pathophysiology of autoimmune epilepsies – from antibodies to … · 2017-06-20 · limbic...

3rd Congress of the European Academy of Neurology

Amsterdam, The Netherlands, June 24 – 27, 2017

Teaching Course 2

Autoimmune causes of epilepsy - Level 3

Pathophysiology of autoimmune epilepsies – from antibodies to hyperexcitable neuronal

networks

Angela C. Vincent Oxford, United Kingdom

Email: [email protected]

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Pathophysiology of Autoimmune Epilepsies – From antibodies to hyperexcitable neuronal networks

Angela VincentNuffield Department of Clinical Neurosciences

Oxford

With help from Profs Arjune Sen (Oxford), Mala Shah (London) and Holger Lerche (Tuebingen)

Disclosures

AV and University of Oxford receive payments and royalties for MuSK, LGI1

and CASPR2 antibody assays

26/04/2017

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Pathophysiology of Autoimmune Epilepsies – From antibodies to hyperexcitable neuronal networks

Angela VincentNuffield Department of Clinical Neurosciences

Oxford

With help from Profs Arjune Sen (Oxford), Mala Shah (London) and Holger Lerche (Tuebingen)

Disclosures

AV and University of Oxford receive payments and royalties for MuSK, LGI1

and CASPR2 antibody assays

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Plan of presentation

Myasthenia gravis as a model of antibody-mediated diseases

Background to autoimmune epilepsy

Epileptic encephalopathies

What do we mean by autoimmune epilepsy?

How common is it?

How do antibodies alter cellular functions and generate seizures?


Antibodies that bind to extracellular domain of membrane protein on target tissue

Antibodies measured in serum

Antibodies cause loss of the target protein and/or damage to the membrane

Patients can improve with immunotherapies:steroids, plasma exchange, intravenous immunoglobulins

etc

Injection of patient IgG affects target functions in vitro and transfers disease to mice

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Plan of presentation



Epileptic encephalopathies

What do we mean by autoimmune epilepsy?

How common is it?

How do antibodies alter cellular functions and generate seizures?


Antibodies that bind to extracellular domain of membrane protein on target tissue

Antibodies measured in serum

Antibodies cause loss of the target protein and/or damage to the membrane

Patients can improve with immunotherapies:steroids, plasma exchange, intravenous immunoglobulins

etc

Injection of patient IgG affects target functions in vitro and transfers disease to mice

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Mechanisms of antibodies illustrated by AChR-Abs in myasthenia gravis IgG1 and IgG3 antibodies are divalent and cause complement-mediated

damage (a), increased internalisation (b) and occasionally direct inhibition of AChR function (c)

Note that activation of the receptor by antibody is very uncommon

From Crisp, Kullmann and Vincent Nature Reviews Neurology 2016

But MuSK antibodies are IgG4 > IgG1-3.

IgG4 antibodies are hybrid and monovalent because they exchange arms with other IgG4 molecules. They do not activate complement or cause

internalisation. They act mainly by inhibiting the binding of LRP4 to MuSK which is required for clustering AChRs at the neuromuscular junction

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Mechanisms of antibodies illustrated by AChR-Abs in myasthenia gravis IgG1 and IgG3 antibodies are divalent and cause complement-mediated

damage (a), increased internalisation (b) and occasionally direct inhibition of AChR function (c)

Note that activation of the receptor by antibody is very uncommon

From Crisp, Kullmann and Vincent Nature Reviews Neurology 2016

But MuSK antibodies are IgG4 > IgG1-3.

IgG4 antibodies are hybrid and monovalent because they exchange arms with other IgG4 molecules. They do not activate complement or cause

internalisation. They act mainly by inhibiting the binding of LRP4 to MuSK which is required for clustering AChRs at the neuromuscular junction

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Loss of postsynaptic membrane reduces sodium channels and leads to increase in

threshold for CMAP

Ruff and Lennon 1998

Rate of AChR synthesis increases to compensate

Wilson et al 1983, Guyon et al 1994

Release of ACh increases to compensate

Plomp et al 1995Ca2+

Modifying mechanisms can occur at ALL synapses

In addition, modifying mechanisms can operate in MG

Access of antibodies via blood flow/interstitial fluid require changes in BBB and/or intrathecal synthesis

IgG subclass determines potential mechanisms

Reduction in receptor or ion channel numbers or function usually result therefore target should be “inhibitory” not “excitatory”

Morphological damage by complement can contribute

But complement regulators may limit damage

Compensatory pre- and post-synaptic changes likely

Final result is unpredictable!

