(Neuroimmunological) Lessons From Acute Major Inflammatory Demyelinating Disorders of

Disseminated Encephalomyelitis (ADEM) the CNS

•Multiple Sclerosis (MS)

•Acute Disseminated Encephalomyelitis (ADEM)

• 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.)
David N. Irani, M.D.
---------------------------------------------------------------- - - - -
Assistant Professor of Neurology
•Experimental Autoimmune Encephalomyelitis
The Johns Hopkins University
(EAE)
School of Medicine

ADEM: Definitions and Features ADEM: Diagnosis

Clinical •History (antecedent infection or immunization)

•rapid onset •Physical and neurological examination
•focal or multifocal neurologic d y s f u n c t i o n •MRI imaging
•recent infection or immunization •Cerebrospinal fluid (CSF) analysis
•monophasic course
•Response to therapy
Pathological •Clinical and radiographic course over time
•perivascular inflammation, demyelination

Differentiating ADEM From MS

 Neurologic Complications of the Semple Rabies
ADEM: Precipitating Events Vaccine: Human EAE?

Postvaccination encephalomyelitis 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
•rabies
prophylaxis in humans
•others? (influenza, DPT, hepatitis B, etc.)
Postinfectious encephalomyelitis
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
•measles rabies vaccine (sheep or goat brain tissue)
• 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 . )
1920-present : “neuroparalytic accidents” occur
D r u g -i n d u c e d in ~1:400 Semple rabies vaccine recipients
Idiopathic

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

•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 SI ± SEM SI >2.0

uncomplicated vaccine
Day 0 1.3 ± 0.1 0/13
Day 7 0.9 ± 0.2 0/10
Day 14 1.1 ± 0.2 0/16

minor complications 1.2 ± 0.1 0/3

major complications 2.1 ± 0.4 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 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 )
Are Highly Reactive to Myelin Antigens (MBP) Encephalomyelitis: Molecular Mimicry?

Group 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 ,
Measles
AND/OR
encephalomyelitis 11/17*
• 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
uncomplicated disease 5/42 T cells in the periphery
Controls
other demyelinating diseases 3/3 • 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
other neurologic diseases 2/17
normal children 0/6 •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 -DR4

-DR17 -DR5 •it often occurs shortly after a vaccination or
infection

Primary MBP
•many ADEM patients show enhanced immune
Ab epitope 8 4 -9 6 6 1 -8 0 N/A 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?