Rare Neuroimmunologic Disorders:

An Overview
Douglas Kerr MD/PhD
Associate Professor, Neurology
Johns Hopkins Hospital
Director Johns Hopkins TM Center
Director, Johns Hopkins Project
RESTORE
• Johns Hopkins Transverse
Myelitis Center
• Established in Oct 1999
– Clinical care
– Clinical research
– Basic science research
– 1145 patients with acute
non compressive
myelopathies evaluated
• Multi-disciplinary
– Neurology, urology, rehab,
neurosurgery,
rheumatology, anesthesia,
neuroradiology, psychiatry
Myelopathy Type Number %
All 1108 100
Compressive 8 0.7
Non-Compressive, Non- 148 13
inflammatory
ischemia 108 9.8
radiation 8 0.7
Fibrocartilaginous 8 0.7
embolism
Falsely negative 24 2.1
inflammatory
Inflammatory 952 86
Infectious 48 4
Rheum Disease 112 10
Associated
Confined to CNS
NMO 46 4%
ADEM 24 2%
MS 130 12%
Idiopathic 398 36%
Monophasic
Idiopathic 194 18%
Recurrent
TM Diagnostic Criteria
 Acute
Myelopathy
Algorithm
Step I: Define the presence
of myelopathy
 Clinical Presentation

• 4 Symptom groups
– Motor
– Sensory
– Autonomic
– Pain
 Clinical: Motor

• Motor
– Weakness paraplegia
– Legs usually > arms
• Central cord lesion in the C spine can be arms > legs
– Tone is increased, decreased or normal
• Long-standing-increased
• Acute, severe-decreased
 Clinical: Sensory

• Paresthesias
• Numbness
• Warmth
• Try pinprick and temperature on anterior
and posterior torso
 Clinical: Autonomic

• Urinary urgency
– Decreased interval from bladder fullness to evacuation
– Nocturia
• Urinary retention
– “shock” like scenario
• Bowel urgency, retention
• Sexual dysfunction
• More common with intrinsic than extrinsic
 Clinical: Pain

• “Burning” radicular pain

• “Tight squeezing”
• “banding” sensation
Clinical Features of Acute
Myelopathy
Is it Compressive?
Cervical Spondylosis
 Cervical Spondylitic
Myelopathy

• The most common cause of myelopathy in the

elderly
• May have minimal antecedent injury (falling down
stairs or car accident)
• Mechanism most commonly involves hyper-
extension
• Immobilize the neck if unsure of spinal column
stability
• Flexion/extension x-rays and dynamic MRI may
be helpful
Is it Inflammatory?
 Case: Spinal Cavernous
Angioma

• A 61-year-old man with a history of a

subarachnoid hemorrhage 30 years prior to
onset of present illness developed ascending
left leg numbness progressive over a year.
He then rapidly developed bilateral lower
extremity weakness and became
nonambulatory. He was areflexive.
Proprioception was absent on the left and
mildly intact on the right.
T11-T12 level with an
associated intramedullary
hemorrhage from T7-T12
and edema from T7 to the
conus medullaris A
thoracic laminectomy and
resection of the intradural,
intramedullary cavernoma
was performed with
additional microdissection
 Cavernous Angioma (cont)

• Consider spinal cavernous angioma when

the MRI suggests a mixed signal
abnormality within the spinal cord. Further,
if this diagnosis is considered, ask for a
hemosiderin sequence MRI which will
sensitively identify sites of previous
bleeding.
Is there a Contributing
Infection?
 EBV Myelitis

• A 65 year-old male presented with progressive weakness in his lower

extremities and inability to urinate associated with nasal ulcers. In the
proceeding month, he had low back pain and some weakness that he
attributed to a ‘bad back. An MRI revealed two enhancing lesions, at
T5-T6 and at T11-T12. CSF showed 21 WBCs (30% PMNs) elevated
IgG index and an IgG synthesis of 13.1. The patient was started on IV
steroids. PCR of the CSF subsequently came back positive for EBV
from tubes 2 and 4. CSF EBV-specific IgM and IgG were both
positive. The patient was started on IV gancyclovir and was continued
on IV methylprednisolone. Repeat lumbar puncture one week later
showed 4 WBCs (100% monos), protein 68, IgG index 0.5. Repeat
EBV-PCR was again positive. Follow up lumbar puncture an
additional one week later was compeletely normal and the EBV-PCR
was negative. The patient recovered the ability to ambulate a few
steps and to transfer by 3 months after treatment.
 Key Points

• Spinal fluid viral and bacterial cultures and PCR

studies should be obtained in patients with
inflammatory spinal fluid
• Mycoplasma serology and cold agglutinins should
be routinely checked in patients with acute TM
• In patients, with a vesicular rash or burning
dysesthesias suggestive of herpes zoster (shingles)
anti-viral therapy should be initiated empirically
 Presence of Systemic
Rheumatologic Disorder?
 TM Associated with
Rheumatologic Disorders
TM and Rheum (cont)
 Diagnostic criteria for
Sjogren’s Syndrome
1. Ocular symptoms – persistent dry eyes for more than 3 months;
sensation of sand or gravel in the eyes; use of artificial tears
2. Oral symptoms – persistent dry mouth for more than 3 months;
swollen salivary glands; trouble swallowing
3. Ocular signs – positive Schirmer’s test; Rose Bengal score ≥ 4
4. Histopathology – focus score > 1 in a minor salivary gland
biopsy
(focus is an agglomerate of at least 50 mononuclear cells)
5. Salivary gland involvement –
6. Autoantibodies – presence in the serum of autoantibodies – Ro,
La or both
4/6 criteria indicative of primary SS
 Recurrent TM Associates
with SSA+

