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Title: Clinical, immunologic, radiographic, and prognostic heterogeneity of


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Clinical, immunologic, radiographic, and
prognostic heterogeneity of lupus myelitis
  • Julius Birnbaum, MD

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No Relevant Financial Relationships with
Commercial InterestsI will not reference an
unlabeled or unapproved use of a drug or product
in my presentation.
Julius Birnbaum, MD Rheumatology Rounds March
14, 2008
Disclosures
3
Purposes
  • Overall Goal To demonstrate that there are two
    distinct and previously unrecognized syndromes
    constituting lupus myelitis
  • (1) To discuss two informative cases of lupus
    myelitis, disclosing unrecognized clinical
    patterns which have enormously divergent
    mechanistic and therapeutic implications
  • (2) Retrospective cohort Final analysis of
    data illustrating distinguishing clinical,
    immunologic, and prognostic differences between
    these 2 subtypes of lupus myelitis

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Importance of recognizing clinical patterns in
demyelinating syndromes
  • 1980s-1990s Devics syndrome and Multiple
    Sclerosis considered diagnostic variants
  • 1990s to 2008 Well-designed cohort studies
    established that Multiple Sclerosis and Devics
    syndrome are distinct diagnostic entities
  • Multiple Sclerosis Devics Syndrome
  • Transverse Myelitis Longitudinal Myelitis
  • SensorygtMotor Motor/sphincteric
  • No autoantibodies NMO IgG Abs
  • Interferon Rx Immunosuppresant Rx

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No corresponding clinical, mechanistic, or
radiographic heterogeneity recognized for
demyelinating syndromes in rheumatic disease
  • 1980s definition of MS Acute or relapsing
    demyelinating episodes with evidence of discrete
    neurological lesions distributed in time and
    space
  • 1999 ACR Classification Criteria of SLE
    Demyelination Acute or relapsing demyelinating
    episode with evidence of discrete neurological
    lesions distributed in time and space
  • 2008 ACR Classification Criteria of SLE
    Demyelination Acute or relapsing demyelinating
    episode with evidence of discrete neurologic
    lesions distributed in time and space
  • Is lupus myelitis a single diagnostic entity?

6
Case I of Lupus Myelitis
  • 20 yo Caucasian female, 2 yr ho lupus,
    ANA/anti-dsDNA, nasal ulcers, polyarthritis,
    controlled with Plaquenil
  • August, 2006 Worsening arthritis, pleuritic
    CP, echocardiogram showing trace pericardial
    effusion
  • First two weeks, Sept 2006 Fevers, multiple
    episodes of nausea, vomiting
  • Sept 12, 2006 Seen in ER, unable to void, 850
    cc PVR, discharged home with diagnosis of urinary
    tract infection

7
Case I of lupus myelitis
  • September 13, 2006 Wakes up at 8 AM, takes
    shower, feels dizzy goes back to bed.
  • 830 AM Wakes up from nap, tries to stand
    from bed, falls, unable to move legs
  • In ER, 9 AM Found to be completely
    paraplegic, arreflexic,
  • 10 AM T10 sensory level
  • 12 PM T 2 sensory level
  • LP 350 WBCs, 1200 Total protein, glucose
    30mg/dL
  • MRI Consistent with lupus myelitis Rxed
    Prednisone, PLEX, Cytoxan.

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Outcome of Case I
  • August, 2007 Complete paraplegic, arreflexic,
    will never walk again.
  • Early clues as to etiology
  • (1) Hyperacute evolution of paraplegia
  • (2) Lower motor neuron (flaccidity,
    arreflexia), instead of upper motor neuron signs
    (Babinski) suggestive of gray matter injury

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CATASTROPHIC MYELITIS
  • Catastrophic because of acuity, severity,
    irreversibility, intractability to treatment
  • Catastrophic acuity Clinical nadir reached
    within hours
  • Catastrophic severity At clinical nadir,
    lower extremities completely paralyzed, absent
    sensation below sensory cord level, completely
    catheter-dependent
  • Catastrophic irreversibility At one year
    follow-up, absolutely no improvement in motor,
    sensory, sphincteric function. At age 20, will
    be wheelchair-bound for the rest of her life
  • Catastrophic intractability to treatment No
    response to pulse Solumedrol, Cytoxan, IvIG, or
    plasmapharesis

