Your Brain in Health and Disease: Antibody Mediated Dementias. Faculty Disclosures. Key discoveries over the past decade 10/14/2015

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1 Your Brain in Health and Disease: Antibody Mediated Dementias Jeffrey M. Gelfand, MD, MAS Assistant Professor of Clinical Neurology University of California, San Francisco UCSF Mini Medical School for the Public October 2015 Faculty Disclosures Consulting: Medimmune: Consulting on a scientific advisory board Medical legal consulting related to CNS inflammatory disease Funding: NIH National Center for Advancing Translational Research KL2TR (recipient) National MS Society Institutional Clinician Training award (PI) Quest Diagnostics: Development of a dementia care pathway (through UCSF) This talk includes discussion of off label treatments for encephalitis Key discoveries over the past decade Some rapidly progressive dementias are autoimmune and readily treatable Antibodies can target neurons and cause brain dysfunction Antibody mediated brain disorders provide fascinating insights about how the brain works & how people can recover and reclaim memory after a dementing illness 1

2 What is an antibody? A protein that recognizes and binds to a target protein (antigen) Key part of the immune system Fight infection, cancer and injury Designer antibodies can also be used as a medicine (i.e. to target harmful proteins in the body) these agents are called biologics Antibodies can also aberrantly attack the host autoimmunity Definitions to frame our discussion ENCEPHALOPATHY: Impairment of brain structure or function Confusion, altered consciousness, behavior change Many potential causes Can occur in dementia but also other situations (delirium) ENCEPHALITIS: 1) Brain inflammation (clinical and/or pathological) 2) Encephalopathy secondary to brain inflammation MENINGITIS: Meningeal inflammation (without abnormal brain function) Encephalitis is a major public health problem UNITED STATES $2.0 billion USD hospital charges in 2010 >260,000 U.S. hospitalizations ~20,000 hospitalizations per year 5.7% fatal, 10.1% if HIV/AIDS, 17.1% transplant ENGLAND, ITALY, AUSTRALIA 5 6/100,000 incidence REFERENCES: Vora, et al. Neurology, 2014; George, et al. PLOS One, 2014.; Thakur, et al. Neurology, 2013; Khetsuriani, et al. CID, 2002; Granerod, et al. EID, 2013; Huppatz, et al. EID, 2009; Barbadoro, et al. Epidemiolog Infect,

3 Clinical Syndrome of Encephalitis Non Primary Inflammatory Other cause of encephalopathy Autoimmune Paraneoplastic (Cancer Associated) Cause of Encephalitis is Often Unsolved, Paraneoplastic, Autoimmune, Unknown / Idiopathic? Singh, et al. Neurology Year Population Inflammatory / Autoimmune 2015 for Adults Unknown Mayo Clinic 48% 22% 30% Pillai, et al. Pediatrics 2015 for Children Sydney/NSW 38% 34% 28% Saraya, et al. BMC Neurology Granerod, et al. Lancet ID Mailles, et al. CID Olsen, et al. EID 2013 for for for for Children/Adults Thailand 24% 25% 52% Children/Adults England 42% 21% 37% Children/Adults France 52% Not sampled 48% Children/Adults Thailand 36% Not sampled 64% Glaser, et al. CID 2006 Children/Adults CA Enceph Project 29% 8% 63% COMPLETE REFERENCES: Pillai SC, et. al. and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome. Pediatrics Mar 23. pii: peds [Epub ahead of print]; Singh TD, et. al. The spectrum of acute encephalitis: causes, management, and predictors of outcome. Neurology Jan 27;84(4): ;Granerod J, et. al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.. Lancet Disease Dec;10(12): ; Mailles, et. al. encephalitis in france in 2007: a national prospective study. CID Dec 15;49(12): ; Olsen, Et. al. causes of encephalitis and meningoencephalitis in Thailand, Feb;21(2):280-9; Glaser, CA, et. al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. CID Dec 15;43(12): Why is it so challenging to pinpoint specific causes of encephalitis? >100 infectious agents can cause encephalitis in humans disease testing is limited by technical challenges, sample volume, cost and the need for a targeted approach Many previously unsolved cases are increasingly recognized as autoimmune and new syndromes are still actively being discovered 3

4 Evaluating for infectious causes of encephalitis Clinical judgment Tests for specific microbes (i.e. PCRs) Tests for specific antibodies to known microbes (i.e. acute and convalescent serologies) Try to grow the bug via culture Brain biopsy as a last resort Unbiased next generation metagenomic sequencing techniques have the potential to vastly improve diagnosis of CNS infectious diseases Next Generation Metagenomic Sequencing Pipeline Tissue Sample Raw Sequence RNA/DNA Remove Human reads Fragment and PCR Amplify Use the remainder to search in large genetic databases (i.e. GenBank) Sequence the genomes many times over Modified from and courtesy of Drs. Michael Wilson and Joe Derisi, UCSF Match hits to taxonomy Find the infection if one exists! Wilson, et. al. NEJM,

