Autoimmune encephalopathieslatest. Prof Belinda Lennox Department of Psychiatry, University of Oxford

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1 Autoimmune encephalopathieslatest advances Prof Belinda Lennox Department of Psychiatry, University of Oxford RCP Advanced Medicine 20 th June 2016

2 Declarations of Interest No income or interest in antibody testing I run a joint neuropsychiatry clinic in Oxford for autoimmune encephalitis with Dr Buckley, Dr Leite, Prof Vincent I am a psychiatrist

3 Overview Expanding range of neuronal cell surface antibodies Expanding phenotype VGKC antibody Expanding phenotype NMDAR antibodies

4 Neuronal cell surface antibodies = pathogenic and treatment responsive Control: IgG Patient 1: IgG NR1/NR2B/EGFP NR1/NR2B/EGFP

5 Evolving range of neuronal cell surface antibodies: Voltage Gated Potassium Channel complex (LGI1, CASPR2, contactin-2) 2001, 2004 N-Methyl-D-aspartate (NMDA) 2007 Glycine 2008 AMPA 2009 GABA-B 2013 GABA-A 2014 D2 2014

6 Clinical phenotype of LGI-1 antibodies limbic encephalitis Faciobrachio-dystonic seizures Subacute amnesia Seizures Autonomic dysfunction Hyponatraemia Imaging T2/FLAIR hyperintensities medial temporal hippocampal atrophy

7 Responsive to immunotherapy Vincent A et al. Brain 2004;127: The Guarantors of Brain 2004

8 cognitive impairment with VGKC abs Higher baseline titre = worse eventual memory Butler et al JNNP 2014

9 Neuropsychiatric presentation CASPR2 antibodies encephalitis peripheral nerve hyperexcitability, (Morvan s syndrome). Hallucinations, Insomnia Seizures, Autonomic dysfunction. Neuropathic pain

10 What about non-lgi-1/caspr2 VGKC abs?: Adult onset treatment refractory seizures (Iorio et al Eur J Neurol 2015) Pain (Klein et al Neurology 2012) Psychosis Also irrelevant: CJD Healthy controls

11 A high antibody titre is usually clinically relevant Ross W Paterson et al. J Neurol Neurosurg Psychiatry 2014;85: by BMJ Publishing Group Ltd

12 Suggested Clinical pathway Relevant clinical history VGKC RIA titre>400pm Cell Based Assay CASPR2/LGI1 Investigations MRI/EEG/CSF/neurops ych positive All negative immunotherapy Non autoimmune

13 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 )

14 Psychosis common as an early feature NMDAR ab encephalitis Cortical Subcortical Irani et al Brain 2010

15 Responsive to early immunotherapy Irani et al Brain 2010

16 Reduced fronto-temporal functional connectivity in NMDAR ab encephalitis Finke et al Biological Psychiatry 2015

17 Are NMDAR abs always clinically relevant? Creutzfeld Jacob Disease (Maat et al Neurol Neuroimmunol Neuroinflamm. 2015) Herpes Simplex Encephalitis (assoc. relapse) (Bamford et al J Pediatric Infect Dis Soc 2015) Schizophrenia (Zandi et al 2014)

18 26 F NMDAR Inpatient 1 st episode psychosis 1 month confusion, paranoid delusions, auditory hallucinations, insomnia, agitated, catatonic, posturing 2 days antipsychotics, stopped. Disorientated, poor recall, perseverative, poor frontal function (verbal fluency, proverb interpretation) MRI normal EEG non specific frontal slow waves at times

19 Treatment Steroids, plasma exchange Very disruptive on neurology ward. Required specialling Memory and psychosis improved after 2 weeks Back at work after 2 months Relapse at 8 months. Further steroid and plasma exchange, further response Maintained on mycophenylate mofetil No antipsychotics

20 Higher levels of serum CBA NMDAR antibodies usually relevant J Neurol Neurosurg Psychiatry (epub 22 Sep 2014): 56 positive cases from ~1000 screened Addenbrooke s and Queen Square

21 Live cell based assay versus commercial fixed antigen assays Commercial fixed slides are less sensitive and specific but can provide a quick answer

22 Relevant clinical history Serum NMDAR CBA positive Investigations MRI/EEG/CSF/neuropsych Immunotherapy

23 Summary Autoimmune encephalitides require early detection and assertive treatment for optimal outcomes Clinicians should also consider antibodies in restricted phenotypes that are resistant to symptomatic treatments Investigations CSF, EEG, MRI, neuropsychology can help There is potentially a large population of patients in psychiatric services that need treating in a different way This will be a challenge to psychiatry and neurology services

24 Acknowledgements Prof Angela Vincent, Dr Camilla Buckley, Dr M. Isabel Leite, Dr Ester Coutinho, Dr Sarosh Irani, Dr Leslie Jacobsen Neuroimmunology Group, NDCN, University of Oxford Prof. Alasdair Coles, Dr Mike Zandi Therapeutic Immunology Group, University of Cambridge Dr Emma Palmer, Prof Paul Harrison Department of Psychiatry, University of Oxford Prof. Peter Jones, Dr Julia Deakin Department of Psychiatry, University of Cambridge 37 PIs and CRN: Mental Health staff across England Funding support: National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute.