pathophysiology of autoimmune epilepsies – from antibodies to … · 2017-06-20 · limbic...
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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?
Myasthenia gravis as a model of antibody-mediated diseases
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
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?
Myasthenia gravis as a model of antibody-mediated diseases
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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Background to autoimmune epilepsy
Kasper et alBrain 2010
Corsellis JAN, Goldberg GJ, Norton AR 1968
Not all patients had a tumour
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Background to autoimmune epilepsy
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
Irani et al Brain 2010
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
Irani et al Brain 2010
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
Irani et al Brain 2010
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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Lalic et al Epilepsia 2010
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
26/04/2017
11
Lalic et al Epilepsia 2010
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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15
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
M. Toledano et al. Neurology 2014;82:1578-158616
The Mayo Clinic definition of autoimmune epilepsy?
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M. Toledano et al. Neurology 2014;82:1578-1586
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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M. Toledano et al. Neurology 2014;82:1578-1586
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
26/04/2017
21
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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22
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
26/04/2017
23
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)?
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