Recurrent Controls P
TM N=12 Value
N=13
Women (%) 11 (85) 6 (50) 0.064
Mean Age at Onset, 51.5 (4.8) 45.2 0.329
yrs (SE) (4.2)
Ro + (%) 10 (77) 4 (33) 0.047
ANA + (%) 10 (77) 7 (58) 0.320
Optic Neuritis 3 1 0.315
(NMO*)

Hummers et al., 2003

 Sarcoidosis

• Relapsing/steroid • MRI
response • CSF
• Spinal,optic,brain, • OPHTHO. EXAM
meninges • GALLIUM/PET
• Hydrocephalus,menin • ACE (insensitive)
gitis, mass, peripheral
• Ca, IgG, ESR, CPK
n., systemic
 Key Points

• All TM patients should be investigated for signs,

symptoms and serologic evidence of systemic
autoimmune disease
• Sjogren’s syndrome, sarcoidosis and lupus should
always be considered in a patient with TM
• Patients with TM in association with systemic
autoimmune disease are more likely to have
recurrent neurologic disease and should be
considered for chronic immunomodulatory
treatment.
Multifocal Within CNS?
Multifocal CNS inflammation
Which CNS Inflammatory
Disorder?
 Myelopathy as the First
Presentation of MS

• Multiphasic by history or exam

• Imaging characteristics: lesion that occupies less than ½ the cord

diameter and less than 2 rostral-caudal spinal segments and the
presence of 2 or more brain lesions

• Clinical presentation often milder: sensory >motor, always incomplete

• Oligoclonal bands much more likely in MS

• Brain MRI is often helpful in distinguishing MS from TM

• Several studies now suggest that in certain patients, treatment of patients

at high risk of developing MS may delay conversion
 Key Points
• Radiologic features that suggest TM is part of MS include
a lesion that occupies less than ½ the cord diameter and
less than 2 rostral-caudal spinal segments and the presence
of 2 or more brain lesions
• Clinical features that suggest TM is part of MS include
mild, asymmetric, predominantly sensory symptoms
• History, examination, evoked potentials or MRI imaging
may confirm a mutiphasic, multifocal process and would
suggest the need for instituting immunomodulatory
treatment
Monophasic vs. Recurrent TM
 What is TM?

• Acute inflammatory disorder of a part of the spinal cord

• Immune-mediated
• Four symptom groups: motor dysfunction (weakness,
spasticity), sensory dysfunction (numbness, paresthesias,
dysesthesias), pain, autonomic dysfunction (sexual , bowel
and bladder)
• Monophasic
• Monofocal
 What is TM?

• In most cases, TM is likely post-infectious and

involves breakdown of immune tolerance for self
antigens
– Molecular mimicry
– Superantigen mediated T lymphocyte activation
• Why the focality?
– Unique inflammatory trigger
– Unique lymphocyte trafficking or permeability
– Unique immune response in the spinal cord
Acute TM: inflammation!
 Results of Inflammation
Demyelination: Damage to Necrosis/Axonal Injury:
Injury Tissue
myelin producing cells damage secondary to vascular
resulting in loss of the changes and/or inflammation.
insulation around nerves Neuronal/axonal death
Case: Necrotizing TM in an 11
month old infant
 Case Presentation: MG

• 12 mo twin, 10 days
following HepB, HIB
and VZV Vaccination

• Sudden onset of
quadriplegia, areflexia
 Clinical Findings:MG

• complete loss of • 14-3-3 +

sensation/motor • evoked potentials-no
• cognitively unchanged conduction rostral to
• CSF: C5
– all pcr studies negative
– all cx negative
Sequential MRIs: MG
Axial MRI Images:MG
Severe Tissue Injury in the
Spinal Cord: MG
IL-6 and TM
 Genes/Environment

Trigger

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New Treatments???
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CNS Injury CNS Dysfunction

Acute TM Depression Relapse

Elevated CSF IL-6
Group Average of TM
Cytokine Elevation
 IL-6
• Pro-inflammatory cytokine
• Stimulates HPA axis to produce cortisol.
• Induced by TNF-α
• IL6-R on neurons, astrocytes and
oligodendrocytes
• Acts through a JAK/STAT pathway to stimulate
iNOS production in the heart.
• iNOS implicated in causing CNS injury.
• Does IL6 activation stimulate further
inflammation and/or direct neural injury?
Quantitative Serum and CSF
IL-6 Analysis
Acute CSF IL-6 Correlates
with Sustained Disability
IL-6 Correlates with
CSF Nitric Oxide
Production
Prognostic Impact of Acute
CSF IL-6
IL-6 Infused Rats Become
Weak
Plastic Sections of IL-6
Infused Rats
Pathology of TM
 Summary

• IL-6 is markedly elevated in the CSF of

patients with acute TM
• CSF IL-6 levels correlate with long term
disability and with markers of neural injury
• IL-6 is capable of inducing neural injury in
model systems
• IL-6 acts through the JAK/STAT system
resulting in iNOS and PARP activation
 Genes/Environment
Genetic Screening Genetic Screening
Trigger
Thalidomide TNF­α
IL­6
Erythropoietin
STAT3
Statin
iNOS
Minocycline
CNS Injury CNS Dysfunction

PARP  Acute TM Depression Relapse

Inhibitor

Free Radical  Rehabilitation Antidepressant: 

5­HT/NE, 
Adduct  CRH antagonist,
Repair IL­6 antagonist