Epilepsy Research (2014) 108, 592—596

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SHORT COMMUNICATION

Lack of antibodies to NMDAR or VGKC-complex in GAD and cardiolipin antibody-positive refractory epilepsy Suvi Liimatainen a,b,∗, Jukka Peltola a, Aki Hietaharju a, Lidia Sabater c, Bethan Lang d a

Department of Neurosciences and Rehabilitation, Tampere University Hospital, Tampere, Finland Department of Emergency Medicine, Tampere University Hospital, Tampere, Finland c Service of Neurology and Institut d Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain d Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford OX3 9DS, UK b

Received 1 August 2013; received in revised form 29 November 2013; accepted 5 December 2013 Available online 6 January 2014

KEYWORDS Neuronal antibody; Seizure; Autoimmune encephalitis; New-onset epilepsy; Refractory epilepsy; Polyautoimmunity

Summary Background: Over the last few years autoantibodies against neuronal proteins have been identified in several forms of autoimmune encephalitis and epilepsy. NMDA receptor (NMDAR) and voltage gated potassium channel (VGKC) complex antibodies are mainly associated with limbic encephalitis (LE) whereas glutamic acid decarboxylase antibodies (GADA) and anticardiolipin (ACL) antibodies are more commonly detected in patients with chronic epilepsy. Clinical features vary between these antibodies suggesting the specificity of different neuronal antibodies in seizures. Methods: Serum samples of 14 GADA positive and 24 ACL positive patients with refractory epilepsy were analyzed for the presence of VGKC or NMDAR antibodies. Results: No positive VGKC or NMDAR antibodies were found in these patients. Conclusions: The results confirm the different significance of these neuronal antibodies in seizure disorders. Different autoantibodies have different significance in seizures and probably have different pathophysiological mechanisms of actions. © 2014 Elsevier B.V. All rights reserved.

Abbreviations: Ab, antibody; ACL, anticardiolipin; AED, antiepileptic drug; AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2, contactin-associated protein-like 2; DTX, dendrotoxin; FLE, frontal lobe epilepsy; GABA B, gamma amino butyric acid B; GAD, glutamic acid decarboxylase; GADA, glutamic acid decarboxylase antibody; Ig, immunoglobulin; IGE, idiopathic generalized epilepsy; JME, juvenile myoclonic epilepsy; LE, limbic encephalitis; LGI1, leucine-rich, glioma inactivated 1; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor; OLE, occipital lobe epilepsy; SPS, stiff person syndrome; T1D, type 1 diabetes; TLE, temporal lobe epilepsy; TLE + HS, temporal lobe epilepsy associated with hippocampal sclerosis; VGKC, voltage-gated potassium channel. ∗ Corresponding author at: Department of Neurosciences and Rehabilitation, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland. Tel.: +358 3 31166339; fax: +358 3 31164351. E-mail address: suvi.liimatainen@fimnet.fi (S. Liimatainen). 0920-1211/$ — see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.12.015

