AUTOIMMUNE MOVEMENT DISORDERS Autoimmune Movement Disorders in Adults As antibodies to neuronal targets are described, we see the clinical spectrum and pathophysiology of autoimmune movement disorders more clearly. Bettina Balint, MD

Neuroimmunology is a rapidly developing field. Cell-surface Intracellular Intracellular With the description of new antibodies and antigens synaptic antigens cytoplasmic/nuclear new syndromes, both the clinical spectrum and antigens our insights into disease pathophysiology and 1 Pathogenic anti- Controversial role Markers of paraneo- treatment expand. These developments also gens are acces- in pathogenesis plastic syndrome; reflect on movement disorders associated with sible in vivo; typi- antigen may be poor prognosis poor 2 neuronal antibodies, a field that is continuously broadening. cally play important transiently treatment response, Although these conditions are rare overall, they are a not-to- roles in synaptic accessible during autoimmunity miss diagnosis because of the treatment implications: the ear- transmission, synaptic vesicle mainly via cytotoxic lier immunotherapy is initiated, the better the outcome. The plasticity, or fusion and uptake T-cells; antigens classic paraneoplastic (onconeuronal) antibodies are indica- excitability inaccessible in vivo tive of an underlying neoplasm; neuronal surface antibodies CASPR2, DPPX, GAD, amphiphysin Hu, Ri, CRMP5/CV2, are less frequently associated with malignancy and have an D2R, GABAAR, Ma2 overall better outcome (Figure). To facilitate prompt immuno- GABABR, GlyR, therapy, new diagnostic criteria for autoimmune encephalitis LGI1, NMDAR highlight the importance of clinical recognition.3 Movement disorders may be the first or most prominent presentation of autoimmune encephalitis and can present with characteristic phenotypes, with associated red flags or other diagnostic clues (Box). Importantly, they may also be a differential diagnosis of degenerative disease, particularly when develop slowly. This review provides an overview of the clinical spectrum of movement disorders with neuronal antibodies; Figure. Categories of autoantibodies to neuronal antibodies, supplementary Table e1 in the online version of the article pathogenic roles, examples, treatment responses and tumor provide a reference and glossary for the antibodies discussed. associations. Adapted with permission from Balint B, Vincent A, Meinck HM, Irani SR, Bhatia KP. Movement disorders with Chorea, , and Stereotypies neuronal antibodies: syndromic approach, genetic parallels Chorea may occur as a paraneoplastic syndrome, in par- and pathophysiology. Reproduced with permission from Brain. ticular with antibodies to Hu and collapsin response-mediator 2018;141(1):13-36. protein-5 (CRMP5) often combined with other signs. With antiCRMP5, additional signs include cognitive decline, neu- Antibodies to phosphodieserase 10A (antiPDE10A) have ropathy, optic neuritis, and myelitis; with antiHu, gastrointes- been recently described as a new marker of paraneoplastic tinal pseudoobstruction, and sensorineuronal hearing loss are chorea (and other movement disorders) with onset at medi- seen. Both often feature fluid attenuated inversion recovery an age 70 at equal rates in men and women.4 The full clinical sequence (FLAIR) MRI hyperintensities in white matter, basal and radiologic spectrum (basal ganglia FLAIR hyperintensities ganglia, and the temporomesial lobe. AntiHu and antiCRMP5, reported) remains to be determined. Similar to the classic as well as amphiphysin antibodies, can cause a dorsal root paraneoplastic antibodies, the PDE10A is an intracellular anti- ganglionopathy with sensory and pseudoathetosis. gen, with autoimmunity likely conveyed by cytotoxic T cells.

