the spectrum of autoimmune cns disorders · the spectrum of autoimmune cns disorders andrew mckeon,...

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The Spectrum of Autoimmune CNS Disorders

Andrew McKeon, MD Mayo Clinic

©2017 MFMER | 3643498-2

Disclosures

• I receive research support from Medimmune & Euroimmun

• I have consulted for Medimmune, Euroimmun & Grifols (no personal compensation)

• I have patents applications for GFAP and MAP1B Abs as markers of neurological disease and cancer

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Learning Objectives

• Recognize key characteristics of autoimmune CNS disorders

• Request appropriate antibody testing for those disorders

• Choose appropriate immune therapies

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Outline

• What are Autoimmune CNS Disorders?

• How do patients present?

• Why do they occur?

• How do I evaluate further?

• Basic serum/CSF testing

• Neural antibody (Ab) testing

• Treatment trial in suspected cases ‘The diagnostic test’

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What are Autoimmune CNS Disorders?

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Autoimmune CNS Disorders

• CNS disorders caused by aberrant immune response

• Antigen-specific

• May be paraneoplastic or idiopathic

• Often unified by Ab marker detected in serum or cerebrospinal fluid (CSF)

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How Do Patients Present?

• Subacute onset symptoms

• Fluctuating course

• Can affect any neurological domain

• Often multifocal

• Think rostrocaudal

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Cortex

Visual System

Basal ganglia

Cerebellum

Brainstem

Cervical cord

Thoracic cord

Conus medullaris

Lumbosacral roots

Nerve

roots

Dorsal horn

Anterior horn

Nerve

NMJ

Muscle

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Autonomic Nervous System

Smooth Muscle

Secretory Epithelia

Arteriolar Central

Autonomic Neuron

Autonomic Ganglion

E

N

S

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What Are the Risk Factors?

• Sometimes none

• Coexisting autoimmune disease, e.g. thyroid disease, type 1 diabetes mellitus

• Cancer history

• Smoking history

• Family history of autoimmune disease or cancer

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How Do I Evaluate Further?

• Determine extent of neurological involvement

• Neurological examination

• Mental status testing

• Neuropsychometric testing

• MRI imaging

• Electrophysiology (EEG, EMG, SSEPs)

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How Do I Evaluate Further?

• Ab testing, serum

• Non-neural Abs: e.g. thyroid peroxidase Abs, connective tissue cascade

• Neural Abs: main subject of this course

• CSF testing Protein, white cell count, IgG index and synthesis rate, oligoclonal bands, neural Abs

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Why Do Autoimmune Neurological Diseases Occur?

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McKeon & Pittock, Acta Neuropath 2011

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Neural Abs Overview IgG Antibodies targeting

Neuronal nuclear,

cytoplasmic antigens

Neural cell surface antigens

(ion channels, receptors, synapses)

e.g. ANNA-1, PCA-1, CRMP-5 IgG e.g. VGKC complex Ab,

NMDA-R Ab, GlyR

Oncological therapy Immunotherapy

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Classic Paraneoplastic Autoantibodies Antibody Oncological association

ANNA-1 (anti-Hu) Small-cell carcinoma

ANNA-2 (anti-Ri) Small-cell carcinoma

Breast adenocarcinoma

ANNA-3 Aerodigestive carcinomas

AGNA (SOX-1) Small-cell carcinoma

PCA-1 (anti-Yo) Gynecological adenocarcinomas


PCA-2 Small-cell carcinoma

PCA-Tr (DNER) Hodgkin lymphoma

CRMP-5 IgG (anti-CV2) Small-cell carcinoma

Thymoma

Amphiphysin IgG

Small-cell carcinoma


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Synaptic Autoantibodies Antibody Oncological association

VGKC- complex Small-cell lung carcinoma, thymoma,

adenocarcinoma of breast, prostate

NMDA receptor 50% Ovarian teratoma

AMPA receptor 70% Thymoma, lung carcinoma, breast

carcinoma

GABA-B receptor 50% Small-cell lung carcinoma

P/Q and N type calcium channel Small-cell carcinoma, breast or gynecological

adenocarcinoma

Muscle AChR Thymoma, thymic carcinoma, lung carcinoma,

endometrial carcinoma, prostate carcinoma

Neuronal ganglionic AChR Adenocarcinoma, thymoma, small-cell

carcinoma

NMO-IgG Uncommon (breast adenocarcinoma>

carcinoid, teratoma, thymoma, lymphoma)

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How Are Patients Evaluated in the Laboratory?