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Case II
  • 45 yo AA F, SLE diagnosed in 1981, ANA, anti
    dsDNA, malar rash, nasal ulcers, controlled on
    Plaquenil
  • 1986 Develops R optic neuritis
  • 1989-2006 Develops 12 attacks of recurrent
    longitudinal myelitis
  • Dx Lupus myelitis, Rxd with
    Prednisone/Imuran/Cytoxan
  • At age 45, needs to go into nursing home

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Devics Syndrome/Neuromyelitis Optica (NMO)
  • Clinically defined by demyelinating attacks
    restricted to optic nerve and spinal cord
  • 2006 diagnostic criteria of Devics syndrome
    Requires attacks of optic neuritis and myelitis,
    along with two of the following three features
  • (1) Myelitis which is longitudinally
    extensive (LETM), spanning three or more
    vertebral segments
  • (2) Brain MRI which is nondiagnostic of MS
  • (3) NMO-IgG antibody positivity (70 sensitive,
    94 specific)
  • Despite LETM, minimal functional deficits after
    initial attacks, with loss of independent
    ambulatory capacity often occurring 4 or 5
    attacks

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Expanding the spectrum of NMO
  • NMO-IgG Autoantibody Recognizes aquaporin-4
    protein
  • NMO-IgG autoantibody has been associated with
    form frustes of NMO syndromes, i.e. single
    episodes of LETM with NMO-IgG positivity, but
    without attacks of optic neuritis.
  • NMO Spectrum of disorders (NMOS) Includes
    recurrent attacks of LETM or optic neuritis with
    NMO-IgG positivity,
  • In these patients, utility of NMO-IgG antibody
    as a prognostic as well as diagnostic marker
  • Earlier treatment may prevent grim prognosis,
    where at least 50 of patients will be wheelchair
    bound or blind within 5 to 10 years

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Clinical, mechanistic, and therapeutic
heterogeneity encompassed under nostrum of lupus
myelitis
  • Catastrophic myelitis
    Demyelinating Myelitis
  • Occurs with clinically active SLE Occurs with
    quiescent lupus
  • Monophasic Polyphasic
  • Gray-Matter Necrosis White-Matter
    Demyelination
  • Irreversible paraplegia Reversible paraparesis
  • Hypotonia, Arreflexia Spasticity, Hyperreflexia
  • Conclusions Clinical heterogeneity encompassed
    under spectrum of lupus myelitis likely just as
    mechanistically discrepant as the differences
    between Devics syndrome and MS!

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Overall hypotheses
  • Overall hypothesis (1) That the nostrum of
    lupus myelitis encompasses two clinically
    distinct clinical patterns
  • (a) Catastrophic myelitis Initially
    characterized by lower-motor neuron findings at
    nadir, with catastrophic acuity, severity,
    irreversibility, and intractability to therapy
  • (b) Demyelinating myelitis Initially
    characterized by clinical features suggestive of
    white-matter disease i.e. spasticity,
    hyperrefexia, Babinski signs

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Catastrophic versus demyelinating myelitis also
represent two distinct syndromes
  • Second hypothesis To graduate from asserting
    that these subtypes are distinct clinical
    patterns, to asserting that they represent
    nosologically and mechanistically distinct
    syndromes, we hypothesized that these subtypes
  • (1) Different relationships to systemic lupus
    disease
  • (2) Different relationships to clinical or
    serologic features suggestive of NMO/Devics
    syndrome
  • (3) Different immunologic patterns (i.e.
    different patterns of autoantibodies)
  • (4) Different CSF profiles
  • (5) Different features on MRI
  • (6) Different prognoses and response to
    treatment

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Why do we care?
  • (1) As clinicians
  • In the general population, the prevalence of
    myelitis is approximately one in 1,000,000
  • In SLE patients, the prevalence of myelitis has
    been estimated to be
  • one in 100
  • We are entrusted to caring for patients who have
    1000-fold greater prevalence of a condition
    which places young adults in wheelchairs and
    nursing homes in the adult prime of their lives!