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the N-methyl d aspartate receptor (NMDAR), predomi- Box . When to Suspect a Movement nantly in girls and women (age 8 months to 85 years; sex Disorder With Neuronal Antibodies ratio 4:1), normally with other features of .2,8,9 The younger the individual, the more likely is a movement Characteristic Syndromes disorder-predominant presentation. (See AntiNMDAR- • Faciobrachial dystonic –antiLGI1 Associated Movement Disorders and Trending Autoantibodies • Leg myoclonus–antiCaspr2 in Movement Disorders in this issue.) • Orofacial and limb dyskinesias in states of reduced Antibodies to neurexin-3α seem to cause as part consciousness–antiNMDAR of an encephalopathy, but are quite rare. • Finalistic movements in NREM sleep–antiIgLON5 • Painful tonic –antiAQP4 Dystonia, Pseudodystonia, and Stiff Person Red Flags Spectrum Disorders • Hyponatraemia, episodic bradycardia–antiLGI1 Dystonia, typically with other signs or symptoms, can be a • Sleep disorders /breathing disorders /dysphagia–antiIgLON5 manifestation of neuronal antibody-related disease. Dystonia in autoimmune disease, however, features neither the pattern • Longlasting diarrhea–antiDPPX of isolated, idiopathic (hitherto called primary) dystonia nor a • Headache and blurred vision-antiGFAP geste antagoniste. The term pseudodystonia implies a different • New symptoms after recent herpes simplex encephalitis phenomenology and underlying mechanism from classical Other dystonia,10 which may be more appropriate for some of the • Unilateral signs without lesion on imaging descriptions of immune-mediated dystonia. Craniocervical • Rapid evolution dystonia including jaw closing or opening dystonia is seen • Inflammatory CSF or MRI with antiRi, a paraneoplastic antibody occurring predomi- nantly in women age 47 to 87 (peak in 60s, sex ratio 4:1) and • Propensity to autoimmunity/history of malignancy; treatment 11 with immune-checkpoint inhibitors indicating breast cancer. The spectrum of antiRi syndrome is broad, with (most frequent sign), other movement disorders, oculomotor disturbances, and encepha- Chorea may also occur with antibodies to neuronal sur- lopathy. As a feature in a broader encephalopathic syndrome, face antigens (eg, leucine-rich glioma inactivated 1 [LGI1] or dystonia has been described with a variety of antibodies, contactin-associated protein-like 2 [CASPR2]) with a lower including antibodies to Ma2, CRMP5, PDE10A, GABAAR, and likelihood of an underlying tumour. AntiLGI1 occurs more IgLON5, and is particularly frequent with antiNMDAR.9 frequently in men age 60 to 70 (sex ratio 2:1) and antiCASPR2 Classic pseudodystonia is seen in Miller-Fisher-Syndrome or occurs more frequently in men age 50 to 60 (sex ratio 8:1).5 chronic inflammatory demyelinating polyradiculoneuropathy AntiCASPR2 often indicate a thymoma (20%-50%), whereas with ganglioside, neurofascin and CNTN1 antibodies because other tumors are rarely detected in CASPR2- or LGI1-related of proprioceptive sensory loss.12 autoimmunity. AntiCASPR2-associated disease also presents Muscle stiffness, sometimes leading to abnormal postures with signs of peripheral nerve hyperexcitability, such as neuro- and pseudodystonia-like lumbar hyperlordosis or foot plantar myotonia or , which can resemble chorea. flexion is a core feature of stiff person spectrum disorders The clinical spectrum of antiCASPR2 includes also lim- (SPSD; see Stiff-Person Syndrome in this issue), besides super- bic encephalitis with cognitive decline, seizures, behavioral imposed muscle spasms and excessive startle (hyperekplexia). change, myoclonus (see below), ataxia, and , which can Additional signs may occur (eg, cerebellar ataxia, focal epi- be an important diagnostic clue.6 AntiLGI1 cause faciobrachial lepsy), particularly with antiGAD; other signs in dystonic seizures (FBDS) more often than chorea. progressive encephalomyelitis with rigidity and myoclonus Antibodies to immunoglobulin-like cell adhesion mole- [PERM], often with antiGlyR; long-lasting diarrhea with anti- cule 5 (IgLON5) also cause chorea equally in men and women DPPX; with antiamphiphysin). However, the in their 40s to 70s (peak in 60s).7 Diagnostic clues include clinical spectrum is broad, and the phenotype does not nec- sleep disorders (see below), prominent bulbar symptoms, essarily predict the underlying antibody, which is still impor- or breathing difficulties. AntiIgLON5-associated disease may tant to identify because of possibly associated neoplasia and have a slowly progressive course and feature cognitive decline. comorbidities (antiGlyR: thymoma; antiamphiphysin: breast In the context of chorea, it can resemble Huntington disease or lung cancer; antiGAD: type 1 diabetes, thyroid disease, per- (see below for parkinsonian manifestations). nicious anaemia; antiDPPX: infrequently B-cell neoplasms).13 Chorea, focal or more complex dyskinesia, stereotypies, Very rarely, a SPSD phenotype has been reported with Ri or or combinations thereof may be caused by antibodies to GABAAR antibodies.