What factors might determine whether antibodies cause neuronal hyperexcitability in CNS neurons?

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Loss of postsynaptic membrane reduces sodium channels and leads to increase in

threshold for CMAP

Ruff and Lennon 1998

Rate of AChR synthesis increases to compensate

Wilson et al 1983, Guyon et al 1994

Release of ACh increases to compensate

Plomp et al 1995Ca2+

Modifying mechanisms can occur at ALL synapses

In addition, modifying mechanisms can operate in MG

Access of antibodies via blood flow/interstitial fluid require changes in BBB and/or intrathecal synthesis

IgG subclass determines potential mechanisms

Reduction in receptor or ion channel numbers or function usually result therefore target should be “inhibitory” not “excitatory”

Morphological damage by complement can contribute

But complement regulators may limit damage

Compensatory pre- and post-synaptic changes likely

Final result is unpredictable!

What factors might determine whether antibodies cause neuronal hyperexcitability in CNS neurons?

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Kasper et alBrain 2010

Corsellis JAN, Goldberg GJ, Norton AR 1968

Not all patients had a tumour

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Kasper et alBrain 2010

Corsellis JAN, Goldberg GJ, Norton AR 1968

Not all patients had a tumour

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a. b.

GluR3 antibodies in Rasmussen’s encephalitis and response to plasma exchange. Rogers, Andrews….McNamarra Science 1994

NOT FOUND Watson……………….Lang Neurology 2004 BUT

Jim McNamarra

A B

RE HC DC0

1

2

3

4

Samples

CB

A S

core

Positive cutoff

UPDATE 2017: AMPAR2/3 (GluR2/3) antibodies in 2/54 Rasmussen’s encephalitis patients but GluR2/3 Abs may be secondary, not primary.

Hem

isph

eric

ratio

Hem

isph

eric

ratio

Anjan Nibber, Beth Lang, Christian Bien et al EJPN 2016

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a. b.

GluR3 antibodies in Rasmussen’s encephalitis and response to plasma exchange. Rogers, Andrews….McNamarra Science 1994

NOT FOUND Watson……………….Lang Neurology 2004 BUT

Jim McNamarra

A B

RE HC DC0

1

2

3

4

Samples

CB

A S

core

Positive cutoff

UPDATE 2017: AMPAR2/3 (GluR2/3) antibodies in 2/54 Rasmussen’s encephalitis patients but GluR2/3 Abs may be secondary, not primary.

Hem

isph

eric

ratio

Hem

isph

eric

ratio

Anjan Nibber, Beth Lang, Christian Bien et al EJPN 2016

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Four patients

Young onset, subacute, intractable TLE, verbal and visual memory defects, affective disorders.

Increased T2 signal in limbic structues, inflammation on biopsy.

No virus or tumour identified

Non-paraneoplastic limbic encephalitis should be included in the differential diagnosis of adult patients with temporal lobe epilepsy.

Neurology 2000

Acquired neuromyotonia – an autoimmune voltage-gated potassium channel (VGKC) disease causing neuronal

hyperexcitability

Peripheral nerve hyperexcitability

Twitching, cramps, weakness, sweating

Improves after plasma exchange or IvIg

VGKC-Abs detected in some patients

Some had CNS involvement

Hart et al al Ann Neurol 1997; Brain 2002; Turner et al JNNP 2006

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Four patients

Young onset, subacute, intractable TLE, verbal and visual memory defects, affective disorders.

Increased T2 signal in limbic structues, inflammation on biopsy.

No virus or tumour identified

Non-paraneoplastic limbic encephalitis should be included in the differential diagnosis of adult patients with temporal lobe epilepsy.