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Why do we care?
  • (2) As clinician-investigators
  • Several clinical indices of lupus activity
    (i.e. SLAM, BILAG), assumes lupus myelitis is a
    homogeneous diagnostic entity
  • So we are 30 years behind the idiopathic
    demyelinating syndromes (Devics versus MS), in
    conducting cohort studies to which can detect
    heterogeneous clinical, immunologic and
    radiographic pattterns

22
Study Methods
  • Overall hypothesis That catastrophic
    myelitis versus demyelinating myelitis in SLE
    patients have discriminating clinical,
    radiographic, and immunologic features
  • Retrospective review of 22 consecutive patients
    with SLE and myelitis evaluated at the Johns
    Hopkins Lupus Cohort, and the Johns Hopkins
    Transverse Myelitis Center, between 1994 and 2007

23
Does catastrophic versus demyelinating myelitis
have discriminating clinical features at time of
nadir of first attack?
24
Demographic features associated with catastrophic
versus demyelinating myelitis
25
Is demyelinating versus catastrophic myelitis
associated with clinical features suggestive of
NMO/Devics disease, or NMO-spectrum of
disorders
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Does catastrophic versus demyelinating myelitis
have inflammatory prodromes suggestive of active
systemic lupus disease?
27
Does catastrophic versus demyelinating myelitis
occur in the context of active systemic lupus
disease?
28
Does demyelinating versus catastrophic myelitis
have different autoantibody profiles?
29
Did catastrophic versus demyelinating myelitis
differ with regard to intensity of
immunosupresant therapy?
30
Considering more intensive immunosuppresant
therapy in the catastrophic group, what was the
prognostic outcome comparing catastrophic versus
demyelinating myelitis?
31
Considering more florid clinical and serologic
features of inflammation associated with
catastrophic variant, did the catastrophic versus
demyelinating variant have more inflammatory
features within the CSF compartment?
32
Does catastrophic versus demyelinating myelitis
have distinguishing neuroimaging/MRI features?
33
Summary of important demographic, clinical,
immunologic, radiographic, and prognostic
differences between catastrophic and
demyelinating myelitis
34
Summary of distinguishing demographic, clinical,
immunologic, prognostic, and radiographic
differences between catastrophic and
demyelinating myelitis
35
Summary of distinguishing demographic, clinical,
immunologic, prognostic, and radiographic
differences between catastrophic and
demyelinating myelitis
36
Mechanistic and therapeutic implications of
identifying catastrophic versus demyelinating
myelitis
  • Three key clues in suggesting mechanism of
    catastrophic myelitis
  • (1) Prolonged inflammatory prodromes, and
    relationship to systemic lupus disease
  • (2) Hierarchical evolution, of urinary symptoms
    preceding catastrophic paraplegia
  • (3) Spinal cord MRI
  • (a) Swollen cord BUT
  • (b) Why, despite florid inflammatory symptoms,
    is catastrophic myelitis not associated with
    Gadollinium-enhancing lesions?

37
Mechanistic implications Lack of Gadoliniuim
enhancement in context of swollen cords
  • MRI showing Gadollinium enhancementindicative
    of inflammation, in presence of a breached
    blood-brain barrier
  • But Gadollinium depends on a perfusion gradient
    across the spinal cord !
  • We know that the cords of catastrophic myelitis
    are swollen and engorged at time of clinical
    nadir
  • Cords become progressively swollen during period
    of systemic inflammation and systemically active
    lupus
  • What are the consequences of an engorging spinal
    cord which is encased in a fixed anatomical space?