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Paroxysmal Dyskinesia Parkinsonism Classic, “primary” paroxysmal dyskinesias are a group Autoimmune parkinsonism is a differential diagnosis of of inherited disorders that manifest early in life and are atypical parkinsonism that rarely occurs as an isolated syn- characterised by brief self-limiting attacks of involuntary drome and typically features other signs and symptoms not movement without impaired consciousness. The classic anti- compatible with a diagnosis of simple Parkinson disease. body-related paroxysmal is FBDS with Often, the tempo of the disease course cautions against a antiLGI1.14 FBDS are very characteristic, brief (<3 seconds), diagnosis of neurodegenerative disease. frequent (hundreds/ day) episodes of abnormal posturing, Paraneoplastic encephalitis with antiMa2 may manifest as a typically of the ipsilateral face and arm, although the affect- syndrome resembling progressive supranuclear palsy (PSP)— ed side may alternate. Involvement of the legs gives raise to predominantly rigid parkinsonism with gait instability, drop attacks, and various combinations of affected body supranuclear vertical gaze palsy, and eye closure resembling parts including bilateral involvement can be seen. Although lid opening apraxia.22 Further distinctive features such as EEG findings are typically normal, some individuals may have weight gain and prominent sleep disorders including exces- automatisms, sensory aura, postictal fear or speech arrest. sive daytime sleepiness, rapid eye movement (REM) behavior Brain MRI may show basal ganglia hyperintensities on T1- or sleep disorder (RBD), and narcolepsy-cataplexy reflect the T2-weighted sequences.15 Because FBDS, similar to episodic association of antiMa2 with hypothalamic-pituitary dysfunc- bradycardia and hyponatraemia, may precede the devel- tion. The possible features of antiMa2 encephalitis are broad opment of “full-blown” limbic encephalitis with cognitive and include limbic, diencephalic, and brainstem encephalitis, impairment, early recognition and timely initiation of immu- myelopathy, and radiculoplexopathy. Radiologically, antiMa2 notherapy are of paramount importance. AntiLGI1 occur encephalitis has a typical MRI pattern with thalamic and predominantly in men age 60 or more. In contrast, girls and hypothalamic T2 hyperintensities. Basal ganglia involvement women with a paroxysmal acquired movement disorder can be seen, but is more typical of paraneoplastic parkinson- are more likely to have tonic spasms related to demyelinat- ism with antiCRMP5.23 Notably, there are rare reports of ing disease. Painful tonic spasms occur more frequently in paraneoplastic parkinsonism without an identified antibody neuromyelitis optica spectrum disorders (NMOSD) than in and with large T2 hyperintensities on MRI. multiple sclerosis, and seemingly more with antibodies to Parkinsonism has been reported with some neuronal sur- aquaporin-4 (AQP4) than to myelin oligodendrocyte glyco- face antibodies without an underlying malignancy (antiLGI1, protein (MOG).16 Rarely, brief dystonic posturing in young antiCASPR2, antiDPPX, and in children, anti-NMDAR or, rare- women is seen with antiNMDAR. ly antidopamine type 2 receptors [antiD2R]; See Autoimmune Movement Disorders in Children in this issue).18,24-26 Myoclonus Parkinsonism with antiIgLON5 may pose a diagnostic Myoclonus may be a feature in various antibody-related challenge because symptoms may develop slowly over years movement disorders and can be a fairly indistinct feature as in classic neurodegenerative disease. The core features of (eg, encephalitis with antiNMDAR) or a more prominent antiIgLON5-related disease are sleep disturbances, bulbar sign (eg, antiGABAAR encephalitis, diagnostic clue: intracta- symptoms (eg, dysphagia, dysarthria, or vocal cord ), ble seizures; or antidipeptidyl aminopeptidase-like protein 6 and breathing difficulties