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Paraneoplastic movement disorders: phenomenology, diagnosis, and treatment

      Highlights

      • Acute-onset movement disorders should be promptly recognized by clinicians.
      • Different tumors are associated with different paraneoplastic movement disorders.
      • Paraneoplastic movement disorders are possibly treatable conditions.
      • Early diagnosis and immunotherapy might modify the disease course.
      • Management of these conditions requires both oncologists and neurologists.

      Abstract

      Paraneoplastic syndromes include, by definition, any symptomatic and non-metastatic condition associated with a neoplasm. Paraneoplastic movement disorders are a heterogeneous group of syndromes encompassing both hyperkinetic and hypokinetic conditions, characterized by acute/sub-acute onset, rapidly progressive evolution, and multifocal localizations with several overlapping features. These movement disorders are immune-mediated, as shown by the rapid onset and by the presence of antineuronal antibodies in biological samples of patients, fundamental for the diagnosis. Antineuronal antibodies could be targeted against intracellular or neuronal surface antigens. Paraneoplastic movement disorders associated with anti-neuronal surface antigens antibodies respond more frequently to immunotherapy. The underlying tumors may be different, according to the clinical presentation, age, and gender of patients. Our search considered articles involving human subjects indexed in PubMed. Abstracts were independently reviewed for eligibility criteria by one author and validated by at least one additional author. In this review, we sought to critically reappraise the clinical features and the pathophysiological mechanisms of paraneoplastic movement disorders, focusing on diagnostic and therapeutic strategies. Our main aim is to make clinicians aware of paraneoplastic movement disorders, and to provide assistance in the early diagnosis and management of these rare but life-threatening conditions.

      Keywords

      Abbreviations:

      AMPA-R (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), ANNA-3 (antineuronal nuclear antibody 3), AP3B2/Nb (AP3B2/Nb Antibodies), PCA2 (Purkinje cell cytoplasmic antibody type 2), CASPR2 (contactin-associated protein 2), CRMP-5 (collapsin-response mediated protein 5), CSF (cerebrospinal fluid), CT (computerized tomography), DPPX (dipeptidyl-peptidase-like protein 6), FDG (fluorodeoxyglucose), GABAA/B-R (gamma-aminobutyric acid-A/B receptor), GAD (glutamic acid decarboxylase), GluRε2 (GluR epsilon 2 antibodies), GQ1b (GQ1b ganglioside antibodies), GT1a (GT1a antibodies), HNK-1 (human natural killer 1), Hu/ANNA-1 (anti-neuronal nuclear antibody 1), i. v. (intravenous), IgLON5 (IgLON family member 5), LGI1 (leucine-rich glioma inactivated 1), MRI (magnetic resonance imaging), NMDA-R (N-methyl-d-aspartate receptor), NSA (neuronal surface), NR2A (glutamate receptor NR2A antibodies), NR2B (glutamate receptor NR2B antibodies), NSCLC (non-small cell lung cancer), OMS (opsoclonus-myoclonus ataxia syndrome), PERM (progressive encephalitis with rigidity and myoclonus), PET (positron emission tomography), PMDs (paraneoplastic movement disorders), PNS (paraneoplastic neurological syndromes), Ri/ANNA-2 (antineuronal nuclear antibody 2), SCLC (small cell lung cancer), SPS (stiff-person-syndrome), VGCC (voltage-gated calcium channels), TG (thyroglobulin antibodies), TPO (thyroid peroxidase), VGKC (voltage gated potassium channel)
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      References

        • Dalmau J.
        • Rosenfeld M.R.
        Paraneoplastic syndromes of the CNS.
        Lancet Neurol. 2008; 7: 327-340https://doi.org/10.1016/S1474-4422(08)70060-7
        • Darnell R.B.
        • Posner J.
        Paraneoplastic syndromes involving the nervous system.
        N Engl J Med. 2003; 349: 1543-1554https://doi.org/10.1056/NEJMra023009
        • Pittock S.J.
        • Lucchinetti C.F.
        • Parisi J.E.
        • Benarroch E.E.
        • Mokri B.
        • Stephan C.L.
        • et al.
        Amphiphysin autoimmunity: paraneoplastic accompaniments.
        Ann Neurol. 2005; 58: 96-107https://doi.org/10.1002/ana.20529
        • Viala K.
        • Béhin A.
        • Maisonobe T.
        • Léger J.M.
        • Stojkovic T.
        • Davi F.
        • et al.
        Neuropathy in lymphoma: a relationship between the pattern of neuropathy, type of lymphoma and prognosis?.
        J Neurol Neurosurg Psychiatry. 2008; 79: 778-782https://doi.org/10.1136/jnnp.2007.125930
        • Giometto B.
        • Grisold W.
        • Vitaliani R.
        • Graus F.
        • Honnorat J.
        • Bertolini G.
