Encephalitis with leucine-rich glioma-inactivated-1 (LGI1) immunoglobulin G (IgG) anti-bodies classically presents with cognitive impairment and characteristic faciobrachial dystonicseizures.1In a murine model, human LGI1 IgG caused reduction of Kv1.1 channels andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor receptors resulting in neuro-nal hyperexcitability indicating probable pathogenicity of LGI1 antibodies.2LGI1 autoimmu-nity is associated with malignancy in less than 10% of cases, including small cell lung cancer,prostate and colon cancer, squamous cell skin carcinoma, and neuroendocrine pancreaticcancer.3,4We present a case of LGI1 encephalitis only partially responsive to immunotherapywith eventual complete resolution after resection of a squamous cell lung carcinoma

Dalakas, Marinos

Desai, Neeja

Mintzer, Scott

Ratliff, Jeffrey

Virupakshaiah, Akash

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Department of Neurology Faculty Papers Department of Neurology 10-9-2020 LGI1 encephalitis with squamous lung-cell carcinoma: Resolution after tumor resection. Akash Virupakshaiah Marinos Dalakas Neeja Desai Scott Mintzer Jeffrey Ratliff Follow this and additional works at: https://jdc.jefferson.edu/neurologyfp  Part of the Neurology Commons Let us know how access to this document benefits you This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Neurology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. CLINICAL/SCIENTIFIC NOTES OPEN ACCESSLGI1 encephalitis with squamous lung-cellcarcinoma: Resolution after tumor resectionAkash Virupakshaiah,MD,Marinos C. Dalakas, MD, Neeja Desai, MD, ScottMintzer, MD, and Jeffrey Ratliff, MDNeurol Neuroimmunol Neuroinflamm 2021;8:e905. doi:10.1212/NXI.0000000000000905CorrespondenceDr. RatliffJeffrey.Ratliff@Jefferson.eduEncephalitis with leucine-rich glioma-inactivated-1 (LGI1) immunoglobulin G (IgG) anti-bodies classically presents with cognitive impairment and characteristic faciobrachial dystonicseizures.1 In a murine model, human LGI1 IgG caused reduction of Kv1.1 channels andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor receptors resulting in neuro-nal hyperexcitability indicating probable pathogenicity of LGI1 antibodies.2 LGI1 autoimmu-nity is associated with malignancy in less than 10% of cases, including small cell lung cancer,prostate and colon cancer, squamous cell skin carcinoma, and neuroendocrine pancreaticcancer.3,4 We present a case of LGI1 encephalitis only partially responsive to immunotherapywith eventual complete resolution after resection of a squamous cell lung carcinoma.Case reportA 78-year-old woman was seen for evaluation of worsening cognition and brief spasmodicepisodes affecting the arm and face. On examination, she had stereotyped episodes of gri-macing and left arm posturing, without impairment of awareness, lasting 2–4 seconds,consistent with faciobrachial seizures. She also had dysarthria, hypophonia, and mild left handbradykinesia. Her mental status examination showed impaired orientation to our clinic,impairment in delayed recall, and working memory deficits in reversed spelling and serialsubtraction tasks.A brain MRI showed an incidental CSF cyst on the anterior pole of the left lateral ventricle andbilateral subcortical microvascular changes, but no signs of limbic encephalitis. The CSF wasnormal with only mild protein elevation of 68 mg/dL and negative for JC virus and neuro-syphilis. Continuous EEG monitoring demonstrated no EEG correlation with her dystonicevents. She was hyponatremic, with sodium concentrations ranging from 127–132 mmol/L.Initial serologic testing was positive for antibodies to the voltage-gated potassium channel(VGKC) complex (0.11 nmol/L), but the results did not indicate specific protein targets(i.e., LGI1 or Caspr2). She was treated with high-dose IV immunoglobulin and methylpred-nisolone, and levetiracetam and clonazepam, but with only partial improvement of her dystonicseizures. She hadmoderate improvement in her cognitive functioning with partial improvementin delayed recollection and working memory. Follow-up testing for antibody specificity withinthe VGKC complex by a different laboratory was negative. However, 2 months later, repeatedserum tested at the same laboratory using