Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-14T09:31:55.480Z Has data issue: false hasContentIssue false

Chapter 9 - Seizures and Antibodies Against Surface Antigens

from Section 3 - Specific Syndromes and Diseases

Published online by Cambridge University Press:  27 January 2022

Josep Dalmau  and
Francesc Graus
Josep Dalmau
Affiliation:
Universitat de Barcelona
Francesc Graus
Affiliation:
Universitat de Barcelona
Get access

Summary

Seizures are common in all types of autoimmune encephalitis, but their frequency and severity are particularly relevant in anti-NMDAR, anti-GABAbR, anti-GABAaR, and anti-LGI encephalitis. Seizures occur in>70% of patients in the acute phase of anti-NMDAR encephalitis without specific or distinctive features that may suggest this disorder. In anti-GABAbR and particularly anti-LGI1 encephalitis, seizures may precede in weeks the development of cognitive and psychiatric symptoms. Faciobrachial dystonic seizures (FBDS) are very typical of anti-LGI1 encephalitis and their recognition is important to make an early diagnosis. New-onset refractory status epilepticus (NORSE) is a clinical presentation of epilepsy that occurs in patients without previous history of seizures. When NORSE is preceded by a febrile episode, the term FIRES (febrile infection-related epilepsy syndrome) is frequently used, particularly in the paediatric literature. FIRES is considered a subtype of NORSE that may occur at any age. Only a small number of patients with anti-NMDAR or anti-GABAbR encephalitis presents as NORSE. The term FLAMES (FLAIR-hyperintense Lesions in anti-MOG associated encephalitis with seizures) has been used to describe the encephalitis of some patients with MOG antibodies. The clinical presentation includes seizures associated with isolated or predominantly unilateral cortical hyperintense lesions in FLAIR MRI images.

Keywords

Autoimmune encephalitisanti-GABAaR encephalitisanti-NMDAR encephalitisanti-LGI1 encephalitisfaciobrachial dystonic seizures (FBDS)new-onset refractory status epilepticus (NORSE)febrile infection-related epilepsy syndrome (FIRES)FLAIR-hyperintense lesions in anti-MOG associated encephalitis with seizures (FLAMES).
Type
Chapter
Information
Autoimmune Encephalitis and Related Disorders of the Nervous System , pp. 255 - 289
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Marchi, N, Granata, T, Janigro, D. Inflammatory pathways of seizure disorders. Trends Neurosci 2014;37:55–65.Google Scholar
Korff, CM, Dale, RC. The immune system in pediatric seizures and epilepsies. Pediatrics 2017;140:e20163534.Google Scholar
van Vliet, EA, Aronica, E, Vezzani, A, Ravizza, T. Review: neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy – emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol 2018;44:91–111.Google Scholar
Vezzani, A, Dingledine, R, Rossetti, AO. Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother 2015;15:1081–1092.CrossRefGoogle ScholarPubMed
Geis, C, Planaguma, J, Carreno, M, Graus, F, Dalmau, J. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–940.Google Scholar
Kim, SY, Senatorov, VV Jr., Morrissey, CS, et al. TGFbeta signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci Rep 2017;7:7711.CrossRefGoogle ScholarPubMed
Vezzani, A, Balosso, S, Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 2019;15:459–472.CrossRefGoogle ScholarPubMed
Yeshokumar, AK, Coughlin, A, Fastman, J, et al. Seizures in autoimmune encephalitis-A systematic review and quantitative synthesis. Epilepsia 2021;62:397–407.CrossRefGoogle ScholarPubMed
Sillevis, SP, Kinoshita, A, De, LB, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 2000;342:21–27.Google Scholar
de Graaff, E, Maat, P, Hulsenboom, E, et al. Identification of Delta/Notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol 2012;71:815–824.CrossRefGoogle ScholarPubMed
Sabater, L, Gaig, C, Gelpi, E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 2014;13:575–586.Google Scholar
Gaig, C, Graus, F, Compta, Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017;88:1736–1743.CrossRefGoogle ScholarPubMed
Dalmau, J, Geis, C, Graus, F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839–887.Google Scholar
Graus, F, Titulaer, MJ, Balu, R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.Google Scholar