38
Swelling of cord precipitates ischemia to
watershed zone in central gray matter
39
Herniation of the spinal cord during increasing
systemic lupus activity
  • There is limited room for intramedullary
    expansion of the spinal cordi.e. the spinal cord
    becomes strangulated in a fixed anatomic space,
    leading to increased venous hypertension
  • This increasing venous hypertension, during
    systemic inflammatory lupus, represents a
    potentially treatable ischemic phase
  • At critical juncture
  • Pressure in dorsal venous plexuspressure in
    spinal radicular arteriesCATASTROPHIC VENOUS
    HYPERTENSION!!
  • Clinical manifestation, no blood flow to spinal
    cord Gray-matter necrosis
  • Radiographic manifestation, no blood flow to
    spinal cord Gadollinium is prevented from being
    transported across a breached blood-brain
    barrier!

40
Mechanistic implications of catastrophic myelitis
  • Can we prevent catastrophic venous hypertension?
  • In 8 of 11 patients, hierarchical evolution of
    spinal cord symptoms, of sphincteric symptoms
    heralding catastrophic paraplegia.
  • These 8 patients sought medical attention,
    either through PMD or in ER, complaining of
    inability to void!
  • Severity Ranging from subjective complaints of
    difficulty voiding, to having bladders with
    greater than 1 Liter of post-void residual!
  • This period of sphincteric symptomsi.e. a
    lower motor neuron bladder lesion, represents
    compromised blood flow to spinal cord due to
    swelling and venous hypertension

41
Hierarchical evolution of spinal cord symptoms
due to venous hypertension
  • In animal models of spinal cord injury
  • (1) The gray-matter represents the axial
    watershed zone
  • Clinical implications Therefore, see
    gray-matter before white-matter damage
  • (2) Selective vulnerability of sphincteric
    (i.e. Onufs nuclei, involved in micturition),
    compared to motor and sensory nuclei
  • Clinical implications Need to recognize
    unexplained sphincteric symptoms in SLE patients
    as a neurological emergency!

42
Therapeutic implications
  • Catastrophic patients treated much more
    aggressively demyelinating variant, yet
    invariably had a uniformly worse outcome, with
    all patients losing independent ambulatory
    capacity
  • Immunosuppresant treatment cannot affect
    necrotizing injury
  • But appropriate recognition of unexplained
    micturition symptoms in a SLE patient as a sign
    of impending spinal cord herniation (i.e. the
    anatomic equivalent of a blown pupil!) can
    potentially salvage motor function
  • Mechanistic implications of the catastrophic
    variant That perhaps these patients can be
    treated, and not be indicted to a lifetime of
    decades in a wheelchair

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Mechanistic and therapeutic implications of
recognizing the demyelinating variant
  • Most patients with the demyelinating variant
    have opticospinal syndromes due to the
    Neuromyelitis Optica Spectrum of Syndromes
    (NMOS)
  • NMOS in lupus patients represents a distinct and
    coincidental autoimmune disease
  • Not all myelitis in SLE patients due to the
    diathesis of lupus
  • Interesting and surprising observation Why is
    the demyelinating variant associated with aPL
    antibodies and syndromes?

44
Target of NMO-IgG is aquaporin-4 on abluminal
surface of astrocytic foot processes, and may be
upregulated by aPL antibodies
45
Role of antiphospholipid antibodies in
demyelinating variant/NMO
  • Animal models show upregulation of aquaporin-4
    during ischemic stress
  • Regional ischemia induced by aPL antibodies may
    increase burden of pathogenic aquaporin-4
    antibodies
  • aPL antibodies may also lead to upregulation of
    endothelial adhesion molecules, and faciliate
    diapedesis across the blood-brain barrier

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Conclusions
  • Just as MS and NMO syndrome are now considered
    to be distinct syndromes, lupus myelitis
    encompasses two syndromes which are just as
    clinically and mechanistically discrepant.
  • Catastrophic versus demyelinating myelitis
    Different syndromes, with distinguishing
    demographic, clinical, immunologic, radiographic,
    and prognostic differences
  • Treatment of catastrophic myelitis depends on
    recognition of micturition symptoms as an ominous
    indicator of catastrophic venous hypertension
  • Recognition of demyelinating variant as
    consistent with NMO/Devics syndrome can lead to
    earlier immunosuppresant treatment, especially
    when associated with anti-Ro or NMO-IgG antibodies

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Acknowledgments
  • Douglas Kerr, MD/PhD
  • Michelle Petri, MD
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