosis
 Venous thrombosis
 Thrombocytopenia
 Livedo reticularis
 Catastrophic APS
 acute multifocal manifestations
 Other antibodies
 Anti-SS-A (Ro) neonatal LE,
 Anti-SS-B (La) photosensitivity, rash
 Neuropsychiatric Lupus related ab:
 features may be due to combos of these ab
 anti-NR2 ab to glutamate receptor  neuronal injury
 anti-ribosomal- P
 psychosis, depression
 anti-neuronal
 non-specific for SLE or certain NP features
 anti-Neuro Myelitis Optica Ab
 Devic’s disease = optic neuropathy, myelitis
 anti-aquaporin-4 ab: astrocyte foot processes, water channels,
immune complex formation
 NP Lupus Rheum Dise Clin N Am 31:273
 Neuropsychiatric Lupus
 Part of Criteria:
 Seizures, psychosis
 More varied manifestations:
 Central nervous system
 Psychiatric: Psychosis - paranoia, hallucinations
 Seizures - general or focal
 Aseptic meningitis
 Thrombotic: CVA/TIA
 Other: Chorea, headache, Pseudotumor cerebri,
myelopathy, cognitive
 Peripheral nervous system
 GBS
 autonomic neuropathy
 mononeuritis multiplex, polyneuropathy
 ACR Criteria A & R 1999 42:599
 NP Manifestations
 Most common  Least common
 cognitive 50-80%  < 2-3%
 HA 25-70%  movement dx

 mood 15-60%  demyelinating

 cerebrovascular 5-20%  myelitis

 seizures 5-50%  MG

 GBS
 neuropathy 10-30%
 autonomic
 psychosis 5-10%
 aseptic
meningitis
Epidemiology
 ACR case definitions
 up to 90% of all SLE pts have some sx
 many of these sx are also in 50% non-
SLE persons: low specificity
 if case defs exclude: HA, anxiety, mild
depression, mild cognitive, neuropathic
sx w/ normal studies
 then define NP sx in 46% of SLE pts
 7% non-SLE persons
 specificity 93%
 ACR Criteria A & R 1999 42:599
 SLE patient
Neuropsychiatric sx

primary neurologic feature primary psychiatric feature secondary NP feature

due to SLE due to SLE due to complication
50-70%

CVA psychosis complication complication

vasculopathy of SLE of treatment
embolic

seizures cognitive disorder neurologic: corticosteroid, medication

generalzied uremia side effect
focal hypertensive crisis

organic brain syndrome functional psychiatric: infections

dementia pseudodementia reactive depression other
cognitive defects conversion disorder affective disorder
coma adjustment disorder

optic neuritis anxiety

myelitis depression

meningitis

neuropathies
Pathophysiology - Multifactorial
 autoantibodies
 get thru weakened BBB, intrathecal production
 anti-neuronal, anti-ribosomal P, APS, NMO
 vascular
 microangiopathy
 small vessel vasculitis - large vessel RARE
 non-inflammatory vasculopathy
 thrombosis, microinfarcts, ASVD
 often due to secondary causes not 1º due to SLE
 inflammatory mediators; cytokines
 measured in CSF, serum - not clinically used now
 ICAM-1, IL-6, IL-8, IL-10, TGF-, interferon-
 increased nitric oxide
Pathogenesis
FOCAL DIFFUSE
Vasculopathy +++ +
Autoantibodies
Anti-neuronal - +
Anti-ribosomal - ++
APS +++ +
Inflammatory mediators + ++

