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1 Study Supplementary information S1 (table) : Additional data of studies examining patients with anti- LGI1 antibodies Number of patients Male Age median (range) in years Tumour Tumour type Relapses Irani et al. 55* 67% 0% Lai et al % 60 (30 80) 11% Thyroid (n= 2), lung, renal, ovarian, thymoma 6 of 33 (18%) Median follow- up 1.5 years Irani et al. 29 Ϯ 66% 64 (36 83) 0% Paterson et al. 8 63% 65 (18 86) Olberg et al % 64 (53 74) 20% Lip; thyroid Irani et al % 68 (29 92) 4 of 10 (40%) Median follow- up 1.5 years Shin et al % 61 (41 78) 7% Renal 2 of 4 (50%) Follow- up 1 month to 2 years Rocamora et 3 67% 39 (35 52) al Irani et al. 5 20% 65 (48 73) Malter et al % 55 (32 67) 0% 0 of 9 (0%) Median follow- up 2 years Flanagan et al % % Prostate (n =2) (37 78) Steriade et al. 9 56% 54 (15 80) 0% Gao et al % 51.5 (27 75) 0% 3 of 10 (30%) Follow- up 2 30 months Li et al % Mean 58 (34 78) 10% Lung 0 of 9 (0%) Mean follow- up 10.2 months

2 Van Sonderen et al % 64 (31 84) 11% Neuroendocrine pancreas tumour, thymoma, mesothelioma, rectum carcinoma in situ Arino et al % Mean 61 7% Prostate, gastric neuroendocrine (32 80) tumour, colon carcinoma Finke et al % Mean 66 10% Neuroendocrine tumour jejunum, breast cancer, oesophageal adenocarcinoma *8 patients overlap., not provided. 6 of 17 (35%) Median follow- up 42 months 13 of 48 (27%) Median follow- up 39 months

3 S2 (table) : Additional data of studies examining patients with anti- Caspr2 antibodies Study No. of Male Age median Tumour Tumour type Relapses patients (range) in years Irani et al % 32%* Thymoma (n = 5), endometrial adenocarcinoma Lancaster et al. 8 88% 60.5 (46 77) 0% Malter et al % 47 (38 69) 0% 0 of 3 (0%) follow- up months Sunwoo et al % 43.5 (8 65) Joubert et al. 18* 94% 64.5 (53 75) 17% Prostate adenocarcinoma plus chronic lymphoid leukaemia, thyroid cancer (n = 2) Van Sonderen et 38 89% 66 (25 77) 19% al Thymoma (n = 4), lung adenocarcinoma (n = 2, one without biopsy), carcinoma in situ of sigmoid 6 of 16 (38%) follow- up months 7 of 28 (25% ) follow- up 1 14 years Bien et al % 63 (33 75) 10% * 33 patients were included, but only in only 18 detailed clinical details could be extracted, 62 patients were included; only 27 of 62 were described in detail; two had no IgG antibodies; five no cerebrospinal fluid tested or confirmatory testing., not provided.

4 S3 (table) : Patients with Caspr2 antibodies identified in cohort screening (no extensive clinical description provided) Study Cohort Caspr2- positive patients Antibodies confirmed* Male Age median (range) in years Suleiman et al. Pediatric new- onset epilepsy n =3 No 67% 7 (0.5 10) (n = 114) Ekizoglu et al. Patients with focal epilepsy n = 4 No 25% 37 (35 40) (n = 81) Baysal- Kirac et Patients with autonomic seizures n = 5 Yes, 4/5 confirmed 20% 30 (15 36) al (n = 58) Vanli- Yavuz et al. Patients with epilepsy and hippocampal sclerosis n = 11 No 18% 17 (0 49) (n = 111) Wright et al Pediatric epilepsy (n = 178) n = 4 Yes, 2/4 confirmed 100% 9.7 ( ) *Antibody confirmation with addition laboratory techniques or cerebrospinal fluid analysis. Commercial cell- based assay followed by in- house cell- based assay and immunohistochemistry. In- house cell- based assay followed by staining with live hippocampal neurons.