Darnell, RB, Posner, JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–1554.CrossRefGoogle ScholarPubMed
Peltola, J, Kulmala, P, Isojarvi, J, et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 2000;55:46–50.Google Scholar
Giometto, B, Nicolao, P, Macucci, M, et al. Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies. Lancet 1998;352:457.CrossRefGoogle ScholarPubMed
Bien, CG, Granata, T, Antozzi, C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454–471.Google Scholar
Iizuka, T, Kanazawa, N, Kaneko, J, et al. Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy. Neurol Neuroimmunol Neuroinflamm 2017;4:e396.CrossRefGoogle ScholarPubMed
Gaspard, N, Foreman, BP, Alvarez, V, et al. New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology 2015;85:1604–1613.CrossRefGoogle ScholarPubMed
Zhou, JY, Xu, B, Lopes, J, Blamoun, J, Li, L. Hashimoto encephalopathy: literature review. Acta Neurol Scand 2017;135:285–290.Google Scholar
Alink, J, de Vries, TW. Unexplained seizures, confusion or hallucinations: think Hashimoto encephalopathy. Acta Paediatr 2008;97:451–453.Google Scholar
Jarius, S, Paul, F, Aktas, O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 2018;15:134.Google Scholar
Hamid, SHM, Whittam, D, Saviour, M, et al. Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease. JAMA Neurol 2018;75:65–71.CrossRefGoogle ScholarPubMed
Dubey, D, Hinson, SR, Jolliffe, EA, et al. Autoimmune GFAP astrocytopathy: prospective evaluation of 90 patients in 1 year. J Neuroimmunol 2018;321:157–163.Google Scholar
de Bruijn, M, van Sonderen, A, van Coevorden-Hameete, MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–e2196.Google Scholar
Irani, SR, Stagg, CJ, Schott, JM, et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013;136:3151–3162.CrossRefGoogle Scholar
Jeffery, OJ, Lennon, VA, Pittock, SJ, et al. GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 2013;81:882–887.Google Scholar
Hoftberger, R, Titulaer, MJ, Sabater, L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81:1500–1506.CrossRefGoogle Scholar
Spatola, M, Petit-Pedrol, M, Simabukuro, MM, et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology 2017;88:1012–1020.CrossRefGoogle ScholarPubMed
Petit-Pedrol, M, Armangue, T, Peng, X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276–286.Google Scholar
Titulaer, MJ, McCracken, L, Gabilondo, I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.Google Scholar
Schmitt, SE, Pargeon, K, Frechette, ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012;79:1094–1100.Google Scholar
Sonderen, AV, Arends, S, Tavy, DLJ, et al. Predictive value of electroencephalography in anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 2018;89:1101–1106.CrossRefGoogle ScholarPubMed
Aurangzeb, S, Symmonds, M, Knight, RK, et al. LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures. Seizure 2017;50:14–17.CrossRefGoogle ScholarPubMed
Steriade, C, Mirsattari, SM, Murray, BJ, Wennberg, R. Subclinical temporal EEG seizure pattern in LGI1-antibody-mediated encephalitis. Epilepsia 2016;57:e155–160.CrossRefGoogle ScholarPubMed
van Sonderen, A, Thijs, RD, Coenders, EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 2016;87:1449–1456.Google Scholar
Arino, H, Armangue, T, Petit-Pedrol, M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759–765.Google Scholar
Hoftberger, R, van Sonderen, A, Leypoldt, F, et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 2015;84:2403–2412.Google Scholar
Lai, M, Hughes, EG, Peng, X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65:424–434.Google Scholar
van Sonderen, A, Arino, H, Petit-Pedrol, M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology 2016;87:521–528.Google Scholar
Joubert, B, Saint-Martin, M, Noraz, N, 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 2016;73:1115–1124.Google Scholar
van Sonderen, A, Schreurs, MW, de Bruijn, MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692–1699.Google Scholar
Spatola, M, Sabater, L, Planaguma, J, et al. Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 2018;90:e1964–e1972.CrossRefGoogle ScholarPubMed
Dale, RC, Merheb, V, Pillai, S, et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 2012;135:3453–3468.CrossRefGoogle ScholarPubMed
