Antibody-mediated diseases

1. Autoimmune encephalopathies Angela Vincent, Suhkvir Wright, Yael Hacohen, Ming Limand the Neuroimmunololgy GroupNuffield Department of Clinincal Neurosciences and Evelina Childrens Hospital,UKDisclosures: AV and Oxford University hold patents and receive royalties/payments for antibody assays

2. Antibody-mediated diseases Antibodies that bind to extracellular domain of membrane protein on target tissue Antibodies measured easily in serum (and CSF) Antibodies cause loss of the target protein and/or damage to the cell Patients can improve with immunotherapies: steroids, plasma exchange, intravenous immunoglobulins

3. “Grey matter” antibody diseases in children VGKC-complex-Abs with autoimmune encephalitis NMDAR-Ab encephalitis GlyR-Ab encephalomyelitis GABA A receptor-Ab encephalitis

4. Acquired neuromyotonia – an autoimmune voltage-gated potassium channel (VGKC) disease? Spontaneous muscle activity due to peripheral nerve hyperexcitability Improves after plasma exchange or immunotherapies Voltage-gated potassium channel (VGKC)-Abs detected in some patients Some CNS involvement? Hart et al al Brain 2002; Turner et al JNNP 2006 Video available with publication

5. Limbic encephalitis with VGKC-complex Abs >400 pM Quite common, usually non-paraneoplastic Seizures and cognitive dysfunction MRI signs restricted to medial temporal lobes (and amygdala) LOW plasma sodium common VGKC-Abs in serum >> CSF and fall with immunotherapies and substantial clinical improvement Mainly older adults Buckley et al 2001 Vincent et al 2004, Thieben et al 2004

6. 6000 5000 4000 Steroids, Pl Ex, IvIg Serum VGKC antibody (pM) 3000 2000 1000 0 0 10 20 30 40 Months from Jan 1 2001 VGKC-complex-Ab Monophasic disease with good recovery Schott et al 2003. Video with publication Vincent et al 2004

7. The antibodies are directed at VGKC-complexes present in brain extracts Antibodies to any of these proteins can immunoprecipitate the VGKCs LGI1 Contactin-2 CASPR2 Kv1s Other? 125I-DTX Kv1 VGKC PSD95 PSD93 Irani, Alexander, Waters, Kleopa et al Brain 2010

8. Limbic encephalitis: VGKC-complex/LGI1 Abs most common Patient antibodies bind (green) to LGI1 expressed on hippocampal neurons (Irani et al 2010; Lai et al 2010) LGI1 Contactin-2 CASPR2 Other? Kv1s Kv1 VGKC PSD95 PSD93 LGI1 is mutated in autosomal dominant lateral temporal lobe epilepsy with auditory hallucinations

9. Faciobrachial dystonic seizures Very frequent brief dystonic events - often precede limbic encephalitis >90% associated with VGKC-complex/LGI1Abs Very steroid responsive, often AED unresponsive Irani et al Neurology 2008; Irani et al Ann Neurol 2011; Irani et al Brain 2013

10. Basal ganglia show hypermetabolism in FBDS Irani et al Ann Neurol 2011 Is this epilepsy or a movement disorder?

11. Limbic encephalitis with VGKC-complex Abs >400 pM in adults Quite common, usually non-paraneoplastic Often preceded by FBDS MRI signs restricted to medial temporal lobes (and amygdala) LOW plasma sodium common Antibodies fall with immunotherapies and substantial clinical improvement Mainly older adults Vincent et al 2004, Thieben et al 2004 In children, limbic encephalitis rare and relationship to VGKC-Abs less clear R Dale, CG Bien studies Dhamija R et Paed Neurol 2011 Hacohen et al JNNP 2012 Hacohen et al Neurology 2015

12. VGKC-complex antibodies in children A retrospective assessment of disease associations and pathogenic role High levels (>400pM) more common in children with neuroinflammatory diseases than non-inflammatory diseases But not exclusively associated with autoimmune forms of encephalitis Target of antibodies unclear – very seldom against LGI1 or CASPR2, may be intracellular epitopes Hacohen et al JNNP 2012 and Neurology 2015

13. LGI1 Contactin-2 CASPR2 Kv1s Other? 25% Morvan’s or neuromyotonia PSD95 PSD93 VGKC-complex Abs not always pathogenic, may be a secondary biomarker of neuroinflammatory disease Hacohen et al Neurology Aug 2015 Also Paterson et al JNNP 2014 Huda et al J Neurol 2015

14. NMDAR Abs in young females with ovarian teratoma-associated encephalopathies Dalmau et al Ann Neurol 2007 Dalmau et al Lancet Neurology 2008 600+ cases described Reviewed in Dalmau et al 2011, Titulaer et al 2012 “Anti-NMDAR encephalitis”

