New Frontiers in Infectious & Autoimmune Encephalitis Michael - - PDF document

2/1/2018 1

Michael Wilson, MD, MAS

Assistant Professor of Neurology

Jeffrey M. Gelfand, MD, MAS, FAAN

Assistant Professor of Clinical Neurology

UCSF MS and Neuroinflammation Center Weill Institute for Neurosciences

New Frontiers in Infectious & Autoimmune Encephalitis

Recent Advances in Neurology February 2018

Disclosures

• Dr. Wilson reports: Research support to UCSF from Genentech
• Dr. Gelfand reports research support to UCSF from Genentech, Quest Diagnostics,
• MedDay. He is PI of a National MS Society Institutional Clinician Training Award. Personal

fees for medical legal consulting. Prior personal fees for consulting for Genentech.

Talk Outline

• Update on Encephalitis Epidemiology
• Conventional ID diagnostics
• New Frontiers in infectious diagnostics (metagenomic deep

sequencing, other panels)

• Conventional autoantibody diagnostics
• New Frontiers in antibody discovery
• Update on AE Phenotypes, New Antibodies
• Q&A

2/1/2018 2

Encephalitis is morbid and costly

UNITED STATES

‐ $2.0 billion USD U.S. encephalitis hospital charges 2010

‐ >260,000 U.S. hospitalizations 1998‐ 2010 ‐ 20,000 hospitalizations per year, 7.3/100,000 hospitalization rate ‐ 5.7% fatal, 10.1% if HIV/AIDS, 17.1% transplant‐associated

ENGLAND ‐ 5.2‐6 cases / 100,000 incidence AUSTRALIA ‐ 5.2 / 100,000 hospitalization rate (1990‐2007) ITALY ‐ 5.9 / 100,000 hospitalization rate

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 Iro, et. al. Lancet ID. 2017 Huppatz, et al. EID, 2009 Barbadoro, et al. Epidemiolog Infect, 2012

Iro, et. al. Lancet Infectious Disease, 2017 Measles Encephalitis Mumps Encephalitis Encephalitis Unknown Cause Herpes Encephalitis

Encephalitis trends in England over 30 years…

‐ Vaccine‐preventable encephalitis has plummeted ‐ Encephalitis of Unknown Cause is on the rise

Encephalitis in the Early 21st Century ‐ 2

Infectious, Paraneoplastic, Autoimmune, Unknown / Idiopathic?

Year Population Infectious Inflammatory / Autoimmune Unknown

Singh, et al. Neurology 2015 for 2000‐2012 Adults Mayo Clinic

48% 22% 30%

Pillai, et al. Pediatrics 2015 for 1998‐2010 Children Sydney/NSW

38% 34% 28%

Saraya, et al. BMC Neurology 2013 for 2010‐2012 Children/Adults Thailand

24% 25% 52%

Granerod, et al. Lancet ID 2010 for 2005‐2006 Children/Adults England

42% 21% 37%

Mailles, et al. CID 2009 for 2007 Children/Adults France

52%

Not sampled

48%

Olsen, et al. EID 2015 for 2003‐2005 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. Infectious and Autoantibody-Associated Encephalitis: Clinical Features and Long-term Outcome. Pediatrics. 2015 Mar 23. pii: peds.2014-2702. [Epub ahead of print]; Singh TD, et. al. The spectrum of acute encephalitis: causes, management, and predictors of outcome. Neurology. 2015 Jan 27;84(4):359-66.;Granerod J, et. al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.. Lancet Infectious Disease. 2010 Dec;10(12):835-44.; Mailles, et. al. Infectious encephalitis in france in 2007: a national prospective study. CID. 2009. Dec 15;49(12):1838-47; Olsen, Et. al. Infectious causes of encephalitis and meningoencephalitis in Thailand, 2003-2005. 2015 Feb;21(2):280-9; Glaser, CA, et. al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. CID. 2006 Dec 15;43(12):1565-77.