Hara, M, Arino, H, Petit-Pedrol, M, et al. DPPX antibody-associated encephalitis: main syndrome and antibody effects. Neurology 2017;88:1340–1348.CrossRefGoogle ScholarPubMed
Tobin, WO, Lennon, VA, Komorowski, L, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 2014;83:1797–1803.Google Scholar
Carvajal-Gonzalez, A, Leite, MI, Waters, P, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014;137:2178–2192.Google Scholar
Schuler, V, Luscher, C, Blanchet, C, et al. Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 2001;31:47–58.Google Scholar
Prosser, HM, Gill, CH, Hirst, WD, et al. Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol Cell Neurosci 2001;17:1059–1070.Google Scholar
Waldmeier, PC, Kaupmann, K, Urwyler, S. Roles of GABAB receptor subtypes in presynaptic auto- and heteroreceptor function regulating GABA and glutamate release. J Neural Transm (Vienna) 2008;115:1401–1411.Google Scholar
Ohkawa, T, Satake, S, Yokoi, N, et al. Identification and characterization of GABA(A) receptor autoantibodies in autoimmune encephalitis. J Neurosci 2014;34:8151–8163.CrossRefGoogle ScholarPubMed
Hirose, S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 2014;213:55–85.Google Scholar
Planaguma, J, Leypoldt, F, Mannara, F, et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 2015;138:94–109.Google Scholar
Planaguma, J, Haselmann, H, Mannara, F, et al. Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity. Ann Neurol 2016;80:388–400.Google Scholar
Ladepeche, L, Planaguma, J, Thakur, S, et al. NMDA receptor autoantibodies in autoimmune encephalitis cause a subunit-specific nanoscale redistribution of NMDA receptors. Cell Rep 2018;23:3759–3768.Google Scholar
Mikasova, L, De Rossi, P, Bouchet, D, et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 2012;135:1606–1621.Google Scholar
Wright, S, Hashemi, K, Stasiak, L, et al. Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model. Brain 2015;138:3159–3167.CrossRefGoogle Scholar
Forrest, D, Yuzaki, M, Soares, HD, et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 1994;13:325–338.Google Scholar
Nakazawa, K, Quirk, MC, Chitwood, RA, et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 2002;297:211–218.CrossRefGoogle ScholarPubMed
Shimizu, E, Tang, YP, Rampon, C, Tsien, JZ. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 2000;290:1170–1174.CrossRefGoogle ScholarPubMed
Korotkova, T, Fuchs, EC, Ponomarenko, A, von Engelhardt, J, Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 2010;68:557–569.Google Scholar
Ohkawa, T, Fukata, Y, Yamasaki, M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1–ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161–18174.CrossRefGoogle ScholarPubMed
Petit-Pedrol, M, Sell, J, Planaguma, J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144–3159.Google Scholar
Fukata, Y, Lovero, KL, Iwanaga, T, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci USA 2010;107:3799–3804.Google Scholar
Zhou, YD, Lee, S, Jin, Z, et al. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 2009;15:1208–1214.Google Scholar
Fukata, Y, Adesnik, H, Iwanaga, T, et al. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 2006;313:1792–1795.Google Scholar
Seagar, M, Russier, M, Caillard, O, et al. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proc Natl Acad Sci US 2017;114:7719–7724.Google Scholar
Boillot, M, Lee, CY, Allene, C, et al. LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development. Sci Rep 2016;6:21769.Google Scholar
Gleichman, AJ, Panzer, JA, Baumann, BH, Dalmau, J, Lynch, DR. Antigenic and mechanistic characterization of anti-AMPA receptor encephalitis. Ann Clin Transl Neurol 2014;1:180–189.CrossRefGoogle ScholarPubMed
Peng, X, Hughes, EG, Moscato, EH, et al. Cellular plasticity induced by anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies. Ann Neurol 2015;77:381–398.CrossRefGoogle ScholarPubMed
Haselmann, H, Mannara, F, Werner, C, et al. Human autoantibodies against the AMPA receptor subunit GluA2 induce receptor reorganization and memory dysfunction. Neuron 2018;100:91–105.Google Scholar
Shimshek, DR, Jensen, V, Celikel, T, et al. Forebrain-specific glutamate receptor B deletion impairs spatial memory but not hippocampal field long-term potentiation. J Neurosci 2006;26:8428–8440.Google Scholar
