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Brains on Fire – Autoimmune
causes of psychosis
Dr Belinda Lennox
Department of Psychiatry,
University of Oxford
RCPsych Brighton 16th
October 2014
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Overview
• The new disorders of antibody mediated
encephalitis – psychiatric relevance
• Prevalence of pathogenic antibodies in
psychosis
• Early experience and challenges of
treating patients with psychosis with
immunotherapy
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New disorders antibody
mediated encephalitis • Voltage Gated Potassium Channel complex
(LGI1, CASPR2, contactin-2) 2001
• N-Methyl-D-aspartate receptor (NMDA) 2008
• AMPA receptor 2009
• GABA-B 2008
• Glycine receptor 2012
• D2 receptor 2013
• GABA-A receptor 2014
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NR1/NR2B/EGFP
Patient 1: IgG Control: IgG
NR1/NR2B/EGFP
Neuronal cell surface antibodies =
pathogenic
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VGKC Antibody Encephalitis (Vincent et al 2004)
Subacute amnesia
Seizures,
Hallucinations,
behavioural change,
sleep impairment, depression
Hyponatraemia
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Responsive to immunotherapy
Vincent A et al. Brain 2004;127:701-712
The Guarantors of Brain 2004
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NMDA-receptor encephalitis:
• Progessive life threatening limbic
encephalitis,
• Fits, cognitive impairment, autonomic
instability, coma and dystonic movement
disorder
• 20-50% paraneoplastic (ovarian teratomas)
• 66-80% women, age 5-80 (mean 23)
• 1% all admissions to ITU (Dalmau et al Lancet Neurology 2008, Irani et al Brain
2010 )
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Psychosis common as an early feature
Irani et al Brain 2010
Cortical
Subcortical
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Better outcome with first and second line immunotherapy
Titulaer et al Lancet 2013
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NMDA dysfunction as a model for schizophrenia
Pathology Genes ketamine
Harrison and Weinberger Mol
Psych 2005
Glantz and Lewis
Arch Gen Psych 2000
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Prevalence of pathogenic antibodies in first
episode psychosis
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First episode psychosis cohort
Serum collected prospectively from 46 patients on
entry to Early Intervention Psychosis service.
Follow up for 3 years where possible.
Screened for NMDAR and VGKC antibodies
Patients with antibodies seen retrospectively by
neurologist.
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• All three of the patients have DSMIV schizophrenia.
• None of the patients had developed further neurological
symptoms or signs. Normal MRI, negative paraneoplastic
screen, no other autoimmune disorder
• None of the group as a whole developed typical autoimmune
encephalitis or other neurological diagnosis.
• 2 had NMDAR antibodies (score 2, score 1.5).
• 1 had VGKC-complex antibodies (1435 pM; normal<100).
3 of 46 patients with first episode psychosis had
pathogenic antibodies, prevalence 6.3% (1.9-16.5) (Zandi et al J Neurol 2011)
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Do patients with psychosis and
antibodies respond to treatment with
immunotherapy rather than
antipsychotics?
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Typical m
ax
Typical F
U
Atypica
l max
Atypica
l FU
0
1
2
3
4
5
p=0.883
p=0.002 p=0.07
NM
DA
R-A
b s
co
re (
0-4
)
No difference in Ab scores between
encephalitis and psychosis. Significant drop
in level after treatment
Morris et al Neurology 2014
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Typical
Typical
FU
Atypi
cal
Atypi
cal F
U
0
2
4
6
p=0.014
p=<0.001 p=0.009m
Rs
sco
re
Atypical patients lower mRs to start, still
respond to treatment
Morris et al Neurology 2014
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Neurolological assessment and treatment
needed
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Barriers to change: Psychiatric
• “We don’t do blood tests”
• “We don’t see patients”
• “We don’t believe it”
• “If there’s a cause then its not
schizophrenia”
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Barriers to change: Neurological
• “Psychosis doesn’t warrant treatment”
• “Patients are too difficult to manage in
neurology ward”
• “Its psychiatric (ie not a proper brain
disorder)”
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Cause No.
Moral
Domestic trouble 3
Religious excitement 8
Business and pecuniary 4
Mental anxiety and worry 8
Fright and various shocks 3
Physical
Intemperance 8
Accident and injury 1
Puerperal 5
Brain disease and general paralysis
6
Brain disease with epilepsy 10
Other forms of brain disease 4
Sunstroke 2
Hereditary 7
Congenital 1
Unascertained 27
Categories of illness (from annual report of St Lawrence's Hospital, 1877)
The nature of ‘psychiatric’ disease has evolved
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Next steps
• Blinded RCT of immunotherapy in those
with psychosis and antibodies
• Further discovery science – what’s
causing the other 90% ?
• System change in mental
health/neurological services to enable
detection and treatment
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Who to test
• Acute onset paranoid psychosis
• Psychosis with prodromal illness (fever,
headaches, malaise)
• Psychosis with cognitive impairment
(disorientation, poor recall)
• Psychosis with movement disorder (orofacial
dykinesia, catatonia)
• Adverse reaction to antipsychotics, ?NMS
(collapse, blood pressure drop)
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What to test
• Send serum for: NMDAR and VGKC abs (clinical immunology request form)
• Also test: ANA, CRP, ESR, FBC, U+E (low sodium in VGKC abs)
• If strong suspicion: EEG (if suggestive of encephalopathy would support early treatment)
• MRI head (medial temporal hyperintensity would support early treatment)
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Acknowledgements
• All 37 EI teams and PIs on MRC PPIP study
• Professor Angela Vincent, Dr Sarosh Irani, Dr Camilla
Buckley, Dr Ester Coutinho, Dr Katrina Morris
Neuroimmunology Group, University of Oxford
• Prof. Peter Jones, Dr Julia Deakin,
Department of Psychiatry, University of Cambridge
CAMEO, Cambridgeshire and Peterborough NHS Foundation Trust
• Dr. Alasdair Coles, Dr Mike Zandi, Dr Amanda Cox
Therapeutic Immunology Group, University of Cambridge
Cambridge University Hospitals NHS FoundationTrust
• Funding support National Institute for Health Research,
Medical Research Council NIHR CRN Mental Health