2/1/2018 3

Encephalitis in the Early 21st Century Update: The Rise of Autoimmune Encephalitis

• Incidence in Olmsted County, MN 1995‐2015:

– Infectious Encephalitis 0.8/100,000 – Autoimmune 1.0/100,000 – Autoimmune 1995‐2005 0.4/100,000 – Autoimmune 2006‐2015 1.2/100,000

Dubey, et. al. Annals of Neurology, 2018

3x increase in AE ‐‐> Attributable to detection, new antibodies! Incidence is now similar between Autoimmune and Infectious (i.e. autoimmune no longer should be considered as rare)

Emerging Infections

• Nearly half of 175 emerging infections are viruses
• 80% have a zoonotic source
• Highest concentration of emergence events

– United States – Europe – Japan – Southeast Asia

• Rate of severe neurological symptoms caused by

emerging viruses

– 39% commonly do so – 10% rarely or occasionally do so

• Tyler KL. Arch Neurol. 2009 August; 66(8): 939–948

Examples of Emerging Infections in the U.S.

• HHV6 encephalitis in bone marrow transplant
• PML in HIV and other immunosuppressed patients
• Arenavirus (LCMV‐like) in solid organ transplant pts
• Dengue virus in the Florida Keys
• West Nile virus
• Periodic measles, mumps outbreaks
• Neurologic complications of H1N1
• Chikungunya virus
• Zika virus
• Powassan virus
• Tyler KL. Arch Neurol. 2009 August; 66(8): 939–948

2/1/2018 4 Emerging Neurotropic Viruses: Global

• Toscana virus
• Tick‐borne encephalitis virus
• Chandipura virus
• Bat lyssaviruses
• Monkeypox virus
• H1N1 influenza virus
• Poliovirus
• Enterovirus 71 (Cambodian outbreak)
• Nipah and Hendra viruses
• Japanese encephalitis virus
• Rabies virus
• Zika virus
• Chikungunya virus
• Ebola virus

Clinical Syndrome

• f Encephalitis

Clinical Syndrome

• f Encephalitis

Infectious Infectious

Non‐Infectious Inflammatory Non‐Infectious Inflammatory Other cause of encephalopathy Other cause of encephalopathy Autoimmune Autoimmune Paraneoplastic Paraneoplastic

Clinical Syndrome

• f Encephalitis

Clinical Syndrome

• f Encephalitis

Infectious Infectious

Non‐Infectious Primary Inflammatory Non‐Infectious Primary Inflammatory Other cause of encephalopathy Other cause of encephalopathy

Neuronal Intracellular Antibody Neuronal Intracellular Antibody Neuronal Cell‐Surface / Synaptic Antibody Neuronal Cell‐Surface / Synaptic Antibody Clinical +/‐ Research based testing negative Clinical +/‐ Research based testing negative

‐ Usually responsive to immunosuppression ‐ Can be frustratingly refractory to conventional immunosuppression, though a minority may benefit ‐ Identifying the cancer, when there, is a priority ‐ Variable response

2/1/2018 5

‐ Inflammatory process of the brain with associated neurological dysfunction

Infectious Disease Society of America, Encephalitis Clinical Practice Guidelines, 2008

‐ Encephalopathy >24 hours plus ≥2 of the following:

‐

Fever (within 72 hours of presentation) ‐ Seizures (not fully attributable to a preexisting seizure disorder) ‐ New focal neurological findings ‐ Inflammatory CSF (pleocytosis) ‐ EEG abnormalities indicative of encephalitis (excluding medication / metabolic effects) ‐ Neuroimaging abnormalities indicative of encephalitis

International Encephalitis Consortium, Consensus Statement, CID, 2013

REFERENCES: Tunkel AR, et al. The management of encephalitis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008; 47:303–27; Venkatesen A, et. al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013 Oct;57(8):1114-28; Granerod J, et. al. Lancet Infectious Disease. 2010 Dec;10(12):835-44.

Encephalitis: Classical “Infectious Disease” Definition

Graus, et. al. Lancet Neurology 2016 ‐ Subacute onset (rapid progression of less than 3 months) of working memory deficits, AMS (lethargy, personality change, decreased LOC) or psychiatric symptoms Possible At least one of the following: ‐ New focal CNS finding ‐ Seizures (not explained by a previously known seizure disorder) ‐ MRI features of encephalitis ‐ CSF pleocytosis Definite ‐ MRI features of encephalitis ‐ CSF pleocytosis ‐ EEG with epileptic or slow wave activity

‐ ‐Or if not all of the above‐ a neuronal autoantibody

Reasonable exclusion of other causes (infection, tumor, ND, metabolic, etc)

Why is it so challenging to pinpoint specific causes of encephalitis?

