“Paraneoplastic and autoimmuneaz9194.vo.msecnd.net/pdfs/121201/204.04.pdfDalmau et al., . Lancet...
Transcript of “Paraneoplastic and autoimmuneaz9194.vo.msecnd.net/pdfs/121201/204.04.pdfDalmau et al., . Lancet...
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American Epilepsy Society | Annual Meeting
“Paraneoplastic and autoimmune
encephalitis resulting in refractory
status epilepticus”
Josep Dalmau, MD, PhD
ICREA Research Professor at IDIBAPS/Hospital Clinic,
University of Barcelona
Adjunct Professor of Neurology, University of Pennsylvania.
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Disclosure
Dr. Dalmau has received license fee payments from
Euroimmun. He receives royalties from Athena Diagnostics
and Euroimmun for patents related to Ma2 and NMDA
receptor antibody testing
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Lancaster and Dalmau, Nat Review Neurol 2012;8:380-390
Intracellular
HuD; Ma2, CRMP5
• Encephalomyelitis
• Limbic encephalitis
Synaptic
intracellular
Amphiphysin;
GAD65
• Limbic
encephalitis,
• Refractory seizures
Cell surface/
synaptic
receptors
NMDAR; AMPAR;
GABA(B); LGI1;
Caspr2; other
• Psychosis
• Limbic encephalitis
• Dyskinesias
• Seizures
• Level of
consciousness,
• Sleep dysfunction
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Anti-Ma2 encephalitis: pathological features
Dalmau et al., Brain 2004;127:1831-1844
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Syndrome Clinical
significance
Response to
immunotherapy
GluR3
(AMPA
receptor)
Rasmussen’s
encephalitis (?) Low
Infrequent/
moderate
TPO Hashimoto’s
encephalitis Low Frequent
NR2A, NR2B
(NMDAR)
Non-specific,
lupus, stroke,
Rasmussen’s
None Unclear
Other antibodies associated to epilepsy
(usually non-paraneoplastic)
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Lancaster et al.
Neurology, 2011;
77:179-89.
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Prodrome
Agitation, psychosis,
catatonia, memory
deficit, speech reduction,
abnormal movements
+/- seizures
coma,
hypoventilation,
+/- dysautonomia
Clinical Worsening
Clinical Improvement
Anti-NMDAR encephalitis
Dalmau et al., . Lancet Neurol 2011;10:63-74
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Slide Unavailable
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Anti-NMDAR encephalitis in 577 patients:
First symptom
Seizures
Movement disorder
Level of consciousness
Speech disturbances
Behavior
Cognition
Memory loss
Other
Age < 12 years Age 12-17 years Age ≥ 18 years
Titulaer et al., Lancet Neurol, in press
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EEG in Anti-NMDAR encephalitis
Florance et al., Ann Neurol 2009;66:11-18
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Extreme Delta Brush: a unique EEG pattern of
anti-NMDAR encephalitis
Schmitt S et al. Neurology 2012;79:1094-1100
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Anti-NMDAR encephalitis in 501 patients:
Improvement (median follow-up 24 months)
Patients 501 450 382 307 252
0%
20%
40%
60%
80%
100%
4 8 12 18 24
6
5
4
3
2
1
0
months
Modified
Rankin Scale
Titulaer et al., Lancet Neurol, in press
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Patient’s antibodies decrease the clusters of NMDAR
Dalmau et al.
Lancet Neurol
2008;7:1091
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Patients’ antibodies decrease synaptic NMDAR currents
Hughes et al., J Neurosci 2010;30:5866-5875
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Patients’ antibodies decrease NMDAR
cluster density in vivo
Hughes et al., J Neurosci 2010;30:5866-5875
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Disorders of synaptic/cell surface autoimmunity
Antigen Syndrome and main features
NMDA-R Anti-NMDAR encephalitis
GABA-B Limbic encephalitis with prominent seizures, status
AMPA Limbic encephalitis, psychosis
LGI1 Limbic encephalitis, myoclonus, hyponatremia
Caspr2 Encephalitis and/or neuromyotonia
GlyR Stiff-person syndrome, hyperekplexia, PERM
mGluR5 Ophelia syndrome
DPPX (Kv4.2) Agitation, myoclonus, tremor, seizures, diarrhea
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20 mV
5 sec
Control CSF (1%), 24 hours
Patients’ antibodies block GABABR function
100 µM
Baclofen
Patient CSF (1%), 24 hours
100 µM
Baclofen
Lancaster et al., not reported
Slide Unavailable
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LGI1
“VGKC-
complex
antibodies”
Encephalitis,
neuromyotonia
Morvan’s syndrome,
painful neuropathy
CASPR2
Limbic encephalitis,
hyponatremia,
myoclonic-like
movements (tonic
seizures, facio-brachial
dystonic seizures)
Multiple disorders Unknown
antigens
Rosenfeld M et al., Neurology: Clin Practice 2012; 1(September):215-222
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LGI1
•Secreted synaptic protein
•Associates with VGKCs and AMPA
receptors via the ADAM proteins
•LGI1-null mice have seizures,
early death
•Human mutations associate with
“autosomal dominant lateral
temporal lobe epilepsy”
Post-synaptic
Pre-synaptic
LGI1
ADAM23
ADAM22 AMPA-R
VGKC
LGI1
LGI1
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Tonic seizures
in anti-LGI1
encephalitis
Andrade et al., Neurology
2011;76:1355-1357
Irani et al., Ann Neurol 2010, Oct 28.
doi: 10.1002/ana.22307
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Clinical, neuroimaging,
serum and CSF evaluation
Exclusion of other
disorders
Tumor surveillance,
chronic mmunosuppression
Response
Rituximab,
cyclophosphamide
No response
Antibodies to intraneuronal
proteins
Onconeuronal antigens
Hu, Ma2, CRMP5, amphiphysin
Oncologic treatment +
T-cell suppression
Antibodies to cell surface or
synaptic proteins
NMDAR,, GABA(B)R, AMPAR, LGI1,
Caspr2, GlyR, unknown antigens
Corticosteroids, IVIg, plasma exchange +
tumor removal if present
Autoimmune Encephalitis: Diagnosis and Treatment
Lancaster et al., Neurology 2011;77:179-189