        Paraneoplastic neurologic syndrome in the PNS euronetwork database: a European study from 20 centers.
        Arch Neurol. 2010; 67: 330-335https://doi.org/10.1001/archneurol.2009.341
        • Graus F.
        • Delattre J.Y.
        • Antoine J.C.
        • Dalmau J.
        • Giometto B.
        • Grisold W.
        • et al.
        Recommended diagnostic criteria for paraneoplastic neurological syndromes.
        J Neurol Neurosurg Psychiatry. 2004; 75: 1135-1140https://doi.org/10.1136/jnnp.2003.034447
        • Chan A.
        • Baehring J.
        Paraneoplastic neurological syndromes: a single institution 10-year case series.
        J Neuro-Oncol. 2019; 141: 431-439https://doi.org/10.1007/s11060-018-03053-3
        • Baizabal-Carvallo J.F.
        • Jankovic J.
        Movement disorders in autoimmune diseases.
        Mov Disord. 2012; 27: 935-946https://doi.org/10.1002/mds.25011
        • Fahn S.
        • Jankovic J.
        • Hallett M.
        Principles and Practice of Movement Disorders.
        2nd ed. 2011https://doi.org/10.1016/C2009-0-44357-5
        • Albert M.L.
        • Austin L.M.
        • Darnell R.B.
        Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration.
        Ann Neurol. 2000; 47: 9-17https://doi.org/10.1002/1531-8249(200001)47:1<9::AID-ANA5>3.0.CO;2-I
        • Dalmau J.
        • Gleichman A.J.
        • Hughes E.G.
        • Rossi J.E.
        • Peng X.
        • Lai M.
        • et al.
        Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
        Lancet Neurol. 2008; 7: 1091-1098https://doi.org/10.1016/S1474-4422(08)70224-2
        • Fukuda T.
        • Motomura M.
        • Nakao Y.
        • et al.
        Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome.
        Ann Neurol. 2003; 53: 21-28https://doi.org/10.1002/ana.10392
        • Honorat J.A.
        • Komorowski L.
        • Josephs K.A.
        • Fechner K.
        • Louis E.K.S.
        • Hinson S.R.
        • et al.
        IgLON5 antibody - neurological accompaniments and outcomes in 20 patients.
        Neurol Neuroimmunol Neuroinflamm. 2017; 4e385https://doi.org/10.1212/NXI.0000000000000385
        • Vernino S.
        • Low P.A.
        • Fealey R.D.
        • Stewart J.D.
        • Farrugia G.
        • Lennon V.A.
        Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.
        N Engl J Med. 2000; 343 (343(12):847–55)https://doi.org/10.1056/NEJM200009213431204
        • Edwards M.
        • Stamelou M.
        • Quinn N.
        • Bhatia K.
        Parkinson's Disease and Other Movement Disorders.
        Oxford Univ Press, 2016
        • Armangue T.
        • Sabater L.
        • Torres-Vega E.
        • Martinez-Hernandez E.
        • Arino H.
        • Petit-Pedrol M.
        • et al.
        Clinical and immunological features of opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies.
        JAMA Neurol. 2016; 73: 417-424https://doi.org/10.1001/jamaneurol.2015.4607
        • Bataller L.
        • Graus F.
        • Saiz A.
        • Vilchez J.J.
        Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus.
        Brain. 2001; 124: 437-443
        • Bataller L.
        • Rosenfeld M.R.
        • Graus F.
        • Vilchez J.J.
        • Cheung N-K V.
        • Dalmau J.
        Autoantigen diversity in the opsoclonus-myoclonus syndrome.
        Ann Neurol. 2003; 53: 347-353https://doi.org/10.1002/ana.10462
        • Arino H.
        • Hoftberger R.
        • Gresa-Arribas N.
        • Martinez-Hernandez E.
        • Armangue T.
        • Kruer M.C.
        • et al.
        Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies.
        JAMA Neurol. 2015; 72: 874-881https://doi.org/10.1001/jamaneurol.2015.0749
        • Blaes F.
        • Dharmalingam B.
        Childhood opsoclonus-myoclonus syndrome: diagnosis and treatment.
        Expert Rev Neurother. 2016; 16: 641-648https://doi.org/10.1080/14737175.2016.1176914
        • Lamotte G.
        • Danaila T.C.
        • Jaillon-Riviere V.
        • Hitier M.
        • Defer G.L.
        Paraneoplastic opsoclonus myoclonus with autoantibodies to glutamic acid decarboxylase.
        Rev Neurol (Paris). 2014; 170: 50-51https://doi.org/10.1016/j.neurol.2013.03.010
        • Lie G.
        • Morley T.
        • Chowdhury M.
        Paraneoplastic cerebellar degeneration as a marker of endometrial cancer recurrence.