that can be severe enough to require (DPPX) encephalitis, often combined with other neurologic tracheostomy. Gaze palsies, cognitive decline including execu- or autonomic signs, particularly long-lasting diarrhea.17-19 tive dysfunction, apraxia or hallucinations, cerebellar ataxia, Moreover, there are characteristic myoclonus syndromes, chorea, and also occur with antiIgLON5 disease. such as coarse myoclonus affecting predominantly the legs Depending on the combination of signs and symptoms, and hampering stance and gait with antiCASPR2).20 This antiIgLON5 disease may be in the differential for multisystem phenomenology is distinctive and often accompanied by atrophy (MSA) if RBD, ataxia and dysautonomia are present, diagnostic clues like neuropathic pain or cognitive decline. PSP if there is a vertical supranuclear gaze palsy and postural Another characteristic myoclonus-syndrome is opsoclonus- instability, or corticobasal syndrome (CBS) if asymmetric par- myoclonus syndrome (OMS), a generalised myoclonus with kinsonism occurs with apraxia.7,27 chaotic-multidirectional saccades. OMS can be a paraneo- plastic (in childhood with neuroblastoma, early adulthood Movement Disorders in Sleep with teratomas, and later adulthood mostly with lung and Sleep disturbances including movement disorders during breast cancer) or postinfectious (eg, HIV seroconversion), sleep are common in autoimmune encephalitis.28 AntiIgLON5 with various but not disease-defining antibodies. Brainstem was identified by a characteristic nonREM (NREM) parasom- myoclonus with tactile or acoustic startle is part of SPSD, nia with fine, purposeful movements (eg, manipulating an particularly the PERM variant.13,21 object or preparing food) that are different from the thrash-

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ing, violent movements seen in RBD.29 The spectrum of sleep abdominal dyskinesia caused by neuromyotonia seen in disorders in antiIgLON5 disease is broad, however, encom- antiIgLON5 disease,36 trunk flexion or abdominal wall con- passing RBD, periodic leg movements of sleep (PLMS), and tractions superficially resembling psychogenic propiospinal sleep apnea. RBD or dream enactment can be also a feature of myoclonus with antiCASPR2,37 or movement disorders that antiMa2-, antiLGI1-, or antiNMDAR-encephalitis. PLMS was defy classic movement disorder terminology in antiNDMAR- 18,28 9,38 found in encephalitis with antiDPPX, antiMa2 or antiLGI1. or antiGABAAR-associated encephalitis. Symptoms of restless legs syndrome (RLS) were reported by patients with antiLGI1 or antiNMDAR.28 The most classic Conclusions and Future Perspectives sleep disorders in autoimmune disease are, however, status Nearly all movement disorders categories and mimics with dissociatus (disintegration of wake/non-REM and REM sleep peripheral pathology may be seen with autoantibodies to boundaries with motor hyperactivity) and agrypnia excitata neuronal antigens. A high index of suspicion and knowledge (insomnia, motor and autonomic hyperactivity), which are of clinical phenotypes are key to identifying who might ben- hallmark features of Morvan syndrome with antiCASPR2. efit from immunotherapy. Some presentations are charac- Less commonly status dissociatus and agrypnia excitata have teristic, if not pathognomonic for antibody-related disease, been observed in antiLGI1-, antiNMDAR-, and antiGABABR- and sometimes there are distinct associated features pointing associated encephalitis.2,28 towards a specific antibody (Box). Sometimes, however, more general considerations (eg, unilateral symptoms without a , Myorhythmia, and More corresponding lesion on imaging), typical MRI or cerebro- Autoimmune tremor syndromes typically occur in the spinal fluid (CSF) findings, or a propensity to autoimmunity, context of a cerebellar syndrome (See Immune-Mediated whether paraneoplastic, genetic, postinfectious, or idiopathic, Cerebellar in this issue),2 