• >100 pathogens cause human encephalitis… and new

autoimmune causes are being discovered!

• Infectious disease testing is limited by technical

challenges, sample volume, cost

• Limitations and inefficiencies in antibody discovery –

many likely autoimmune cases remain “antibody”

• negative. Challenging to prove non‐antibody mediated

pathologies (i.e. primarily T cell mediated processes, immune dysregulation, etc)

2/1/2018 6

Gelfand, et. al., JAMA Neurology, 2015 ‐‐ 58 patients with encephalitis on brain biopsy at between 1983‐2011, the final pathologic diagnosis was “Encephalitis Not Otherwise Specified” (ENOS) in 49 (84%) ‐‐ Clinical follow‐up led to a more specific diagnosis in 6/19 (32%) with ENOS and 6/11 : Primary CNS lymphoma (2), Rasmussen encephalitis (2), paraneoplastic (CV2/CRMP5 and Ma2), Listeria monocytogenes ‐‐ Clinical follow‐up led to a more specific diagnosis in 6/11 (55%) w/o additional material: TB, HSV2, Toxo, bacterial abscess, LGI1 encephalitis, gliomatosis cerebri (on autopsy)

Even with brain biopsy, ENOS is the most common pathological encephalitis diagnosis. Better diagnostics are needed.

Clinical Syndrome

• f Encephalitis

Clinical Syndrome

• f Encephalitis

Infectious Infectious

Non‐Infectious Inflammatory Non‐Infectious Inflammatory Other cause of encephalopathy Other cause of encephalopathy Autoimmune Autoimmune Paraneoplastic Paraneoplastic

Conventional Diagnostics for Infectious Encephalitis

• Clinical phenotyping & judgment
• Culture (bacterial, AFB, fungal, viral)
• PCR
• Acute and Convalescent serologies (antibodies)
• Antigen based tests
• Biopsy (histology, EM, micro)

Requires a “spreadsheet” level of attention to detail (what many of us love about neurology, but a barrier in practice):

‐ Limited sample volume (CSF) ‐ Cost ($$$) ‐ Access (i.e. CDC only tests) ‐ Time (several weeks for AFB cultures)

2/1/2018 7

• Faria NR, et al. Science 2016

Zika Virus

• Phylogenetic analyses indicate Zika was

introduced to Brazil in 2013

• 18 months before it was detected
• Nearly 2 years before recognized as a cause of

microcephaly, meningoencephalitis and Guillain‐Barré syndrome

Metagenomic Next‐Generation Sequencing

• Analyzing all the genetic material in an

environmental sample

• Massively parallel sequencing approach

Sequencing Library Prep

2/1/2018 8

Abbreviations: NT, nucleotide; NR, non‐redundant protein.

Sequencing Library Prep

Rare Pathogens

• Wilson MR, et al. NEJM 2014
• Wilson MR, et al. Ann Neurol 2015

Novel Phenotypes

• Wilson MR, et al. Ann Neurol 2017

2/1/2018 9

Case 1

• 40 year‐old physician with 15 years of

relapsing myelitis and arachnoiditis

• Immigrated to US from India at age 22; lived in

AZ, NY and MD

• No history of intravenous drug use
• No known animal, mosquito or tick exposures

Case 1 Case 1

• 2002: Treated for TB meningitis for 3 months (had

to stop due to abdominal pain)

• 2006: Non‐diagnostic laminectomy at L5‐S1

– 1 more year of anti‐TB therapy

• 2015: valacyclovir + prednisone followed by…

– > 35 mg of daily prednisone plus…

• Mycophenolate mofetil (up to 3000mg daily) for 8 months
• Methotrexate (Jan 2017 to present)
• Etanercept
• Anakinra