5 S4 (table) : VGKC antibody- positive patients without LGI1 and Caspr2 antibodies; identified in cohort screening (no extensive clinical description provided) Study Cohort VGKC positive patients (LGI1 and Caspr2 neg) Male Age median (range) in years Suleiman et al Pediatric new- onset epilepsy n = 4 75% 3 ( ) (n= 114) Brenner et al Epilepsy n = 19 63% (n = 416) Hacohen et al. Pediatric autoimmune encephalopathy n = (6 15) * (n = 48) Hacohen et al Pediatric acute demyelinating disorder n = 3 67% 9 (6 14) (n = 65) Baysal Kirac et al. Patients with autonomic seizures n = 3 67% 26 (24 57) (n = 58) Vanli Yavuz et al. Patients with epilepsy and hippocampal sclerosis n = 4 50% 6 (0 13) (n = 111) Borusiak et al Pediatric focal epilepsy n = 3 33% 5 (2 6) (n = 124) Wright et al Pediatric epilepsy n = 3 33% 4 ( ) (n = 178) Hacohen et al., Pediatric brainstem encephalitis (n = 57) n = 3 *Overlap with Hacohen et al, Neurology 2015., not provided.

6 Study S5 (table) : VGKC- positive patients, analyzed (predominantly) irrespective of LGI1 and Caspr2 antibody result Additional inclusion criteria No. of patients Antibody classification Male Age median (range) in years Syndrome VGKC median titre in pm (range) Haberlandt et Pediatric LE 4 25% 14 (3 16) LE 180 al ( ) Dhamija et al. Pediatric 12 33% (8 mo 14 y) Cornelius et al NA 15 60% 56 (17 80) 33% LE 27% MoS Somers et al. NA % 59 (2 87) 44% neuropsychiatric symptoms Jaben et al. PE 5 40% 59 (46 76) 80% LE % NMT Irani et al. MoS 29 6/27 Caspr2 93% 57 (19 80) MoS (38% (23 VGKC 3/27 LGI1 thymoma) positive) 15/27 LGI1+Caspr2 Klein et al. NA /316 LGI /316 Caspr2 Lilleker et al. Seizures & Titer>400pM 6 1/6 LGI1 1/6 Caspr2 Diverse Pain in 50% 83% Mean 52.5 (27 77) Treatment effect Diverse 7/7 (100%) minor/major improvement * 1,510 (90 4,860) 150 (30 14,500) Follow- up and outcome 1/4 (25%) recovered, 1/4 (25%) died 9/11 (82%) improved 11/21 (52%) improved * ( ) 3/5 (60%) improved 17/27 improved (63%) 13/16 (81%) pain reduction * Seizures ( ) 6/6 (100%) improved 31% died LE 7 1/7 LGI1 Baumgartner et 71% 61 (26 71) LE al /7 Caspr2 Frisch et al LE 15 53% 57 (38 73) LE Majority improved

7 Sarkis et al. LE 4 75% 59 (29 80) LE Liewluck et al. CFS 9 2/7 LGI1 89% 45 (12 62) CFS 3/4 (75%) /7 Caspr2 improved * Kotsenas et al Seizures 42 22/32 LGI1 3/32 Caspr2 52% 56 (8 79) Seizures Huda et al. NA 57 3/19 LGI /19 Caspr2 56% 59 (25 77) 21% LE 37% PNH 2% MoS 40% Other 61% Mean 58 (19 86) 251 ( ) 20/23 (87%) improved * LE 36 16/36 LGI1 LE 16 5/16 LGI1 Urbach et al. LE /36 Caspr2 Wagner et al. 63% 55 (19 72) LE 1, /16 Caspr2 (427 7,655) O Sullivan et al. NA 62 Diverse *Many patients remained untreated; selection bias. Three patients also described in Irani et al, Brain Klein JAMA Neurol 2013 excluded due to substantial overlap in patients with Klein Neurology CFS, cramp fasciculation syndrome; LE, limbic encephalitis; MoS, Morvan s syndrome; NA, not applicable; NMT, neuromyotonia;, not provided; PE, plasma exchange; PNH, peripheral nerve hyperexcitability syndrome.

