EDITORIAL

Another autoimmune encephalitis? Not yet

Israel Steiner, MD Stephan Rüegg, MD

Correspondence to Dr. Steiner: [email protected] Neurology® 2015;84:1192–1193

Over the last decade, the discovery of neurologic disorders associated with antibodies directed against extracellular CNS antigens located on cellular surfaces and synaptic epitopes has revolutionized the diagnosis, therapy, and prognosis of a spectrum of conditions formerly unknown or mischaracterized. The autoimmune encephalopathies, in fact encephalitic conditions, have an impressive gamut of symptomatology and include limbic encephalitis, stiff person disorders, epilepsy, psychosis, movement abnormalities, and sleep disturbances (reviewed in reference 1). In some, but not all, the pathogenic role of the antibodies has been demonstrated. The discovery of overlap among these CNS disorders and other immune-mediated conditions, and the detection of autoimmune encephalitis following viral infection,2,3 paves the way to elucidate the etiology and pathogenesis of these illnesses. The novelty of these autoimmune encephalitides encompasses several aspects: (1) they can occur without an underlying tumor, (2) the target of the autoantibodies is extracellular, (3) the antibodies alter the function or localization of the target antigen, and (4) the conditions are responsive to immunotherapy in 70%–80% of patients.4 Diagnosis is based on the clinical findings and on detecting relevant antibodies in patients’ serum and CSF. Target epitopes include the NMDA receptor (NMDAR), the a-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor (AMPAR), leucine-rich, glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the g-aminobutyric acid B receptor (GABABR). There are 2 classes of receptors to g-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the brain. While the GABABR is composed as a homodimer or heterodimer of 2 subunits and is linked to G proteins, the GABAAR is a hetero-pentamer ion channel containing 5 subunits from a diversity of 19 known specific subunits grouped into 8 families: a, b, g, d, e, u, p, and the r family. The presence of some subunits in the GABAAR isoforms is associated with specific clinical effects against fear and anxiety.5,6 The main isoform of the receptor is composed of 2 a1, 2 b2, and 1 g1 subunit.7 Antibodies against the B receptor

GABABR are associated with limbic encephalitis and seizures, and in half of the patients there is an underlying lung or neuroendocrine tumor.8 The GABAAR is a new and upcoming participant in this arena. Antibodies against GABAAR isoforms containing a1 or b3 subunits were recently reported in 18 patients. Six who had CSF antibodies had prominent seizures and status epilepticus, with extensive cortical and subcortical fluidattenuated inversion recovery/T2 signal abnormalities. The other 12 in whom low serum titers but no CSF antibodies were detected had variable symptomatology, seizures in some, opsoclonus in 2 patients, and stiffperson syndrome in 4.9 In this issue of Neurology®, Pettingill et al.10 report a meticulous retrospective large-scale study focusing on the antibodies against the a1 and g2 subunits of GABAAR. Sera (2,548 samples) were examined for the presence of such antibodies directed against the 3 subunits of the receptor and 45 tested positive. These included 40 out of 2,046 sera that had been negative for other antibodies and 5 out of 502 that tested positive for additional CNS-targeted antibodies. Only 40% were immunoglobulin G (IgG) while the rest were low titer immunoglobulin M (IgM) antibodies. Partial clinical information is available only on 15 patients, emphasizing the main drawback of the study: lack of sufficient clinical correlation data, resulting from the retrospective nature of this work. Nonetheless, the significance of the current study lies in the fact that it is complementary to the study by Petit-Pedrol et al.9 and solidifies another cell surface– directed antibody as a possible cause of encephalitis. The findings may also shed additional light on the function and dysfunction of GABAAR. This receptor is of clinical import in other contexts. Congenital alterations of its b3 subunit were associated with developmental and autistic spectrum disorders, while changes in the g2 subunit have been linked with decreased efficiency of benzodiazepines.11 Thus the observation that antibodies against the b3 subunit cause severe status epilepticus while those against g2 provoke more cognitive and psychiatric symptoms is unexpected. On a more practical note, these findings

See page 1233 From the Department of Neurology (I.S.), Rabin Medical Center, Petah Tiqva, Israel; and the Department of Neurology (S.R.), University Hospital Basel, Switzerland. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1192

