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MRI of Autoimmune Encephalitis: an Interactive Tutorial eEdE-22 Control #: 1230
William B. Zucconi, DO Assistant Professor of Diagnostic Radiology Associate Residency Program Director, Diagnostic Radiology Vahe M. Zohrabian, MD Assistant Professor of Diagnostic Radiology Richard A. Bronen, MD Professor of Diagnostic Radiology & Neurosurgery Vice Chair of Academic Affairs Control #: 1230 Title: MRI of Autoimmune Encephalitis: An Interactive Tutorial eEdE#: eEdE-22 (Shared Display)
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Disclosure: No conflict of interest
Dr. Zucconi: No disclosures Dr. Zohrabian: No disclosures Dr. Bronen: Consultant: Bristol-Myers Squibb
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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. Click to continue… Try again! Previous slide Next slide Return to multiple Choice question Return to presentation A B C D Click letter to answer multiple choice questions
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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.
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Clinically proven cases of AIE are used for the exercise.
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.
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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.
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Epidemiology Encephalitis (all causes) 2-3/100,000 annually Half 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
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- Membrane: Receptors in cell membrane
Immune mechanisms: - Membrane: Receptors in cell membrane - Intracellular: Cytoplasmic proteins Membraneous: Glutamate –main excitatory neurotransmitter NMDA: N-methyl-D-aspartate AMPA: 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 G G G Glutamate receptors VGKC Complex NMDA AMPA LGI1 VGKC CV2 Amphiphysin cell membrane Na+, Ca+2 Intracellular
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Glutamate – main excitatory neurotransmitter NMDA: N-methyl-D-aspartate Antibody competitively inhibits G AMPA: 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 ab Glutamate receptors VGKC Complex NMDA AMPA LGI1 VGKC CV2 G G ab ab Amphiphysin G Treatment: 1. Remove instigating source Resect ovarian teratoma antigens 2. Remove antibody Immune modulation; plasmapheresis Intracellular
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Q: When was limbic encephalitis first described?
(Click on letter) 1960s A 1970s B 1980s C 2000s D
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Q: When was limbic encephalitis first described?
CORRECT!! One of the first references was from 1966, by Dr. a 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’s A Click to continue…
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Q: When was limbic encephalitis first described?
CORRECT!! One of the first references was from 1966, by Dr. a Q: When was limbic encephalitis first described? 1960s A 1970s - No, sorry… even earlier ! B 1980s C 2000s D
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Q: When was limbic encephalitis first described?
CORRECT!! One of the first references was from 1966, by Dr. a Q: When was limbic encephalitis first described? 1960s A 1970s B 1980s – Nope, earlier than this. C 2000s D
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Q: When was limbic encephalitis first described?
CORRECT!! One of the first references was from 1966, by Dr. a Q: When was limbic encephalitis first described? 1960s A 1970s B 1980s C 2000s – Sorry, that’s incorrect. Quite a bit earlier… D
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Q: “Limbic encephalitis” was considered untreatable until…
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Q: “Limbic encephalitis” was considered untreatable until…
2000s – Correct! VGKC IgG immune therapy responsive D
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History of Limbic Encephalitis (LE)
Increasing neuroimaging awareness All MRI 1960 LE Paraneoplastic synd LE & SCLC VGKC IgG Immune therapy responsive NMDAR Described LE always assoc tumors, not treatable
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The challenge: Diagnose AIE early
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…) A B Continue to presentation C D 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 early treatment & better outcomes
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The challenge: Diagnose AIE early
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…) Human Herpes Virus HHV6 A B Continue to presentation C D 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 early treatment & better outcomes
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The challenge: Diagnose AIE early
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…) A B Herpes Simplex Virus 1 HSV1 Continue to presentation C D 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 early treatment & better outcomes
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The challenge: Diagnose AIE early