        BMJ Case Rep. 2016; 2016https://doi.org/10.1136/bcr-2016-215286
      1. Matschke J, Kromminga A, Erbersdobler A, Lamszus K, Anders S, Köfüncü E. Paraneoplastic cerebellar degeneration and anti-Yo antibodies in a man with prostatic adenocarcinoma. J Neurol Neurosurg Psychiatry 2007;78(7):775–7. doi:https://doi.org/10.1136/jnnp.2006.112961.

        • Meglič B.
        • Graus F.
        • Grad A.
        Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with gastric adenocarcinoma.
        J Neurol Sci. 2001; 185: 135-138https://doi.org/10.1016/S0022-510X(01)00467-1
        • Rojas I.
        • Graus F.
        • Keime-Guibert F.
        • Rene R.
        • Delattre J.Y.
        • Ramon J.M.
        • et al.
        Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies.
        Neurology. 2000; 55: 713-715
        • Debes J.
        • Lagarde S.
        • Hulsenboom E.
        • et al.
        Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of the gastroesophageal junction.
        Dig Surg. 2007; 24: 395-397https://doi.org/10.1159/000107782
        • Bernal F.
        • Shams'ili S.
        • Rojas I.
        • Sanchez-Valle R.
        • Saiz A.
        • Dalmau J.
        • et al.
        Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease.
        Neurology. 2003; 60: 230-234https://doi.org/10.1212/01.WNL.0000041495.87539.98
        • Mason W.P.
        • Graus F.
        • Lang B.
        • Honnorat J.
        • Delattre J.Y.
        • Valldeoriola F.
        • et al.
        Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome.
        Brain. 1997; 120: 1279-1300
        • Sabater L.
        • Höftberger R.
        • Boronat A.
        • Saiz A.
        Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer.
        PLoS One. 2013; 8: 8-11https://doi.org/10.1371/journal.pone.0060438
        • Graus F.
        • Lang B.
        • Pozo-Rosich P.
        • Saiz A.
        • Casamitjana R.
        • Vincent A.
        P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer.
        Neurology. 2002; 59: 764-766https://doi.org/10.1212/WNL.59.5.764
        • Yu Z.
        • Kryzer T.J.
        • Griesmann G.E.
        • Kim K.
        • Benarroch E.E.
        • Lennon V.A.
        CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity.
        Ann Neurol. 2001; 49: 146-154https://doi.org/10.1002/1531-8249(20010201)49:2<146::AID-ANA34>3.0.CO;2-E
        • Chan K.H.
        • Vernino S.
        • Lennon V.A.
        ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity.
        Ann Neurol. 2001; 50: 301-311https://doi.org/10.1002/ana.1127
        • Hasadsri L.
        • Lee J.
        • Wang B.H.
        • Yekkirala L.
        • Wang M.
        Anti-yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung.
        Case Rep Neurol Med. 2013; 2013: 725936https://doi.org/10.1155/2013/725936
        • Takasugi J.
        • Shimamura M.
        • Koda T.
        • Kishikawa T.
        • Hanamoto A.
        • Inohara H.
        • et al.
        Paraneoplastic cerebellar degeneration and Lambert-Eaton Myasthenic syndrome associated with neuroendocrine carcinoma of the oropharynx.
        Intern Med. 2018; 57: 587-590https://doi.org/10.2169/internalmedicine.9333-17
        • Dalmau J.
        • Rosenfeld M.R.
        Autoimmune encephalitis update.
        Neuro-Oncology. 2014; 16: 771-778https://doi.org/10.1093/neuonc/nou030
        • Titulaer M.J.
        • McCracken L.
        • Gabilondo I.
        • Armangue T.
        • Glaser C.
        • Iizuka T.
        • 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: 157-165https://doi.org/10.1016/S1474-4422(12)70310-1
        • Hoftberger R.
        • van Sonderen A.
        • Leypoldt F.
        • Houghton D.
        • Geschwind M.
        • Gelfand J.
        • et al.
        Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients.
        Neurology. 2015; 84: 2403-2412https://doi.org/10.1212/WNL.0000000000001682
        • Irani S.R.
        • Pettingill P.
        • Kleopa K.A.
        • Schiza N.
        • Waters P.
        • Mazia C.
        • et al.
        Morvan syndrome: clinical and serological observations in 29 cases.
        Ann Neurol. 2012; 72: 241-255https://doi.org/10.1002/ana.23577
        • Graus F.
        • Titulaer M.J.
        • Balu R.
        • Benseler S.
        • Bien C.G.
        • Cellucci T.
        • et al.
        A clinical approach to diagnosis of autoimmune encephalitis.
        Lancet Neurol. 2016; 15: 391-404https://doi.org/10.1016/S1474-4422(15)00401-9
        • Petit-Pedrol M.
        • Armangue T.
        • Peng X.
        • Bataller L.
        • Cellucci T.
        • Davis R.
