MRI of Autoimmune Encephalitis: an Interactive Tutorial eEdE-22 Control #: 1230 Richard A. Bronen,...
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Transcript of MRI of Autoimmune Encephalitis: an Interactive Tutorial eEdE-22 Control #: 1230 Richard A. Bronen,...
MRI of Autoimmune Encephalitis:an Interactive Tutorial
eEdE-22Control #: 1230
Richard A. Bronen, MDProfessor of Diagnostic Radiology & NeurosurgeryVice Chair of Academic Affairs
Vahe M. Zohrabian, MDAssistant Professor of Diagnostic Radiology
William B. Zucconi, DOAssistant Professor of Diagnostic Radiology
Associate Residency Program Director, Diagnostic Radiology
Disclosure: No conflict of interest
• Dr. Zucconi: No disclosures• Dr. Zohrabian: No disclosures• Dr. Bronen: Consultant: Bristol-Myers Squibb
Instructions:
• Use “action buttons” whenever available to navigate the presentation. Some will only make a sound.
• If there is no action button, you may click anywhere on slide to advance a slide, bulleted list or other animation.
Previousslide
Nextslide
Try again!
Return to multipleChoice question
Click to continue…
Return to presentation
A B C DClick letter to answer
multiple choice questions
Purpose of this exercise:
• To update and engage the learner in an interactive tutorial on autoimmune encephalitis (AIE). The activity is intended for those with a beginning or intermediate level of understanding of this topic.
Approach:
• Novel memory aids and "clickable" items (questions, findings within MRI images, etc.) are embedded within the presentation in an interactive format to provide immediate feedback.
• Clinically proven cases of AIE are used for the exercise.
• Cases of clinically proven alternative diagnoses with similar imaging features also are included.
• A literature review was performed and salient points presented.
Autoimmune Encephalitis: Introduction
• Advances in the understanding of the pathophysiology and incidence of AIE necessitate rapid dissemination to the radiology community.
• Autoimmune encephalitis, formerly known as “Limbic encephalitis” may account for over 20% of encephalitis cases.
• From a radiologist's perspective, it is useful to separate those causes involving the limbic system from those which typically do not.
• Differentiation also is made between causes of AIE which are commonly paraneoplastic and those that are not associated with tumors.
Epidemiology
• Encephalitis (all causes) 2-3/100,000 annuallyHalf as common as MS – European
data– 40% infections– 40% unknown– 20+% autoimmune
• Auto-antibodies are formed to central nervous system antigens
– Anti-NMDA-R Antibody to: N-methyl D-aspartate receptor
– Anti-VGKC Antibody to: membrane and intracellular Voltage Gated K+ channel complex constituents:
• LGI1, VGKC, Amphiphysin, CV2
Membraneous: Glutamate –main excitatory neurotransmitter
NMDA: N-methyl-D-aspartateAMPA: alpha- amino-3HO-5-methyl-isoxazoleproprionic
acid
VGKC complex –Voltage gated potassium channel complex, assoc proteins
Membrane: LGI1 – Leucine rich glioma inactivated protein 1
Intracellular: CV2/CRMP5; Amphiphysin
Intracellular
VGKC Complex
NMDA AMPA
Glutamate receptors
LGI1 VGKC CV2
Am
phiphysinG G
G
cell membrane
Na+, Ca+2
Immune mechanisms: - Membrane: Receptors in cell membrane- Intracellular: Cytoplasmic proteins
Glutamate – main excitatory neurotransmitterNMDA: N-methyl-D-aspartate Antibody competitively
inhibits GAMPA: alpha- amino-3HO-5-methyl-isoxazoleproprionic acid
VGKC complex –Voltage gated potassium channel complex, assoc proteins
Membrane: LGI1 – Leucine rich glioma inactivated protein 1
Intracellular: CV2/CRMP5; Amphiphysin
Intracellular
VGKC Complex
NMDA AMPA
Glutamate receptors
LGI1 VGKC CV2
Am
phiphysin
G
Gab
Gab
ab
Treatment: 1. Remove instigating source Resect ovarian teratoma antigens2. Remove antibody Immune modulation; plasmapheresis
Q: When was limbic encephalitis first described?
1960s
1970s
1980s
2000s
A
B
C
D
(Click on letter)
Q: When was limbic encephalitis first described?
CORRECT!! One of the first references is from 1966, by L. Brain et al, in Lancet describing a patient with Hashimoto’sA
Click to continue…
Q: When was limbic encephalitis first described?
1960s
1970s - No, sorry… even earlier !
1980s
2000s
A
B
C
D
Q: When was limbic encephalitis first described?
1960s
1970s
1980s – Nope, earlier than this.
2000s
A
B
C
D
Q: When was limbic encephalitis first described?
