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
All Compressive Non-Compressive, Noninflammatory ischemia radiation Fibrocartilaginous embolism Falsely negative inflammatory Inflammatory Infectious Rheum Disease Associated Confined to CNS NMO ADEM MS Idiopathic Monophasic Idiopathic Recurrent

1108 8 148 108 8 8 24 952 48 112 46 24 130 398 194

100 0.7 13 9.8 0.7 0.7 2.1 86 4 10 4% 2% 12% 36% 18%

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 hyperextension • 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 TM N=13 11 (85) 51.5 (4.8) 10 (77) 10 (77) 3 Controls N=12 6 (50) 45.2 (4.2) 4 (33) 7 (58) 1 P Value 0.064 0.329 0.047 0.320 0.315

Women (%) Mean Age at Onset, yrs (SE) Ro + (%) ANA + (%) Optic Neuritis (NMO*)

Hummers et al., 2003

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

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 myelin producing cells resulting in loss of the insulation around nerves Necrosis/Axonal Injury: Tissue Injury damage secondary to vascular changes and/or inflammation. 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 sensation/motor • cognitively unchanged • CSF:
– all pcr studies negative – all cx negative

• 14-3-3 + • evoked potentials-no conduction rostral to C5

Sequential MRIs: MG

Axial MRI Images:MG

Severe Tissue Injury in the Spinal Cord: MG

IL-6 and TM

Genes/Environment Trigger New Treatments??? ???? ??????? ?????? CNS Injury Acute TM CNS Dysfunction Depression Relapse

Elevated CSF IL-6

Group Average of TM Cytokine Elevation

• • • • 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

• 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

Genetic Screening Thalidomide Erythropoietin Statin Minocycline PARP  Inhibitor Free Radical  Adduct 

Genes/Environment Trigger IL­6 STAT3 iNOS CNS Injury Acute TM Rehabilitation Repair TNF­α

Genetic Screening

CNS Dysfunction Depression Antidepressant: 
5­HT/NE,  CRH antagonist, IL­6 antagonist