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…) A B Continue to presentation C Autoimmune D 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 early treatment & better outcomes
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The challenge: Diagnose AIE early
Which of the 2 cases below are autoimmune in etiology? (Click letter to see…) A B Continue to presentation Autoimmune C D 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 early treatment & better outcomes
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The challenge: Diagnose AIE early
Can we differentiate AIE from Viral Encephalitidies? Which of the 2 cases below are autoimmune in etiology? 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 Human Herpes Virus HHV6 Herpes Simplex Virus 1 HSV1 Autoimmune Autoimmune
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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 VGKC: LGI1 GLUTAMATE: NMDA-R, AMPA-R Hu, Ma2, Yo, CV2, Amphiphysin NMDA-R, LGI1, Hu, Ma2 Yo, CV2, Amphiphysin Hu, Ma2, Yo, CV2 LGI1, GAD
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Classification Schemes
(Common AIE antibodies) The antigens can be organized according to this scheme in the following cell pictograph:
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Classification Schemes 1. Membraneous vs Intracellular
(Common AIE antibodies) 2. Limbic vs rarely limbic 3. Paraneoplastic vs rarely assoc w/ tumors AMPA-R GABAB-R Yo Hu CV2 Ma2 Amphiphysin INTRACELLULAR NMDA-R GAD LGI1 CELL MEMBRANE ANTIGENS
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Classification Schemes 1. Membraneous vs Intracellular
(Common AIE antibodies) 2. Limbic vs rarely limbic 3. Paraneoplastic vs rarely assoc w/ tumors MRI localization Limbic Rarely Limbic AMPA-R GABAB-R Yo Hu CV2 Ma2 Amphiphysin INTRACELLULAR NMDA-R GAD LGI1 CELL MEMBRANE ANTIGENS
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Classification Schemes 1. Membraneous vs Intracellular
(Common AIE antibodies) 2. Limbic vs rarely limbic 3. Paraneoplastic vs rarely assoc w/ tumors MRI localization Limbic Rarely Limbic AMPA-R GABAB-R Yo Hu CV2 Paraneoplastic Ma2 Amphiphysin Precedes tumor dx 70% INTRACELLULAR NMDA-R Rarely Paraneoplastic GAD LGI1 CELL MEMBRANE ANTIGENS
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Cytotoxic T-Cell Intracellular Antibody AIE - Usually Paraneoplastic
In concert with with cytotoxic T-cell immune response Primary cause of CNS immune toxicity Intracellular Antibody AIE - Usually Paraneoplastic Tumor Immune Response Example of Anti-CV2 antibody Tumor with Brain CV2 Antigen Glutamate receptors VGKC Complex NMDA AMPA LGI1 VGKC CV2 Amphiphysin ab ab ab Intracellular
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Intracellular Antigen AIE (classic example)
Ma (anti-Ma2 encephalitis) Hypothalamic or brainstem dysfunction Limbic > hypothalamic, diencephalon, brainstem ± nodular enhancement Testicular tumor in younger males 27 yo male with testicular cancer Asymmetric limbic & hypothalamic changes, nodular enhancement months later
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Intracellular Antigen AIE (examples of classic)
Ma (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 27 yo male with testicular cancer Asymmetric limbic & hypothalamic changes, nodular enhancement months later
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Intracellular Antigen antibodies (classic)
44 yo presented with vertigo, unable to walk. Rhomboencephalitis associated with tumor 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 1 year later
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Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see… Rarely paraneoplastic –occaisonally with Lung Ca MRI is abnormal in only 1/3 of cases Clinical presentation: Prodrome Psychiatric problems Associated with ovarian teratoma in 10-50% of cases May present with classic facio-brachial dystonic seizure
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Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see… Rarely paraneoplastic –occaisonally with Lung Ca MRI is abnormal in only 1/3 of cases CORRECT!! Clinical presentation: Prodrome Psychiatric problems Associated with ovarian teratoma in 10-50% of cases May present with classic facio-brachial dystonic seizure
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Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see… Rarely paraneoplastic –occaisonally with Lung Ca MRI is abnormal in only 1/3 of cases Clinical presentation: Prodrome Psychiatric problems WELL DONE!!! Associated with ovarian teratoma in 10-50% of cases May present with classic facio-brachial dystonic seizure
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Of the 2 common membrane receptor antibody AIEs, which of the following are associated with antiNMDAR Encephalitis (compared with LGI1) ? Click to see… Rarely paraneoplastic –occaisonally with Lung Ca MRI is abnormal in only 1/3 of cases Clinical presentation: Prodrome Psychiatric problems Associated with ovarian teratoma in 10-50% of cases May present with classic facio-brachial dystonic seizure YES!