8 Reference List 1. Irani,S.R. et al. Antibodies to Kv1 potassium channel- complex proteins leucine- rich, glioma inactivated 1 protein and contactin- associated protein- 2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 133, (2010). 2. Lai,M. et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 9, (2010). 3. Irani,S.R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, (2011). 4. Paterson,R.W., Zandi,M.S., Armstrong,R., Vincent,A., & Schott,J.M. Clinical relevance of positive voltage- gated potassium channel (VGKC)- complex antibodies: experience from a tertiary referral centre. J. Neurol. Neurosurg. Psychiatry 85, (2014). 5. Olberg,H., Haugen,M., Storstein,A., & Vedeler,C.A. Neurological manifestations related to level of voltage- gated potassium channel antibodies. J. Neurol. Neurosurg. Psychiatry 84, (2013). 6. Irani,S.R. et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 136, (2013). 7. Shin,Y.W. et al. VGKC- complex/lgi1- antibody encephalitis: clinical manifestations and response to immunotherapy. J. Neuroimmunol. 265, (2013). 8. Rocamora,R. et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure. 23, (2014). 9. Irani,S.R., Gelfand,J.M., Bettcher,B.M., Singhal,N.S., & Geschwind,M.D. Effect of rituximab in patients with leucine- rich, glioma- inactivated 1 antibody- associated encephalopathy. JAMA Neurol. 71, (2014). 10. Malter,M.P. et al. Outcome of limbic encephalitis with VGKC- complex antibodies: relation to antigenic specificity. J. Neurol. 261, (2014). 11. Flanagan,E.P. et al. Basal ganglia T1 hyperintensity in LGI1- autoantibody faciobrachial dystonic seizures. Neurol. Neuroimmunol. Neuroinflamm. 2, e161 (2015).

9 12. Steriade,C., Mirsattari,S.M., Murray,B.J., & Wennberg,R. Subclinical temporal EEG seizure pattern in LGI1- antibody- mediated encephalitis. Epilepsia 57, e155 e160 (2016). 13. Gao,L. et al. Clinical characterization of autoimmune LGI1 antibody limbic encephalitis. Epilepsy Behav. 56, (2016). 14. Li,Z., Cui,T., Shi,W., & Wang,Q. Clinical analysis of leucine- rich glioma inactivated- 1 protein antibody associated with limbic encephalitis onset with seizures. Medicine (Baltimore) 95, e4244 (2016). 15. van Sonderen,A. et al. Anti- LGI1 encephalitis: Clinical syndrome and long- term follow- up. Neurology 87, (2016). 16. Arino,H. et al. Anti- LGI1- associated cognitive impairment: Presentation and long- term outcome. Neurology 87, (2016). 17. Finke,C. et al. Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine- Rich, Glioma- Inactivated 1 Antibodies. JAMA Neurol 74, (2017). 18. Lancaster,E. et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann. Neurol. 69, (2011). 19. Sunwoo,J.S. et al. Clinical manifestations of patients with CASPR2 antibodies. J. Neuroimmunol. 281, (2015). 20. Joubert,B. et al. Characterization of a Subtype of Autoimmune Encephalitis With Anti- Contactin- Associated Protein- like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures. JAMA Neurol. 73, (2016). 21. van Sonderen,A. et al. The clinical spectrum of Caspr2 antibody- associated disease. Neurology 87, (2016). 22. Bien,C.G. et al. Anti- contactin- associated protein- 2 encephalitis: relevance of antibody titres, presentation and outcome. Eur. J. Neurol 24, (2017). 23. Suleiman,J., Brilot,F., Lang,B., Vincent,A., & Dale,R.C. Autoimmune epilepsy in children: case series and proposed guidelines for identification. Epilepsia 54, (2013). 24. Ekizoglu,E. et al. Investigation of neuronal autoantibodies in two different focal epilepsy syndromes. Epilepsia 55, (2014). 25. Baysal- Kirac,L. et al. Neuronal autoantibodies in epilepsy patients with peri- ictal autonomic findings. J. Neurol. 263, (2016).