Neurology 2000

Acquired neuromyotonia – an autoimmune voltage-gated potassium channel (VGKC) disease causing neuronal

hyperexcitability

Peripheral nerve hyperexcitability

Twitching, cramps, weakness, sweating

Improves after plasma exchange or IvIg

VGKC-Abs detected in some patients

Some had CNS involvement

Hart et al al Ann Neurol 1997; Brain 2002; Turner et al JNNP 2006

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Limbic encephalitis: A treatable or spontaneously improving form of limbic encephalitis – mostly >40 years, M>F

Unexplained onset of severe memory loss, confusion, personality changes,seizures

Inflammation in the hippocampuson magnetic resonance imaging or neuropathology

Tumours <10%Hyponatraemia common

VGKC-Ab positive – 100+ per year in UK

Buckley et al Neurology 2001; Vincent et al Brain 2004

But the antibodies are directed at VGKC-complexes

Antibodies to any of these proteins can be positive in the125I-D-dendrotoxin-VGKC-complex Ab assay

Irani et al Brain 2010

Oth

er?

LGI1

CAS

PR2

Con

tact

in-2

Kv1s

PSD95 PSD93

Kv1 VGKC

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Limbic encephalitis: A treatable or spontaneously improving form of limbic encephalitis – mostly >40 years, M>F

Unexplained onset of severe memory loss, confusion, personality changes,seizures

Inflammation in the hippocampuson magnetic resonance imaging or neuropathology

Tumours <10%Hyponatraemia common

VGKC-Ab positive – 100+ per year in UK

Buckley et al Neurology 2001; Vincent et al Brain 2004

But the antibodies are directed at VGKC-complexes

Antibodies to any of these proteins can be positive in the125I-D-dendrotoxin-VGKC-complex Ab assay


Oth

er?

LGI1

CAS

PR2

Con

tact

in-2

Kv1s

PSD95 PSD93

Kv1 VGKC

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VGKC-complex/LGI1 Abs most commonLGI1 expressed on cultured hippocampal neurons

Strongly associated with limbic encephalitis

LGI1 is mutated in autosomal dominant lateral temporal lobe epilepsy with auditory hallucinations

Heterozygous transgenic mice cause seizure susceptibility. Fukata group, Japan

Oth

er?

LGI1

CAS

PR2

Con

tact

in-2

Kv1s

PSD95 PSD93

Kv1 VGKC

LGI1-Ab Neuron

Antibodies to cell-surface, extracellular antigensLive cell-based assays

Patient does nothave specificantibodies

CASPR2

Most labs use fixed tissue/fixed cells

Antigen + EGFP Antigen + EGFP

Patient hasspecific

antibodies,Intensity can

be scored visually

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VGKC-complex/LGI1 Abs most commonLGI1 expressed on cultured hippocampal neurons

Strongly associated with limbic encephalitis

LGI1 is mutated in autosomal dominant lateral temporal lobe epilepsy with auditory hallucinations

Heterozygous transgenic mice cause seizure susceptibility. Fukata group, Japan

Oth

er?

LGI1

CAS

PR2

Con

tact

in-2

Kv1s

PSD95 PSD93

Kv1 VGKC

LGI1-Ab Neuron

Antibodies to cell-surface, extracellular antigensLive cell-based assays

Patient does nothave specificantibodies

CASPR2

Most labs use fixed tissue/fixed cells

Antigen + EGFP Antigen + EGFP

Patient hasspecific

antibodies,Intensity can

be scored visually

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Pre-tre

atmen

t

Post-tr

eatm

ent

0

2

4

6

P<0.0001

Mod

ified

Ran

kin

Scor

es in

Lgi

1-Ab

pos

itive

pat

ient

s


Death

Normal

Improvement in modified Rankin Scoresfollowing variable immunotherapies in 45 adult patients with

VGKC-Ab limbic encephalitis

20 Oxford patients, years after successful treatment. Majority LGI1-Abs. Epilepsy remits readily in most.

Neuropsychology testing shows normalisation in most modalities but verbal memory is still impairedButler et al JNNP 2014

LGI1 antibodies associated with poor memory recovery and hippocampal atrophyMalter……..Bien J Neurol 2014

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

Extracellular potentials recorded in the stratum lucidum ofCA3 pyramidal cell layer with extracellular stimulation of mossy

fibres

Lalic et al Epilepsia 2010

LGI1-antibody positive IgG increased burst activity in CA3

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10

Pre-tre

atmen

t

Post-tr

eatm

ent

0

2

4

6

P<0.0001

Mod

ified

Ran

kin

Scor

es in

Lgi

1-Ab

pos

itive

pat

ient

s


Death

Normal

Improvement in modified Rankin Scoresfollowing variable immunotherapies in 45 adult patients with