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Of the 2 common membrane receptor antibody AIEs, which of the following are associated with anti-NMDAR (as compared with LGI1) ? Click to see… Rarely paraneoplastic –occaisonally with Lung Ca MRI is abnormal in only 1/3 of cases LGI1, VGKC NMDA-R Clinical presentation: Prodrome Psychiatric problems NMDA-R Associated with ovarian teratoma in 10-50% of cases May present with classic facio-brachial dystonic seizure NMDA-R LGI1, VGKC
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AIE due to antibodies to: Neuronal Surface Antigen
Anti-NMDAR Anti-LGI1 Freq (approx) 55% 30% Clinical Prodromal Psych, seizure, amnesia 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 Modified from Leypoldt Europ Neurol Review, 2013
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Anti-NMDA Case 1: Insular & ± amygdala
Case 3: Bilat asymmetric hippocampal & amygdala ∆s Case 2: Bilat symmetric hippo
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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
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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
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Classification Schemes 1. Membraneous vs Intracellular
(Common AIE antibodies) 2. Limbic vs rarely limbic 3. Paraneoplastic vs rarely assoc w/ tumors MRI localization Limbic Rarely Limbic AMPA-R GABAB-R Yo Hu CV2 Paraneoplastic Ma2 Amphiphysin Precedes tumor dx 70% INTRACELLULAR NMDA-R Rarely Paraneoplastic GAD LGI1 CELL MEMBRANE ANTIGENS
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Anti LGI1 Case 1: Predominantly wm & unilat hippocampus
Case 2: Bilat asym hippo/amygdala DWI & contrast - neg Case 3: Bilat symmetric hippo 1 month
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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: CSF: unremarkable, HSV PCR neg Diagnosis at outside hospital: Creutzfeldt-Jacob Disease Yoo. JAMA Neurol. 2014;71(1):79-82
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Case 4: Anti- LGI1 encephalitis
Yale 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 mo p intial MRI 2 year f/u
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Classification Schemes 1. Membraneous vs Intracellular
(Common AIE antibodies) 2. Limbic vs rarely limbic 3. Paraneoplastic vs rarely assoc w/ tumors MRI localization Limbic Rarely Limbic AMPA-R GABAB-R Yo Hu CV2 Paraneoplastic Ma2 Amphiphysin Precedes tumor dx 70% INTRACELLULAR NMDA-R Rarely Paraneoplastic GAD LGI1 CELL MEMBRANE ANTIGENS
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Differential Diagnosis Limbic Encephalitis
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 Ddx LE includes SLE, Sjogrens, Primary angiitis CNS – MRI abnormalities very rare Modified from Leypoldt Europ Neurol Review, 2013
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Differential Diagnosis: Bilateral Temporal Hyperintensities
Clinical Lobe Feature DWI SWI Gd Limbic Encephalitis Memory Med - HSV Fever, sz Med; Ant Restrict Blood Gyriform MTS CPS Hippo atrophy Gliomatosis Cerebri HA, sz White matter Retrospective review of records , n=65 Modified from Sureka, Jakkani BJR 2012
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Herpes simplex vs Autoimmune Encephalitis
Oyanguren Eur J Neurol 2013 Features p<0.05 HSV (%) AIE (%) Psychiatric presentation 0 60 Acute onset 92 10 Fever 92 20 Aphasia 67 20 MRI Findings - abn Insular 91 33 Diffuse temp lobe 91 33 No basal ganglia Only mesial 9 67 --- Lots of overlap --- (MR∆ not signif: bilat, DWI, Gd, hippo & amygdala, thal, par, front, occ, midbrain) : 12 HSV1 vs 10 AIE
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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
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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
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