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Tissue-based Immunofluorescence

PCA-1 PCA-1 ANNA-1

NMO-IgG NMDA-R IgG

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How are Abs Detected? Indirect Immunofluorescence Screening

• Confirmation by

• Western blot

• Cell based assay

• Immunoprecipitation

• Immunoprecipitation assay screening

• Cell based assay screening

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Examples of Autoimmune CNS Disorders

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Encephalitis

• Memory, mood, personality changes, seizures: Limbic encephalitis

• Diverse autoantibody associations

• ANNA-1, 2 (anti Hu, Ri)

• CRMP-5 IgG

• VGKC complex IgGs

• GAD65 Ab (High titer)

• AMPA, GABA-B receptor Abs

• mGluR5 Ab

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NMDA-R Encephalitis

• Stereotyped course

• Psych → seizures, encephalopathy

• → movement disorder, dysautonomia

• → hypoventilation+coma

• F>M

• 50% have ovarian teratoma

• CSF testing: More sensitive and specific

• Treatment: Steroids/IVIg or PLEX/rituximab/cyclophosphamide

• 80% get to mild or no disability

Titulaer: Lancet Neurology, 2013

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Cognitive Disorders

• Patients may present with cognitive-predominant presentations, not typical for limbic encephalitis

• May have coexisting neurological problems (e.g. tremor, neuropathy)

• Thyroid autoimmunity common

• VGKC complex Abs>GAD65 Ab>N or P/Q type calcium channel Abs> ANNA-1 (anti-Hu)

• Pre- and post objective testing helpful in defining treatment response

Flanagan et al: Mayo Clinic Proceedings, 2010

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Autoimmune Epilepsy

• May have seizure predominant presentation

• Scan may be normal at onset in half

• Dx: EEG, CSF, Ab testing

• VGKC complex Abs > GAD65 Ab > CRMP-5 IgG > Ma2 = NMDA receptor Ab

Quek et al, Arch Neurol 2012

Mesial temporal

Neocortical

temporal

Precentral

Localizations

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GABA-B Receptor IgG

• Limbic encephalitis

• Seizures often prominent

• Some present with status epilepticus

• Rare reports of OMS & ataxia

• Cancer detected in 50% (usually small cell carcinoma)

Lancaster et al, Lancet Neurol 2010; Jeffrey et al, Neurology, 2013 Hoftberger et al, Neurology, 2013

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Opsoclonus-Myoclonus

• Children

• Neuroblastoma

• ANNA-1 in a minority

• Adults

• 15% paraneoplastic

• ANNA-2 > ANNA-1 = NMDA-R Ab

• Frequently idiopathic autoimmune (immunotherapy responsive)

Klaas et al, Arch Neurol 2012

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Opsoclonus OR Myoclonus

• ‘Opsoclonus only’

• ANNA-2 (anti-Ri)

• Breast adenocarcinoma

• ‘Whole body tremor’

• Small amplitude generalized polymyoclonus

• No opsoclonus

• 25% have autoimmune cause

• Occult cancer possible

• VGKC, Alpha 3 ganglionic, CRMP-5 IgG

McKeon et al, Arch Neurol, 2007

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Chorea

• Paraneoplastic or idiopathic autoimmune

• Paraneoplastic

• CRMP-5 IgG

• ANNA-1

• GAD65

• Idiopathic autoimmune

• Lupus, APL Ab syndrome

• CASPR2

O’Toole et al, Neurology 2013

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Chorea

• Paraneoplastic patients more likely

• Older

• Male

• More frequent weight loss

• More frequent coexisting peripheral neuropathy

• Some improved with immunotherapy/cancer therapy

• Idiopathic

• Often milder course

• Improved/resolved with steroids

O’Toole et al, Neurology 2013

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Movement Disorder or Epilepsy?