        • 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: 276-286https://doi.org/10.1016/S1474-4422(13)70299-0
        • Mathew R.M.
        • Vandenberghe R.
        • Garcia-Merino A.
        • Yamamoto T.
        • Landolfi J.C.
        • Rosenfeld M.R.
        • et al.
        Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.
        Neurology. 2007; 68: 900-905https://doi.org/10.1212/01.wnl.0000252379.81933.80
        • Dalmau J.
        • Graus F.
        • Villarejo A.
        • Posner J.B.
        • Blumenthal D.
        • Thiessen B.
        • et al.
        Clinical analysis of anti-Ma2-associated encephalitis.
        Brain. 2004; 127: 1831-1844https://doi.org/10.1093/brain/awh203
        • Lancaster E.
        • Lai M.
        • Peng X.
        • Hughes E.
        • Constantinescu R.
        • Raizer J.
        • et al.
        Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.
        Lancet Neurol. 2010; 9: 67-76https://doi.org/10.1016/S1474-4422(09)70324-2
        • Moon J.
        • Lee S.-T.
        • Shin J.-W.
        • Byun J.-I.
        • Lim J.-A.
        • Shin Y.-W.
        • et al.
        Non-stiff anti-amphiphysin syndrome: clinical manifestations and outcome after immunotherapy.
        J Neuroimmunol. 2014; 274: 209-214https://doi.org/10.1016/j.jneuroim.2014.07.011
        • Sahashi K.
        • Sakai K.
        • Mano K.
        • Hirose G.
        Anti-Ma2 antibody related paraneoplastic limbic/brain stem encephalitis associated with breast cancer expressing Ma1, Ma2, and Ma3 mRNAs.
        J Neurol Neurosurg Psychiatry. 2003; 74: 1332-1335https://doi.org/10.1136/jnnp.74.9.1332
        • Vigliani M.C.
        • Honnorat J.
        • Antoine J.-C.
        • Vitaliani R.
        • Giometto B.
        • Psimaras D.
        • et al.
        Chorea and related movement disorders of paraneoplastic origin: the PNS EuroNetwork experience.
        J Neurol. 2011; 258: 2058-2068https://doi.org/10.1007/s00415-011-6074-1
        • O'Toole O.
        • Lennon V.A.
        • Ahlskog J.E.
        • Matsumoto J.Y.
        • Pittock S.J.
        • Bower J.
        • et al.
        Autoimmune chorea in adults.
        Neurology. 2013; 80: 1133-1144https://doi.org/10.1212/WNL.0b013e3182886991
        • Vernino S.
        • Tuite P.
        • Adler C.H.
        • Meschia J.F.
        • Boeve B.F.
        • Boasberg P.
        • et al.
        Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma.
        Ann Neurol. 2002; 51: 625-630https://doi.org/10.1002/ana.10178
        • Balint B.
        • Vincent A.
        • Meinck H.M.
        • Irani S.R.
        • Bhatia K.P.
        Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology.
        Brain. 2018; 141: 13-36https://doi.org/10.1093/brain/awx189
        • Pittock S.J.
        • Parisi J.E.
        • McKeon A.
        • Roemer S.F.
        • Lucchinetti C.F.
        • Tan K.M.
        • et al.
        Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri).
        Arch Neurol. 2010; 67: 1109-1115https://doi.org/10.1001/archneurol.2010.209
        • Pruss H.
        • Voltz R.
        • Flath B.
        • Rudolph B.
        • Klingebiel R.
        • Zschenderlein R.
        • et al.
        Anti-Ta-associated paraneoplastic encephalitis with occult testicular intratubular germ-cell neoplasia.
        J Neurol Neurosurg Psychiatry. 2007; 78: 651-652https://doi.org/10.1136/jnnp.2006.101964
        • Yap S.M.
        • Lynch T.
        • MacMahon P.
        • Murray B.
        Paraneoplastic atypical parkinsonism with anti CRMP 5 antibodies and severe caudate and putaminal hypometabolism on 18 fluorodeoxyglucose positron emission tomography of the brain.
        Mov Disord Clin Pract. 2017; 4: 263-265https://doi.org/10.1002/mdc3.12370
        • Hinson S.R.
        • Lopez-Chiriboga A.S.
        • Bower J.H.
        • Matsumoto J.Y.
        • Hassan A.
        • Basal E.
        • et al.
        Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders.
        Neurol Neuroimmunol Neuroinflammation. 2018; 5e438https://doi.org/10.1212/NXI.0000000000000438
        • Caviness J.N.
        • Forsyth P.A.
        • Layton D.D.
        • McPhee T.
        The movement disorder of adult opsoclonus.
        Mov Disord. 1995; 10: 22-27https://doi.org/10.1002/mds.870100106
        • Luque F.A.
        • Furneaux H.M.
        • Ferziger R.
        • Rosenblum M.K.