5 Annals of Neurology, 2015 Unbiased sequencing of CSF: Balamuthia 74 yo woman with meningoencephalitis Staining confirms free living amoeba Brain biopsy: Necrotizing Vasculitis Clinical Syndrome of Encephalitis Non Primary Inflammatory Other cause of encephalopathy Autoimmune Paraneoplastic (Cancer Associated) Key Discovery: Some antibodies can bind to targets in the brain and cause neurological disease Immunohistochemistry Healthy Hu Cell based assay Western blot Target 40kDa 30kDa Healthy Hu Positive result Cell Based Assay (HEK 293, express known antigen) Cultured dissociated hippocampal neurons (Rat) Stain against rodent brain slices DENATURED INTRACELLULAR NEURONAL CELL SURFACE Best results if preserve native 3D conformation Image references: Far right from Boronat,, et. al, AON, 2013; WB / CBA courtesy of Dr. Sarosh Irani, Oxford 5

6 Emerging Paradigm of CNS Antibody Disorders Neuronal Intracellular (Classical Paraneoplastic) Neuronal Cell Surface/Synaptic (Autoimmune) Astrocytes Myelin Other Brain proteins CRMP 5, Hu (ANNA 1), Yo (Purkinje cells), Ri, Ma, amphiphysin... NMDA, VGKC LGI 1, CASPR, AMPA, GABA B, VGCC AQP4 (NMO) MOG (NMO like syndromes) A beta (CAA I) CANCER associated Usually NOT cancer (i.e. autoimmune) Not cancer Not Cancer Not Cancer Poor Good Good Good Poor *Note that Thyroid antibodies do not have a known antigenic target in the CNS Common autoimmune encephalitis syndromes Approx number of published cases (mid 2014) Classic Expanding Tumor NMDAR LGI1 CASPR2 AMPAR GABAb Glycine >700 in 6 Diffuse encephalitis, neuropsychiatric features, movement disorder, seizures, autonomic Pure neuropsychiatric; post partum psychosis; milder cases Ovarian teratoma (~30%) ~250 in 3 LE: Amnesia, seizures, hyponatremia FBDS, Bradycardia prodrome, cryptogenic <10% (various) Morvan s syndrome: dysautonomia, neuropsychiatric, neuromyotonia; Sometimes LE Cryptogenic, GBS like (~30%) ~25 in 4 ~60 in 5 LE LE Progressive encephalomyel itis with rigidity and myoclonus (PERM) Psychosis (atypical) Lung, breast, thymoma Lung (~50%) LE, brainstem syndromes, (<10%) Post HSV encephalitis Adapted from Irani, Gelfand, Al Diwani, Vincent, Annals of Neurology, 2014 Common autoimmune encephalitis syndromes Approx number of published cases (mid 2014) Classic Expanding Tumor NMDAR LGI1 CASPR2 AMPAR GABAb Glycine >700 in 6 Diffuse encephalitis, neuropsychiatric features, movement disorder, seizures, autonomic Pure neuropsychiatric; post partum psychosis; milder cases Ovarian teratoma (~30%) ~250 in 3 LE: Amnesia, seizures, hyponatremia FBDS, Bradycardia prodrome, cryptogenic <10% (various) Morvan s syndrome: dysautonomia, neuropsychiatric, neuromyotonia; Sometimes LE Cryptogenic, GBS like (~30%) ~25 in 4 ~60 in 5 LE LE Progressive encephalomyel itis with rigidity and myoclonus (PERM) Psychosis (atypical) Lung, breast, thymoma Lung (~50%) LE, brainstem syndromes, (<10%) Post HSV encephalitis Adapted from Irani, Gelfand, Al Diwani, Vincent, Annals of Neurology,

7 NMDAR Antibody Encephalitis 1 Disease of the young 95% <45 old; 37% < 18 old Characteristic Clinical Syndrome Vague prodrome (HA, fever, N/V, URI like) Acute neuropsychiatric symptoms sometimes even triaged to the psychiatry service Amnesia, language dysfunction Seizures Subset with coma and autonomic dysfunction Abnormal movements NMDAR Antibody Encephalitis 2 CSF Inflammation (but can be normal) MRI usually normal or nonspecific EEG slowing or epileptiform (seizure like) activity Diagnostic Test CSF or serum NMDAR antibodies Associated with ovarian teratoma, a tumor that has a component of neuronal tissue and can express the NMDAR, ~50% in women aged diagnose via ultrasound and MRI Immunosuppression is favorable 2.7x better odds for good outcome with aggressive treatment in largest series to date of 577 pts (Titulaer, Lancet Neuro, 2013) More common than infectious encephalitis in children (CA Encephalitis Project) Can occur following HSV brain infection post infectious inflammation Cahalan, Simon and Schuster,