1960s
1970s
1980s
2000s – Sorry, that’s incorrect. Quite a bit earlier…
A
B
C
D
Q: “Limbic encephalitis” was considered untreatable until…
1960s
1970s
1980s
2000s
A
B
C
D
Q: “Limbic encephalitis” was considered untreatable until…
1960s
1970s
1980s
2000s – Correct! VGKC IgG immune therapy responsive D
1975 1980 1985 1990 1995 2000 2005 2010 20150
1
2
3
4
5
6
7
MRI Human Autoimmune Brain Publications
Autoimmune and MRI
# P
ubli
cati
ons
History of Limbic Encephalitis (LE)
All Autoimmune
MRI350
300
250
200
150
100
50
All
VGKC IgGImmune therapy
responsive
NMDAR
1960
LE Paraneoplastic synd LE & SCLC LE always assoc
tumors, not treatable
Increasing neuroimaging awareness
Described
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…)
The challenge: Diagnose AIE early
A
C D
B
Con
tin
ue t
o
pre
sen
tati
on
The challenge: Diagnose AIE early
Human Herpes VirusHHV6
C D
BA
Con
tin
ue t
o
pre
sen
tati
on
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…)
Herpes Simplex Virus 1HSV1
The challenge: Diagnose AIE early
C D
BA
Con
tin
ue t
o
pre
sen
tati
on
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…)
Autoimmune
The challenge: Diagnose AIE early
C D
BA
Con
tin
ue t
o
pre
sen
tati
on
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…)
Autoimmune
The challenge: Diagnose AIE early
B
C D
A
Con
tin
ue t
o
pre
sen
tati
on
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…)
Which of the 2 cases below are autoimmune in etiology?
The challenge: Diagnose AIE early
AutoimmuneAutoimmune
Herpes Simplex Virus 1HSV1
Human Herpes VirusHHV6
Can we differentiate AIE from Viral Encephalitidies?Maybe not. But ….
awareness of imaging features of autoimmune encephalitis allows us to suggest the diagnosis
Imaging, with clinical & lab features, can provide a ddx/dx
Early diagnosis may lead to better outcomes
Classification Schemes of AIE
• Cellular location of the CNS antigen– Membrane
– Intracellular
• Area of Brain Involvement– Limbic– Rarely limbic/ extra-limbic
• Tumor association (Yes or no)– Paraneoplastic– Rarely associated with tumor
GLUTAMATE: NMDA-R, AMPA-R
Hu, Ma2, Yo, CV2, Amphiphysin
NMDA-R, LGI1, Hu, Ma2
Yo, CV2, Amphiphysin
Hu, Ma2, Yo, CV2
LGI1, GAD
VGKC: LGI1
Classification Schemes (Common AIE antibodies)
The antigens can be organized according to this scheme in the following cell pictograph:
Classification Schemes 1. Membraneous vs Intracellular (Common AIE antibodies) 2. Limbic vs rarely limbic
3. Paraneoplastic vs rarely assoc w/ tumors
Ma2
HuCV2
Amphiphysin
LGI1
GAD
AMPA-RGABAB-R
Yo
NMDA-RINTRACELLULAR
CELL MEMBRANE ANTIGENS
Classification Schemes 1. Membraneous vs Intracellular (Common AIE antibodies) 2. Limbic vs rarely limbic
3. Paraneoplastic vs rarely assoc w/ tumors
Ma2
HuCV2
Amphiphysin
LGI1
GAD
AMPA-RGABAB-R
Yo
Limbic Rarely Limbic
NMDA-R
MRI localization
INTRACELLULAR
CELL MEMBRANE ANTIGENS
Classification Schemes 1. Membraneous vs Intracellular (Common AIE antibodies) 2. Limbic vs rarely limbic
3. Paraneoplastic vs rarely assoc w/ tumors
Ma2
HuCV2
Amphiphysin
LGI1
GAD
AMPA-RGABAB-R
Yo
Limbic Rarely Limbic
NMDA-R
MRI localization
INTRACELLULAR
Paraneoplastic
Rarely Paraneoplastic
Precedes tumor dx 70%
CELL MEMBRANE ANTIGENS
Intracellular Antigen AIE (classic example)
27 yo male with testicular cancer. Asymmetric limbic & hypothalamic changes, nodular enhancement
------------------- 6 months later ----------------------
• Ma2 (anti-Ma2 encephalitis)– Hypothalamic or brainstem dysfunction– Limbic > hypothalamic, diencephalon, brainstem – ± nodular enhancement– Testicular tumor in younger males
• Ma2 (anti-Ma2 encephalitis)– Hypothalamic or brainstem dysfunction– Limbic > hypothalamic, diencephalon, brainstem – ± nodular enhancement– Testicular tumor in younger males
• Yo (anti-Yo encephalitis)– Most common paraneoplastic cerebellar AIE– Cerebellar atrophy– Intracellular antigens in Purkinje cells– Ovarian & breast ca
Intracellular Antigen AIE (examples of classic)
27 yo male with testicular cancer. Asymmetric limbic & hypothalamic changes, nodular enhancement
------------------- 6 months later ----------------------
• Ma2 – Hypothalamic or brainstem dysfunction– Limbic > diencephalon, brainstem– Testicular germinal cell tumor in younger males
(Lung/breast ca)
• Yo (anti-Yo encephalitis)– Most common paraneoplastic cerebellar AIE– Cerebellar atrophy– Intracellular antigens in Purkinje cells– Ovarian & breast ca
Intracellular Antigen antibodies (classic)
44 yo presented with vertigo, unable to walk. Rhomboencephalitis associated with tumor
1 year later
Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see…
Clinical presentation:• Prodrome• Psychiatric
problems
MRI is abnormal in only 1/3
of cases
Associated with ovarian teratoma
in 10-50% of cases
May present with classic
facio-brachial dystonic seizure
Rarely paraneoplastic –occaisonally with
Lung Ca
Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see…
CORRECT!!