cell-based assay was positive specifically for LGI1.Sevenmonths after her initial presentation, a CT of the chest showed a right lung mass. Surgicalresection demonstrated a moderately differentiated squamous cell carcinoma. After surgery, shehad a complete resolution of faciobrachial dystonic seizures; her cognitive dysfunction alsoresolved, both subjectively and on follow-up examination. All previously applied neurologictherapies were discontinued. She had remained seizure free for over 1 year, through her mostrecent follow-up.From the Department of Neurology (A.V., M.C.D., N.D., S.M., J.R.), Thomas Jefferson University, Philadelphia, PA; and Neuroimmunology Unit (M.C.D.), Department of Pathophys-iology Faculty of Medicine, National and Kapodistrian University of Athens, Greece.Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by the authors.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1To explore the association of her squamous cell lung cancer withencephalitis, we tested sections from her paraffin-embeddedtumor tissue for expression of LGI1 antigen. After deparaffini-zation, rehydration, antigen retrieval, and blocking, as previouslydescribed,5 the tissue sections were incubated overnight with acommercial rabbit polyclonal antibody against LGI1/EPT(Abcam 30868) 10 μg/mL diluted in 1:20 normal goat se-rum, followed by rhodamine-conjugated goat anti-rabbit IgG.5Strong staining of many tumor cells was observed (figure, A).Incubation of tumor sections with the same rhodamine-conjugated secondary antibody, omitting the primary anti-LGI1, showed no staining of tumor cells (figure, B), confirmingthe specificity of the reaction. Immunostaining with LGI1-positive serum from an autoimmune patient with encephalitisdiluted at 1:50 also showed that LGI1 was expressed in manytumor cells with a patchy membrane staining (not shown).DiscussionWe present an association of LGI1 autoimmune encephalitiswith squamous cell lung carcinoma with dramatic resolutionof all clinical phenomena after surgical resection. The casebroadens the spectrum of paraneoplastic association withLGI1 encephalitis and demonstrates that the response toimmunotherapy can be insufficient.Although initial testing for the antibody was negative, thepatient eventually tested positive for LGI1 antibodiesconfirming previous reports that LGI1 antibodies mayinitially show only seropositivity for antibodies to theVGKC complex.6 The connection of the encephalitis to thetumor was strengthened by finding that the tumor stronglyexpressed LGI1 antigen, although it was unclear whichspecific tumor cells express LGI1. A study of gene ex-pression in oral squamous cell cancer has shown that LGI1expression may be elevated in the surrounding mucosa ofearly squamous cell tumors, perhaps reflecting a mecha-nism of tumor suppression.7 The neurologic autoimmunitydeveloped in our patient likely represents a paraneoplasticmechanism with cross-reactive autoimmunity triggered byLGI1 antigen expression within the neoplastic or the sur-rounding non-neoplastic tumor cells as supported by thecomplete resolution of the patient’s symptoms after tumorresection.Although still rare, the association of the typical neurologicphenotype of LGI1 encephalitis with cancer and the completeclinical response to tumor resection suggests an increasedneed to evaluate for malignancy in future cases, especiallywhen the initial clinical response to immunotherapy isincomplete.AcknowledgmentThe authors express our appreciation to Sofia Akrivou andDr.Harry Alexopoulos in Dr. Dalakas’s neuroimmunologylaboratory for performing the tissue immunostaining.Publication was made possible in part by support from theThomas Jefferson University Open Access Fund.Study fundingNo targeted funding reported.DisclosureA. Virupakshaiah reports no relevant disclosures.M. C. Dalakas is an Associate Editor for Neurology® Neu-roimmunology & Neuroinflammation. N. Desai reports norelevant disclosures. S. Mintzer reports no relevant dis-closures. J. Ratliff is the Deputy Section Editor for Podcastsfor the journal Neurology. Go to Neurology.org/NN for fulldisclosures.Publication historyReceived by Neurology: Neuroimmunology & NeuroinflammationDecember 12, 2019. Accepted in final form September 11, 2020.Figure Immunohistochemical