VGKC-Ab limbic encephalitis

20 Oxford patients, years after successful treatment. Majority LGI1-Abs. Epilepsy remits readily in most.

Neuropsychology testing shows normalisation in most modalities but verbal memory is still impairedButler et al JNNP 2014

LGI1 antibodies associated with poor memory recovery and hippocampal atrophyMalter……..Bien J Neurol 2014

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

Extracellular potentials recorded in the stratum lucidum ofCA3 pyramidal cell layer with extracellular stimulation of mossy

fibres


LGI1-antibody positive IgG increased burst activity in CA3

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LGI1-antibody positive IgG increased the release probability of mossy fibre-CA3 pyramidal cell synapses

Effects similar to blocking Kv1s with dendrotoxin

Reduced no of “failures” in evoked excitatory postsynaptic

currents (EPSCs) – more hyperexcitability

LGI1 forms bridge between pre and postsynaptic membranesLGI1-Abs mainly IgG4; direct block of LGI1 function

LGI1-Abs disrupt binding of LGI1 to ADAM22 and reduce postsynaptic AMPARs

Ohkawa et al J Neurosci 2013

LGI

1

ADAM

22LG

I1

AMPARO

ther

s

Presynaptic

Postsynaptic

LGI1

CAS

PR2

Kv1s

ADAM

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LGI1-Ab Neuron

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LGI1-antibody positive IgG increased the release probability of mossy fibre-CA3 pyramidal cell synapses

Effects similar to blocking Kv1s with dendrotoxin

Reduced no of “failures” in evoked excitatory postsynaptic

currents (EPSCs) – more hyperexcitability

LGI1 forms bridge between pre and postsynaptic membranesLGI1-Abs mainly IgG4; direct block of LGI1 function

LGI1-Abs disrupt binding of LGI1 to ADAM22 and reduce postsynaptic AMPARs

Ohkawa et al J Neurosci 2013

LGI

1

ADAM

22LG

I1

AMPARO

ther

s

Presynaptic

Postsynaptic

LGI1

CAS

PR2

Kv1s

ADAM

23

LGI1-Ab Neuron

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Majority of VGKC/LGI1 antibodies are IgG4 but nevertheless the pathology includes neuronal loss, T cell infiltrates and immunoglobulin and complement deposits. How is this?

See Bien et al Brain 2012

er animal models?

Knut shaking off after a swim in September 2010Disputes between the two zoos continued into 2009. On 19 May, the Berlin Zoo offered to buy Knut

VGKC/LGI1 antibodies in cats cause a similar syndrome with similar pathology

Pakozdy et al 2014; Klang et al 2014

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Majority of VGKC/LGI1 antibodies are IgG4 but nevertheless the pathology includes neuronal loss, T cell infiltrates and immunoglobulin and complement deposits. How is this?

See Bien et al Brain 2012

er animal models?

Knut shaking off after a swim in September 2010Disputes between the two zoos continued into 2009. On 19 May, the Berlin Zoo offered to buy Knut

VGKC/LGI1 antibodies in cats cause a similar syndrome with similar pathology

Pakozdy et al 2014; Klang et al 2014

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Neuropsychiatric and movement disorders with NMDAR-Abs

Dalmau et al 2007; 2008Video courtesy of the patient and

Dr G Vasello, Manchester

Presented with neuropsychiatric features, amnesia, seizures

Became mute

Developed facial grimacing and chewing, choreoathetoid limb movementsLoss of consciousnessNo tumour found

Very good recovery

Seizures are found in 70% of children and adults Titulaer et al Lancet Neurology 2012

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Neuropsychiatric and movement disorders with NMDAR-Abs

Dalmau et al 2007; 2008Video courtesy of the patient and

Dr G Vasello, Manchester

Presented with neuropsychiatric features, amnesia, seizures

Became mute

Developed facial grimacing and chewing, choreoathetoid limb movementsLoss of consciousnessNo tumour found

Very good recovery

Seizures are found in 70% of children and adults Titulaer et al Lancet Neurology 2012

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Irani et al Brain 2010 Vincent, Bien, Irani, Waters Lancet Neurology review 2011