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stress the need to rule out a GABAAR-mediated immune etiology in epilepsy cases that respond poorly to benzodiazepines or to barbiturates, drugs whose target is the GABAAR. The study raises several important questions. If indeed the culprit, why should a single antibody cause such divergent clinical symptomatology (seizures, psychiatric phenomena, cognitive impairment)? Is it possible that other unidentified antibodies are responsible for some clinical abnormalities? Anti-GABAAR antibodies were detected in serum only; are they present in CSF and in what concentration? It is possible that some patients without serum anti-GABAAR antibodies harbor CSF antibodies only, as is the case in 15%–20% of anti-NMDAR antibody-mediated limbic encephalitis. What is the effect of immunotherapy (only 2 patients in this study) for anti-GABAAR antibodies and are antibody titers a reliable marker of disease course? The pathogenic role of these specific anti-GABAAR antibodies remains unclear, but one test for this would be to do patch clamp recordings from isolated hippocampal pyramidal cells or slices, bathed in the antibody-containing serum of patients, and measure the effect on inhibitory GABA currents. Additionally, the utmost majority of antibodies directed against cell surface antigens associated with this group of disorders are of the IgG class. Do IgM antibodies, at low titers as is the case here, have a true clinical pathogenic role? The control sera that tested negative for antiGABAAR antibodies were obtained from healthy controls. Are there patients with chronic neurologic conditions or acute CNS damage (such as those post trauma or stroke) who might develop a similar abnormality? A recent study detected antineuronal autoantibodies of any subtype in high prevalence in normal persons as well as neuropsychiatric patients, questioning their role in pathogenesis of brain diseases.12 For all these reasons, the clinical importance of the antibodies reported in the present study requires additional proof. ACKNOWLEDGMENT The authors thank Drs. Gilad Rosenberg and Felix Benninger for critical reading of the manuscript.

STUDY FUNDING No targeted funding reported.

DISCLOSURE I. Steiner has served as an expert consultant to Teva, Hoffman la Roche, and Actelion, and currently receives research grants from Teva. S. Rüegg received unconditional research grants from UCB; honoraria from serving on the scientific advisory boards of Desitin, Eisai, GlaxoSmithKline, and UCB; travel grants from GlaxoSmithKline, Janssen-Cilag, and UCB; and speaker fees from UCB and from serving as a consultant for Eisai, GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB. He is a coapplicant of Swiss National Foundation. Go to Neurology.org for full disclosures.

REFERENCES 1. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann NY Acad Sci Epub 2014 Oct 14. 2. Pruss H, Finke C, Holtje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012;72:902–911. 3. Schäbitz WR, Rogalewski A, Hagemeister C, Bien CG. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology 2014;83:2309–2311. 4. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011;77:179–189. 5. Smith KS, Engin E, Meloni EG, Rudolph U. Benzodiazepineinduced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. Neuropharmacology 2012;63:250–258. 6. Rowlett JK, Platt DM, Lelas S, Atack JR, Dawson GR. Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc Natl Acad Sci USA 2005;102:915–920. 7. Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem 2012;287:40224–40231. 8. 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. 9. 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. 10. Pettingill P, Kramer HB, Coebergh JA, et al. Antibodies to GABAA receptor a1 and g2 subunits: clinical and serologic characterization. Neurology 2015;84:1233–1241. 11. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5:553–564. 12. Dahm L, Ott C, Steiner J, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 2014;76:82–94.

Neurology 84

March 24, 2015

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Another autoimmune encephalitis?: Not yet Israel Steiner and Stephan Rüegg Neurology 2015;84;1192-1193 Published Online before print January 30, 2015 DOI 10.1212/WNL.0000000000001325 This information is current as of January 30, 2015 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/84/12/1192.full.html

References

This article cites 11 articles, 5 of which you can access for free at: http://www.neurology.org/content/84/12/1192.full.html##ref-list-1

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This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Autoimmune diseases http://www.neurology.org//cgi/collection/autoimmune_diseases Psychosis http://www.neurology.org//cgi/collection/psychosis

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Another autoimmune encephalitis? Not yet.

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