Shimshek, DR, Bus, T, Kim, J, et al. Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors. PLoS Biol 2005;3:e354.CrossRefGoogle ScholarPubMed
Lu, W, Shi, Y, Jackson, AC, et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 2009;62:254–268.Google Scholar
Pinatel, D, Hivert, B, Boucraut, J, et al. Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis. Front Cell Neurosci 2015;9:265.Google Scholar
Poliak, S, Salomon, D, Elhanany, H, et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 2003;162:1149–1160.Google Scholar
Horresh, I, Poliak, S, Grant, S, et al. Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. J Neurosci 2008;28:14213–14222.CrossRefGoogle ScholarPubMed
Jia, Z, Lu, Y, Henderson, J, et al. Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn Mem 1998;5:331–343.Google Scholar
Lu, YM, Jia, Z, Janus, C, et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 1997;17:5196–5205.Google Scholar
Witkin, JM, Baez, M, Yu, J, Eiler, WJ, 2nd. mGlu5 receptor deletion does not confer seizure protection to mice. Life Sci 2008;83:377–380.Google Scholar
Guo, W, Molinaro, G, Collins, KA, et al. Selective disruption of metabotropic glutamate receptor 5-homer interactions mimics phenotypes of fragile X syndrome in mice. J Neurosci 2016;36:2131–2147.Google Scholar
Sun, W, Maffie, JK, Lin, L, et al. DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons. Neuron 2011;71:1102–1115.CrossRefGoogle ScholarPubMed
Lin, L, Murphy, JG, Karlsson, RM, et al. DPP6 loss impacts hippocampal synaptic development and induces behavioral impairments in recognition, learning and memory. Front Cell Neurosci 2018;12:84.Google Scholar
Crisp, SJ, Dixon, CL, Jacobson, L, et al. Glycine receptor autoantibodies disrupt inhibitory neurotransmission. Brain 2019;142:3398–3410.Google Scholar
Shiang, R, Ryan, SG, Zhu, YZ, et al. Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993;5:351–358.CrossRefGoogle ScholarPubMed
Buckwalter, MS, Cook, SA, Davisson, MT, White, WF, Camper, SA. A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death. Hum Mol Genet 1994;3:2025–2030.Google Scholar
Findlay, GS, Phelan, R, Roberts, MT, et al. Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant. J Neurosci 2003;23:8051–8059.Google Scholar
Gresa-Arribas, N, Planaguma, J, Petit-Pedrol, M, et al. Human neurexin-3alpha antibodies associate with encephalitis and alter synapse development. Neurology 2016;86:2235–2242.Google Scholar
Missler, M, Zhang, W, Rohlmann, A, et al. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 2003;423:939–948.Google Scholar
Aoto, J, Foldy, C, Ilcus, SM, Tabuchi, K, Sudhof, TC. Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. Nat Neurosci 2015;18:997–1007.Google Scholar
Yao, L, Yue, W, Xunyi, W, et al. Clinical features and long-term outcomes of seizures associated with autoimmune encephalitis: a follow-up study in East China. J Clin Neurosci 2019;68:73–79.Google Scholar
Lancaster, E, Lai, M, Peng, X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9:67–76.CrossRefGoogle Scholar
Zhao, XH, Yang, X, Liu, XW, Wang, SJ. Clinical features and outcomes of Chinese patients with anti-gamma-aminobutyric acid B receptor encephalitis. Exp Ther Med 2020;20:617–622.CrossRefGoogle ScholarPubMed
Dogan Onugoren, M, Deuretzbacher, D, Haensch, CA, et al. Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry 2015;86:965–972.Google Scholar
Maureille, A, Fenouil, T, Joubert, B, et al. Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis. J Neurol 2019;266:195–206.Google Scholar
Chen, X, Liu, F, Li, JM, et al. Encephalitis with antibodies against the GABAB receptor: seizures as the most common presentation at admission. Neurol Res 2017;39:973–980.Google Scholar
Cui, J, Bu, H, He, J, et al. The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy. Int J Neurosci 2018;128:627–633.Google Scholar
McKay, JH, Dimberg, EL, Lopez Chiriboga, AS. A systematic review of gamma-aminobutyric acid receptor type B autoimmunity. Neurol Neurochir Pol 2019;53:1–7.Google Scholar
Boronat, A, Sabater, L, Saiz, A, Dalmau, J, Graus, F. GABAB receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 2011;76:795–800.Google Scholar
Kruer, MC, Hoeftberger, R, Lim, KY, et al. Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of gamma-aminobutyric acid type B receptor autoimmunity. JAMA Neurol 2014;71:620–623.Google Scholar
