Autoimmune encephalitis: theoretical and clinical perspectives

Ming Lim

Evelina Children’s Hospital

Clinical Neurology Laboratory, Oxford University

Overview of immune system

INNATE IMMUNITY

• First line of defence

• Rapid action

• Not specific

• Limited diversity / flexibility

• No memory

• Phagocytes, DCs, NKs, mast cells, eosinophils, basophils

• Complement, cytokines, defensins

ADAPTIVE IMMUNITY

• Role in eliminating infection

• Time lag (days)

• Antigen specific

• Diverse and flexible

• Memory response

• Lymphocytes

• Antibodies, cytokines

Inflammation in the brain

The molecular effectors Compromise of the blood brain barrier

Lim 2011 DMCN 53: 298-304

Astrocytes Microglia

Upregulation of the adaptive immune system

Inflammation in the brain

Cell type Condition

Th1 MS, ADEM, Rassmussen

encephalitis

Th2 SLE

B cell MS, NMO, demyelination, autoimmune encephalitis

Innate

HLH, SLE, Behcet, Sarcoid

Anti neural-antibodies and CNS autoimmunity

Antibodies against neuronal surface antigens

• VGKC (LGI1, CASPR2, Contactin-2), AMPAR, GABA(B)R, NMDAR, Glycine R, Dopamine-2 R

Antibodies against intracellular antigens

• Onconeural antibodies; Hu, Yo, Ri, CV2, amphipysin, Ma2, GAD

Graus at al., 2010 J Neurol. 257(4); 509-17

Vincent et al., 2011 Lancet Neurol. 10(8):759-72

Pathogenic role autoantibodies

Presence of autoantibody

Autoantigen/antibody as part of the disease

IgGs/autoantibodies can target CNS

IgGs are at target sites in CNS

Serum CSF

3.125

6.25

12.5

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50

100

200

400

800

1600

3200

6400

3.125

6.25

12.5

25

50

100

200

400

800

1600

3200

6400

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Dilu

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of C

SF

Mechanisms of antibody-induced

pathology

Direct block

Internalisation

Complement-

dependent lysis

Cell-based assays

Antigen

Patient has antibodies

Binding can be scored visually or titrations

performed

Clinical syndromes in CNS autoimmunity

• Limbic encephalitis • Seizures

• FBDS • PERM • Catastrophic/severe seizures

• Movement disorder • Encephalitis lethargica

• Neuropsychiatric • Others

• Cross over with peripheral syndromes • Demyelination

Case 1 15yr F

• GTCS • 1/52 feeling unwell/rundown. Known to social services for

violent episodes and regular cannabis use. • Generalised +Rt Focal seizures. I+V for seizure control. • Hallucination (auditory and visual), complaining of extreme

pruritis, violent outbursts, delirious state. • EEG slow wave Rt>Lt. Sharp wave Rt fronto-temporal

parietal. • MRI hyperintensity involving both hippocampi and

amygdala, swelling of mesial temporal structures. High dose steroids, IVIG good response

Case 1

Sub-acute onset of memory loss, seizures and personality change

Sometimes seizures or psychosis only

Often low plasma sodium

VGKC-complex antibodies often

very high titre

<10% tumours

Most respond well to immunotherapies

A treatable form of limbic encephalitis

Buckley et al., 2011 Ann Neurol. Jul;50(1):73-8.

Vincent et al., 2004 Brain 127; 701-12

Antibodies against the VGKC- complex

• At least three accessory proteins; CASPR2, LGI1 and Contactin-2 • CASPR2 found in patients with Morvan’s syndrome or neuromyotonia,

– Many of whom have a thymoma

• LGI1 found in patients with medial temporal lobe seizures associated with limbic encephalitis

– Non paraneoplastic

Irani et al., 2010 Brain 133(9):2734-48

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Lai et al., 2010 Lancet Neurol 9: 776-85

Other forms of limbic encephalitis

• Glutamic acid decarboxylase Malter et al., 2010 Ann Neurol 67; 470-478

• Younger and often only had seizures without the

other limbic feature

• None had tumours

• CSF active (OLB Positive)

• More chronic disease

• Thyroid antibodies – Hacohen et al., 2013 J Child Neurol Mar 20 Epub

– Haberlandt et al., 2011 Arch Dis Child 96(2):186-91

Case from Irani et al., 2011 Ann Neurol 69(5): 892-900

Faciobrachial Dystonic Seizures (FBDS)

• Seen in limbic encephalitis with VGKC-complex-Abs (mostly LGI1)

• Can precede neuropsychiatric and MRI features of limbic encephalitis

• Often poor response to AEDs and adverse reactions

• Good and surprisingly fast response to prednisolone

Irani et al., 2011 Ann Neurol 69(5): 892-900

54-year old prison officer presenting with whole-body jerks triggered

by auditory and tactile stimuli

Video from Hutchinson et al., 2008 Neurology 71(16):1291-2

Hutchinson et al., 2008 Neurology 71(16):1291-2

Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody

VGKC antibodies in paediatric encephalitis presenting with status epilepticus

• 10 patients with unexplained encephalitis presenting with status epilepticus and refractory seizures

• 4 patients positive for VGKC antibodies. • These antibodies are not directed against LGI1 and Caspr2.