8 "Knut der Eisbär Januar 2011" by Nicola at German Wikipedia. Licensed under CC BY SA 3.0 via Commons uar_2011.jpg#/media/file:knut_der_eisb%c3%a4r_januar_2011.jpg 10/14/2015 Autoimmune Causes of Brain Dysfunction Breaking down barriers between Neurology and Psychiatry 2% of women with postpartum psychosis had NMDAR encephalitis (in a cohort of women cared for in a dedicated mother child psychiatric unit in the Netherlands) Another 2% exhibited abnormal staining to unknown antigens on brain slice assays American Journal of Psychiatry September 2015 Editorial, American Journal of Psychiatry September 2015 Common autoimmune encephalitis syndromes Approx number of published cases (mid 2014) Classic Expanding Tumor NMDAR LGI1 CASPR2 AMPAR GABAb Glycine >700 in 6 Diffuse encephalitis, neuropsychiatric features, movement disorder, seizures, autonomic Pure neuropsychiatric; post partum psychosis; milder cases Ovarian teratoma (~30%) ~250 in 3 LE: Amnesia, seizures, hyponatremia FBDS, Bradycardia prodrome, cryptogenic <10% (various) Morvan s syndrome: dysautonomia, neuropsychiatric, neuromyotonia; Sometimes LE Cryptogenic, GBS like (~30%) ~25 in 4 ~60 in 5 LE LE Progressive encephalomyel itis with rigidity and myoclonus (PERM) Psychosis (atypical) Lung, breast, thymoma Lung (~50%) LE, brainstem syndromes, (<10%) Post HSV encephalitis Adapted from Irani, Gelfand, Al Diwani, Vincent, Annals of Neurology,

9 VGKC antibody complex associated Limbic Encephalitis (LE) Disease of middle age to later Subacute onset Amnesia (memory loss), seizures, low serum sodium (hyponatremia) Can have an unusual seizure syndrome (FBDS) or bradycardia requiring a pacemaker as a prodrome +/ Psychiatric features Dysautonomia Sleep ~10% cancer associated (~90% of cases are autoimmune) Usually normal or mild CSF inflammation MRI with temporal lobe hyperintensities but can be normal 30% cases have normal CSF + MRI Vincent et al. Brain 2004; Thieben et al Neurology 2004; Lai et al. Lancet Neurology Nassan et al. JAMA Neurology Common autoimmune encephalitis syndromes Approx number of published cases (mid 2014) Classic Expanding Tumor NMDAR LGI1 CASPR2 AMPAR GABAb Glycine >700 in 6 Diffuse encephalitis, neuropsychiatric features, movement disorder, seizures, autonomic Pure neuropsychiatric; post partum psychosis; milder cases Ovarian teratoma (~30%) ~250 in 3 LE: Amnesia, seizures, hyponatremia FBDS, Bradycardia prodrome, cryptogenic <10% (various) Morvan s syndrome: dysautonomia, neuropsychiatric, neuromyotonia; Sometimes LE Cryptogenic, GBS like (~30%) ~25 in 4 ~60 in 5 LE LE Progressive encephalomyel itis with rigidity and myoclonus (PERM) Psychosis (atypical) Lung, breast, thymoma Lung (~50%) LE, brainstem syndromes, (<10%) Post HSV encephalitis Adapted from Irani, Gelfand, Al Diwani, Vincent, Annals of Neurology, 2014 Neurology 2015 AMPA Receptor Antibody Encephalitis Limbic encephalitis prominent amnesia Median age in the 60s Cancer associated in the majority (64%) About half of pts have more than one antibody value of panel based testing Can have substantial atrophy and neurodegeneration Robust hippocampal staining (CSF of AMPA encephalitis pt Graus, et. al. Neurology

10 DPPX Encephalitis Annals of Neurology, 2013 Neurology, 2014 GI prodrome with intense diarrhea (Note that the gut has more neurons than the spinal cord and gut neurons (myenteric plexus) express these antigens) Hyperexcitability seizures, myoclonus, exaggerated startle Encephalopathy UCSF Precision Medicine Model: Meningitis and Encephalitis Goals of Immunosuppressive Therapy for Autoimmune Encephalitis Improve symptoms acutely Induce remission of the pathological inflammatory process Maintain remission Minimize risk from immunosuppression Treat symptoms: i.e. neuropsychiatric, seizures, pain, concentration, fatigue, sleep Promotion of neurorehabilitation 10

11 Acknowledgements Our patients and their families UCSF MS Center and Memory and Aging Center Colleagues Michael Geschwind, Carolyn Fredericks Michael Wilson, Joe Derisi, Felicia Chow, Sam Pleasure, Charles Chiu & Precision Medicine Team Stephen Hauser, Bruce Miller, Ari Green, Bruce Cree JosepDalmau(Barcelona), Sean Pittock (Mayo), Angela Vincent and Sarosh Irani (Oxford) Many other colleagues/collaborators (true team science) Your Brain in Health and Disease: Antibody Mediated Dementias Jeffrey M. Gelfand, MD, MAS Assistant Professor of Clinical Neurology MS and Neuroinflammation Center University of California, San Francisco UCSF Mini Medical School for the Public October