        • Wray S.H.
        • Schold S.C.
        • et al.
        Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer.
        Ann Neurol. 1991; 29: 241-251https://doi.org/10.1002/ana.410290303
        • Gallerini S.
        • Marsili L.
        • Marconi R.
        Opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies: a message for clinicians.
        JAMA Neurol. 2016; 73: 891https://doi.org/10.1001/jamaneurol.2016.1161
        • Graus F.
        • Ariño H.
        • Dalmau J.
        Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas.
        Blood. 2014; 123: 3230-3238https://doi.org/10.1182/blood-2014-03-537506
        • Peterson K.
        • Rosenblum M.K.
        • Kotanides H.
        • Posner J.B.
        Paraneoplastic cerebellar degeneration. I. a clinical analysis of 55 anti-Yo antibody-positive patients.
        Neurology. 1992; 42: 1931-1937https://doi.org/10.1212/WNL.42.10.1931
        • Shams'Ili S.
        • Grefkens J.
        • De Leeuw B.
        • Van den Bent M.
        • Hooijkaas H.
        • Van der Holt B.
        • et al.
        Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
        Brain. 2003; 126: 1409-1418https://doi.org/10.1093/brain/awg133
        • Storstein A.
        • Raspotnig M.
        • Vitaliani R.
        • Giometto B.
        • Graus F.
        • Grisold W.
        • et al.
        Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes.
        J Neurol. 2016; 263: 1001-1007https://doi.org/10.1007/s00415-016-8090-7
        • Verschnuren J.
        • Chuang L.
        • Rosenblum M.K.
        • Lieberman F.
        • Pryor A.
        • Posner J.B.
        • et al.
        Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo-associated paraneoplastic cerebellar degeneration.
        Acta Neuropathol. 1996; 91: 519-525https://doi.org/10.1007/s004010050460
        • Giometto B.
        • Marchiori G.C.
        • Nicolao P.
        • Scaravilli T.
        • Lion A.
        • Bardin P.G.
        • et al.
        Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system.
        Neuropathol Appl Neurobiol. 1997; 23: 468-474https://doi.org/10.1111/j.1365-2990.1997.tb01323.x
        • Rojas-Marcos I.
        • Graus F.
        • Sanz G.
        • Robledo A.
        • Diaz-Espejo C.
        Hypersomnia as presenting symptom of anti-Ma2-associated encephalitis: case study.
        Neuro-Oncology. 2007; 9: 75-77https://doi.org/10.1215/15228517-2006-013
        • Venkatraman A.
        • Opal P.
        Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.
        Ann Clin Transl Neurol. 2016; 3: 655-663https://doi.org/10.1002/acn3.328
        • Henke C.
        • Rieger J.
        • Hartmann S.
        • Middendorp M.
        • Steinmetz H.
        • Ziemann U.
        Paraneoplastic cerebellar degeneration associated with lymphoepithelial carcinoma of the tonsil.
        BMC Neurol. 2013; 13: 147https://doi.org/10.1186/1471-2377-13-147
        • Lancaster E.
        The diagnosis and treatment of autoimmune encephalitis.
        J Clin Neurol. 2016; 12: 1-13https://doi.org/10.3988/jcn.2016.12.1.1
        • Leypoldt F.
        • Wandinger K.-P.
        • Bien C.G.
        • Dalmau J.
        Autoimmune encephalitis.
        Eur Neurol Rev. 2013; 8 (31–7)https://doi.org/10.17925/enr.2013.08.01.31
        • Schein F.
        • Gagneux-Brunon A.
        • Antoine J.C.
        • Lavernhe S.
        • Pillet S.
        • Paul S.
        • et al.
        Anti-N-methyl-d-aspartate receptor encephalitis after herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges.
        Infection. 2017; 45: 545-549https://doi.org/10.1007/s15010-016-0959-y
        • van der Meulen A.A.E.
        • van der Hoeven J.H.
        • de Jong B.M.
        • Elting J.W.J.
        Extreme delta brushes in anti NMDA receptor encephalitis – muscle artefact or an EEG phenomenon? A case report.
        Clin. Neurophysiol. 2017; 128: 1835-1836https://doi.org/10.1016/j.clinph.2017.06.256
        • Varley J.A.
        • Webb A.J.S.
        • Balint B.
        • Fung V.S.C.
        • Sethi K.D.
        • Tijssen M.A.J.
        • et al.
        The movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study.
        J Neurol Neurosurg Psychiatry. 2018; https://doi.org/10.1136/jnnp-2018-318584
        • Lai M.
        • Huijbers M.G.M.
        • Lancaster E.
        • Graus F.
        • Bataller L.
        • Balice-Gordon R.
        • et al.
        Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.
        Lancet Neurol. 2010; 9: 776-785https://doi.org/10.1016/S1474-4422(10)70137-X
        • Granerod J.