FOCAL DIFFUSE

Complications of Non-SLE NP
SLE or Rx complications
Specific NP Features

 May occur any time in course

 often an early feature
 prior to clearcut SLE
 with multiorgan flare
 when SLE seems to be quiescent
Cognitive
 Most with mild deficits on NP testing
 20-80% of pts
 attention, memory, visual-spatial processing,
reasoning, speed, higher level functioning
 reflects overall brain health
 outcome
 impairment improves in most
 15% continued impairment; 5% persistent or
worsening over 5 yr f/u
 5 yr longitudinal Rheumatology 2002 41:411
 any NP event in course associated with some
cognitive decline
 Serology: Anticardiolipin Ab: IgG and IgA
Psychiatric Manifestations
 Psychosis 10%
 hallucinations - mostly auditory
 distinguish from drugs, depression, schizophrenia
 depression, anxiety 25-60%
 common in general non-SLE pop
 more often 2º to an non-SLE etiology
 Serology:
 anti-ribosomal P
 psychosis, depression 4-10 X odds ratio

 antiphospholipid ab 1.5 X odds ratio

Seizures

 Generalized and focal

 5-50%
 severe multisystem flare
 1º due to SLE or 2º renal, HTN, infection
 isolated events
 Serology:
 Antiphospholipid ab with microthrombi
Meningitis

 In up to 10-15%
 Must consider 2 causes
 meds: NSAIDs
 higher incidence of ibuprofen induced in
SLE pts
 infection
 CSF:
 lymphocytes
 hi protein
Cerebrovascular Disease
 Rule out embolic source
 Libman-Sacks
 Multifactorial
 5-20%
 stroke, TIA
 HTN, renal disease
 accelerated ASVD
 5-10 X odds ratio

 Prothrombotic state
 APS, hyperhomocysteinemia
Posterior Reversible
Encephalopathy Syndrome
 PRES - similar to SLE NP features
 Acute  mental status, HA, seizure, vision loss
 MRI - white matter  bilateral parieto-occipital area
 etiology:
 sudden BP , distention cerebral vessels; fluid extravasation
 HTN, CRF; meds: CTX, hi dose steroids, others

 Imaging is crucial:
 MRI- FLAIR- inversion recovery suppress CSF - edema 94%
 DWI - diffusion weighted imaging
  signal;  in cerebral ischemia

 Resolves in 1-4 wks

 Rx: BP/seizure control, med changes when possible
 PRES - CNS SLE Lupus 2007 16:436
Headache

 True pathologic relationship with

SLE controversial
 prevalence 20-70%
 but HA 40% in non-SLE pop
 controlled studies
 no increase in HA compared to non-SLE
 HA common but more likely not
directly due to SLE
 Lupus 2003 12:947
Myelopathy, chorea
 Rare features
 1-3% of pts
 demyelination
 may look like from MS

 ? Overlapping
autoimmune dx
 transverse myelitis

 chorea

 Serology
 anticardiolipin ab: thrombotic,
interaction with basal ganglia
 NMO ab 94% specificity
Peripheral Nervous System
Neuromuscular
 Neuropathy up to 30%
 mononeuritis multiplex
 autonomic
 sensorimotor
 cranial
 Neuromuscular:
 myositis, vasculitic, myasthenia-like
 drug induced: steroid >>>antimalarial drug
 Bx: small fiber neuropathic, vascular 
 Course: 2/3 stable over long term f/u
 Diagnostic Testing
 Labs
 CSF analysis
 Retinal exam
 CT - bleed/stroke
 MRI
 FLAIR

 DWI

 PET scan
 SPECT scan
 NP testing
NP disease: Assessment
 Lab:
 assess disease activity: C3, C4, anti-DNA
 specific serology: anti-P ab, APS, NMO
 CSF: ALWAYS RULE OUT INFECTION
 unclear if CSF ab or cytokines help SLE dx
 Imaging structure and function:
 CT - acute bleed
 MRI, FLAIR, Functional
 MRA less useful
 small vessel vasculopathy does not show up
 PET - changes in glucose metabolism
 SPECT - cerebral blood flow
 Neuropsychologic testing
Treatment for NP Lupus
 First step: rule out SLE vs other cause
 active inflammation
 vs complication of disease or Rx