Guasp, M, Landa, J, Martinez-Hernandez, E, et al. Thymoma and autoimmune encephalitis: clinical manifestations and antibodies. Neurol Neuroimmunol Neuroinflamm 2021;8:e1053.Google Scholar
Pettingill, P, Kramer, HB, Coebergh, JA, et al. Antibodies to GABAA receptor alpha1 and gamma2 subunits: clinical and serologic characterization. Neurology 2015;84:1233–1241.Google Scholar
Armangue, T, Olive-Cirera, G, Martinez-Hernandez, E, et al. Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study. Lancet Neurol 2020;19:234–246.Google Scholar
O’Connor, K, Waters, P, Komorowski, L, et al. GABAA receptor autoimmunity: a multicenter experience. Neurol Neuroimmunol Neuroinflamm 2019;6:e552.Google Scholar
Simabukuro, MM, Petit-Pedrol, M, Castro, LH, et al. GABAA receptor and LGI1 antibody encephalitis in a patient with thymoma. Neurol Neuroimmunol Neuroinflamm 2015;2:e73.Google Scholar
Figlerowicz, M, Kemnitz, P, Mania, A, et al. Autoimmune encephalitis with GABAA receptor antibodies in a 10-year-old girl. Clin Neurol Neurosurg 2018;164:160–163.Google Scholar
Florance, NR, Davis, RL, Lam, C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009;66:11–18.Google Scholar
Armangue, T, Titulaer, MJ, Malaga, I, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis: clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;162:850–856.Google Scholar
Qu, XP, Vidaurre, J, Peng, XL, et al. Seizure characteristics, outcome, and risk of epilepsy in pediatric anti-N-methyl-D-aspartate receptor encephalitis. Pediatr Neurol 2020;105:35–40.Google Scholar
Chavez-Castillo, M, Ruiz-Garcia, M, Herrera-Mora, P. Characterization and outcomes of epileptic seizures in Mexican pediatric patients with anti-N-methyl-D-aspartate receptor encephalitis. Cureus 2020;12:e8211.Google Scholar
Irani, SR, Bera, K, Waters, P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133:1655–1667.Google Scholar
Dalmau, J, Gleichman, AJ, Hughes, EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098.Google Scholar
Viaccoz, A, Desestret, V, Ducray, F, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 2014;82:556–563.Google Scholar
Gofshteyn, JS, Yeshokumar, AK, Jette, N, et al. Clinical and electrographic features of persistent seizures and status epilepticus associated with anti-NMDA receptor encephalitis (anti-NMDARE). Epileptic Disord 2020;22:739–751.Google Scholar
Liu, X, Yan, B, Wang, R, et al. Seizure outcomes in patients with anti-NMDAR encephalitis: a follow-up study. Epilepsia 2017;58:2104–2111.Google Scholar
Haberlandt, E, Ensslen, M, Gruber-Sedlmayr, U, et al. Epileptic phenotypes, electroclinical features and clinical characteristics in 17 children with anti-NMDAR encephalitis. Eur J Paediatr Neurol 2017;21:457–464.Google Scholar
Favier, M, Joubert, B, Picard, G, et al. Initial clinical presentation of young children with N-methyl-D-aspartate receptor encephalitis. Eur J Paediatr Neurol 2017;22:404–411.Google Scholar
Ariño, H, Muñoz-Lopetegi, A, Martinez-Hernandez, E, et al. Sleep disorders in anti-NMDAR encephalitis. Neurology 2020;95:e671–e684.Google Scholar
Munoz-Lopetegi, A, Graus, F, Dalmau, J, Santamaria, J. Sleep disorders in autoimmune encephalitis. Lancet Neurol 2020;19:1010–1022.Google Scholar
Gillinder, L, Warren, N, Hartel, G, Dionisio, S, O’Gorman, C. EEG findings in NMDA encephalitis: a systematic review. Seizure 2019;65:20–24.Google Scholar
Veciana, M, Becerra, JL, Fossas, P, et al. EEG extreme delta brush: an ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav 2015;49:280–285.Google Scholar
da Silva-Junior, FP, Castro, LH, Andrade, JQ, et al. Serial and prolonged EEG monitoring in anti-N-methyl-D-aspartate receptor encephalitis. Clin Neurophysiol 2014;125:1541–1544.CrossRefGoogle ScholarPubMed
Tan, YL, Tan, K, Tan, NC. Antiepileptic treatment for anti-NMDA receptor encephalitis: the need for video-EEG monitoring. Epileptic Disord 2013;15:468.Google Scholar
Howard, CM, Kass, JS, Bandi, VDP, Guntupalli, KK. Challenges in providing critical care for patients with anti-N-methyl-D-aspartate receptor encephalitis. Chest 2014;145:1143–1147.Google Scholar
Chanson, E, Bicilli, E, Lauxerois, M, et al. Anti-NMDA-R encephalitis: should we consider extreme delta brush as electrical status epilepticus? Neurophysiol Clin 2016;46:17–25.Google Scholar