        • Ambrose H.E.
        • Davies N.W.S.
        • Clewley J.P.
        • Walsh A.L.
        • Morgan D.
        • et al.
        Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.
        Lancet Infect Dis. 2010; 10: 835-844https://doi.org/10.1016/S1473-3099(10)70222-X
        • Andrade D.M.
        • Tai P.
        • Dalmau J.
        • Wennberg R.
        Tonic seizures: a diagnostic clue of anti-LGI1 encephalitis?.
        Neurology. 2011; 76: 1355-1357https://doi.org/10.1212/WNL.0b013e3182152808
        • Irani S.R.
        • Michell A.W.
        • Lang B.
        • Pettingill P.
        • Waters P.
        • Johnson M.R.
        • et al.
        Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.
        Ann Neurol. 2011; 69: 892-900https://doi.org/10.1002/ana.22307
        • Lancaster E.
        • Huijbers M.G.M.
        • Bar V.
        • Boronat A.
        • Wong A.
        • Martinez-Hernandez E.
        • et al.
        Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.
        Ann Neurol. 2011; 69: 303-311https://doi.org/10.1002/ana.22297
        • 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: 795-800https://doi.org/10.1212/WNL.0b013e31820e7b8d
        • Rosenfeld M.R.
        • Eichen J.G.
        • Wade D.F.
        • Posner J.B.
        • Dalmau J.
        Molecular and clinical diversity in paraneoplastic immunity to Ma proteins.
        Ann Neurol. 2001; 50: 339-348https://doi.org/10.1002/ana.1288.abs
        • Matsumoto L.
        • Yamamoto T.
        • Higashihara M.
        • Sugimoto I.
        • Kowa H.
        • Shibahara J.
        • et al.
        Severe hypokinesis caused by paraneoplastic anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes.
        Mov Disord. 2007; 22: 728-731https://doi.org/10.1002/mds.21314
        • Castle J.
        • Sakonju A.
        • Dalmau J.
        • Newman-Toker D.E.
        Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease.
        Nat Clin Pract Neurol. 2006; 2: 566-572https://doi.org/10.1038/ncpneuro0287
        • Hoffmann L.A.
        • Jarius S.
        • Pellkofer H.L.
        • Schueller M.
        • Krumbholz M.
        • Koenig F.
        • et al.
        Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases.
        J Neurol Neurosurg Psychiatry. 2008; 79: 767-773https://doi.org/10.1136/jnnp.2007.118588
        • Attarian H.
        • Applebee G.
        • Von Lepel A.
        Paraneoplastic myoclonus with papillary thyroid carcinoma.
        Eur Neurol. 2007; 58: 182-183https://doi.org/10.1159/000104721
        • Klaas J.P.
        • Ahlskog J.E.
        • Pittock S.J.
        • Matsumoto J.Y.
        • Aksamit A.J.
        • Bartleson J.D.
        • et al.
        Adult-onset opsoclonus-myoclonus syndrome.
        Arch Neurol. 2012; 69: 1598-1607https://doi.org/10.1001/archneurol.2012.1173
        • Honorat J.A.
        • McKeon A.
        Autoimmune movement disorders: a clinical and laboratory approach.
        Curr Neurol Neurosci Rep. 2017; 17: 4https://doi.org/10.1007/s11910-017-0709-2
        • Gresa-Arribas N.
        • Planagumà J.
        • Petit-Pedrol M.
        • Kawachi I.
        • Katada S.
        • Glaser C.A.
        • et al.
        Human neurexin-3α antibodies associate with encephalitis and alter synapse development.
        Neurology. 2016; https://doi.org/10.1212/WNL.0000000000002775
        • Mohammad S.S.
        • Fung V.S.C.
        • Grattan-Smith P.
        • Gill D.
        • Pillai S.
        • Ramanathan S.
        • et al.
        Movement disorders in children with anti-NMDAR encephalitis and other autoimmune encephalopathies.
        Mov Disord. 2014; 86: 2235-2242https://doi.org/10.1002/mds.25999
        • Mohammad S.S.
        • Wallace G.
        • Ramanathan S.
        • Brilot F.
        • Dale R.C.
        Antipsychotic-induced isia and neuroleptic malignant syndrome in anti-NMDAR encephalitis.
        Ann Clin Psychiatry. 2014; 26: 297-298
        • Vincent A.
        • Buckley C.
        • Lang B.
        • Irani S.
        Clinical spectrum of voltage-gated potassium channel autoimmunity.
        Neurology. 2009; 72: 99https://doi.org/10.1212/01.wnl.0000339405.94708.8
        • Tobin W.O.
        • Lennon V.A.
        • Komorowski L.
        • Probst C.
        • Clardy S.L.
        • Aksamit A.J.
        • et al.
        DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.
        Neurology. 2014; 83: 1797-1803https://doi.org/10.1212/WNL.0000000000000991
        • Grant R.