Lack of antibodies to NMDAR or VGKC-complex in GAD

Introduction There is rapidly increasing amount of evidence on the importance of autoimmunity in the etiology for refractory epilepsy. Several autoantibodies such as antibodies against components of the voltage-gated potassium channel (VGKC) complex, glutamatergic N-methyl-D-aspartic acid receptor (NMDAR) and glutamic acid decarboxylase antibodies (GADA) have been found in patients with different seizure disorders (Palace and Lang, 2000; Peltola et al., 2000a,b; Vincent et al., 1999; Ranua et al., 2004; Liimatainen et al., 2009; Bien and Scheffer, 2011; Vincent and Bien, 2008; Suleiman et al., 2011; Quek et al., 2012; Brenner et al., 2013; Hacohen et al., 2013). However, a question regarding the specificity of these autoantibodies has been raised because clinical features vary in different antibody-associated disorders such as acute onset encephalitis, new-onset epilepsy and long-standing refractory epilepsy. In our previous studies GADA have shown association with refractory temporal lobe epilepsy (TLE), and patients with epilepsy and GADA have been positive for several other autoantibodies suggesting the presence of polyautoimmunity of these patients (Peltola et al., 2000b; Liimatainen et al., 2010). VGKC complex and NMDAR antibodies have mainly been observed in limbic encephalitis (LE) with seizures. In these cases immunotherapeutic agents have been shown to be effective in diminishing the symptoms and decreasing the titer of antibodies supporting the role of the autoantibodies in pathophysiology of these disorders (Vincent et al., 2004; Dalmau et al., 2008; Irani et al., 2008). High titer GADA antibodies have also been detected in cohorts of new-onset TLE initiated by LE where they appear to define a cohort of hardto-treat nonparaneoplastic LE patients (Malter et al., 2010). However, variance of antibody titers as a result of therapeutic interventions has also been demonstrated LE with GADA (Kanter et al., 2008). VGKC complex and NMDAR antibodies belong to surface antigens whereas antibodies to GADA are thought to be directed against intracellular epitopes with a diagnostic significance but without known pathophysiological mechanisms (Bien et al., 2012). Although the suggested therapeutic interventions are currently quite similar regardless of the different autoantibodies, there are emerging differences (e.g. GAD vs. NMDAR antibodies) underlying the important issues of specificity of these autoantibodies. In another set of studies we have demonstrated that patients with recurring seizures or with various developmental disorders and epilepsy had more immunoglobulin (Ig) G class anticardiolipin (ACL) antibodies compared to healthy controls subjects (Liimatainen et al., 2009; Lehtimäki et al., 2011; Peltola et al., 2000a). The significance or specificity of these ACL antibodies is far less established compared with GADA, NMDAR or VGKC antibodies. The purpose of this study was to analyze serum samples from our previously published data on ACL (Liimatainen et al., 2009) or GADA (Liimatainen et al., 2010) positive patients for the presence of NMDAR or VGKC antibodies to evaluate the significance of these antibody-positive patients with refractory epilepsy.

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Materials and methods We have previously analyzed GADA titer in 253 patients with refractory epilepsy (Liimatainen et al., 2010). One hundred eighty-six patients had refractory focal epilepsy with persistent seizures after administrating two antiepileptic drugs (AEDs) sequentially or in combination and a duration of epilepsy at least two years (Kwan et al., 2010). All available modern antiepileptics were used in these patients. 209 patients had focal epilepsy, 34 patients had generalized epilepsy and in 10 patients focal epilepsy type was unknown. In this study 15 patients had positive GADA titer, seven of them with high GADA [≥1000 relative units (RU)/ml]. Only 1 had type 1 diabetes (T1D) (GAD titer 1680 RU/ml). In another set of study we measured ACL antibodies in 105 patients with refractory focal epilepsy, this study cohort was a part of GADA study cohort; positive ACL IgG titer was observed in 27 patients (Liimatainen et al., 2009). No post-stroke epilepsy patients were included. We measured VGKC-complex and NMDAR antibodies in patients with either GADA or IgG ACL to rule out whether these antibodies were only concurrent antibodies in the setting of a more complex autoantibody response. The serum samples of 13 patients with GADA and 24 patients with IgG ACL antibodies were tested for antibodies to VGKC-complex antibodies by immunoprecipitation of 125I-␣-dendrotoxin (DTX)-labelled rabbit whole brain extract, and were considered positive if the individual titer exceeded 100 pM; 3 standard deviations above the mean titer observed in healthy controls (McKnight et al., 2005). Antibodies to NMDAR and to VGKC-complex proteins (LGI1 and CASPR2) were determined by a cell-based assay as previously described (Brenner et al., 2013). The study was approved by the local Ethics Committee, and all the patients gave a written informed consent. The work was carried out in accordance with Declaration of Helsinki and Uniform Requirements for manuscripts submitted to Biomedical journals.

Results Clinical characteristics of the study patients are presented in Tables 1 and 2 (see for details Liimatainen et al., 2009, 2010). We did not find any increased concentrations of NMDAR or LG1/CASPR2-antibodies in our patients. High GADA values were consistent with our previous results supporting the reliability of these different analysis methods. Two ACL positive patients had positive GADA titer, one of them with very high titer GADA (142,520 RU/ml).