May present with classic
facio-brachial dystonic seizure
Rarely paraneoplastic –occaisonally with
Lung Ca
Clinical presentation:• Prodrome• Psychiatric
problems
MRI is abnormal in only 1/3
of cases
Associated with ovarian teratoma
in 10-50% of cases
Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see…
May present with classic
facio-brachial dystonic seizure
Rarely paraneoplastic –occaisonally with
Lung Ca
WELL DONE!!!
Clinical presentation:• Prodrome• Psychiatric
problems
MRI is abnormal in only 1/3
of cases
Associated with ovarian teratoma
in 10-50% of cases
Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see…
May present with classic
facio-brachial dystonic seizure
Rarely paraneoplastic –occaisonally with
Lung Ca
YES!
Clinical presentation:• Prodrome• Psychiatric
problems
MRI is abnormal in only 1/3
of cases
Associated with ovarian teratoma
in 10-50% of cases
Of the 2 common membrane receptor antibody AIEs, which of the following are associated with anti-NMDAR (as compared with LGI1) ? Click to see…
May present with classic
facio-brachial dystonic seizure
Rarely paraneoplastic –occaisonally with
Lung Ca
Clinical presentation:• Prodrome• Psychiatric
problems
MRI is abnormal in only 1/3
of cases
Associated with ovarian teratoma
in 10-50% of cases
LGI1, VGKC
LGI1, VGKC
NMDA-R
NMDA-R
NMDA-R
Anti-NMDAR Anti-LGI1
Freq (approx) 55% 30%
Clinical 1. Prodromal2. Psych, seizure,
amnesia3. Movement,
autonomic dysfunction
Limbic encephalitis,Facio-brachial dystonic seizure
MRI abn 33% >80%
MRI findings • 25% limbic• Enhancement is rare
Limbic
CSF pleocytosis
95% 40%
Tumor 10-50%• Ovarian teratoma
<10%• Lung, thymoma
Relapses <25% 15%
Misc EEG abn 90% • Hyponatremia
AIE due to antibodies to: Neuronal Surface Antigen
Modified from Leypoldt Europ Neurol Review, 2013
Anti-NMDA
Case 1: Insular & ± amygdala
Case 2: Bilat symmetric hippo
Case 3: Bilat asymmetric hippocampal & amygdala ∆s
Case 4: Anti NMDAR Encephalitis
• 19 yo F with 2-3 mo progressive confusion, flat affect (Phase 2)
• MRI neg • EEG bilat, CSF: pleocytosis• Treatment: Acyclovir, antibiotics
Transferred to Yale• CSF: pleocytosis
viral PCR & culture– neg• Repeat EEG – extreme delta brush pattern, repeat MRI neg• Treated with 5 days Solumedrol• Confusion worsened, started on IVIg
Case 4: Anti NMDAR Encephalitis
10d later• Developed oro-facial dyskinesia, tachycardia, tachypnea,
with periods of apnea (Phase 3: movement disorders & autonomic instability)
• 3rd MRI - subtle bilateral asymmetric hippocampal signal changes
• Results: CSF & serum anti-NMDA antibodies• Paraneoplastic screening commenced:
– CT chest/abd/pelvis; Pelvic US & MRI negative; no ovarian teratoma
• No improvement
Classification Schemes 1. Membraneous vs Intracellular (Common AIE antibodies) 2. Limbic vs rarely limbic
3. Paraneoplastic vs rarely assoc w/ tumors
Ma2
HuCV2
Amphiphysin
LGI1
GAD
AMPA-RGABAB-R
Yo
Limbic Rarely Limbic
NMDA-R
MRI localization
INTRACELLULAR
Paraneoplastic
Rarely Paraneoplastic
Precedes tumor dx 70%
CELL MEMBRANE ANTIGENS
Anti LGI1Case 1: Predominantly wm & unilat hippocampus
Case 2: Bilat asym hippo/amygdala DWI & contrast - neg
1 month Case 3: Bilat symmetric hippo
Case 4: Anti- LGI1 encephalitis
Clinical