chronic inflammatory demy- may point to the diagnosis (Box). elinating neuropathy (CIDP), or as an indistinctive feature in It is likely that we will see an increase in autoimmunity and an encephalopathic syndrome, but not as isolated tremor. antibody-related syndromes, including movement disorders, Beside the classic antibodies to myelin associated glyco- with the wider use of of immune checkpoint inhibitors (ICIs) protein (MAG), several newly described antibodies have to treat cancer.4,39,40 ICIs are monoclonal antibodies that target been identified as the cause of CIDP; these target proteins and inhibit immune checkpoints, thereby unleashing an anti- close to the node of Ranvier (eg, contactin 1 [CNTN1], neu- tumor immune response. Although ICIs are efficacious in can- rofascin 155 [NF155], neurofascin 140/186 [NF140/186], and cer treatment and have been a major step forward for treating contactin-associated protein-1 [CASPR1]).30 many malignancies, they can also break immune tolerance to Antibodies that target glial fibrillary acidic protein (GFAP) self-antigens. ICI-related autoimmunity can present with classic are typically associated with meningomyeloencephalitis with paraneoplastic antibodies, neuronal surface antibodies or as a a characteristic MRI findings of radial linear periventricular or seronegative syndrome.40-42 Moreover, those as yet seronega- cerebellar gadolinium enhancement and tremor and ataxia tive syndromes will continue to be unriddled as illustrated in up to 40% of cases.31,32 Headache caused by and with the recent discoveries of new antibodies in cerebellar blurred vision owing to optic disc edema may be diagnostic ataxia and new antibody-identification techniques.43-46 n clues, although the phenotypic spectrum of antiGFAP-asso- 1. Lancaster E, Dalmau J. Neuronal autoantigens--pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. ciated disease keeps expanding, possibly because of frequent 2012;8(7):380-390. co-occurrence of other antibodies in up to one-third of 2. Balint B, Vincent A, Meinck HM, Irani SR, Bhatia KP. Movement disorders with neuronal antibodies: syndromic approach, genetic 31 parallels and pathophysiology. Brain. 2018;141(1):13-36. cases. GFAP is located intracellularly, but the tumor associa- 3. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. tion (~20%) is less strong than with classic paraneoplastic 4. Zekeridou A, Kryzer T, Guo Y, et al. Phosphodiesterase 10A IgG: A novel biomarker of paraneoplastic neurologic autoimmunity. Neurology. 2019;93(8):e815-e822. antibodies to intracellular proteins. 5. Michael S, Waters P, Irani SR. Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Practical Myorhythmia is typically associated with Whipple disease, Neurology. 2020:practneurol-2019-002494. 6. Dawes JM, Weir GA, Middleton SJ, et al. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to particularly if occurring as oculomasticatory myorhyth- enhanced primary afferent excitability. Neuron. 2018;97(4):806-822.e810. 7. Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743. mia with vertical gaze palsy; however, myorhythmia can 8. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA be also a feature of autoimmune disease, particularly with receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165. 33,34 35 9. Varley JA, Webb AJS, Balint B, et al. The movement disorder associated with NMDAR antibody-encephalitis is complex and antiIgLON5 but also in antiNMDAR encephalitis. characteristic: an expert video-rating study. J Neurol Neurosurg Psychiatry. Vol 90.2019:724-726. Movement disorders in autoimmune disease are often diffi- 10. Berlot R, Bhatia KP, Kojović M. Pseudodystonia: a new perspective on an old phenomenon. Parkinsonism Relat Disord. 2019;62:44-50. 11. Simard C, Vogrig A, Joubert B, et al. Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibod- cult to classify—because of the overlap with psychiatric symp- ies. Neurol Neuroimmunol Neuroinflamm. 