• No other antibodies were detected.

Suleiman et al., 2011 Neurology 76 ; 1252-5

Febrile infection-related epilepsy

syndrome (FIRES) Baalen et al., 2010 Epilepsia 51(7); 1323-1328

• Idiopathic catastrophic Baxter et al., 2003 Seizure 12; 379-87

• Devastating epileptic encephalopathy in school age children (DESC) Mikaeloff et al., 2006 Epilepsy Res 69; 67-69

• Acute encephalitis with refractory, repetitive partial seizures (AERRPS) Sakuma et al., 2010 Acta Neurol Scand 121(4); 251-6

• New Onset Refractory Status Epilepticus Costello et al., 2009 J Neurol Sci. 15;277(1-2); 26-31

Previously well

Febrile prodrome followed by encephalopathy and fulminant seizures

Refractory seizures (not invariable)

Acute encephalopathy with inflammation-mediated status epilepticus

Nabbout et al., 2011 Lancet Neurol. 10(1); 99-108

Nabbout 2012 Epilepsia 2012 53 Suppl 4; 58-62

Case 2

• 22 months

• Seizures

• Agitation

• Relentless choreo athetoid movements

• Bulbar dysfunction

• Autonomic instability

Agrawal et al., 2010 ADC 95(4); 312

Case 2

Presentation 4 months

Courtesy or family and Dr E Wassmer, BCH

NMDAR antibody encephalitis

• Antibodies to the N-methyl-D-aspartate subtype of glutamate receptors

• Both paraneoplastic and non-paraneoplastic forms

• Young women with ovarian teratomas

• Presentation with seizures, cognitive problems or psychiatric features

Dalmau et al., 2007 Ann Neurol 61(1); 25-36

Titulaer et al., 2013 Lancet Neurol.12(2):157-65

Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.

Titulaer et al., 2013 Lancet Neurol 12(2):157-65

Titulaer et al., 2013 Lancet Neurol. 12(2):157-65

Titulaer et al., 2013 Lancet Neurol. 12(2):157-65

Titulaer et al., 2013 Lancet Neurol 12(2):157-65

Esseveld et al., 2012 Am J Psychiatry 170 21-2

Finke et al., 2013 Ann Neurol April 26 Epub

Case 2 -1 year later

Spectrum of NMDAR antibody mediated disease

• Dyskinetic form of encephalitis lethargica Dale et al., 2009 Ann Neurol 66:704-709

• Anti-NMDA receptor encephalitis presenting with focal non-convulsive status epilepticus in a child

Goldberg et al., 2011 Neuropediatrics;42(5):188-90.

• Isolated hemidystonia associated with NMDA receptor antibodies

Rubio-Agustí et al 2011 Mov Disord 1;26(2):351-2.

• Disease-relevant autoantibodies in first episode schizophrenia Zandi MS et al., 2011 J Neurol 258(4):686-8.

NMDAR antibody mediated movement disorder

Presentation 6 weeks later

NMDAR antibody mediated movement disorder?

Dale et al., 2012 J Child Neurol. 27(11):1470-81

Autoimmune basal ganglia disorders

D2R antibodies in basal ganglia encephalitis

• 12/17 children (age 0.4-15yrs) • Movement disorders, parkinsonism, dystonia

and chorea. • Psychiatric disturbance with emotional lability,

attention deficit and psychosis • Elevated IgG to extracellular D2R • No binding to D1,3,5 and DAT. • D2R Abs in 10/30 SC, 4/44 TS, 0/22 PANDAS

Dale et al., 2012 Brain 135(Pt 11):3453-68

Infection and auto-immunity in schizophrenia

Increased risk of autoimmunity in patients

Benros et al., 2012 Ann N Y Acad Sci. 1262:56-66

Increased risk of infection

HLA associations in schizophrenia

• Common disease, common variant model.

• A region of association of common SNPs with schizophrenia was identified at the MHC region.

• Pathway analysis of GWAS: pathways consistently found relate to metabolism of glutamate, the process of apoptosis, inflammation, and immune system.

Stefansson et al., 2009 Nature 460(7256): 744–747

Jia et al., 2010 Schizophr Res. 122(1-3):38-42

Innate system upregulation in schizophrenia

• Activated microglia in post-mortem studies.

• Increased blood brain-barrier permeability.

• Elevated levels of IL6 and altered IL2/IFN-g system regulation.

Strous & Schoenfeld 2006 J Autoimmun. 27(2):71-80.

Autoimmunity and neuropsychiatric disorders

Presence of autoantibodies against brain, brain structures and receptors

Jones et al., 2005 Immunol Cell Biol. 83(1):9-17 Tanaka et al., 2003 Neuroimmunol. 141(1-2):155-64.

