Autoimmune encephalitis: theoretical and clinical perspectives. Ming Lim Evelina Children s Hospital Clinical Neurology Laboratory, Oxford University

Transcription

1 Autoimmune encephalitis: theoretical and clinical perspectives Ming Lim Evelina Children s Hospital Clinical Neurology Laboratory, Oxford University

2 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

3 Inflammation in the brain Microglia Astrocytes The molecular effectors Compromise of the blood brain barrier Upregulation of the adaptive immune system Lim 2011 DMCN 53:

4 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

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

6 Dilution of serum Dilution of CSF Pathogenic role autoantibodies Presence of autoantibody Serum CSF IgGs/autoantibodies can target CNS IgGs are at target sites in CNS Autoantigen/antibody as part of the disease

7 Mechanisms of antibody-induced pathology Direct block Complementdependent lysis Internalisation

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9 Cell-based assays Antigen Patient has antibodies Binding can be scored visually or titrations performed

10 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

11 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

12 Case 1

13 A treatable form of limbic encephalitis 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 Buckley et al., 2011 Ann Neurol. Jul;50(1):73-8. Vincent et al., 2004 Brain 127;

14 Contactin-2 CASPR2 Kv1s Other ADAM22/23? LGI1 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): Lai et al., 2010 Lancet Neurol 9:

15 Other forms of limbic encephalitis Glutamic acid decarboxylase Malter et al., 2010 Ann Neurol 67; 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

16 Case from Irani et al., 2011 Ann Neurol 69(5):

17 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):

18 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

19 Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody Hutchinson et al., 2008 Neurology 71(16):1291-2

20 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 ;

21 Febrile infection-related epilepsy syndrome (FIRES) Baalen et al., 2010 Epilepsia 51(7); Idiopathic catastrophic Baxter et al., 2003 Seizure 12; Devastating epileptic encephalopathy in school age children (DESC) Mikaeloff et al., 2006 Epilepsy Res 69; Acute encephalitis with refractory, repetitive partial seizures (AERRPS) Sakuma et al., 2010 Acta Neurol Scand 121(4); New Onset Refractory Status Epilepticus Costello et al., 2009 J Neurol Sci. 15;277(1-2); 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); Nabbout 2012 Epilepsia Suppl 4; 58-62

22 Case 2 22 months Seizures Agitation Relentless choreo athetoid movements Bulbar dysfunction Autonomic instability Agrawal et al., 2010 ADC 95(4); 312

23 Case 2 Presentation 4 months Courtesy or family and Dr E Wassmer, BCH

24 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

25 Treatment and prognostic factors for longterm outcome in patients with anti-nmda receptor encephalitis: an observational cohort study. Titulaer et al., 2013 Lancet Neurol.12(2):157-65

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

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

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

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

30 Esseveld et al., 2012 Am J Psychiatry

31 Finke et al., 2013 Ann Neurol April 26 Epub

32 Case 2-1 year later

33 Spectrum of NMDAR antibody mediated disease Dyskinetic form of encephalitis lethargica Dale et al., 2009 Ann Neurol 66: Anti-NMDA receptor encephalitis presenting with focal nonconvulsive status epilepticus in a child Goldberg et al., 2011 Neuropediatrics;42(5): Isolated hemidystonia associated with NMDA receptor antibodies Rubio-Agustí et al 2011 Mov Disord 1;26(2): Disease-relevant autoantibodies in first episode schizophrenia Zandi MS et al., 2011 J Neurol 258(4):686-8.

34 NMDAR antibody mediated movement disorder Presentation 6 weeks later

35 NMDAR antibody mediated movement disorder?

36 Autoimmune basal ganglia disorders Dale et al., 2012 J Child Neurol. 27(11):

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38 D2R antibodies in basal ganglia encephalitis 12/17 children (age yrs) 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):

39 Infection and auto-immunity in schizophrenia Increased risk of infection Increased risk of autoimmunity in patients Benros et al., 2012 Ann N Y Acad Sci. 1262:56-66

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

41 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.

42 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):

43 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

44 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

45 Immune neuropsychiatric disorders 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

46 Hacohen et al J Neurol Neurosurg Psychiatry 84 (7);

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

48 Lim 2012 SETPEG, ECH

49 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

50 Do antibodies alter neuronal excitability?

51 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 VGKC/Lgi1 IgG increases burst activity in CA3 Reduces no of failures to stimulation Effects similar to dendrotoxin Lalic et al., 2011 Epilepsia 52(1):121-31

52 Patient CSF reduces dendritic density of GluN2B and GluN2A Prevents LTP of glutamate synapses Mikasova et al., 2012 Brain 135;

53 Antibodies internalise NMDARs in hippocampal neurons and reduce NMDARs after injection into mice Hughes et al., 2010 J Neurosci. 28;30(17):

54 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):

55 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):

56 Tumours contain neuronal cells and express NMDAR Tuzun et al., 2009 Acta Neuropathol 118(6):737-43

57 Working out the biology of receptors Paoletti et al., 2013 Nat Rev Neurosci 14(6):

58 Paoletti et al., 2013 Nat Rev Neurosci 14(6):

59 The role of immunotherapy maybe beyond immune suppression Zito and Scheuss 2009

60 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: /epi.12127

61 Paediatric epilepsy cohorts Dutch and Australian cohort of children with first onset seizures Positive Negative Total NMDA VGKC VGKC+NMDA GLYCINE CONTACTIN-2 CASPR2 Epilepsy (no. of patients) Controls (no. of patients) 35* Total Suleiman & Wright et al., (submitted)

62 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): , December 13, DOI: /01.wnl 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. 2