2020;7(3). toms and mixed presentations (eg, , clonic or tonic 12. Lehmann HC, Burke D, Kuwabara S. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2019;90(9):981-987. perseverations, or a combination with peripheral movement 13. Balint B, Meinck HM. Pragmatic treatment of stiff person spectrum disorders. Mov Disord Clin Pract. 2018;5(4):394-401. disorder mimics) or because of the unusual phenomenol- 14. Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures: the influence of immunotherapy on control and prevention of cognitive impairment in a broadening phenotype. Brain. 2013;136(Pt 10):3151-3162. ogy of the movement disorders. Examples of this included (Continued on page 40)

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(Continued from page 33) 15. Flanagan EP, Kotsenas AL, Britton JW, et al. Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e161. 16. Kim SM, Waters P, Woodhall M, et al. Utility of aquaporin-4 antibody assay in patients with neuromyelitis optica spectrum disorders. Mult Scler. 2013;19(8):1060-1067. 17. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol. 2013;73(1):120-128. 18. Tobin WO, Lennon VA, Komorowski L, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology. 2014;83(20):1797-1803. 19. 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(3):276-286. 20. Gövert F, Witt K, Erro R, et al. Orthostatic myoclonus associated with Caspr2 antibodies. Neurology. 2016;86(14):1353-1355. 21. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies. Neurology. 2014;82(17):1521-1528. 22. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain. 2004;127(Pt 8):1831-1844. 23. Tada S, Furuta M, Fukada K, et al. Severe parkinsonism associated with anti-CRMP5 antibody-positive paraneoplastic neurological syndrome and abnormal signal intensity in the bilateral basal ganglia. J Neurol Neurosurg Psychiatry. 2016;87:907-910. 24. Kurtis MM, Toledano R, García-Morales I, Gil-Nagel A. Immunomodulated parkinsonism as a presenting symptom of LGI1 antibody encephalitis. Parkinsonism Relat Disord. 2015;21(10):1286-1287. 25. Kannoth S, Nambiar V, Gopinath S, Anandakuttan A, Mathai A, Rajan PK. Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia. Neurol Sci. 2018;39(3):455-460. 26. Dale RC, Merheb V, Pillai S, et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiat- ric disorders. Brain. 2012;135(Pt 11):3453-3468. 27. Fuseya K, Kimura A, Yoshikura N, Yamada M, Hayashi Y, Shimohata T. Corticobasal Syndrome in a Patient with Anti- IgLON5 Antibodies. Mov Disord Clin Pract. 2020;7:557-559. 28. Blattner MS, de Bruin GS, Bucelli RC, Day GS. Sleep disturbances are common in patients with autoimmune encepha- litis. J Neurology. 2019;266(4):1007-1015. 29. 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(6):575-586. 30. Delmont E, Brodovitch A, Kouton L, et al. Antibodies against the node of Ranvier: a real-life evaluation of incidence, clinical features and response to treatment based on a prospective analysis of 1500 sera. J Neurol. 2020; https://doi.org/ 10.1007/ s00415-020-10041-z 31. Kunchok A, Zekeridou A, McKeon A. Autoimmune glial fibrillary acidic protein astrocytopathy. Curr Opin Neurol. 2019;32(3):452- 458. 32. Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoen- cephalomyelitis. JAMA Neurol. 2016;73(11):1297-1307. 33. Honorat JA, Komorowski L, Josephs KA, et al. IgLON5 antibody: neurological accompaniments and outcomes in 20 patients. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e385-e385. 34. Morales-Briceño H, Cruse B, Fois AF, et al. IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease. Neurology. 2018;90(24):1113-1115. 35. Camacho A, Núñez N, Armangué T, Simón R. Myorhythmia-like dyskinesia affecting the face and ear Associated With Anti-N-Methyl-d-Aspartate Receptor Encephalitis. Movement Disord Clin Pract. 2015;3(4):425-426. 36. Wenninger S. Expanding the clinical spectrum of IgLON5-syndrome. J Neuromuscul Dis. 2017;4(4):337-339. 