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
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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?

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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

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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

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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

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Does catastrophic versus demyelinating myelitis
have discriminating clinical features at time of
nadir of first attack?
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Demographic features associated with catastrophic
versus demyelinating myelitis
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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?
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Does catastrophic versus demyelinating myelitis
occur in the context of active systemic lupus
disease?
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Does demyelinating versus catastrophic myelitis
have different autoantibody profiles?
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Did catastrophic versus demyelinating myelitis
differ with regard to intensity of
immunosupresant therapy?
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Considering more intensive immunosuppresant
therapy in the catastrophic group, what was the
prognostic outcome comparing catastrophic versus
demyelinating myelitis?
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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?
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Does catastrophic versus demyelinating myelitis
have distinguishing neuroimaging/MRI features?
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Summary of important demographic, clinical,
immunologic, radiographic, and prognostic
differences between catastrophic and
demyelinating myelitis
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Summary of distinguishing demographic, clinical,
immunologic, prognostic, and radiographic
differences between catastrophic and
demyelinating myelitis
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Summary of distinguishing demographic, clinical,
immunologic, prognostic, and radiographic
differences between catastrophic and
demyelinating myelitis
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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?

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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?

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Swelling of cord precipitates ischemia to
watershed zone in central gray matter
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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!

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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

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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!

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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?

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Target of NMO-IgG is aquaporin-4 on abluminal
surface of astrocytic foot processes, and may be
upregulated by aPL antibodies
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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