15. NMDAR-Abs Often prodrome of fever, headache leading up to: Subacute presentation with neuropsychiatric features and seizures Movement disorders, autonomic dysfunction, loss of consciousness White cells in CSF common, MRI findings usually normal or unhelpful Reviewed by Dalmau et al 2011, Titulaer et al 2013 Vincent, Bien, Irani, Waters et al 2011

16. NMDA receptor antibody encephalitisNeuropsychiatric presentations and movement disorders Teenage girl, presented with neuropsychiatric features, amnesia, seizures 10 d later, facial grimacing and chewing and choreoathetoid limb movements Mutism, reduced consciousness, autonomic lability No ovarian teratoma Very good response to immunotherapies Video courtesy of the patient and Dr G Vasello, Manchester

17. Antibodies reversibly bind and lead to loss of NMDARs on hippocampal neurons in culture and cause NMDAR loss and cognitive defects in mice Hughes et al 2010; Dalmau et al Lancet Neurology 2011; Planaguma et al Brain 2014

18. NMDAR (NR1/NR2B) antibodies in serum than in CSF NMDAR Score 4 NMDAR/ EGFP ANTI-IgG Is intrathecal synthesis essential for CNS disease? Do systemic and intrathecal antibodies have different effects?

19. NMDAR-Ab encephalitis common in children Biancheri et al J Ped 2011 4-year-old girl presenting with behavioural disorder and seizures after viral-like symptoms Video is available with publication

20. 22 month child with behavioural changes, sleep disturbance, general seizures, and then movement disorder. Eventually responded to immunotherapies but recovery not complete. Need for quicker and more effective treatments During on-going treatment Courtesy Dr Sukhvir Wright and the Consultants at Birmingham Children's Hospital. Video unpublished and not available

21. 66% only 1st line (Steroids/IvIg) 33% had 2nd line (Ritux/Cyclosporin) immunotherapy Trend towards better outcomes in patients who received PLEX as well as other treatments Sukhvir Wright et al ADC 2015

22. NMDAR antibodies in children (n=46, six centres in UK) measured by live cell assays in Oxford 28/46 (60%) definite NMDAR-Ab encephalitis 8 atypical/partial phenotypes Only 1/8 encephalopathic 10 “white matter” syndromes Brainstem encephalitis, ADS, or post-HSV encephalitis Hacohen et al Neurology N2 2014

23. NMDAR-Abs in 2 year old male with HSV encephalitis treated, followed by clinical deterioration, movement disorder, leukoencephalopathy and appearance of NMDAR antibodies Hacohen et al Neurology Neuroinmunology, Neuroinflammation 2014

24. Widening spectrum of NMDAR-Abs in adults and children Classic NMDAR-Ab encephalitis Partial phenotypes with predominant seizures, psychosis, cognitive impairment Relapses after HSV encephalitis Patients with white matter imaging changes Prompt and affective treatment required Many make very good recoveries, but not all Hacohen et al Neurology N2 2014 Armangues et al 2013

25. GlyR-Abs in adults Associated variably with rigidity, spasms, sweating, stiffness, and autonomic disturbance Thymomas and lymphomas 10% Appear to be mainly treatment-responsive Identified in a few children Good treatment responses

26. Progressive encephalomyelitis with rigidity and myoclonus (PERM) with glycine receptor antibodies Relapses precipitated by infections or stress Relapses less severe and less frequent with IvIg Damasio et al JAMA Neurology 2013. Video available with publication GLyR-Abs occasionally in encephalopathies/seizure disorders (eg. Wuerfel et al JNS 2014)

27. High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures or refractory status epilepticus

28. VGKC-complex, CASPR2 or NMDAR Abs found in around 10% but generally low levels “Because antibodies more frequent in paediatric patients with new-onset epilepsy of “unknown cause”, often with focal epilepsy features, this group might benefit from screening for antibodies and consideration of immunotherapies”

29. J Pediatrics 2013 Presentations are more “neurological” in children Seizures only at onset not uncommon in 10-18 yr olds

30. Intraventricular injection of NMDAR-Abs increases seizure susceptibility in mice Sukhvir Wright with Louise Upton (OXION) Wright et al Brain Nov 2015 A C B A B Plasma IgG injected once into lateral ventricle 7 days after implantation of electrodes Pro-convulsant PTZ injected 48 hours later C E D

31. General conclusions from studies of paediatric autoimmune encephalitis Paediatric diseases similar to adults in general Encephalopathy, seizures, cognitive and behavioural changes Often apyrexial at presentation, not always high CSF cell counts, not all have MRI abnormalities Often diagnosed by a specific antibody, but lack of known antibody should not rule out the diagnosis and treatment AND co-existing or previous infections (eg HSV) quite common and do not rule out an autoimmune aetiology And some antibodies may not be directly pathogenic Hacohen et al 2012, 2013, 2015

32. Yael Hacohen and Sukhvir WrightMing LimSarosh IraniPatrick WatersLeslie JacobsonIsabel LeiteCamilla Buckley Bethan Lang Many pediatric and adult neurologistsin UK and elsewhere