autoimmune-mediated encephalitis in the modern era€¦ · challenge: improving rates of diagnosis...

Autoimmune-Mediated Encephalitis

in the Modern Era

August 7th, 2015

Gregory Day, MD, MSc, FRCPC (Neurology) Eugene M Johnson, Jr. Weston Brain Institute Postdoctoral Fellow

© GS Day, 2015

Disclosures of Interest

GS Day is the Eugene M Johnson, Jr. Weston Brain Institute Postdoctoral

Fellow, and a recipient of the American Academy of Neurology Clinical

Research Training Fellowship.

GS Day is a founding member of the Anti-NMDA Receptor Encephalitis

Foundation (Inc., Canada), and currently serves as the Clinical Director.

The Foundation is supported by private donations. No compensation is

provided for Foundation work.

Current (unrelated) research projects are supported by an in-kind gift of

radiopharmaceuticals from Avid Radiopharmaceuticals.

GS Day holds stocks (>$10,000) in ANI Pharmaceuticals (a generic

pharmaceutical company).

© GS Day, 2015

Objectives

1. Review the history of AutoImmune-Mediated Encephalitis

(AIME).

2. Identify clinical and paraclinical features associated with

AIME.

3. Prioritize diagnostic investigations in patients with suspected

or confirmed AIME.

4. Recognize challenges in the acute and chronic management

of patients with AIME.

© GS Day, 2015

Neurology:

The Dark Ages

© GS Day, 2015

‘Saint Catherine of Siena Exorcising a Possessed Woman’

Girolamo di Benvenuto, circa 1500

The Dark History of Neurology

© GS Day, 2015

The Dark History of Neurology

Woman acting bizarrely

Is her uterus wandering?

Fix it! Is she demon-possessed?

Is she a witch? Perform an exorcism

Too late: we already burned her

Burn her! Did it work?

Yes No

No Yes

Yes

No

Yes No

© GS Day, 2015

Early Modern Period:

Age of Discovery

© GS Day, 2015

Cases of “derangement” or “encephalitis”, with

accompanying respiratory infection dot the clinical literature

over the past centuries. A “para-infectious” process is

hypothesized.

Putnam, 1895—Am J Med Sci

Florance and Dalmau, 2010—Ann Neurol

1900 2015

The History of AIME

© GS Day, 2015

2015 1900 1956

PND

Guichard et al. 1956—Lyon Medicale

“Paraneoplastic” causes are included in the differential diagnosis

of a group of patients with metastatic neoplasms presenting with

multiple neuropathies, but without evidence of neoplastic

invasion.

The History of AIME

© GS Day, 2015

2015 1900 1956

“Mental disorder” described in association with lung cancer.

Charatan and Brierly, 1956—Br Med J

The History of AIME

PND

© GS Day, 2015

2015 1900 1956

Wilkinson and Zeromski, 1965—Brain

Organ-specific antibodies against saline extracts of brain

detected using “novel” immunofluorescent techniques in 5 of 34

patients with PND associated with carcinoma.

1965

The History of AIME

AIME

PND

© GS Day, 2015

2015 1900 1956 1965

The History of AIME

© GS Day, 2015

2015

1900

1956 1965

Lancaster and Dalmau, Nat Review Neurol., 2012

Intracellular

Hu, Ma2, CRMP5

• Encephalomyelitis

• Limbic encephalitis

AIME

LE

PND

1900

The History of AIME

© GS Day, 2015

2015

1900

1956 1965

Intracellular

Hu, Ma2, CRMP5

• Encephalomyelitis


1900

Gozzard et al. 2015—Neurology

N=264 PND N=24 (9.4%)

- LEMS

- Sensory

neuronopathy

- Limbic

encephalitis

The History of AIME

© GS Day, 2015


• Refractory seizures

Synaptic intracellular

Amphiphysin, GAD65

AIME

LE

PND

2015 1900 1956 1965 2001

The History of AIME

© GS Day, 2015




Amphiphysin, GAD65

2015 1900 1956 1965 2001

AIME

LE

PND

Honnorat et al. 2001—Arch Neurol

The History of AIME

© GS Day, 2015




Amphiphysin, GAD65

Korff et al. 2011—Arch Neurol

Mishra et al. 2014—J Child Neurol

2015 1900 1956 1965 2001

The History of AIME

© GS Day, 2015

2015 1900 1956 1965 2001

The History of AIME

Church et al. 2002—Neurology

AIME

LE

PNS

“Some humor”—1686

Ischemia—1860

Hysteria—1894

Infection—1903

Inflammation—1920

Post-infectious—1956

2002

© GS Day, 2015

2015 1900 1956 1965 2001

2007

Autoantibodies targeting central nervous system NMDA

receptors in 12 women with ovarian teratomas, psychiatric

symptoms and progressive encephalopathy.

