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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
• Limbic encephalitis
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
• Limbic encephalitis
• Refractory seizures
Synaptic intracellular
Amphiphysin, GAD65
AIME
LE
PND
2015 1900 1956 1965 2001
The History of AIME
© GS Day, 2015
• Limbic encephalitis
• Refractory seizures
Synaptic intracellular
Amphiphysin, GAD65
2015 1900 1956 1965 2001
AIME
LE
PND
Honnorat et al. 2001—Arch Neurol
The History of AIME
© GS Day, 2015
• Limbic encephalitis
• Refractory seizures
Synaptic intracellular
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
• Limbic encephalitis
• 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
Early Modern Period:
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
Pillai et al. 2015—Pediatrics
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
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- 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
Pillai et al. 2015—Pediatrics
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
Hacohen et al. 2013—JNNP
CSF studies
Neuroimaging
- Normal structural imaging at
presentation (66-73%)
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
Titulaer et al, 2014—Lancet Neurol
CSF studies
Neuroimaging
- Normal structural imaging at
presentation (66-73%)
- Non-specific changes
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
Heine et al. 2015—Neuroscience
CSF studies
Neuroimaging
- Normal structural imaging at
presentation (66-73%)
- Non-specific changes
- Temporal lobe hyperintensities
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
CSF studies
Neuroimaging
EEG
- Abnormal (70-91%) at presentation
- Slowing (60-83%)
- Electrographic seizures (~20-60%)
Hacohen et al. 2014—JNNP
Pillai et al. 2015—Pediatrics
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
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
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
- May be associated with an autoantibody.
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
- May be associated with an autoantibody.
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
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
- May be associated with an autoantibody.
- May be associated with a tumor.
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
- May be associated with an autoantibody.
- May be associated with a tumor.
Discovery of tumor - Rare in pediatric cases
- Risk increases with age
© GS Day, 2015
Recognizing AIME
Autoimmune Mediated Encephalopathy - Syndrome of neurological and/or psychiatric dysfunction affecting
one or more brain systems.
- Associated with an immune-response compromising brain function.
- May be associated with an autoantibody.
- May be associated with a tumor.
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
Early Modern Period:
Industrial Revolution
© GS Day, 2015
Paraneoplastic Testing (Mayo)
Testing for AIME?
© GS Day, 2015
AutoAb-Mediated Testing (Mayo)
Testing for AIME?
© 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?
© 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
Early Modern Period:
Romantic Era
© GS Day, 2015
Outcomes?
Outcomes in pediatric AIME remain “good” following diagnosis
and treatment with immunosuppressive therapies.
Pillai et al. 2015—Pediatrics
LOS IV-V
All encephalitis 68.8%
Infectious 30.5%
AIME 74.5%
Hacohen et al. 2014—JNNP
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
Pillai et al. 2015—Pediatrics
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
Challenge: Improving Rates of Diagnosis
1. Increasing diagnostic suspicion.
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
Challenge: Improving Rates of Diagnosis
1. Increasing diagnostic suspicion.
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
Challenge: Improving Outcomes From Surviving to Thriving
1. Improved detection of deficits in follow-up.
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
Challenge: Improving Outcomes From Surviving to Thriving
1. Improved detection of deficits in follow-up.
2. Improved detection of patients at greatest risk of suffering
adverse long-term consequences.
3. Improved disease-specific treatments.
© GS Day, 2015
© 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