• 58 yo M rapidly progressive intermittent confusion, memory loss, & twitching of tongue and face
• EEG – bilat temp
MRI
• R caudate & putamen: DWI+, ADC-
• Bilateral limbic
Lab• Na: 125
• CSF: unremarkable, HSV PCR neg
Diagnosis at outside hospital: Creutzfeldt-Jacob Disease
Yoo. JAMA Neurol. 2014;71(1):79-82
Case 4: Anti- LGI1 encephalitisYale• New onset seizure, fluctuating cognitive & behavioral ∆,
periodic facial contortions, hand periodic dystonia• Faciobrachial dystonic seizures (pathognomonic anti-
LGI1), misdiagnosed as at outside hospital as myoclonus• Anti-LGI1 ab – positive • Treatment: Complete resolution of symptoms
MRI – hippocampal & brain atrophy
2 year f/u2 mo p intial MRI
Classification Schemes 1. Membraneous vs Intracellular (Common AIE antibodies) 2. Limbic vs rarely limbic
3. Paraneoplastic vs rarely assoc w/ tumors
Ma2
HuCV2
Amphiphysin
LGI1
GAD
AMPA-RGABAB-R
Yo
Limbic Rarely Limbic
NMDA-R
MRI localization
INTRACELLULAR
Paraneoplastic
Rarely Paraneoplastic
Precedes tumor dx 70%
CELL MEMBRANE ANTIGENS
Differential Diagnosis Limbic Encephalitis
Ddx LE includes SLE, Sjogrens, Primary angiitis CNS – MRI abnormalities very rare
HSV1 Simplex HHV6 VZV Zoster
Clinical Seizure, HA, fever, confusion, personality
Confusion, HA memory loss, seizure
HA confusion, fever, meningeal signs, rash
MR: Limbic (unilat/bilat)
90% Frequent 40-70%
HSV HHV6 Status epilepticus
Modified from Leypoldt Europ Neurol Review, 2013
Differential Diagnosis: Bilateral Temporal Hyperintensities
Clinical LobeFeature
DWI SWI Gd
LimbicEncephalitis
Memory Med - - -
HSV Fever, szMed; Ant
Restrict
Blood
Gyriform
MTS CPS MedHippo atrophy
- - -
GliomatosisCerebri
HA, szMed; Ant
White matter
- - ±
Modified from Sureka, Jakkani BJR 2012Retrospective review of records 2007-2010, n=65
Herpes simplex vs Autoimmune Encephalitis
Features p<0.05 HSV (%) AIE (%)Psychiatric presentation 0 60Acute onset 92 10Fever 92 20Aphasia 67 20
MRI Findings - abn 100 60Insular 91 33Diffuse temp lobe 91 33No basal ganglia 82 0Only mesial 9 67
--- Lots of overlap ---(MR∆ not signif: bilat, DWI, Gd, hippo & amygdala, thal, par, front, occ, midbrain)
Oyanguren Eur J Neurol 2013
1999-2012: 12 HSV1 vs 10 AIE
Autoimmune Encephalitis: Summary
• AIE appears to be almost as common as HSV• Prompt recognition – allows early Rx & improve
outcomes
• MR findings:– Often limbic, but also extralimbic– Amygdala & hippocampal: unilat, bilat sym, bilat
asym– Other AIE: brainstem, cerebellar – Atypical features: restricted diffusion or
enhancement
• Ddx: Few differences to distinguish AIE from HSV, HHV6, ictal changes or viruses at the level of an individual patient– PCR or specific electro-clinical features critical to
diagnosis
Saket Neurographics 2011
Acknowledgements & References
• Acknowledgements – cases & material– Jiyeoun Yoo– Pue Farooque– Joachim Baehring– Larry Hirsch
• Key References– Leypoldt European Neurological Review, 2013;8(1):31-7– Saket Neurographics 2011 – Autoimmune Encephalitis EFNS Guidelines Eur J Neurol
2010– Sureka Jakkani BJR 2012– Oyanguren Eur J Neurol 2013– Varadkar Lancet Neurology 2014– Bien. European consensus statement Brain 2005– Bien Neurology 2002; Pradeep Acta Neurol Scand 2013– Bien Ann Neurology 2002– Ramussen Neurology 1958