ANTI-NMDA-RECEPTOR ENCEPHALITIS

Joint Program for European Medical StudiesNantes, 17th October 2014

Felix Gassert - Universität Ulm, GermanySara Mahmoud – Université d'Angers, France Sindy Sim – Université de Nantes, FranceBorbàla Szepes – University of Szeged, Hungary César Terán Zea – Universidad Espíritu Santo, Ecuador

Tutor: Dr. Franck Letournel

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

ConclusionMCQ at the end!

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

INTRODUCTIONneuropsychiatric immune-mediated disease

NMDA receptor involved: NR-1 subunit

often paraneoplastic

treatable

diagnosis: CSF sample +++

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

• 1

ligand gated cation channel

selective agonist N-methyl-D-aspartate and glutamate

Ca2+ and Na+ into the cell and K+ out of the cell

ubiquitously expressed in the brain

requirement for activation: glutamate + co-agonist (glycine or d-serine)

NMDA RECEPTOR

SUBTYPE COMPOSITION

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

CLINICAL FEATURES

psychiatric

neurological

others

• anxiety (initialacute)• behavioral changes,

psychosis• dementia

• short-term memory deficit• seizures• decreased consciousness

• autonomic instability• hypoventilation

PARACLINIC & DIAGNOSIS

• MRI often normal but possible fluid attenuation (T2)

• diagnosis by CSF samples

At symptoms presentation After recovery

paraneoplatic syndrome:tumors contain nervous tissue (express the NMDA receptor +++)ovarian teratomas +++women older than 18 testis teratomas

non-paraneoplasticsyndrome:auto-immunechildren ø tumorother immunology triggers (cf.physiopathlogy)

PARANEOPLASTICITY

paraneoplastic anti-NMDAR encephalitis auto-immune anti-NMDAR encephalitis

CHILDREN

• mostly non-paraneoplastic syndrome • psychosis less obvious• autonomic manifestations less severe

similar clinical features BUT:

• acute behavioral changes • seizures • dystonia or diskinesia

anti-NMDAR encephalitis suspected with:

EXPERIMENTAL APPROACH

Antibodies in CSF or serum react with extra cellular epitope of NR1 subunit

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

receptor

which?

NMDA-R

loss

how?

internalization

by

what way?

NR-1 subunittargeting

autoantibodies

what type?

IgG

PHYSIOPATHOLOGICALBACKGROUND

• what is anti-NMDA receptor encephalitis indeed on a molecular and cellular level?

IMMUNOLOGICAL TRIGGER

antibodies attack a physiologically present receptor abberant self-non-self differentiation

the disease can occur as a paraneoplastic syndromean existing tumor expresses NMDA-receptorsectopic receptor expression leads to the breakdown of immunological tolerance

unknown cause

leakyBBB

intrathecalsynthesis

circumventricularorgans

pathologicallybroken barrier

regionssensitive to

systematicalchanges

local plasma

cells

SOURCE OF ANTIBODIES

post synaptic site

NMDA

NMDA

AMPA

A M P A

NMDA

appearance of IgG antibodiesIgGs bind NR-1 NMDA-R subunit

internalisation in endocytotic vesicle

receptor cross-linkage

WHAT DO THESE CHANGES MEAN INFUNCTIONALITY?

• altered synaptic transmission and plasticitychange in receptor distribution

• insufficient glutamate signalingreduced receptor number

• LTP/LTD alterations• manifests as psychosis, memory deficitdecrease in mEPSC

LTD: long-term depressionLTP: long-term potentiationmEPSC: miniature excitatory end-plate current

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

TREATMENT

slow response

tumor resection

immunotherapy

Alemtuzumab

based on clinical symptoms, not on Ab titers

Introduction•NMDA Receptor•Clinical features•Physiopathology•Treatment

Conclusion

CONCLUSION

Routine medical assessments

Slow recovery

Prompt diagnosis

and treatment:

• better outcome

MCQ

Which of the following statements is/are true?A) The NMDAR consists out of two subunits, both binding

glycineB) Paraneoplastic syndrome is mostly observed in people

younger than 18C) ANRE is an autoimmune-mediated neuropsychiatric

diseaseD) NMDA-R internalisation is triggered by IgM antibodies,

resulting in irreversible receptor loss and cell deathE) Alemtuzumab is used as a first-line treatment in ANRE

THANK YOU VERY MUCH FOR YOUR ATTENTION!References:

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