MRI of Autoimmune Encephalitis: an Interactive Tutorial eEdE-22 Control #: 1230 Richard A. Bronen, MD Professor of Diagnostic Radiology & Neurosurgery.

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.

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Return to multipleChoice question

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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)


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…


1960s

1970s - No, sorry… even earlier !

1980s

2000s

A

B

C

D


1960s

1970s

1980s – Nope, earlier than this.

2000s

A

B

C

D


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


Human Herpes VirusHHV6

C D

BA

Con

tin

ue t

o

pre

sen

tati

on


Herpes Simplex Virus 1HSV1


C D

BA

Con

tin

ue t

o

pre

sen

tati

on


Autoimmune


C D

BA

Con

tin

ue t

o

pre

sen

tati

on


Autoimmune


B

C D

A

Con

tin

ue t

o

pre

sen

tati

on


Which of the 2 cases below are autoimmune in etiology?


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



Ma2

HuCV2

Amphiphysin

LGI1

GAD

AMPA-RGABAB-R

Yo

Limbic Rarely Limbic

NMDA-R

MRI localization

INTRACELLULAR




Ma2

HuCV2

Amphiphysin

LGI1

GAD

AMPA-RGABAB-R

Yo


NMDA-R

MRI localization

INTRACELLULAR

Paraneoplastic

Rarely Paraneoplastic

Precedes tumor dx 70%


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


CORRECT!!




Lung Ca


problems


of cases


in 10-50% of cases





Lung Ca

WELL DONE!!!


problems


of cases


in 10-50% of cases





Lung Ca

YES!


problems


of cases


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…




Lung Ca


problems


of cases


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



Ma2

HuCV2

Amphiphysin

LGI1

GAD

AMPA-RGABAB-R

Yo


NMDA-R

MRI localization

INTRACELLULAR

Paraneoplastic




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



Ma2

HuCV2

Amphiphysin

LGI1

GAD

AMPA-RGABAB-R

Yo


NMDA-R

MRI localization

INTRACELLULAR

Paraneoplastic




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

MRI of Autoimmune Encephalitis: an Interactive Tutorial eEdE-22 Control #: 1230 Richard A. Bronen, MD Professor of Diagnostic Radiology & Neurosurgery.

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