2/1/2018 10

Case 1

• mNGS of RNA extracted from CSF

– 62,890 (1.1%) of the 5,750,572 sequence pairs were non‐redundant, non‐human – 1,493 (2.2%) of the 62,890 non‐redundant, non‐ human sequence pairs aligned to the genus Taenia with a best match to Taenia solium

• Confirmatory qPCR and cestode antigen assay

were markedly positive in the CSF

– NIAID Laboratory of Parasitic Diseases (Dr. Theodore Nash)

Clinical Syndrome

• f Encephalitis

Clinical Syndrome

• f Encephalitis

Infectious Infectious

Non‐Infectious, Primary Inflammatory Non‐Infectious, Primary Inflammatory Other cause of encephalopathy Other cause of encephalopathy

Neuronal Intracellular Antibody Neuronal Intracellular Antibody Neuronal Cell‐Surface / Synaptic Antibody Neuronal Cell‐Surface / Synaptic Antibody Clinical +/‐ Research based testing negative Clinical +/‐ Research based testing negative

‐ Usually responsive to immunosuppression ‐ Can be frustratingly refractory to conventional immunosuppression, though a minority may benefit ‐ Identifying the cancer, when there, is a priority ‐ Variable response

Conventional testing for “Paraneoplastic” or “Autoimmune Encephalitis” Antibodies?

Healthy Hu

Immunohistochemistry

Healthy Hu 40kDa 30kDa

Western blot Cell‐based assay

Target Positive result

NEURONAL CELL‐SURFACE Best results if preserve native 3D conformation DENATURED INTRACELLULAR Cell‐Based Assay (HEK‐293, express known antigen) Cultured dissociated hippocampal neurons (Rat) Stain against rodent brain slices

Image references: Far right from Boronat,, et. al, AON, 2013; WB / CBA courtesy of Dr. Sarosh Irani, Oxford

2/1/2018 11

Evolving Paradigm of CNS Antibody Disorders

Neuronal Intracellular (Classical Paraneoplastic) Neuronal Cell‐Surface/Synaptic (Autoimmune)

Astrocyte Myelin ?Other CRMP‐5, Hu (ANNA‐1), Yo (Purkinje cells), Ri, Ma, amphiphysin.... NMDA, VGKC‐c/LGI‐1 /CASPR2, AMPA, GABA‐A, GABA‐B, DPPX… AQP4

(NMO)

GFAP

(meningoencephaliti s/myelitis)

MOG

(NMO or ADEM‐like syndrome)

A‐beta

(?CAA‐I)

Usually associated with cancer Sometimes cancer related but some predominantly autoimmune, post‐infectious Variable

(rare for NMO; reported with GFAP)

Not not Cytotoxic T‐cell Response; Antibodies are probably an epiphenomenon of tumoral autoimmunity Antibody/complement mediated with T cell response Antibody/compl ement mediated with T cell response ? ? Frequently poor response to immunosuppression Usually good response to immunosuppression

Good Good Variable *Note that Thyroid antibodies do not have a known antigenic target in the CNS

Antibody Discovery Pipeline

• Rodent brain slice staining
• Immunoprecipitation  Mass spectrometry
• Programmable phage display

– All possible 49 amino acid peptides from every protein encoded in the human genome with 24 amino acid

• verlap

– Collection of phage each expressing 1 of these possible 731,000 peptides on the surface of their major capsid protein – Rapid, high‐throughput, and quantitative assay for autoantigen discovery and characterization

• Larman B, et al. Nat Biotechnol 2011

Constructing the Peptidome Constructing the Peptidome

• All human proteins including known isoforms/variants in Refseq collapsed on 99% sequence identity
• All human proteins including known isoforms/variants in Refseq collapsed on 99% sequence identity
• split into 49 amino acid peptides with a sliding window of 24
• split into 49 amino acid peptides with a sliding window of 24

Strep Strep FLAG FLAG Strep Strep FLAG FLAG Strep Strep FLAG FLAG

49 aa 49 aa 24 aa 24 aa 24 aa 24 aa

Human Protein X Human Protein X

147 nt 147 nt 189 nt 189 nt

2/1/2018 12

Peptidome Case 2

Evolving Paradigm of CNS Antibody Disorders

Neuronal Intracellular (Classical Paraneoplastic) Neuronal Cell‐Surface/Synaptic (Autoimmune)