        • Graus F.
        Paraneoplastic movement disorders.
        Mov Disord. 2009; 24: 1715-1724https://doi.org/10.1002/mds.22658
        • Colosimo C.
        • Bak T.H.
        • Bologna M.
        • Berardelli A.
        Fifty years of progressive supranuclear palsy.
        J Neurol Neurosurg Psychiatry. 2014; 85: 938-944https://doi.org/10.1136/jnnp-2013-305740
        • Panzer J.
        • Dalmau J.
        Movement disorders in paraneoplastic and autoimmune disease.
        Curr Opin Neurol. 2011; 24: 346-353https://doi.org/10.1097/WCO.0b013e328347b307
        • Tan J.H.
        • Goh B.C.
        • Tambyah P.A.
        • Wilder-Smith E.
        Paraneoplastic progressive supranuclear palsy syndrome in a patient with B-cell lymphoma.
        Parkinsonism Relat Disord. 2005; 11: 187-191https://doi.org/10.1016/j.parkreldis.2004.09.003
        • Fahn S.
        • Brin M.F.
        • Dwork A.J.
        • Weiner W.J.
        • Goetz C.G.
        • Rajput A.H.
        What is it? Case 1, 1996: rapidly progressive parkinsonism, incontinence, impotency, and levodopa-induced moaning in a patient with multiple myeloma.
        Mov Disord. 1996; 11: 298-310https://doi.org/10.1002/mds.870110314
        • Meinck H.M.
        • Thompson P.D.
        Stiff man syndrome and related conditions.
        Mov Disord. 2002; 17: 853-866https://doi.org/10.1002/mds.10279
        • Ishii A.
        • Hayashi A.
        • Ohkoshi N.
        • Matsuno S.
        • Shoji S.
        Progressive encephalomyelitis with rigidity associated with anti-amphiphysin antibodies.
        J Neurol Neurosurg Psychiatry. 2004; 75: 661-662https://doi.org/10.1136/JNNP.2003.010504
        • Carvajal-González A.
        • Leite M.I.
        • Waters P.
        • Woodhall M.
        • Coutinho E.
        • Balint B.
        • et al.
        Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
        Brain. 2014; 137: 2178-2192https://doi.org/10.1093/brain/awu142
        • 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. 2012; 79: 1136-1144https://doi.org/10.1212/WNL.0b013e3182698cab
        • Vincent A.
        • Pettingill P.
        • Pettingill R.
        • Lang B.
        • Birch R.
        • Waters P.
        • et al.
        Association of Leucine-Rich Glioma inactivated protein 1, contactin-associated protein 2, and contactin 2 antibodies with clinical features and patient-reported pain in acquired neuromyotonia.
        JAMA Neurol. 2018; 75: 1519-1527https://doi.org/10.1001/jamaneurol.2018.2681
        • Linke R.
        • Schroeder M.
        • Helmberger T.
        • Voltz R.
        Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis.
        Neurology. 2004; 63: 282-286https://doi.org/10.1212/01.WNL.0000129983.06983.4E
        • Titulaer M.J.
        • Soffietti R.
        • Dalmau J.
        • Gilhus N.E.
        • Giometto B.
        • Graus F.
        • et al.
        Screening for tumours in paraneoplastic syndromes: report of an EFNS task force.
        Eur J Neurol. 2011; 18: 19-e3https://doi.org/10.1111/j.1468-1331.2010.03220.x
        • Younes-Mhenni S.
        • Janier M.F.
        • Cinotti L.
        • Antoine J.C.
        • Tronc F.
        • Cottin V.
        • et al.
        FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes.
        Brain. 2004; 127: 2331-2338https://doi.org/10.1093/brain/awh247
        • Zoccarato M.
        • Gastaldi M.
        • Zuliani L.
        • Biagioli T.
        • Brogi M.
        • Bernardi G.
        • et al.
        Diagnostics of paraneoplastic neurological syndromes.
        Neurol Sci. 2017; 38: 237-242https://doi.org/10.1007/s10072-017-3031-5
        • Gresa-Arribas N.
        • Titulaer M.J.
        • Torrents A.
        • Aguilar E.
        • McCracken L.
        • Leypoldt F.
        • et al.
        Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study.
        Lancet Neurol. 2014; 13: 167-177https://doi.org/10.1016/S1474-4422(13)70282-5
        • Cervera R.
        • Piette J.C.
        • Font J.
        • Khamashta M.A.
        • Shoenfeld Y.
        • Camps M.T.
        • et al.
        Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.
        Arthritis Rheum. 2002; 46: 1019-1027https://doi.org/10.1002/art.10187
        • Yelnik C.M.
        • Kozora E.
        • Appenzeller S.
        Non-stroke central neurologic manifestations in antiphospholipid syndrome.
