Systemic Lupus Erythematosus and Neuropsychiatric Disease

1
Systemic Lupus Erythematosus and
Neuropsychiatric Disease

• Barbara E. Ostrov, M.D.
• Professor of Pediatrics and Medicine
• Pediatric Rheumatology and Rheumatology
• Penn State Hershey

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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 2protein, 1 RBC
• seems very withdrawn
• dialysis required depressive sx progress

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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

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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

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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

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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

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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 gt in other ethnic groups
• African American, Hispanic, Asian

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Demographics

• Adult onset 80 cases
• Childhood onset SLE 20 of all cases
• lt 5 with onset prior to age 10
• FM ratio 91 in teens/adults
• 51 in children
• Twin studies
• 24 concordance in monozygotic twins
• 2 in dizygotic twins
• HLA-DR2 and DR3
• increases RR 2-3 x in Caucasians

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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.

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Etiology/ Pathogenesis

• Hormones
• relative ? androgens ? estrogens
• Exacerbated by pregnancy in some
• Environmental factors
• UV light
• Viral infection (?EBV, ?CMV)
• Drugs
• Hydralazine, isoniazid, minocycline,
  anticonvulsants

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1997 ACR Criteria

• Malar rash
• Discoid rash
• Photosensitivity
• Oral/nasal ulcers
• Serositis
• Nephritis
• Non-erosive arthritis
• Cytopenias
• Neuropsychiatric

• ANA
• Immunoserology
• dsDNA Antibodies
• Anti-Smith Antibodies
• Antiphospholipid Abs

Aim more homogeneous population in research 4/11
criteria 88 Sensitivity/Specificity
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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

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Treatment for Skin

• Sun block
• 70 are photosensitive
• at least 45 SPF
• antimalarial agents
• NON immune suppressing
• hydroxychloroquine gtgt chloroquine gtgtgt quinacrine
• 70 response rate
• monitor annual eye exams
• occasionally
• dapsone, steroids, azathioprine, rituximab

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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

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Serositis/ Cardio-pulmonary

• Pericarditis is most common cardiac complication
  (30)
• May be subclinical
• Sx precordial chest pain, ? by laying down, ? by
  sitting up and forward
• Constriction, tamponade rare

• Pleural effusions (30) in children
• 2º pleural inflammation or pneumonitis
• or to nephrotic syndrome
• Usually bilateral and small w/o respiratory
  compromise
• Pulmonary hemorrhage - rare
• life threatening complication

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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

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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

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WHO Classification

• Class I
• Class IIA
• Class IIB
• Class III
• Class IV
• Class V
• Class VI

• Normal
• Minimal change
• Mesangial proliferation
• Focal/segmental proliferation
• Diffuse proliferative
• Membranous
• Glomerulosclerosis

DPGN
membranous
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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

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Arthritis

• Non-erosive, Painful or painless
• Jacoud arthropathy
• reversible subluxation due to tenosynovitis
• Symmetric small and large joint involvement

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Treatment of Arthritis

• Most pts respond to common regimen
• NSAIDs
• anti-malarials
• low dose prednisone lt 10 mg a day
• beneficial in gt 75 of pts
• uncommon need for higher doses
• For those who fail
• methotrexate, leflunomide
• consider anti-TNF agents (??drug induced LE)
• consider rituximab

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Cytopenias

• Rule out other causes
• medication induced, sepsis, TTP
• All cell lines can be affected
• Hemolytic Anemia - Coombs positive
• Thrombocytopenia lt 100,000
• Leukopenia
• Lymphopenia (lt1500 cells/mm3)
• Treatment
• steroids 1-2 mg/kg/d prednisone ? pulse
• IVIG
• rituximab
• consider TTP, urgent plasmapheresis

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Positive ANA

• IFA
• Usually peripheral or homogenous pattern
• patterns have poor specificity for SLE
• gt 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

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Positive ANA

• HMC Lab uses Laser Bead technology
• in Power Chart, ANA positive means
• gt 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

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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

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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

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Antiphospholipid Syndrome

• Presentations
• Recurrent fetal loss 2nd, 3rd gt1st trimester
• Arterial thrombosis
• Venous thrombosis
• Thrombocytopenia
• Livedo reticularis
• Catastrophic APS
• acute multifocal manifestations

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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
• Devics disease optic neuropathy, myelitis
• anti-aquaporin-4 ab astrocyte foot processes,
  water channels, immune complex formation
• NP Lupus Rheum Dise Clin N Am 31273

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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 42599

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NP Manifestations

• Most common
• cognitive 50-80
• HA 25-70
• mood 15-60
• cerebrovascular 5-20
• seizures 5-50
• neuropathy 10-30
• psychosis 5-10

• Least common
• lt 2-3
• movement dx
• demyelinating
• myelitis
• MG
• GBS
• autonomic
• aseptic meningitis

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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 42599

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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

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Pathogenesis
Complications of SLE or Rx
Non-SLE NP complications
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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

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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 41411
• any NP event in course associated with some
  cognitive decline
• Serology Anticardiolipin Ab IgG and IgA

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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

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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

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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

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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

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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 16436

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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 12947

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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

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Peripheral Nervous SystemNeuromuscular

• Neuropathy up to 30
• mononeuritis multiplex
• autonomic
• sensorimotor
• cranial
• Neuromuscular
• myositis, vasculitic, myasthenia-like
• drug induced steroid gtgtgtantimalarial drug
• Bx small fiber neuropathic, vascular ?
• Course 2/3 stable over long term f/u

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Diagnostic Testing

• Labs
• CSF analysis
• Retinal exam
• CT - bleed/stroke
• MRI
• FLAIR
• DWI
• PET scan
• SPECT scan
• NP testing

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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

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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

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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

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Morbidity

• Renal
• Musculoskeletal
• Ocular
• Endocrine
• Immunologic
• Heart
• Neurologic

• HTN, dialysis, transplant
• AVN, osteoporosis
• Cataracts, glaucoma
• DM, growth failure, premature ovarian failure
• Infection, malignancy
• Atherosclerosis, valvular dx, cardiomyopathy
• Epilepsy chronic psychosis
• neurocognitive decline
• residual myelopathy, neuropathy

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Mortality

• Improved survival
• 100 at 5 yrs 85 at 10 yrs
• compared to lt 50 at 5 yrs in 1950s
• Infection 1 cause of mortality
• replaces glomerulonephritis
• Other causes
• malignant hypertension, GI bleeding and
  perforation, acute pancreatitis, pulmonary
  hemorrhage, catastrophic APS, neuropsychiatric
  disease

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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

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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

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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

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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

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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

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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