Dalmau et al, 2007—Ann Neurol

The History of AIME

© GS Day, 2015

2015 1900 1956 1965 2001

2007

Lancaster and Dalmau, Nat Review Neurol., 2012

• Psychoses


• Movement disorders

• Autonomic instability

• Sleep disorders

Cell surface/synaptic

receptors

NMDAR, AMPAR,

GABA(B), LGI1,

Caspr2, other

AIME

AME PNS

LE

The History of AIME

© GS Day, 2015

2015 1900 1956 1965 2001

2007

Clinical update describing disease characteristics, response

to treatment and outcomes in 577 patients with NMDA-

receptor encephalitis (NMDAR encephalitis).

Titulaer et al, 2013—Lancet Neurol

Behavioral disturbance; Seizures;

Memory deficit; Cognitive disturbance

Speech disorder; Movement disorder;

Impaired level of consciousness; Other

The History of AIME

© GS Day, 2015


Age of Enlightenment

© GS Day, 2015

Recognizing AIME

?

© GS Day, 2015

From 2000-2010 >230 000 adult patients were hospitalized

within US acute-care hospitals with a diagnosis of encephalitis.

- 7.3±0.2 per 100 000

Recognizing AIME

George et al 2014—PLOS © GS Day, 2015

From 2000-2010 >230 000 adult patients were hospitalized

within US acute-care hospitals with a diagnosis of encephalitis.

- 7.3±0.2 per 100 000

Patients hospitalized with encephalitis due to “Other Specified

Causes”:

- Twice as likely to be females.

- Comprised predominantly of AIME.

Recognizing AIME

George et al 2014—PLOS © GS Day, 2015

Pillai et al. 2015—Pediatrics

Post-

infectious

8%

AIME

34%

Infectious

30%

?

28%

N=164

1998-2010

Recognizing AIME

© GS Day, 2015


Recognizing AIME

© GS Day, 2015

Recognizing AIME

Neurological

- Altered LOC

- Memory loss

- Language / speech impairment

- Cortical disturbance (sensory /

motor / other)

- CNS hyperexcitabilty

- Sleep disturbances

- Seizures

- Movement disorders (ataxia,

chorea, dystonia, automatisms,

stereotypies)

- Neuromyotonia

- Optic neuritis / myelitis

- Focal brainstem findings

- Autonomic instability

- Salt-wasting syndromes

Psychiatric

- Emotional/behavioral disturbances

- Disinhibition

- Apathy, fear, depression, anxiety

- Thought disorder

- Delusions

- Hallucinations (auditory or visual)

- Obsessions / compulsions

- Aggression

- Hypersexuality

- Catatonia

*Symptoms / signs should represent a change from baseline,

with no alternate explanation or more plausible diagnoses.

Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting

one or more brain systems.

© GS Day, 2015

Recognizing AIME



- Associated with an immune-response compromising brain function.

CSF studies

- Leukocytosis (17-80%)

- Increased protein (≤80%)

- Oligoclonal bands (32-60%)

Dalmau et al, 2011—Lancet Neurol

Hacohen et al. 2014—JNNP


© GS Day, 2015

Recognizing AIME





CSF studies

Neuroimaging

- Normal structural imaging at

presentation (66-73%)

© GS Day, 2015

Recognizing AIME




Titulaer et al, 2014—Lancet Neurol

CSF studies

Neuroimaging



- Non-specific changes

© GS Day, 2015

Recognizing AIME




Heine et al. 2015—Neuroscience

CSF studies

Neuroimaging



- Non-specific changes

- Temporal lobe hyperintensities

© GS Day, 2015

Recognizing AIME




CSF studies

Neuroimaging

EEG

- Abnormal (70-91%) at presentation

- Slowing (60-83%)

- Electrographic seizures (~20-60%)



© GS Day, 2015

Recognizing AIME




Schmitt et al, 2012—Neurology

CSF studies

Neuroimaging

EEG

- Abnormal (70-91%) at presentation

- Slowing (60-83%)

- Electrographic seizures (~20-60%)

- Extreme delta brush (30% of

patients with NMDARE)

© GS Day, 2015

Recognizing AIME




- May be associated with an autoantibody.

© GS Day, 2015

Recognizing AIME





Peery et al. 2012—Autoimmunity Rev

Nakahara et al. 2015—J of Neuroimmunology

Detection requiring...

- Immunocytochemistry

- Immunohistochemistry

- Cell-Based Assays

© GS Day, 2015

Recognizing AIME





- May be associated with a tumor.

