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.

Josep.dalmau@uphs.upenn.edu

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

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

Anti-Ma2 encephalitis: pathological features

Dalmau et al., Brain 2004;127:1831-1844

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)

Lancaster et al.

Neurology, 2011;

77:179-89.

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

Slide Unavailable

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

EEG in Anti-NMDAR encephalitis

Florance et al., Ann Neurol 2009;66:11-18

Extreme Delta Brush: a unique EEG pattern of

anti-NMDAR encephalitis

Schmitt S et al. Neurology 2012;79:1094-1100

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

Patient’s antibodies decrease the clusters of NMDAR

Dalmau et al.

Lancet Neurol

2008;7:1091

Patients’ antibodies decrease synaptic NMDAR currents

Hughes et al., J Neurosci 2010;30:5866-5875

Patients’ antibodies decrease NMDAR

cluster density in vivo

Hughes et al., J Neurosci 2010;30:5866-5875

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

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

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

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

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

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