Autoimmunity and neuropsychiatric disorders

• Patients present prominent psychiatric alterations, among other neurological manifestations, usually responsive to immunotherapy

• Autoantibodies against synaptic receptors and trans-synaptic proteins are found

Kayser & Dalmau 2011 J Neuropsychiatry Clin Neurosci 23(1):90-7

Autoimmunity in neuropsychiatric disorders

• Zandi et al., 2011 J Neurol. 258(4):686-8 Almost 9% (4/46) had autoantibodies (NMDAR and VGKC), exhibiting no differentiating clinical features from other psychotic patients

• Kayser et al., JAMA Neurology 2013 July 22 Epub 23/572 NMDAR positive patients had isolated neuropsychiatric syndrome but only 5 were first presentation

• Hammer et al., 2013 Molecular Psychiatry Sept 3 Eub 10% subjects (2817) had NMDAR antibodies

• Rarely occur in isolation Part of a wider encephalopathy

Symptoms can predate for a while

• Primary or secondary

• Paraneoplastic on adults and less so in kids

• Aetiological or still causing a problem?

• Start treatment before results

Need to treat early and long for best outcome

Immune neuropsychiatric disorders

Hacohen et al. 2013 J Neurol Neurosurg Psychiatry 84 (7); 748-55

When to suspect? Modified from Zuliani et al., 2012 J Neurol Neurosurg Psychiatry 83(6):638-45

• Acute or subacute (<12 weeks) onset » Recognisable syndrome

» Viral or fever prodrome

» Previously normal

• Evidence of CNS inflammation (at least one of) » CSF, MRI or inflammatory neuropathology

• Exclusion of infective and life-threatening metabolic causes

Lim 2012 SETPEG, ECH

Professor Angela Vincent.

Dr Bethan Lang

Dr Patrick Waters

Drs C Buckley & M Leite

Dr Yael Hacohen

Dr Sukhvir Wright

Drs M Woodhall & L Jacobs

Children’s Neurosciences

Do antibodies alter neuronal excitability?

VGKC/LGI1 Ab IgG elicits epileptiform activity in the CA3 area of hippocampus in brain slices

Extracellular potentials recorded in the stratum lucidum of CA3 pyramidal cell layer with extracellular stimulation of mossy fibres

Lalic et al., 2011 Epilepsia 52(1):121-31

VGKC/Lgi1 IgG increases burst activity in CA3 Reduces no of failures to stimulation Effects similar to dendrotoxin

Mikasova et al., 2012 Brain 135; 1606–1621

Patient CSF reduces dendritic density of GluN2B and GluN2A

Prevents LTP of glutamate synapses

Hughes et al., 2010 J Neurosci. 28;30(17):5866-75

Antibodies internalise NMDARs in hippocampal neurons

and reduce NMDARs after injection into mice

NMDAR antibodies associated with minimal T cells

VGKC-complex antibodies associated with CD8 T cell

infiltrates and perforin release

Bien et al., 2012 Brain135(Pt 5):1622-38.

VGKC-complex antibodies associated with neuronal

loss and APP deposits.

NMDAR antibodies associated with no neuronal loss or deposits

Bien et al., 2012 Brain135(Pt 5):1622-38.

Tumours contain neuronal cells

and express NMDAR

Tuzun et al., 2009 Acta Neuropathol 118(6):737-43

Working out the biology of receptors

Paoletti et al., 2013 Nat Rev Neurosci 14(6):383-400

Paoletti et al., 2013 Nat Rev Neurosci 14(6):383-400

The role of immunotherapy maybe beyond immune suppression

Zito and Scheuss 2009

Antibodies in epilepsy

235 follow-up and 181 new

onset epilepsy patients

screened plus 148 controls

11%* of patients had

antibodies to one or more

antigen

Brenner et al., 2013 Epilepsia Mar 6. doi: 10.1111/epi.12127

Positive Negative Total

Epilepsy (no. of patients)

35* 255 290

Controls (no. of patients)

11 169 180

Total 46 424 470

8

13 3 1 3

7

NMDA

VGKC

VGKC+NMDA

GLYCINE

CONTACTIN-2

CASPR2

Paediatric epilepsy cohorts

Dutch and Australian cohort of children with first onset seizures

Suleiman & Wright et al., (submitted)

2

VGKC in adults with seizures

Serum antibodies in epilepsy and seizure-associated disorders. McKnight, K; BM, MRCP; Jiang, Y; Hart, Y; MD, FRCP; Cavey, A; Wroe, S; MD, FRCP; Blank, M; Shoenfeld, Y; MD, FRCP; Vincent, A; Palace, J; Lang, B Neurology. 65(11):1730-1736, December 13, 2005. DOI: 10.1212/01.wnl.0000187129.66353.13

Figure 1 Antibodies to voltage-gated potassium channels (VGKCs) in the sera of patients with seizures and controls. Antibodies were measured by immunoprecipitation of [125I]-[alpha]-dendrotoxin-labeled VGKCs and are expressed in pM. Antibody titers were considered positive if greater than 100 pM (mean titer + 3 SD above the mean of the healthy controls). IC = immune cohort; DRC = drug-resistant cohort; REG = referred epilepsy group; MS = multiple sclerosis; OND = other neurologic disease; HCon = healthy controls; Pos = positive-titer serum from patients with neuromyotonia, known to have high VGKC antibody titers.