Jeannin-Mayer, S, Andre-Obadia, N, Rosenberg, S, et al. EEG analysis in anti-NMDA receptor encephalitis: description of typical patterns. Clin Neurophysiol 2019;130:289–296.Google Scholar
Sands, TT, Nash, K, Tong, S, Sullivan, J. Focal seizures in children with anti-NMDA receptor antibody encephalitis. Epilepsy Res 2015;112:31–36.CrossRefGoogle ScholarPubMed
Shen, CH, Fang, GL, Yang, F, et al. Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABAB R encephalitis. Ann Clin Transl Neurol 2020;7:1392–1399.Google Scholar
Santoro, JD, Filippakis, A, Chitnis, T. Ketamine use in refractory status epilepticus associated with anti-NMDA receptor antibody encephalitis. Epilepsy Behav Rep 2019;12:100326.Google Scholar
Millichap, JJ, Goldstein, JL, Laux, LC, et al. Ictal asystole and anti-N-methyl-D-aspartate receptor antibody encephalitis. Pediatrics 2011;127:e781–e786.Google Scholar
Lee, M, Lawn, N, Prentice, D, Chan, J. Anti-NMDA receptor encephalitis associated with ictal asystole. J Clin Neurosci 2011;18:1716–1718.Google Scholar
Sansing, LH, Tuzun, E, Ko, MW, et al. A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol 2007;3:291–296.CrossRefGoogle ScholarPubMed
Kumar, MA, Jain, A, Dechant, VE, et al. Anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. Arch Neurol 2010;67:884–887.Google Scholar
de Montmollin, E, Demeret, S, Brule, N, et al. Anti-N-methyl-D-aspartate receptor encephalitis in adult patients requiring intensive care. Am J Respir Crit Care Med 2017;195:491–499.Google Scholar
Mehr, SR, Neeley, RC, Wiley, M, Kumar, AB. Profound autonomic instability complicated by multiple episodes of cardiac asystole and refractory bradycardia in a patient with anti-NMDA encephalitis. Case Rep Neurol Med 2016;2016:7967526.Google Scholar
Fisher, RS, Acevedo, C, Arzimanoglou, A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475–482.Google Scholar
Zhang, W, Wang, X, Shao, N, Ma, R, Meng, H. Seizure characteristics, treatment, and outcome in autoimmune synaptic encephalitis: a long-term study. Epilepsy Behav 2019;94:198–203.Google Scholar
Gabilondo, I, Saiz, A, Galan, L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology 2011;77:996–999.Google Scholar
Armangue, T, Spatola, M, Vlagea, A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol 2018;17:760–772.Google Scholar
Paolicchi, JM. The timing of pediatric epilepsy syndromes: what are the developmental triggers? Ann N Y Acad Sci 2013;1304:45–51.Google Scholar
Aznar Lain, G, Dellatolas, G, Eisermann, M, et al. Children often present with infantile spasms after herpetic encephalitis. Epilepsia 2013;54:1571–1576.CrossRefGoogle ScholarPubMed
Yildirim, M, Konuskan, B, Yalnizoglu, D, et al. Electroencephalographic findings in anti-N-methyl-D-aspartate receptor encephalitis in children: a series of 12 patients. Epilepsy Behav 2018;78:118–123.Google Scholar
Zhang, Y, Liu, G, Jiang, MD, Li, LP, Su, YY. Analysis of electroencephalogram characteristics of anti-NMDA receptor encephalitis patients in China. Clin Neurophysiol 2017;128:1227–1233.Google Scholar
Mohammad, SS, Soe, SM, Pillai, SC, et al. Etiological associations and outcome predictors of acute electroencephalography in childhood encephalitis. Clin Neurophysiol 2016;127:3217–3224.CrossRefGoogle ScholarPubMed
Gibbs, EL, Gibbs, FA. Extreme spindles: correlation of electroencephalographic sleep pattern with mental retardation. Science 1962;138:1106–1107.Google Scholar
Kirkpatrick, MP, Clarke, CD, Sonmezturk, HH, Abou-Khalil, B. Rhythmic delta activity represents a form of nonconvulsive status epilepticus in anti-NMDA receptor antibody encephalitis. Epilepsy Behav 2011;20:392–394.Google Scholar
Probasco, JC, Benavides, DR, Ciarallo, A, et al. Electroencephalographic and fluorodeoxyglucose-positron emission tomography correlates in anti-N-methyl-D-aspartate receptor autoimmune encephalitis. Epilepsy Behav Case Rep 2014;2:174–178.Google Scholar
Zhang, Y, Llinas, RR, Lisman, JE. Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting. Front Neural Circuits 2009;3:20.Google ScholarPubMed
Gataullina, S, Plouin, P, Vincent, A, et al. Paroxysmal EEG pattern in a child with N-methyl-D-aspartate receptor antibody encephalitis. Dev Med Child Neurol 2011;53:764–767.Google Scholar