        Curr Rheumatol Rep. 2016; 18: 11https://doi.org/10.1007/s11926-016-0568-x
        • Fleetwood T.
        • Cantello R.
        • Comi C.
        Antiphospholipid syndrome and the neurologist: from pathogenesis to therapy.
        Front Neurol. 2018; 9: 1001https://doi.org/10.3389/fneur.2018.01001
        • Dale R.C.
        • Merheb V.
        • Pillai S.
        • Wang D.
        • Cantrill L.
        • Murphy T.K.
        • et al.
        Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders.
        Brain. 2012; 135: 3453-3468https://doi.org/10.1093/brain/aws256
        • Laurent C.
        • Capron J.
        • Quillerou B.
        • Thomas G.
        • Alamowitch S.
        • Fain O.
        • et al.
        Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): characteristics, treatment and outcome in 251 cases from the literature.
        Autoimmun Rev. 2016; 15: 1129-1133https://doi.org/10.1016/j.autrev.2016.09.008
        • Álvarez Bravo G.
        • Yusta Izquierdo A.
        • Carvalho Monteiro G.
        • Sánchez I.
        Cerebellopathy secondary to anti-peroxidase antibody-mediated toxicity. A special case of Hashimoto encephalopathy.
        J Neuroimmunol. 2017; 312: 1-3https://doi.org/10.1016/j.jneuroim.2017.08.007
        • Spatola M.
        • Petit-Pedrol M.
        • Simabukuro M.M.
        • Armangue T.
        • Castro F.J.
        • Artigues M.I.B.
        • et al.
        Investigations in GABAA receptor antibody-associated encephalitis.
        Neurology. 2017; 88: 1012-1020https://doi.org/10.1212/WNL.0000000000003713
        • Hacohen Y.
        • Wright S.
        • Waters P.
        • Agrawal S.
        • Carr L.
        • Cross H.
        • 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. 2013; 84: 748-755https://doi.org/10.1136/jnnp-2012-303807
        • Kirvan C.A.
        • Swedo S.E.
        • Heuser J.S.
        • Cunningham M.W.
        Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea.
        Nat Med. 2003; 9: 914-920https://doi.org/10.1038/nm892
        • Dale R.C.
        • Candler P.M.
        • Church A.J.
        • Wait R.
        • Pocock J.M.
        • Giovannoni G.
        Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease.
        J Neuroimmunol. 2006; 172: 187-197https://doi.org/10.1016/j.jneuroim.2005.10.014
        • Ben-Pazi H.
        • Stoner J.A.
        • Cunningham M.W.
        Dopamine receptor autoantibodies correlate with symptoms in Sydenham's chorea.
        PLoS One. 2013; 8e73516https://doi.org/10.1371/journal.pone.0073516
        • Gaig C.
        • Graus F.
        • Compta Y.
        • Högl B.
        • Bataller L.
        • Brüggemann N.
        • et al.
        Clinical manifestations of the anti-IgLON5 disease.
        Neurology. 2017; 88: 1736-1743https://doi.org/10.1212/WNL.0000000000003887
        • Sabater L.
        • Gaig C.
        • Gelpi E.
        • Bataller L.
        • Lewerenz J.
        • Torres-Vega 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: 575-586https://doi.org/10.1016/S1474-4422(14)70051-1
        • Hatano T.
        • Shimada Y.
        • Kono A.
        • Kubo S.I.
        • Yokoyama K.
        • Yoritaka A.
        • et al.
        Atypical miller fisher syndrome associated with glutamate receptor antibodies.
        BMJ Case Rep. 2011; https://doi.org/10.1136/bcr.08.2010.3228
        • Zuliani L.
        • Sabater L.
        • Saiz A.
        • Baiges J.J.
        • Giometto B.
        • Graus F.
        Homer 3 autoimmunity in subacute idiopathic cerebellar ataxia.
        Neurology. 2007; 68: 239-240https://doi.org/10.1212/01.wnl.0000251308.79366.f9
        • Höftberger R.
        • Sabater L.
        • Ortega A.
        • Dalmau J.
        • Graus F.
        Patient with Homer-3 antibodies and cerebellitis.
        JAMA Neurol. 2013; 70: 506-509https://doi.org/10.1001/jamaneurol.2013.1955
        • Darnell R.B.
        • Furneaux H.M.
        • Posner J.B.
        Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors.
        J Neurosci. 1991; 11: 1224-1230https://doi.org/10.1523/JNEUROSCI.11-05-01224
        • Cardoso F.
        Autoimmune choreas.
        J Neurol Neurosurg Psychiatry. 2017; 88: 412-417https://doi.org/10.1136/jnnp-2016-314475
        • Gilhus N.
        Neuromuscular junction disorders.
        in: Colosimo C. Gil-Nagel A. Gilhus N.E. Rapoport A. Williams O. Handb Neurol Ther. 2015: 177-185