37. Gövert F, Leypoldt F, Junker R, et al. Antibody-related movement disorders–a comprehensive review of phenotype- autoantibody correlations and a guide to testing. Neurol Res Pract. 2020;2(1):6. 38. Vacchiano V, Giannoccaro MP, Rinaldi R, Guarino M, Liguori R. Movement disorders associated with GABAA receptor encephalitis: a video case report. Movement Disord Clin Pract. 2020;7(6):681-683. 39. Dubey D, David WS, Reynolds KL, et al. Severe neurological toxicity of immune checkpoint inhibitors: growing spectrum. Ann Neurol. 2020;87(5):659-669. 40. Vogrig A, Muñiz-Castrillo S, Honnorat J. Value of onconeural antibodies in checkpoint inhibitor-related toxicities. Ann Neurol. 2020;88(1):199-200. 41. 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JAMA Neurol. 2020. Aug 3. https://doi.org/10.1001/jamaneurol.2020.2231

Bettina Balint, MD Department of Neurology, University Hospital Heidelberg, Germany Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London, UK

Disclosure BB reports that she has no disclosures

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TABLE e1. NEURONAL AND GLIAL ANTIBODIES AND ASSOCIATED CLINICAL AND ONCOLOGIC SPECTRUM Antibody target Tumor association Movement disorder signs Other clinical features Antibodies targeting cell-surface antigens Aquaporin-4 (AQP4) (+)/- (rarely; lung or breast Painful tonic spasms Neuromyelitis optica spectrum disorders, cancer, teratoma) typically with optic neuritis, pyramidal weakness, sensory symptoms, bladder disturbance Contactin-associated - Tremor Chronic inflammatory demyelinating protein 1 (CASPR1) polyneuropathy, sensory ataxia Contactin-associated +/- (in ~20%: thymoma Cerebellar ataxia, chorea, Morvan syndrome, limbic encephalitis, protein 2 (CASPR2) >> lung, prostate, sigmoid or neuromyotonia, myokymia neuropathy (rarely Guillain-Barré-like thyroid cancer, myeloma) syndrome), neuropathic pain Contactin-1 (CNTN1) - Tremor Chronic inflammatory demyelinating polyneuropathy, sensory ataxia Dipeptidyl +/- (in ~7%: B-cell neoplasms) Stiff person spectrum Multifocal encephalitis or brainstem enceph- peptidase-like disorder, myoclonus, startle, alitis with prominent gastrointestinal symp- protein 6 (DPPX) ataxia, tremor, parkinsonism, toms (prolonged diarrhea, constipation), opsoclonus myoclonus other dysautonomic signs (urinary or erectile dysfunction, cardiac , thermo- dysregulation, Raynaud phenomenon), sensory disturbance (allodynia, paraesthesia) Dopamine 2 receptor Basal ganglia encephalitis Psychiatric and sleep disturbance (D2R) in children with dystonia, chorea or parkinsonism; Sydenham´s chorea γ-aminobutyric acid A +/- (in ~40%: thymoma, lung Chorea, dystonia or ataxia (as Encephalopathy with epilepsy, behavioral or receptor (GABAAR) carcinoma, rectal cancer, part of a more widespread cognitive problems or reduced consciousness; myeloma) encephalopathy), opsoclonus frequent multifocal T2-hyperintensities; myoclonus syndrome; pos- tendency to autoimmune predisposition (coex- sible association with stiff isting antibodies [eg, antiGAD- or antiNMDAR], person spectrum disorder thyroid autoimmunity, idiopathic thrombocyto- penic purpura, gluten sensitivity or myasthenia g-aminobutyric acid B +/- (in ~60%: small cell lung Opsoclonus myoclonus ataxia Limbic encephalitis with prominent seizures receptor (GABABR) cancer >> breast cancer syndrome, cerebellar ataxia, multiple myeloma, rectal carci- status dissociatus/agrypnia noma, esophageal carcinoma) excitata Glycine receptor +/- (in ~9%: thymoma > small Stiff person spectrum disorder, Brainstem encephalitis; reported in optic (GlyR) cell lung cancer, breast cancer, myoclonus, hyperekplexia, neuritis; limbic / epileptic encephalopathy, Hodgkin lymphoma, chronic ataxia epilepsy, steroid-responsive deafness (clinical lymphocytic leukemia) relevance less clear) IgLON family member - Gait instability, parkinson- Sleep apnea, stridor, dysphagia, oculomotor 5 (IgLON5) ism, chorea, cerebellar ataxia, disturbance, cognitive decline, dysautonomia, myorhythmia, sleep neuromyotonia, fasciculations movement disorders Leucine-rich glioma (+)/- (in ~7% liver carcinoid, Faciobrachial dystonic Limbic encephalitis; hyponatremia, inactivated protein 1 neuroendocrine pancreas seizures, chorea bradycardia (LGI1) tumour, mesothelioma, rectal carcinoma) Myelin-associated gly- ++ Tremor Chronic inflammatory demyelinating coprotein (MAG) polyneuropathy Table continues on p e2