Ikeda, A, Matsui, M, Hase, Y, et al. ‘Burst and slow complexes’ in nonconvulsive epileptic status. Epileptic Disord 2006;8:61–64.Google ScholarPubMed
Clancy, RR, Bergqvist, AGC, Dlugos, DJ. Neonatal electroencephalography. In: Ebersole, JS, Pedley, TA, eds. Current practice of clinical electroencephalography, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2003: 160–234.Google Scholar
Foff, EP, Taplinger, D, Suski, J, Lopes, MB, Quigg, M. EEG findings may serve as a potential biomarker for anti-NMDA receptor encephalitis. Clin EEG Neurosci 2017;48:48–53.Google Scholar
Sankaranarayanan, M, Shah, S, Thomas, P, Kannoth, S, Radhakrishnan, K. Persistent extreme delta brush in anti-NMDA-receptor encephalitis: does it portend a poor prognosis? Epilepsy Behav Rep 2019;12:100324.Google Scholar
Baykan, B, Gungor Tuncer, O, Vanli-Yavuz, EN, et al. Delta brush pattern is not unique to NMDAR encephalitis: evaluation of two independent long-term EEG cohorts. Clin EEG Neurosci 2018;49:278–284.Google Scholar
Heresco-Levy, U, Durrant, AR, Ermilov, M, et al. Clinical and electrophysiological effects of D-serine in a schizophrenia patient positive for anti-N-methyl-D-aspartate receptor antibodies. Biol Psychiatry 2015;77:e27–29.Google Scholar
Gitiaux, C, Simonnet, H, Eisermann, M, et al. Early electro-clinical features may contribute to diagnosis of the anti-NMDA receptor encephalitis in children. Clin Neurophysiol 2013;124:2354–2361.Google Scholar
Brenton, JN, Kim, J, Schwartz, RH. Approach to the management of pediatric-onset anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis: a case series. J Child Neurol 2016;31:1150–1155.Google Scholar
Lai, M, Huijbers, MG, Lancaster, E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776–785.Google Scholar
van Sonderen, A, Petit-Pedrol, M, Dalmau, J, Titulaer, MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 2017;13:290–301.Google Scholar
Irani, SR, Alexander, S, Waters, P, 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 2010;133:2734–2748.Google Scholar
Gadoth, A, Pittock, SJ, Dubey, D, et al. Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol 2017;82:79–92.Google Scholar
Andrade, DM, Tai, P, Dalmau, J, Wennberg, R. Tonic seizures: a diagnostic clue of anti-LGI1 encephalitis? Neurology 2011;76:1355–1357.Google Scholar
Wennberg, R, Steriade, C, Chen, R, Andrade, D. Frontal infraslow activity marks the motor spasms of anti-LGI1 encephalitis. Clin Neurophysiol 2018;129:59–68.Google Scholar
Navarro, V, Kas, A, Apartis, E, et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain 2016;139:1079–1093.Google Scholar
Irani, SR, Michell, AW, Lang, B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.Google Scholar
Vincent, A, Buckley, C, Schott, JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127:701–712.Google Scholar
Borusiak, P, Bettendorf, U, Wiegand, G, et al. Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis. Eur J Paediatr Neurol 2016;20:573–579.Google Scholar
Suleiman, J, Brenner, T, Gill, D, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology 2011;76:1252–1255.Google Scholar
Suleiman, J, Brilot, F, Lang, B, Vincent, A, Dale, RC. Autoimmune epilepsy in children: case series and proposed guidelines for identification. Epilepsia 2013;54:1036–1045.Google Scholar
Wright, S, Geerts, AT, Jol-van der Zijde, CM, et al. Neuronal antibodies in pediatric epilepsy: clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. Epilepsia 2016;57:823–831.Google Scholar
Hacohen, Y, Singh, R, Rossi, M, et al. Clinical relevance of voltage-gated potassium channel-complex antibodies in children. Neurology 2015;85:967–975.Google Scholar
Lopez-Chiriboga, AS, Klein, C, Zekeridou, A, et al. LGI1 and CASPR2 neurological autoimmunity in children. Ann Neurol 2018;84:473–480.Google Scholar
Beimer, NJ, Selwa, LM. Seizure semiology of anti-LGI1 antibody encephalitis. Epileptic Disord 2017;19:461–464.Google Scholar
Thompson, J, Bi, M, Murchison, AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–356.Google Scholar
Lopez Chiriboga, AS, Siegel, JL, Tatum, WO, Shih, JJ, Flanagan, EP. Striking basal ganglia imaging abnormalities in LGI1 ab faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm 2017;4:e336.Google Scholar
Flanagan, EP, Kotsenas, AL, Britton, JW, et al. Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm 2015;2:e161.Google Scholar