• 61-year-old male

• Hx of AIDP, IVIg responsive age 43

• Jan 2010: Spells right facial contraction, left facial contraction, then arm posturing

• Diagnosis ‘Psychogenic’ at home

• Video EEG : ictal activity left frontoparietal region

• VGKC complex Ab positive, 2.58 nmol/L

• Neoplastic evaluation negative

• Seizures stopped, EEG normalized with combined immunotherapy/AED

• Mild residual amnesia

Faciobrachial dystonic seizures’, Irani et al, Ann Neurol, 2010

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Cerebellar Ataxia

• Symptoms frequently overlap with brainstem disorders

• Rapid-onset dysarthria, incoordination, gait disturbance, vertigo

• Prototypic disorder

• PCA-1 (anti-Yo) associated cerebellar degeneration in women with mullerian or breast adenocarcinoma

• Other Abs: P/Q-type calcium channel Ab, GAD65 Ab, PCA-Tr, mGluR1 Ab

Peterson et al, Neurology 1992 McKeon et al, Arch Neurol 2010

Cerebellar atrophy

Non-classic disorders also occur

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mGluR1 Ab

Neurological

• Ataxia

• Limbic symptoms (rare, at onset)

• Dysgeusia (40%, at onset)

Cancer

• Lymphoma (HD, non-HD), prostate adenocarcinoma

Sillevis-Smitt, NEJM, 2000 Lopez et al, Neurology, 2016

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Brainstem

• Eye movement disorders

• Dysphagia, dysarthria

• Parkinsonism

• Sleep disorders

• e.g. ANNA-2, MaTa

• Video

• Initial Dx: PSP

• Parkinsonism, narcolepsy-cataplexy

• Ma1, Ma2 Ab positive

• Tonsillar carcinoma

Pittock et al, Ann Neurol 2003; Dalmau et al, Ann Neurol 2004

Adams et al, Arch Neurol 2011

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• First case seen in 1924

• Reported in 1956 with 13 other cases

Moersch, Woltman. Proc Staff Meet Mayo Clin. 1956

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GlyR-IgG in Stiff-Man Syndrome

Mayo, Barcelona JAMA Neurol, 2013

Classic SMS Variant SMS

GAD65-IgG + N=60 GAD65-IgG - N=21

Classic SMS Variant SMS

N=43 N=16 N=4 N=14

PERM

N=2

2 2

PERM

N=1

4 0 1 1

Hyperekplexia

N=1

0

GlyR-IgG + GlyR-IgG +

10/81 patients tested positive (12%, GlyR cell binding assay)

Improved with immunotherapy

5 of 6 GlyR-IgG + patients

7 of 25 GlyR IgG - patients (p=0.02)

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Sleep Disorders

• VGKC complex-IgG

• DPPX-IgG

• IgLON-5-IgG • 8 patients • Chorea, ataxia • Dysarthria, dysphagia • Sleep apnea • Central hypoventilation • IgG4 Ab • Tauopathy

Cornelius et al, Arch Neurol 2010; Tobin et al, Neurology, 2014 Sabater et al, Lancet Neurology, 2014

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DPPX Autoimmunity, Manifestations in 20 Patients

Neurological Cognitive disorders 16

Brainstem/spinal cord disorders 15

Weight loss 12

Myoclonus or tremor 11

Sleep disorder 9

Gastrointestinal dysautonomia 9

Delirium 8

Cerebellar dysfunction 7

Urinary symptoms 7

Psychosis 4

Depression 4

Seizures 2

Cardiac dysrhythmia 3

Diaphoresis 2

Temperature dysregulation 1

Central hyperexcitability PERM (Rigidity + myoclonus 2

Myoclonus 8

Startle 6

Rigidity 6

Brisk reflexes 6

Stiff-man syndrome 0

Cancer B cell neoplasia 2

Tobin et al, Neurology, 2014

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IgLON5

• Sleep disorders

• Brainstem disorders

• Stiff-person spectrum

• Dysautonomia

• ? Treatment responsive

Kidney Cerebellum

SMA Hippocampus

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Paraneoplastic Myelopathy

• Subacute or insidious onset

• Lung, breast, kidney, thyroid, ovary/endometrium, melanoma, or other

• Amphiphysin IgG, CRMP-5 IgG, ANNA-1, PCA-1, ANNA-3

• Minority improve with treatment

• 50% Wheelchair bound

Flanagan et al, Neurology, 2011.