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TABLE e1. NEURONAL AND GLIAL ANTIBODIES AND ASSOCIATED CLINICAL AND ONCOLOGIC SPECTRUM (continued) Antibody target Tumor association Movement disorder signs Other clinical features Antibodies targeting cell-surface synaptic antigens (continued) Neurofascin - Tremor Chronic inflammatory demyelinating (NF140/186 and NF155) polyneuropathy, sensory ataxia N-methyl-d-aspartate +/-(in ~40% ovarian teratoma, Orofacial and limb dyskine- Prodromal infectious-like symptoms, neuro- receptor (NMDAR) extraovarian teratomas, ovar- sia, chorea, dystonia, myoc- psychatric disturbance, encephalopathy with ian carcinomas; lung, breast, lonus, ataxia, parkinsonism, epilepsy, cognitive deficits, reduced consciousness, testicular and pancreatic paroxysmal dyskinesia dysautonomia, central hypoventilation tumors) Neurexin-3α - Mild orofacial dyskinesia Encephalopathy with epilepsy, reduced conscious- ness, memory deficits, psychomotor agitation Antibodies targeting intracellular antigens Amphiphysin +++(breast cancer,small cell Stiff person spectrum dis- Sensory ganglionopathy, myelopathy lung cancer) order Glutamic acid decar- +/-(rarely, various tumours) Stiff person spectrum disor- Limbic encephalitis; focal epilepsy; often boxylase (GAD) der, cerebellar ataxia concomitant autoimmunity (eg, diabetes type 1, thyroid disease, vitiligo, pernicious anaemia) Antibodies targeting cytoplasmic and nuclear antigens CRMP5/CV2 +++(small cell lung cancer, Chorea, parkinsonism Optic neuritis, myelitis (can mimic neuro- Collapsin response thymoma) myelitis optica), cognitive decline, neuropathy mediator protein 5 Glial fibrillary acidic +/-(in ~25%: teratoma, Cerebellar ataxia, tremor, Meningoencephalomyelitis or limited forms, with protein (GFAP) prostate and gastresophageal, chrorea, parkinsonism headache, cognitive problems, optic, papillitis, adenocarcinomas, myeloma, sensory disturbance, gastrointestinal and urogeni- melanoma, colonic carcinoid, tal dysautonomia, neuropathy; often concomitant parotid pleomorphic autoimmunity (eg, diabetes type 1, thyroid disease, adenoma, other) myasthenia, rheumatoid arthritis, alopecia) Hu/ANNA-1 +++ (small cell lung cancer>> Chorea,cerebellar ataxia, Encephalomyelitis, limbic encephalitis, Hu proteins neuroblastoma or intestinal, opsoclonus myoclonus brainstem encephalitis, sensory neuropathy, (HuD, HuC) prostate, breast, bladder, and ataxia syndrome gastrointestinal pseudoobstruction ovary carcinoma) Ma2/Ta +++ (testis >> lung cancer); Parkinsonism Limbic, diencephalic or brainstem encephalitis, PNMA2 rarely no neoplasia myelopathy or radiculoplexopathy, with enceph-alopathy, hypothalamic-pituitary endocrine dysfunction, weight gain, prominent sleep disorders, eye movement abnormalities (opsoclonus, supranuclear gaze palsy), dysphagia, muscular atrophy, fasciculations Phosphodiesterase ++ (lung >> renal and Chorea >> parkinsonism, Encephalopathy (confusion), hearing loss 10A (PDE10A) pancreatic cancer) ataxia Ri / ANNA-2 +++ (gynecological tumours, Dystonia (jaw closing Brainstem encephalitis with cranial nerve palsies, Nova-1, Nova-2 mainly breast cancer, and dystonia, laryngospasms), nystagmus, dysarthria, ataxia, rigidity, , lung cancer) opsoclonus myoclonus pyramidal signs ataxia syndrome, oculopalatal myoclonus, cerebellar ataxia, stiff person spectrum disorder,

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