Seizures are common at first presentation, but do not dominate

NMDAR-Abs bind to hippocampal neurons and reduce thenumber of NMDARs on both excitatory and inhibitory neurons

Hughes et al 2010; Moscato et al Ann Neurol 2014

In mice, intraventricular infusion of NMDAR-Ab CSFs caused cognitive defects and anhedonia Planaguma et al Brain 2014;

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Irani et al Brain 2010 Vincent, Bien, Irani, Waters Lancet Neurology review 2011

Seizures are common at first presentation, but do not dominate

NMDAR-Abs bind to hippocampal neurons and reduce thenumber of NMDARs on both excitatory and inhibitory neurons

Hughes et al 2010; Moscato et al Ann Neurol 2014

In mice, intraventricular infusion of NMDAR-Ab CSFs caused cognitive defects and anhedonia Planaguma et al Brain 2014;

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F

E

DD1 Insert electrodes D7 Inject IgG icv D9 Inject proconvulsant

pentylenetetrazol (PTZ)

A BHippocampus

Lateral ventricle

50µm

Wright et al Brain 2015

100 µm 100 µm

100µm

DIgG bound ex vivo (CA3 highest) Seizure score related to

IgG bound

No overall loss of NMDARs

How do the NMDAR-Abs cause increased seizure susceptibility in this model?

NMDAR-Ab IgG HC IgG

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F

E

DD1 Insert electrodes D7 Inject IgG icv D9 Inject proconvulsant

pentylenetetrazol (PTZ)

A BHippocampus

Lateral ventricle

50µm

Wright et al Brain 2015

100 µm 100 µm

100µm

DIgG bound ex vivo (CA3 highest) Seizure score related to

IgG bound

No overall loss of NMDARs

How do the NMDAR-Abs cause increased seizure susceptibility in this model?

NMDAR-Ab IgG HC IgG

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GABAAR antibody

Patients selected from archived samples

Alpha and beta subunit antibodies

Six patients higher titres, refractory seizures or SE

Other patients low titre and some had other antibodies eg GAD, GABAR

Routine referralsAlpha1 and gamma2 subunit

IgG antibodies and IgM antibodies

Clinical features at presentation were diverse

Seizures (47%), memory impairment (47%),

hallucinations (33%) or anxiety (20%) but few given

immunotherapy

Pettingill et al Neurology 2015

GABAAR antibody

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GABAAR antibody

Patients selected from archived samples

Alpha and beta subunit antibodies

Six patients higher titres, refractory seizures or SE

Other patients low titre and some had other antibodies eg GAD, GABAR

Routine referralsAlpha1 and gamma2 subunit

IgG antibodies and IgM antibodies

Clinical features at presentation were diverse

Seizures (47%), memory impairment (47%),

hallucinations (33%) or anxiety (20%) but few given

immunotherapy

Pettingill et al Neurology 2015

GABAAR antibody

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Patrick Watersfrom Vincent, Bien, Irani and Waters Lancet Neurology 2011

Extracellular and intracellular antigens relevant to seizure disorders

GABAaRGlyR(AChR)

Can antibodies cause seizures without other evident neurological features?

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Patrick Watersfrom Vincent, Bien, Irani and Waters Lancet Neurology 2011

Extracellular and intracellular antigens relevant to seizure disorders

GABAaRGlyR(AChR)

Can antibodies cause seizures without other evident neurological features?

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Irani et al Neurology 2008; Irani et al Ann Neurol 2011;Irani et al Brain 2013

Very frequent brief dystonic eventswith high VGKC-complex/LGI1Abs often PRECEDE

limbic encephalitis

Thompson……………………..Irani 2017 submitted

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Irani et al Neurology 2008; Irani et al Ann Neurol 2011;Irani et al Brain 2013

Very frequent brief dystonic eventswith high VGKC-complex/LGI1Abs often PRECEDE

limbic encephalitis

Thompson……………………..Irani 2017 submitted

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Autoimmune epilepsy in general

1. Epilepsy associated with autoimmune disorders

Survey from USA health insurance: incidence of epilepsy (0.4% in population) and risk of epilepsy in patients with autoimmune disorders 1.9 – 9.0 (mean 3.8), with

highest risk in antiphospholipid syndrome and SLE. 1.3% of epilepsy cases associated with autoimmune disorder (ie approx 5/100,000 prevalence)

Ong et al JAMA Neurol 2014

M. Toledano et al. Neurology 2014;82:1578-158616

The Mayo Clinic definition of autoimmune epilepsy?