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Neuromyelitis Optica

• Autoimmune CNS disorder distinct from MS

• Severe (including bilateral) optic neuritis

• Myelitis: Long spinal cord lesions

• Intractable hiccoughs, nausea, vomiting

• Encephalopathy (mimicking ADEM) in children

• Can improve dramatically with steroids, PLEX, IVIg

• Need immunosuppression to maintain remission

Wingerchuk, Lancet Neurology 2007 Jacob et al, JNNP 2012

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NMO-IgG/AQP4-IgG

• Distinguishes NMO from classical MS

• Specificity >90%

• Tissue IF: 58% sensitivity

• New antigen-specific assays 70-80% sensitivity

Lennon, et al Lancet 2004 Fryer, et al, N2, 2014

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MOG Ab

• Assay: Cell-based format

• IgG1 anti-human secondary Ab

• Syndromes

• Optic neuritis

• Myelitis

• ADEM or ADEM-like

• Brainstem disorders

• NMO

• Clinical course

• Monophasic, relapsing often ++ steroid responsive

Kitley et al, Neurology, 2012 Rostasy et al, Arch Neurol 2012

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• Inflammatory CNS disorder

• Meningitis

• Encephalitis

• Myelitis

• Inflammatory CSF

• Sometimes paraneoplastic

• Steroid responsive

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GM

WM

CC

A

B

C

D

E

F

G H I

J

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GFAP-IgG

Flanagan et al, Ann Neurol, 2017

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Evaluation for Cancer

• Based on: Specific Ab finding(s)

OR

• Age, sex, family history

• CT chest, abdomen, pelvis

• Pelvic ultrasound (incl. transvaginal views)

• Testicular ultrasound

• Mammogram

• Exploratory surgery

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PET-CT

McKeon et al, Arch Neurol, 2010

*Increased cancer detection rate ~ 20%

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Treatment: Principles

• Trials of immunotherapy

• Measure improvement objectively

• Determining if short-term or long term treatment required

• Consider steroid-sparing agent

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Cytotoxic T Cell Mediated Disorders

• Paraneoplastic disorders

• Do not generally have good responses to steroids, IVIg or plasma exchange

• General approach

• Oncological therapy (surgery, chemotherapy, radiation therapy)

• Cyclophosphamide

Vernino et al, Neuro Oncol. 2004;6:55-62

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Antibody-Mediated Disorders (Definite or Possible)

• Acute (early important)

• Corticosteroids

• Intravenous immune globulin (IVIg)

• Plasma exchange

• Chronic

• Mycophenolate mofetil

• Azathioprine

• Rituximab, cyclophosphamide

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McKeon, Lennon, Pittock, Continuum, 2010.

Confirms diagnosis Chronic treatment

Continue acute IV therapy, and taper or

Oral prednisone taper and

Oral azathioprine or Oral mycophenolate mofetil

or Other options

Objective baseline measurements

Acute treatment, “Diagnostic Test”

IV methylprednisolone or

IVIg or

Plasma exchange

Consider

alternative

acute therapy

or no further

therapy

No

improvement

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Summary

• Autoimmune CNS disorders are important to consider

• Potentially treatable

• May be indicative of occult cancer

• Clues may emanate from

• History

• Examination

• Serum & CSF Ab evaluations

• Response to treatment

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Thank You!

Andrew McKeon

[email protected]

507-266-3196

mailto:[email protected]

the spectrum of autoimmune cns disorders · the spectrum of autoimmune cns disorders andrew mckeon,...

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