 NP SLE is dx of exclusion
 Manage co-existing issues
 HTN, infection, metabolic abnormalities
 Manage symptoms
 antidepressant, anxiolytics
 anti-psychotic
 psychotherapy, cognitive therapy
 migraine Rx
 ?anti-coagulant ?ASA
 immune suppression
Treatment
 No placebo-controlled studies
 Immunosuppression
 pulse and/or hi dose steroids
 30 mg/kg up to 1000 mg
methylprednisolone
 2 mg/kg/day
 cyclophosphamide
 daily oral 2-4 mg/kg/day

 pulse for 3-6 months

 500-1000mg/m2
 other: azathioprine, combined therapies
 new therapies:
 biologic therapy - anti-CD20
 Morbidity
 Renal  HTN, dialysis, transplant
 Musculoskeletal  AVN, osteoporosis
 Ocular  Cataracts, glaucoma
 Endocrine  DM, growth failure,
premature ovarian failure
 Immunologic  Infection, malignancy
 Heart  Atherosclerosis, valvular dx,
cardiomyopathy
 Neurologic  Epilepsy; chronic psychosis
 neurocognitive decline
 residual myelopathy,
neuropathy
Mortality

 Improved survival
 ~100% at 5 yrs; 85% at 10 yrs
 compared to < 50% at 5 yrs in 1950’s
 Infection #1 cause of mortality
 replaces glomerulonephritis
 Other causes:
 malignant hypertension, GI bleeding and
perforation, acute pancreatitis, pulmonary
hemorrhage, catastrophic APS,
neuropsychiatric disease
 Back to Case 1
 40 yo AA F diagnosed with SLE x 6 mos in 2006
arthritis, +labs, rash, cytopenias
 2007 flare with: nephritis, depressive sx, withdrawn
 2007 Course:
 withdrawn sx became catatonia; + seizures
 CSF - protein 100, WBC 300 - aseptic meningitis
 renal failure required dialysis
 Rx: IV steroids, CTX, BP meds, support
 Currently - 2009:
 in remission on mycophenolate, antimalarial, ACE
 labs normal creatinine 0.9
 back to work
Back to Case 2
 15 yo Hispanic girl with ED presentation 2006
 SLE DX with cytopenias, arthritis, nephritis, + Labs
 2006 - Course:
 severe headache and visual loss
 CSF:
 Ophtho exam:
 Dx: pseudotumor cerebri, optic neuritis
 + NMO antibodies
 Rx: pulse corticosteroid, cyclophosphamide
 IVIG, plasmapheresis
 Currently - 2009
 regained most vision
 renal function normal
 on mycophenolate, ASA 81 mg, ACE inhibitor, antimalarial
 back to school
 Back to Case 3
 36 yo WF with SLE x 20 yrs
 arthritis, cytopenias; chorea & adrenal
insufficiency, miscarriages due to APS
 2006 - Course:
 post-partum SLE flare, memory loss
 CSF:
 Dx: chorea at onset; organic brain syndrome
 APS +
 Rx: pulse corticosteroid, cyclophosphamide
 Currently - 2009
 unable to work but stabilized

 continued immunosuppression
 Back to Case 4
 30 yo Asian F with SLE x 15 yrs
 rash, arthritis, cytopenias,+ labs AVN hips
 2001 - fever, HA, rash, tingling feet
 Course:
 severe headache, progressive paresthesias
 CSF - hi protein, few cells; anti-NMO, APS negative
 MRI with ascending cord edema
 Dx: transverse myelitis
 Rx: pulse corticosteroid, cyclophosphamide, apheresis
 Currently - 2009
 T8 paraplegia
 on dialysis for renal failure (dx nephritis 2008)
 back to work as a disability counselor
Summary

 NP SLE should be considered in:

 SLE pt or pt with systemic sx with:
 new-onset confusional or psychiatric
states, stroke, meningitis
 multifocal process affecting the CNS and
PNS are affected
 unexplained cranial neuropathies
 myelopathies, thromboses
 chorea, myopathy, neuropathy
Conclusions
 SLE remains:
 difficult to diagnose in some
 difficult to treat in others
 Neuropsychiatric manifestations and
complications may be amongst most severe
 Morbidity from disease and treatment still
problematic
 Improved understanding  better Rx
 Lower toxicity of treatment
 Improved survival, quality of life and outcome