Discussion Several autoantibodies have been associated with different seizure disorders. Antibodies to neuronal proteins such as NMDAR and VGKC are typically associated with subacute form of LE. There are also LE patients with high titer GADA. In new-onset epilepsy increased titers of ACL and antinuclear antibodies were observed before antiepileptic treatment (Peltola et al., 2000a). An autoimmune pattern of patients with chronic refractory epilepsy seems to be

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Table 1 Clinical characteristics of patients with antibodies to glutamic acid decarboxylase (GADA). Female/male Age (years) GADA titer (IU/ml) Seizure frequency/year Epilepsy type TLE TLE + HS FLE IGE JME Unknown Etiology Demyelinating disease Hippocampal atrophy or sclerosis Idiopathic Trauma Unknown

9/4 Mean 45.1 Mean 32,282.5 Mean 77.2

Range 17—71 Range 6—207,770 Range 0—365

5 patients 2 3 1 1 1 1 3 2 3 4

GADA, antibodies to glutamic acid decarboxylase; TLE, temporal lobe epilepsy; TLE + HS, temporal lobe epilepsy associated with hippocampal sclerosis; IGE, idiopathic generalized epilepsy; FLE, frontal lobe epilepsy; JME, juvenile myoclonic epilepsy.

different from patients with acute disorders. Neuronal antibodies are rarely found, but ACL and GAD antibodies are detected in increased prevalence compared to control subjects. ACL antibodies are common in patients with recurring seizures and high GADA in those with refractory temporal lobe epilepsy and polyautoimmune pattern. Refractory Table 2 Clinical characteristics of patients with IgG class anticardiolipin antibodies (IgG ACL). Female/male Age (years) ACL IgG titer (SGU) Seizure frequency/year Epilepsy type TLE TLE + HS FLE OLE Multifocal Unknown Etiology Cortical dysplasia Hippocampal sclerosis Dual pathology Tumor Vascular malformation Vascular lesion Unknown

13/11 Mean 36 Mean 23.0 Mean 68.7

Range 16—59 Range 15—80 Range 0—365

8 6 7 1 1 1 6 5 1 2 2 1 7

TLE + HS, temporal lobe epilepsy associated with hippocampal sclerosis; TLE, temporal lobe epilepsy; FLE, frontal lobe epilepsy; Multifocal, multifocal epilepsy, OLE, occipital lobe epilepsy; dual pathology, hippocampal sclerosis associated with vascular lesion.

patients with GADA usually have no clear evidence of LE in their history suggesting a different pathophysiological mechanism in acute and chronic phase of seizure generation. The current finding supports this difference. We did not find any overlap between intracellular antibodies GADA and ACL, and synaptic antibodies against NMDAR or VGKC complex suggesting these antibodies in patients with seizures have different phenotype and significance. Clinical and immunological phenotypes are different in acute and chronic seizure disorders. Majority of cases with acute onset disease have several neuropsychiatric symptoms; however there are patients with monosymptomatic disorder with seizures only (Dalmau et al., 2008; Niehusmann et al., 2009). Most commonly found autoantibodies in acute onset disorder are NMDAR, VGKC complex and GAD antibodies. GADA has been observed in both acute LE and refractory epilepsy, and in both conditions initiation of seizures is in temporal lobe. The spectrum of diseases associated with GADA is further supported by several different GADA associated neurological diseases such as stiff person syndrome (SPS) and late onset cerebellar ataxia (Solimena et al., 1990; Honnorat et al., 2001). The finding that none of GADA positive patients harboured antibodies for NMDA or VGKC antibodies gives further support for the concept of these antibodies as a separate entity. Similar findings were made in two previous studies where increased titer of VGKC antibodies were detected in 11% of patients with seizures but high titer GADA in 2%; those were different patients than VGKC positive ones (McKnight et al., 2005; Brenner et al., 2013). Antibodies to neural surface antigens such as LGI1, are usually associated with LE, but patients with chronic epilepsy have also found to have VGKC antibodies, however in many of these cases, the exact antigenic component of the VGKC-complex recognized is unknown (McKnight et al., 2005; Brenner et al., 2013). There is a subgroup of patients with very high GADA titer and a distinct clinical and immunological phenotype. Patients usually have intrathecal synthesis of GADA and oligoclonal bands strongly supporting the immune-mediated origin of epilepsy (Saiz et al., 2008). Brain imaging showed reduction of neuroinhibitory GABA concentrations of GADA positive epilepsy patients (Stagg et al., 2010). In our previous study of 253 patients with refractory epilepsy high titer GADA was found in 7 patients and low titer GADA in 8 patients (Liimatainen et al., 2009). Only 1 patient had T1D. The autoantibodies demonstrated in GADA positive epilepsy patients in our previous study were thyroperoxidase antibodies, GM1 antibodies, Langerhans cell antibodies, thyroglobulin antibodies, antinuclear antibodies, ␤2-glycoprotein 1 antibodies and antigastric parietal cell antibody. The patients with high titer GADA had a median number of 4 other antibodies whereas the patients with low titer GADA had a median number of only 1 other antibody. This polyautoimmunity has also been found in NMDAR encephalitis as well as in patients with AMPA receptor, GABA B receptor, LGI1 and CASPR2 encephalitis (Rosenfeld and Dalmau, 2012). A term autoimmune epilepsy suggests the direct immunological etiology of epilepsy. In our previous studies we did not find increased titers of different antibodies only in probably symptomatic epilepsy; there were different kinds of etiologies such as tumor and