Astrocyte Myelin ?Other CRMP‐5, Hu (ANNA‐1), Yo (Purkinje cells), Ri, Ma, amphiphysin.... NMDA, VGKC‐c/LGI‐ 1/CASPR2, AMPA, GABA‐A, GABA‐B, DPPX… AQP4

(NMO)

GFAP

(meningoencephaliti s/myelitis)

MOG

(NMO or ADEM‐like syndrome)

A‐beta

(?CAA‐I)

Usually associated with cancer Sometimes cancer related but some predominantly autoimmune, post‐infectious Variable

(rare for NMO; reported with GFAP)

Not not Cytotoxic T‐cell Response; Antibodies are probably an epiphenomenon of tumoral autoimmunity Antibody/complement mediated with T cell response Antibody/compl ement mediated with T cell response ? ? Frequently poor response to immunosuppression Usually good response to immunosuppression

Good Good Variable *Note that Thyroid antibodies do not have a known antigenic target in the CNS

2/1/2018 13

Case

FLAIR T1 Gad T2 T1 GAD

GFAP Autoimmune Astrocytopathy

‐ Meningoencephalitis +/‐ myelitis, rare disc edema ‐ CSF testing most sensitive (vs serum); ”false” positive ~1% unaffected controls ‐ Radial perivascular enhancement ‐ Can have longitudinally extensive myelitis ‐ Can coexist with other antibodies (NMDAR, AQP4, VGKC, etc) ‐ Rx with glucocorticoids, MMF, AZA – but need better data

Flanagan, et. al. Annals of Neurology, 2017

MOG‐Antibody Oligodendrocytopathy

Ramanathan, JNNP, 2018 Hyun, JNNP, 2017 Hacohen, JAMA Neuro, 2018 Hamid, JAMA Neuro, 2018 Hennes, Neurology, 2017

‐‐ Optic neuritis, myelitis  “NMO‐like” ‐‐ Parenchymal lesions, seizures, AMS  ”ADEM” ‐‐ Esp in children (but also adults) ‐‐ Can be relapsing‐remitting, esp with persistent high titer MOG antibodies ‐‐ IVIG responsive, also Rituximab, AZA, MMF; poorer response to injection MS therapies ‐‐ Only very recently commercially available in the U.S.

Literature rapidly expanding (i.e.):

2/1/2018 14 Anti‐NMDAR Encephalitis – Updates

NMDAR Antibody Encephalitis ‐ 1

• Disease of the young – 95% <45 years‐old; 37% < 18 years‐old
• Characteristic Clinical Syndrome

– Prodrome (HA, fever, N/V, URI‐like) – Acute neuropsychiatric symptoms – Amnesia, language dysfunction – Seizures – Abnormal movements – Subset with coma and autonomic dysfunction

NMDAR Antibody Encephalitis ‐ 2

• CSF – Pleocytosis, OCBs; but can be normal
• MRI – usually normal or nonspecific
• EEG – slowing or epileptiform activity
• Serology – CSF or serum IgG NMDAR antibodies that

target the GluN1 (NR1) subunit

– 10% of pts will have +CSF serologies when serum is negative – send CSF when high index of suspicion!

‐ Ovarian teratoma (which has a component of neuronal tissue that can express NMDAR) in ~50% in women aged 12‐45 – vaginal ultrasound and pelvic MRI ‐ Immunosuppression is favorable – OR 2.7 for better outcomes with aggressive treatment in largest series to date of 577 pts (Titulaer, Lancet Neuro, 2013)

2/1/2018 15

Post‐Infectious (post‐HSV, VZV) NMDAR Encephalitis Update: A Strong Case for Molecular Mimicry

‐‐ NMDAR immunoreactivity will be found in 27%‐ 30% post‐HSV encephalitis patients if go looking

‐‐ Some have clinical NMDAR encephalitis ‐‐ Much less clear NMDAR immunoreactivity post‐HSV means without clear clinical “relapse” ‐‐ Also reported post‐VZV but not yet post non‐herpesvirae

Linneola, et. al. Neurology Neuroimmunology, 2016 Armangue, et. al. Neurology, 2015 Hacohen, et. al. Movement Disorders, 2014 Pruss, et. al. Annals of Neurology, 2012