Naasan, G, Irani, SR, Bettcher, BM, Geschwind, MD, Gelfand, JM. Episodic bradycardia as neurocardiac prodrome to voltage-gated potassium channel complex/leucine-rich, glioma inactivated 1 antibody encephalitis. JAMA Neurol 2014;71:1300–1304.Google Scholar
Rachdi, A, Dupouy, J, Benaiteau, M, et al. Leucine-rich glioma-inactivated 1 encephalitis: broadening the sphere. Tremor Other Hyperkinet Mov (N Y) 2019;9.Google Scholar
Chen, C, Wang, X, Zhang, C, et al. Seizure semiology in leucine-rich glioma-inactivated protein 1 antibody-associated limbic encephalitis. Epilepsy Behav 2017;77:90–95.Google Scholar
Finke, C, Pruss, H, Heine, J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol 2017;74:50–59.Google Scholar
Shin, YW, Lee, ST, Shin, JW, et al. VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013;265:75–81.Google Scholar
Liu, X, Han, Y, Yang, L, et al. The exploration of the spectrum of motor manifestations of anti-LGI1 encephalitis beyond FBDS. Seizure 2020;76:22–27.Google Scholar
Iranzo, A, Graus, F, Clover, L, et al. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 2006;59:178–181.Google Scholar
Irani, SR, Gelfand, JM, Bettcher, BM, Singhal, NS, Geschwind, MD. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy. JAMA Neurol 2014;71:896–900.Google Scholar
Smith, KM, Dubey, D, Liebo, GB, Flanagan, EP, Britton, JW. Clinical course and features of seizures associated with LGI1-antibody encephalitis. Neurology 2021;97:e1141–e1149.Google Scholar
Striano, P, Belcastro, V, Striano, S. Tonic seizures: a diagnostic clue of anti-LGI1 encephalitis? Neurology 2011;77:2141–2143.Google Scholar
Chatrian, GE, Shaw, CM, Plum, F. Focal periodic slow transients in epilepsia partialis continua: clinical and pathological correlations in two cases. Electroencephalogr Clin Neurophysiol 1964;16:387–393.Google Scholar
Oga, T, Ikeda, A, Nagamine, T, et al. Implication of sensorimotor integration in the generation of periodic dystonic myoclonus in subacute sclerosing panencephalitis (SSPE). Mov Disord 2000;15:1173–1183.Google Scholar
Hirsch, LJ, Gaspard, N, van Baalen, A, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018;59:739–744.Google Scholar
Nabbout, R. FIRES and IHHE: delineation of the syndromes. Epilepsia 2013;54(Suppl. 6):54–56.Google Scholar
van Baalen, A, Hausler, M, Plecko-Startinig, B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43:209–216.Google ScholarPubMed
Lang, B, Makuch, M, Moloney, T, et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry 2017;88:353–361.Google Scholar
Graus, F, Gorman, MP. Voltage-gated potassium channel antibodies: game over. Neurology 2016;86:1657–1658.Google Scholar
Barros, P, Brito, H, Ferreira, PC, et al. Resective surgery in the treatment of super-refractory partial status epilepticus secondary to NMDAR antibody encephalitis. Eur J Paediatr Neurol 2014;18:449–452.Google Scholar
Kaplan, PW, Probasco, J. Limbic and new onset refractory tonic status epilepticus (NORSE) in anti-NMDAR encephalitis. Clin Neurophysiol Pract 2017;2:140–143.Google Scholar
Monti, G, Giovannini, G, Marudi, A, et al. Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19. Seizure 2020;81:18–20.Google Scholar
Sculier, C, Gaspard, N. New onset refractory status epilepticus (NORSE). Seizure 2019;68:72–78.Google Scholar
Hainsworth, JB, Shishido, A, Theeler, BJ, Carroll, CG, Fasano, RE. Treatment responsive GABA(B)-receptor limbic encephalitis presenting as new-onset super-refractory status epilepticus (NORSE) in a deployed U.S. soldier. Epileptic Disord 2014;16:486–493.Google Scholar
Budhram, A, Mirian, A, Le, C, et al. Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome. J Neurol 2019;266:2481–2487.Google Scholar
Specchio, N, Pietrafusa, N. New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome. Dev Med Child Neurol 2020;62:897–905.Google Scholar
Kothur, K, Bandodkar, S, Wienholt, L, et al. Etiology is the key determinant of neuroinflammation in epilepsy: elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus. Epilepsia 2019;60:1678–1688.Google Scholar
Howell, KB, Katanyuwong, K, Mackay, MT, et al. Long-term follow-up of febrile infection-related epilepsy syndrome. Epilepsia 2012;53:101–110.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×