Lack of antibodies to NMDAR or VGKC-complex in GAD hippocampal sclerosis suggesting rather disease modifying role of immune system in such patients. The previous observation of differences between intracellular antibodies (GADA) and antibodies directed to cell surface antigens (NMDAR and VGKC complex antibodies) suggests that intracellular antibodies themselves are not pathogenic but they can be used as biomarkers of autoimmunity whereas antibodies against cell surface antigens are directly pathogenic and measurement of these antibodies will aid to recognize immunotherapy-responsive disorders (Bien et al., 2012). A possible direct pathogenic effect of high titer GADA was supported by experiment in which purified IgG from a SPS patient was injected into the lateral ventricle of a rat and caused a SPS-like motor dysfunction (Hansen et al., 2013). The pathogenic mechanism of NMDAR antibodies includes internationalization of antibody-antigen complexes into intracellular space leading the subacute manifestation of a neuropsychiatric disorder, often associated with a movement disorder, which differs from the usual clinical onset of chronic epilepsy (Dalmau et al., 2008). History for LE was negative for all of our study patients. There was no overlap between ACL antibodies and NMDA or VGKC antibodies. In epilepsy associated with ACL the pathophysiological significance is not well established. Even though ACL has neuroexcitatory properties and may further modulate seizure susceptibility, our finding was that the IgG ACL positivity was associated with recurring seizures in chronic refractory epilepsy (Liimatainen et al., 2009). Serum samples were kept frozen from the original study. Unfortunately we did not have any control samples with the same storage time. However, correctly stored serum samples stay positive for many years. We have previously discovered that antibodies can be detected in over five years old samples of patients who were recognized as having NMDARencephalitis. Furthermore, the original samples for GADA were retested in the present study and similar levels were found compared to those recorded five years earlier. The present study confirms that different autoantibodies in epilepsy have different significance in seizures and probably have different pathophysiological and immunological mechanisms of actions. The occurrence of different autoantibodies is dependent on the phase of seizure disorder. In the future, there is a need for larger multicenter studies of large pool of autoantibodies with focus on newly diagnosed patients (with both epilepsy or LE) to help understanding the regulation of immune system in seizure related disorders.

Conflict of interest Suvi Liimatainen has received support from GlaxoSmithKline, OctaPharma and UCB Pharma. Jukka Peltola has received support from Cyberonics, Eisai, Schwarz-Pharma, Jazz Pharmaceuticals, GlaxoSmithKline, Medtronics, UCB Pharma, Janssen-Cilaq and Pfizer. The remaining authors have no conflicts of interest.

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Lack of antibodies to NMDAR or VGKC-complex in GAD and cardiolipin antibody-positive refractory epilepsy.

Over the last few years autoantibodies against neuronal proteins have been identified in several forms of autoimmune encephalitis and epilepsy. NMDA r...
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