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Autoimmune epilepsy in general

1. Epilepsy associated with autoimmune disorders

Survey from USA health insurance: incidence of epilepsy (0.4% in population) and risk of epilepsy in patients with autoimmune disorders 1.9 – 9.0 (mean 3.8), with

highest risk in antiphospholipid syndrome and SLE. 1.3% of epilepsy cases associated with autoimmune disorder (ie approx 5/100,000 prevalence)

Ong et al JAMA Neurol 2014


The Mayo Clinic definition of autoimmune epilepsy?

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How common are autoimmune epilepsies?78 new patients in 21 months; 13 “autoimmune” (ie. approx 17%)

What other forms of autoimmune epilepsy are there?

2. Status epilepticus occurring with specific neuronal antibodies

Survey from 7 centres , 8 years, only identified 13 patients with status epilepticus

12F, 1MEpilepsy first feature in most

5/13 had tumours8/13 NMDAR-Abs,

no Abs to LGI1 (or GABAAR not available at the time)

Holtzer et al European Neurology 2012

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How common are autoimmune epilepsies?78 new patients in 21 months; 13 “autoimmune” (ie. approx 17%)

What other forms of autoimmune epilepsy are there?

2. Status epilepticus occurring with specific neuronal antibodies

Survey from 7 centres , 8 years, only identified 13 patients with status epilepticus

12F, 1MEpilepsy first feature in most

5/13 had tumours8/13 NMDAR-Abs,

no Abs to LGI1 (or GABAAR not available at the time)

Holtzer et al European Neurology 2012

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3. Typical epilepsy occurring with specific neuronal antibodies

111 patients with long-standing MTLE 2011-2014

25 had antibodies11 CASPR21 GABAAR4 NMDAR

5 GlyR4 VGKC-complex only

Vanli-Yavuz et al JNNP 2016

BUT we need to know when antibody testing performed in relation to onset of seizures – are antibodies primary or secondary to neuroinflammation?

Antibodies to VGKC-complexes found in proportion of patients with unselected epilepsy, particularly focal epilepsies, in adults

and children, but usually low levels and significance unclear

Brenner et al Epilepsia 2013; Also Suleiman et al Dev Med Neurol 2011; Suleiman et al 2013; Quek et al 2012; Lang et al in preparation 2017.

Oth

erLG

I1

CAS

PR2

Con

tact

in-2

125I-DTX

Kv1s

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3. Typical epilepsy occurring with specific neuronal antibodies

111 patients with long-standing MTLE 2011-2014

25 had antibodies11 CASPR21 GABAAR4 NMDAR

5 GlyR4 VGKC-complex only

Vanli-Yavuz et al JNNP 2016

BUT we need to know when antibody testing performed in relation to onset of seizures – are antibodies primary or secondary to neuroinflammation?

Antibodies to VGKC-complexes found in proportion of patients with unselected epilepsy, particularly focal epilepsies, in adults

and children, but usually low levels and significance unclear

Brenner et al Epilepsia 2013; Also Suleiman et al Dev Med Neurol 2011; Suleiman et al 2013; Quek et al 2012; Lang et al in preparation 2017.

Oth

erLG

I1

CAS

PR2

Con

tact

in-2

125I-DTX

Kv1s

22

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Historic cohort of paediatric cases, no immunotherapies.Antibodies were not associated with AED resistance, and some fell spontaneously, or appeared de novo over time. Ie may be secondary, not primary

Historic cases with serum at first study

Pyramidal neuron receives input from dendrites which are controlled by Cav (L,T), HCN and Kv4.2

Pyramidal dendrites and cell body are also modulated by inhibitory neurons via nAChR and GABAAR

Action initial segment initiates activity via Nav1.2;Kv1 and 7 control axonal activity

What controls the pyramidal neuron?

From Lerche, Shah et al J Physiol 2013

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Historic cohort of paediatric cases, no immunotherapies.Antibodies were not associated with AED resistance, and some fell spontaneously, or appeared de novo over time. Ie may be secondary, not primary

Historic cases with serum at first study

Pyramidal neuron receives input from dendrites which are controlled by Cav (L,T), HCN and Kv4.2

Pyramidal dendrites and cell body are also modulated by inhibitory neurons via nAChR and GABAAR

Action initial segment initiates activity via Nav1.2;Kv1 and 7 control axonal activity

What controls the pyramidal neuron?