One Brain, Two Specialties, Converging Mechanisms: AE

• 3% of new onset psychosis patients with pure

psychosis (otherwise indistinguishable to psychiatrists) had serum NMDAR antibodies in a prospective cohort (UK)

• 2% of consecutive postpartum psychosis

cases had serum NMDAR antibodies (Netherlands)

‐ Lennox, et. al. Lancet Psychiatry, 2017 ‐ Bergink, et. al. American Journal of Psychiatry, 2015

Are these true NMDAR “encephalitis” clinically or just immunoreactivity? Better neurological phenotyping is needed

LGI1, CASPR2, “Double‐negative” VGKC – Updates

2/1/2018 16

The VGKC‐complex has several proteins that connect to or shuttle with the channel –

These are the actual antigenic targets in VGKC encephalitis

125I‐

DTX

C A S P R 2 LGI1

C O N T A C T I N 2

Irani, Gelfand, et. al. AON 2014 Lang, Irani, et. al. JNNP. 2017 Patterson, AON, 2017

RADIOIMMUNOPRECIPITATION ASSAY

Limbic Encephalitis – LGI1 > CASPR2 FBDS – LGI1 Cardiac prodrome – LGI1 Tumor (often Thymoma) – CASPR2 Neuromyotonia – mostly CASPR2

‐ “Double‐negative” VGKC (neg LGI1, neg CASPR2) often target cytosolic epitopes of Kv1 (potassium channel) or the radiolabel cofactor ‐ CASPR2 IgG4 inhibits the interaction of CASPR2 with contactin, blocking could work therapeutically

Sonderen, et. al. Neurology, 2016 Potential for early intervention with glucocorticoids here! (Thompson, et. al. Brain, 2017 Clinical relapse in 27% ‐ May need longer maintenance immunosuppression (Arino, et. al. Neurology, 2016)

‐ CSF/MRI normal in 30% ‐ 90% of cases are autoimmune (not‐cancer associated

Additional References: Vincent et al. Brain 2004; Thieben et al Neurology 2004; Lai et al. Lancet Neurology 2010

“Double‐Negative” VGKC (i.e. neg for LGI1/CASRP2) is much less likely to be pathogenic / clinically relevant

‐ “Double‐negative” VGKC commonly binds to KV1 potassium channels (but not neurons in slices or culture) or to the non‐ human alpha‐dendrotoxin used in radiolabeling – both unlikely to be pathogenic ‐ Clinical phenotype compelling for AE in only 28% of double‐ negative VGKC in a Netherlands cohort (i.e. 72% were not clearly inflammatory)

2/1/2018 17

Van Sonderen, et. al. Annals of Neurology, 2016 Lee, et. al. Annals of Neurology, 2016

Netherlands: HLA‐DR7 in 88% of LGI1 (vs 19.6% of controls) HLA‐DRB4 100% of LGI1 (vs 46.5% of controls) Korea: HLA‐DR7 in 91% of LGI1 HAL‐DR4 in 73% of LGI1

Emerging Model

Environmental trigger (unknown) in genetically susceptible  AE

LGI1 Encephalitis – Evidence for Genetic Susceptibility

Hoftberger Neurology 2015 Joubert, JAMA Neuro 2015

‐‐ Limbic encephalitis – prominent amnesia ‐‐ Median age 64 (i.e. favors older age of onset) ‐‐ Cancer associated in the majority (64% in 1 series, 48% in another) ‐‐ About half of pts have more than one antibody – value of panel based testing ‐‐ Can have substantial atrophy and secondary neurodegenerative phenotypes

AMPA Antibody Encephalitis

Graus, et. al. Neurology 2010

Robust hippocampal staining (CSF of AMPA encephalitis pt

Spatola, et. al. Neurology, 2017

‐‐ Median age 40, but wide age range (2.5 months to 62 years) ‐‐ Seizures, movement disorders, multifocal WM lesions ‐‐ Post/Peri‐infectious in children; tumor (esp thymoma) associations in adults ‐‐ Relatively rare (26 cases over 3+ years in Spanish series)

GABA‐A Antibody Encephalitis

Hoftberger, et. al. Neurology, 2013

‐‐ Median age 61 (range 16‐77) ‐‐ Seizures, amnesia, AMS, rare opsoclonus‐myoclonus or ataxia ‐‐ 50% SCLC/paraneoplastic ‐‐ Relatively rare (20 cases over 3+ years in Spanish series)

GABA‐B Antibody Encephalitis

2/1/2018 18

IgLON5 antibody‐associated tau‐opathy: Neurodegenerative vs antibody mediated?