10 26. Vanli- Yavuz,E.N. et al. Neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis. J. Neurol. Neurosurg. Psychiatry 87, (2016). 27. Wright,S. et al. Neuronal antibodies in pediatric epilepsy: Clinical features and long- term outcomes of a historical cohort not treated with immunotherapy. Epilepsia 57, (2016). 28. Brenner,T. et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 54, (2013). 29. Hacohen,Y. et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J. Neurol. Neurosurg. Psychiatry 84, (2013). 30. Hacohen,Y. et al. Autoantibody biomarkers in childhood- acquired demyelinating syndromes: results from a national surveillance cohort. J. Neurol. Neurosurg. Psychiatry 85, (2014). 31. Borusiak,P. et al. Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis. Eur. J. Paediatr. Neurol. 20, (2016). 32. Hacohen,Y. et al. Paediatric brainstem encephalitis associated with glial and neuronal autoantibodies. Dev. Med. Child Neurol. 58, (2016). 33. Haberlandt,E. et al. Limbic encephalitis in children and adolescents. Arch. Dis. Child 96, (2011). 34. Dhamija,R. et al. Neuronal voltage- gated potassium channel complex autoimmunity in children. Pediatr. Neurol. 44, (2011). 35. Cornelius,J.R. et al. Sleep manifestations of voltage- gated potassium channel complex autoimmunity. Arch. Neurol. 68, (2011). 36. Somers,K.J. et al. Psychiatric manifestations of voltage- gated potassium- channel complex autoimmunity. J. Neuropsychiatry Clin. Neurosci. 23, (2011).

11 37. Jaben,E.A. & Winters,J.L. Plasma exchange as a therapeutic option in patients with neurologic symptoms due to antibodies to voltage- gated potassium channels: a report of five cases and review of the literature. J. Clin. Apher. 27, (2012). 38. Irani,S.R. et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann. Neurol. 72, (2012). 39. Klein,C.J., Lennon,V.A., Aston,P.A., McKeon,A., & Pittock,S.J. Chronic pain as a manifestation of potassium channel- complex autoimmunity. Neurology 79, (2012). 40. Lilleker,J.B., Jones,M.S., & Mohanraj,R. VGKC complex antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure. 22, (2013). 41. Baumgartner,A., Rauer,S., Mader,I., & Meyer,P.T. Cerebral FDG- PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J. Neurol. 260, (2013). 42. Frisch,C., Malter,M.P., Elger,C.E., & Helmstaedter,C. Neuropsychological course of voltage- gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis. Eur. J. Neurol. 20, (2013). 43. Sarkis,R.A., Nehme,R., & Chemali,Z.N. Neuropsychiatric and seizure outcomes in nonparaneoplastic autoimmune limbic encephalitis. Epilepsy Behav. 39, (2014). 44. Liewluck,T., Klein,C.J., & Jones,L.K., Jr. Cramp- fasciculation syndrome in patients with and without neural autoantibodies. Muscle Nerve 49, (2014). 45. Kotsenas,A.L. et al. MRI findings in autoimmune voltage- gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. AJNR Am. J. Neuroradiol. 35, (2014). 46. Huda,S. et al. An 11 year retrospective experience of antibodies against the voltage- gated potassium channel (VGKC) complex from a tertiary neurological centre. J. Neurol. 262, (2015). 47. Urbach,H. et al. Supratentorial white matter blurring associated with voltage- gated potassium channel- complex limbic encephalitis. Neuroradiology 57, (2015).

12 48. Wagner,J. et al. Distinct white matter integrity in glutamic acid decarboxylase and voltage- gated potassium channel- complex antibody- associated limbic encephalitis. Epilepsia 57, (2016). 49. O'Sullivan,B.J. et al. When should we test for voltage- gated potassium channel complex antibodies? A retrospective case control study. J. Clin. Neurosci.(2016).