From Lerche, Shah et al J Physiol 2013

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Targets for autoimmune epilepsyAntibodies cause loss of function

Therefore candidate antigens are those for which “loss of function” gene mutations or perhaps modifiers? cause increased excitability

Gene targets

Loss of function mutation

Gain of function mutation

Modifiers of disease

Increased excitability predicted

IgG antibody targets

Kv1.1,1.2 Yes Yes Yes NoLGI1 Yes Yes Yes IgG4>>IgG1

CASPR2 Yes Yes Yes IgG4>IgG1KCa1.1 Yes Yes Yes ?

Kv7.2,7.3 Yes Yes Yes ?

NR1 IgG1

NR2a,b ?GABAARa1,g2 Yes Yes Yes IgG1

Nav1.1, 1.2 Yes Yes Yes UnlikelyCav2.1 Yes Yes Yes UnlikelyHCN Reduced Yes ?Kv4.2 Reduced Yes ?

Taken from Lerche, Shah J Physiol et al 2013

(a) Activation of pyramidal cells by glutamate release onto AMPAR and NMDARs.

Output also stimulates GABAergic neurons via glutamate/NMDARs

GABA release onto pyramidal neuron provides a feedback loop and regulates activity

(b) Antibody-mediated reduction of NMDARs on GABAergic neurons leads to unregulated pyramidal cell activity and seizures

But how do NMDAR-Abs cause seizures?

Wright and Vincent Current Op Neurol 2016

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Targets for autoimmune epilepsyAntibodies cause loss of function

Therefore candidate antigens are those for which “loss of function” gene mutations or perhaps modifiers? cause increased excitability

Gene targets

Loss of function mutation

Gain of function mutation

Modifiers of disease

Increased excitability predicted

IgG antibody targets

Kv1.1,1.2 Yes Yes Yes NoLGI1 Yes Yes Yes IgG4>>IgG1

CASPR2 Yes Yes Yes IgG4>IgG1KCa1.1 Yes Yes Yes ?

Kv7.2,7.3 Yes Yes Yes ?

NR1 IgG1

NR2a,b ?GABAARa1,g2 Yes Yes Yes IgG1

Nav1.1, 1.2 Yes Yes Yes UnlikelyCav2.1 Yes Yes Yes UnlikelyHCN Reduced Yes ?Kv4.2 Reduced Yes ?

Taken from Lerche, Shah J Physiol et al 2013

(a) Activation of pyramidal cells by glutamate release onto AMPAR and NMDARs.

Output also stimulates GABAergic neurons via glutamate/NMDARs

GABA release onto pyramidal neuron provides a feedback loop and regulates activity

(b) Antibody-mediated reduction of NMDARs on GABAergic neurons leads to unregulated pyramidal cell activity and seizures

But how do NMDAR-Abs cause seizures?

Wright and Vincent Current Op Neurol 2016

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Autoimmune epilepsy – some questions

How many immunotherapy-responsive epilepsy patients are there?

Are they being missed or over-diagnosed?

Is positive NMDAR-Ab CSF relevant to autoimmune epilepsy or only to encephalitis?

Can brain damage induce autoantibodies to these antigens (eg. post-HSV encephalitis, NMDAR-Abs)?

Should we be looking at candidate epilepsy antigens (eg.HCN)?

26/04/2017

24

Autoimmune epilepsy – some questions

How many immunotherapy-responsive epilepsy patients are there?

Are they being missed or over-diagnosed?

Is positive NMDAR-Ab CSF relevant to autoimmune epilepsy or only to encephalitis?

Can brain damage induce autoantibodies to these antigens (eg. post-HSV encephalitis, NMDAR-Abs)?

Should we be looking at candidate epilepsy antigens (eg. HCN)?

25

References

• Bien CG, Schulze-Bonhage A, Deckert M, Urbach H, Helmstaedter

C, Grunwald T, Schaller C, Elger CE. Limbic encephalitis not

associated with neoplasm as a cause of temporal lobe epilepsy.

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