© GS Day, 2015

Recognizing AIME






Discovery of tumor - Rare in pediatric cases

- Risk increases with age

© GS Day, 2015

Recognizing AIME






Discovery of tumor - Rare in pediatric cases

- Risk increases with age

- 0-50% of cases of patients

with AIME

Pati

ents

(%

)

Age (years) 0-6 13-18 35-30 37-42 49-54 61-66

0

25

50

75

100

73-78

Tumor identified

Dalmau et al, 2011—Lancet Neurol

NMDA Receptor Encephalitis

© GS Day, 2015

Consider AIME in all patients with:

• 1. Neurological and/or psychiatric dysfunction affecting one or

more brain systems (check two).

New behavioral / mood change

Altered level of consciousness

Seizures

Movement disorder

• 2. Investigations suggesting CNS inflammation (check one).

Neuroimaging

CSF analysis

• 3. No alternate explanation, despite adequate investigations.

Who to Test?

WUSTL- AIME Working Group – Consensus Criteria (in development) © GS Day, 2015

What to Test?

Paraneoplastic neurological syndromes:

- Serum first (consider reflex testing of CSF if negative)

Antibody-Mediated Encephalopathy

- Remains important to test CSF and serum.

© GS Day, 2015

NMDAR Encephalitis: CSF is more sensitive than serum.

100

0

50

CSF Serum

Sensitiv

ity N

=250 c

ases, 1

00 c

ontro

ls

85.6%

Gresa-Arribas et al, 2014—Lancet Neurol

***

Sensitivity

What to Test?

© GS Day, 2015

Outcomes?

Outcomes in pediatric AIME remain “good” following diagnosis

and treatment with immunosuppressive therapies.


LOS IV-V

All encephalitis 68.8%

Infectious 30.5%

AIME 74.5%


Residual Deficit

58% Full Recovery

42%

20

4 2 1

7

0 0

0

5

7 3

Cognitive

Motor

© GS Day, 2015

Outcomes?

Better outcomes associated with:

- Earlier diagnosis

- Earlier treatment


Hacohen et al. 2014—JNNP © GS Day, 2015

Challenge: Improving Rates of Diagnosis

1. Increasing diagnostic suspicion.

Consider AIME in all patients with:

• 1. Neurological and/or psychiatric dysfunction affecting one or

more brain systems (check two):

New behavioral / mood change

Altered level of consciousness

Seizures

Movement disorder

• 2. Investigations suggesting CNS inflammation (check one).

Neuroimaging

CSF analysis

• 3. No alternate explanation, despite adequate investigations. © GS Day, 2015



2. Increasing availability (and affordability) of diagnostic testing.

Additional options for testing:

Locally available (BJC and WUSM) - NMDA receptor autoantibodies

- GAD-65 autoantibodies

Other - Athena Diagnostics

- ARUP Laboratories

- Research Laboratories © GS Day, 2015

? - PANDAS/PANS

- Tourette’s syndrome

- Sydenham’s chorea

- BG encephalitis

- Teratoma-associated

encephalopathy

AIME

AME



2. Increasing availability (and affordability) of diagnostic testing.

3. Promoting clinical characterization and investigation of

“unknown” cases.

1999:

2007: © GS Day, 2015

Challenge: Improving Outcomes From Surviving to Thriving

1. Improved detection of deficits in follow-up.

Requires standardized recommendations for treatment and age-

appropriate measures for follow-up that address the following

domains... Cognitive

Motor © GS Day, 2015



2. Improved detection of patients at greatest risk of suffering

adverse long-term consequences.

Need “retrospective” studies to confirm natural history of specific

diseases, and prospective measures to evaluate the utility of

existing biomarkers in predicting outcomes.

AIME Working Group

© GS Day, 2015

http://centerserv.wustl.edu/



2. Improved detection of patients at greatest risk of suffering

adverse long-term consequences.

3. Improved disease-specific treatments.

© GS Day, 2015

Neurology: John Morris, Anne Fagan, Beau Ances

Bob Bucelli, Amar Dhand, Nupur Ghoshal, Gabriela

DeBruin, Arun Varadhachary, Greg Wu, Matt Brier

Psychiatry: Gene Rubin, Nuri Farber, Eric Lenze

Rheumatology: Tiphanie Vogel, John Atkinson

Radiology: Tammie Benzinger

Pediatrics: Soe Mar, Greg Storch, Brad Schlagger

Infectious Disease: Robyn Klein

Neuropathology: Nigel Cairns, Borris Calderon, Robert Schmidt

WUSTL Efforts in AIME

© GS Day, 2015

?

[email protected]

@AntiNMDA_Inc

© GS Day, 2015

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autoimmune-mediated encephalitis in the modern era€¦ · challenge: improving rates of diagnosis...

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