staining of tumor sectionsfor LGI1 (×40)Deparaffinized sections from the patient’s tumor immunostained with acommercial polyclonal anti-LGI1 antibody, followed by rhodamine-conju-gated secondary antibody (A, top) or only with the same secondary antibodyomitting the anti-LGI1 serum (B, bottom). Many LGI1-positive cells (red) areidentifiedwithin the tumor (A); no tumor cells were stained, other than someconnective tissue or vessels with the rhodamine-conjugated secondaryantibody alone (B). LGI1 = Leucine-rich glioma-inactivated-1.2 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 1 | January 2021 Neurology.org/NNReferences1. Spatola M, Dalmau J. Seizures and risk of epilepsy in autoimmune and other in-flammatory encephalitis. Curr Opin Neurol 2017;30:345–353.2. Petit-Pedrol M, Sell J, Planagumà J, et al. LGI1 antibodies alter K v 1.1 and AMPAreceptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144–3159.3. Gadoth A, Pittock SJ, Dubey D, et al. Expanded phenotypes and outcomes among 256LGI1/CASPR2-IgG–positive patients. Ann Neurol 2017;82:79–92.4. Alexopoulos H, Dalakas MC. The immunobiology of autoimmune encephalitides.J Autoimmun 2019;104:102339.5. Alexopoulos H, Dagklis IE, Akrivou S, Bostantjopoulou S, Dalakas MC. Autoimmuneencephalitis with GABA-b antibodies, thymoma, and GABA-b receptor thymic ex-pression. Neurol Neuroimmunol NeuroInflammation 2014;1:1–3. doi: 10.1016/j.oraloncology.2007.10.011.6. Sweeney M, Galli J, McNally S, et al. Delayed LGI1 seropositivity in voltage-gatedpotassium channel (VGKC)-complex antibody limbic encephalitis. BMJ Case Rep2017;2017:1–4.7. Fialka F, Gruber RM, Hitt R, et al. CPA6, FMO2, LGI1, SIAT1 and TNC aredifferentially expressed in early- and late-stage oral squamous cell carcinoma—a pilotstudy. Oral Oncol 2008;44:941–948.Appendix AuthorsName Location ContributionAkashVirupakshaiah,MDChildren’s Hospitalof Philadelphia,Philadelphia, PAFirst draft of the manuscript,background research, andrevision of the manuscript forintellectual contentMarinos C.Dalakas, MDThomas JeffersonUniversity,Philadelphia, PARevision of themanuscript forintellectual content, collectionand analysis ofimmunohistological data,generation of figuresNeeja Desai,MDRaleigh NeurologyAssociates, Raleigh,NCRevision of themanuscript forintellectual contentScott Mintzer,MDThomas JeffersonUniversity,Philadelphia, PARevision of themanuscript forintellectual contentJeffrey Ratliff,MDThomas JeffersonUniversity,Philadelphia, PABackground research, revisedthemanuscript for intellectualcontent, and layout of figureNeurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 1 | January 2021 3DOI 10.1212/NXI.00000000000009052021;8; Neurol Neuroimmunol Neuroinflamm Akash Virupakshaiah, Marinos C. Dalakas, Neeja Desai, et al. LGI1 encephalitis with squamous lung-cell carcinoma: Resolution after tumor resectionThis information is current as of October 9, 2020ServicesUpdated Information & http://nn.neurology.org/content/8/1/e905.full.htmlincluding high resolution figures, can be found at:References http://nn.neurology.org/content/8/1/e905.full.html##ref-list-1This article cites 7 articles, 0 of which you can access for free at: Subspecialty Collections http://nn.neurology.org//cgi/collection/paraneoplastic_syndromeParaneoplastic syndrome http://nn.neurology.org//cgi/collection/dystoniaDystonia http://nn.neurology.org//cgi/collection/autoimmune_diseasesAutoimmune diseases http://nn.neurology.org//cgi/collection/all_epilepsy_seizuresAll Epilepsy/Seizuresfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://nn.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://nn.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:Academy of Neurology.. All rights reserved. Online ISSN: 2332-7812.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the AmericanPublished since April 2014, it is an open-access, online-only, continuous publication journal. Copyright is an official journal of the American Academy of Neurology.Neurol Neuroimmunol Neuroinflamm 

LGI1 encephalitis with squamous lung-cell carcinoma: Resolution after tumor resection.

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LGI1 encephalitis with squamous lung-cell carcinoma: Resolution after tumor resection.

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