Gaig, et. al. Neurology, 2017.

‐ Phenotypes: ‐ 1) Sleep disordered breathing + parasomnias (NREM) ‐ 2) Bulbar syndrome (dysphagia, stridor, dyspnea, sialorrhea) ‐ 3) PSP‐like syndrome ‐ 4) Dementia +/‐ chorea ‐ Mean age 64 (range 46‐83), M:F similar ‐ MRI may have atrophy but usually unremarkable; CSF bland in up to ~70% ‐ IgG4 predominates, usually both serum and CSF ‐ Striking HLA predominance (HLA DRB1*10:01 87%, 36X expected rate in population) ‐ Variable immune response (poor in European series but late start vs good in French/Mayo series) ‐ Tau on neuropathology ‐‐?primary vs secondary antibody response

Ecudero, et. al. Neurology, 2017. Honorat, et. al. Neurology Neuroimmunology, 2017.

Michael Wilson, MD

Assistant Professor of Neurology

Jeffrey M. Gelfand, MD, MAS, FAAN

Assistant Professor of Clinical Neurology

Weill Institute for Neurosciences UCSF MS and Neuroinflammation Center

New Frontiers in Autoimmune & Infectious Encephalitis

Recent Advances in Neurology February 2018

Extra Slides for Reference

2/1/2018 19

Hashimoto’s Encephalopathy (SREAT) vs Hashimoto’s Thyroid Antibodies + some other cause of RPD

Lancet Neurology 2016 “Diagnosis can be made when all six of the following criteria have been met: 1) Encephalopathy with seizures, myoclonus, hallucinations, or stroke‐like episodes 2) Subclinical or mild overt thyroid disease (usually hypothyroidism) 3) Brain MRI normal or with non‐specific abnormalities 4) Presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies* 5) Absence of well characterised neuronal antibodies in serum and CSF 6) Reasonable exclusion of alternative causes *There is no disease‐specifi c cutoff value for these antibodies (detectable in 13% of healthy individuals) “Steroid responsiveness” and +thyroid antibodies is neither specific nor diagnostic

Summary Approach to Empiric Immunosuppression for Autoimmune Encephalitis

ACUTE THERAPY GLUCOCORTICOIDS GLUCOCORTICOIDS IVIG or PLEX IVIG or PLEX

+/‐

INDUCTION THERAPY (if very ill / severe) CYCLOPHOSPHAMIDE CYCLOPHOSPHAMIDE B‐CELL DEPLETION (anti‐CD20 therapy) B‐CELL DEPLETION (anti‐CD20 therapy)

+/‐

MAINTENANCE THERAPY (if concern for prolonged process

• r relapse)

Usually 1 of the following: Anti‐CD‐20 therapy, CYCLOPHOSPHAMIDE, AZATHIOPRINE, MYCOPHENOLATE MOFETIL, METHOTREXATE, CHRONIC STEROIDS Potential role for: tocilizumab (IL‐6), bortezomib (proteosome inhibitor), ?CD19 or CD38 agents Usually 1 of the following: Anti‐CD‐20 therapy, CYCLOPHOSPHAMIDE, AZATHIOPRINE, MYCOPHENOLATE MOFETIL, METHOTREXATE, CHRONIC STEROIDS Potential role for: tocilizumab (IL‐6), bortezomib (proteosome inhibitor), ?CD19 or CD38 agents Annals of Neurology, 2013 Neurology, 2014 ‐ GI prodrome with intense diarrhea (the myenteric plexus is part of the nervous system and expresses this antigen!) ‐ Hyperexcitability – seizures, myoclonus, exaggerated startle ‐ Encephalopathy

DPPX Encephalitis