(Neuroimmunological) Lessons From Acute Disseminated Encephalomyelitis (ADEM

)

Major Inflammatory Demyelinating Disorders of the CNS

•Multiple Sclerosis (MS)

•Acute Disseminated Encephalomyelitis (ADEM)

David N. Irani, M.D. Assistant Professor of Neurology The Johns Hopkins University School of Medicine

• S i t e -r e s t r i c t e d d i s o r d e r s (t r a n s v e r s e m y e l i t i s , optic neuritis, cerebellitis, etc.) ---------------------------------------------------------------- - - - •Experimental Autoimmune Encephalomyelitis (EAE)

ADEM: Definitions and Features

ADEM: Diagnosis

Clinical •rapid onset •focal or multifocal neurologic d y s f u n c t i o n •recent infection or immunization •monophasic course

•History (antecedent infection or immunization) •Physical and neurological examination •MRI imaging •Cerebrospinal fluid (CSF) analysis

•Response to therapy Pathological •perivascular inflammation, demyelination •Clinical and radiographic course over time

Differentiating ADEM From MS

ADEM: Precipitating Events

Neurologic Complications of the Semple Rabies Vaccine: Human EAE?

Postvaccination encephalomyelitis •rabies •others? (influenza, DPT, hepatitis B, etc.) Postinfectious encephalomyelitis •measles • o t h e r s ( r u b e l l a , m u m p s , h e r p e s v i r u s e s, i n f l u e n z a , m y c o p l a s m a, e t c . ) D r u g -i n d u c e d Idiopathic

1885: Pasteur uses a spinal cord extract from a r a b i e s -i n f e c t e d r a b b i t a s p o s t -e x p o s u r e r a b i e s prophylaxis in humans

1 9 1 1 : S e m p l e d e v e l o p s t h e p h e n o l -i n a c t i v a t e d rabies vaccine (sheep or goat brain tissue)

1920-present : “neuroparalytic accidents” occur in ~1:400 Semple rabies vaccine recipients

“ S A E ” : S e m p l e v a c c i n e -i n d u c e d E ncephalomyelitis

Autoimmune

•156 cases out of 59,597 vaccinees in Bangkok, Thailand between 1961 and 1970 (~1:400)

•61 cases prospectively identified between 4/84 and 6/85 for further study

•major complications (36) included encephalitis, myelitis, polyradiculitis, or meningitis; minor complications (25) included headache, fever, inflammed injection sites, and normal CSF

Lymphoproliferation to Purified Myelin Basic Protein (MBP) in Semple Vaccine Recipients

Group uncomplicated vaccine Day 0 Day 7 Day 14

SI ± SEM

SI >2.0

1.3 ± 0.1 0.9 ± 0.2 1.1 ± 0.2

0/13 0/10 0/16

minor complications major complications

1.2 ± 0.1 2.1 ± 0.4

0/3 4/6

Measles Encephalomyelitis

•complicates 1:1000 cases of acute measles in children > 2 years of age •distinct from both SSPE and inclusion -body encephalitis seen in immunodeficient hosts • 1 0 -2 0 % a c u t e m o r t a l i t y ; l o n g-t e r m n e u r o l o g i c sequelae are common in survivors • E A E -l i k e p a t h o l o g y •no evidence of direct virus infection within the C N S o r v i r u s -s p e c i f i c a n t i b o d y i n t h e C S F

Measles Encephalomyelitis: Circulating T Cells Are Highly Reactive to Myelin Antigens (MBP)

P a t h o g e n e s i s o f M e a s l e s (P o s t i n f e c t i o u s ) Encephalomyelitis: Molecular Mimicry?

Group Measles encephalomyelitis uncomplicated disease Controls other demyelinating diseases other neurologic diseases normal children

SI >2.0

• a n t i g e n-s p e c i f i c T c e l l s g e n e r a t e d a g a i n s t v i r a l p e p t i d e s c r o s s -r e a c t t o s e l f ( m y e l i n ) e p i t o p e s , AND/OR • i n f e c t i o n a c t i v a t e s p r e -e x i s t i n g m y e l i n - s p e c i f i c T cells in the periphery

11/17* 5/42

3/3 2/17 0/6

• a c t i v a t e d , m y e l i n -s p e c i f i c T c e l l s e n t e r t h e C N S

•immune -mediated destruction of myelin (and axons?)

Lymphoproliferation To Human Myelin Basic Protein

Subtle Immunologic Differences in the Human CNS Inflammatory/ Demyelinating Disorders

Conclusions

MS

SAE

ADEM

•ADEM is an inflammatory/ demyelinating C N S disorder, usually with a monophasic course

HLA linkages

- DR2

- DR9 -DR17

-DR4 -DR5 •it often occurs shortly after a vaccination or infection

Primary MBP Ab epitope 8 4 -9 6 6 1 -8 0 N/A •many ADEM patients show enhanced immune responses against myelin antigens (MBP)

ADEM: Are There Immunologic Lessons Which Can Be Applied to TM?

Questions: •Is acute TM associated with elevated cellular and/or humoral immune responses to myelin? • C o u l d t h e r e b e o t h e r s p i n a l c o r d- s p e c i f i c t a r g e t antigens involved? •Can any of these early immune responses be correlated with the clinical course of disease? •How can the identification of such immune responses be translated into more rational therapy?