Anti-Neuronal Autoantibodies in Both Drug Responsive and Resistant Focal Seizures with Unknown Cause

Highlights

• Neuronal Autoimmune antibodies may be detected in patients with focal seizures regardless of prognosis.

• Seropositive patients often have immune-related events in the past history.

• Seropositive patients may benefit from immunosuppressive treatment.

Abstract

Background

and Objective Autoimmunity is an emerging field of research in the etiology of different neurological disorders including epilepsy. We aimed to investigate the presence of neuronal autoantibodies in focal epilepsy with unknown cause and their clinical correlates in both drug-responsive and resistant patients.

Method

Between 2009 and 2010 94 patients were prospectively enrolled, had their antibodies tested and clinically followed." An additional 50 age- and gender-matched controls were also tested for antibodies. Age at examination, gender, age at onset, seizure frequency, risk factors, seizure precipitants, and type of seizures were noted. Plasma obtained from patients was frozen at −80 °C and analysed for autoantibodies against VGKC-complex, VGCC, GAD, LGI1, CASPR2, NMDA, AMPA and GABAB receptors with immunocytochemistry and radioimmunoassay as required.

Results

Thirteen (13.8%) patients, but none of the controls, had antibodies (p = 0.003). Antibodies were directed against the uncharacterized components of VGKC-complex in 5 patients (5.3%), GAD in 4 patients (4.2%), NMDA-R in 1 patient (1%), AMPA-R in 1 patient (1%) and both GAD and VGKC-complex in 2 patients (2.1%). Prognosis of epilepsy, in subsequent follow-up, did not correlate to general presence of anti-neuronal antibodies with slightly more patients with antibodies epilepsy control than without (76.9% vs. 69.1%, not-statistically significant. Three patients with suspected active autoimmunity and epilepsy who were treated, showed a response to treatment with a reduction in the seizure frequency. Although most clinical features were identical between seropositive and seronegative patient groups, seropositive patients were more likely to have inflammatory/autoimmune disorders in their medical history.

Discussion

In keeping with previous studies, we have shown anti-neuronal antibodies in a proportion of focal epilepsy patients. Although autoimmunity might merely occur as a bystander effect in many chronic neurological disorders, association of anti-neuronal antibodies with good response to immunotherapy and coexisting autoimmune disorders suggests that anti-neuronal autoimmunity might participate in seizure formation at least in a subgroup of focal epilepsy patients.

Conclusion

Immunity may play a role in some patients with unknown etiology regardless of prognosis and immunmodulatuar treatment may be helpful in seropositive group.

Introduction

In recent years there have been significant advances in our understanding of the underlying etiologies of the epilepsies, underpinned by developments in neuroimaging and genetic testing. The most common etiologies are structural, genetic, metabolic, infectious and immune-related, the last having been recently included (ILAE webpage). However, the underlying causes cannot be determined in approximately 30–60% of patients despite all the advances in the neurological sciences (Wirrell et al., 2011, Kwan and Brodie, 2000).

Recent studies have demonstrated that the immune system has an important role in the etiology of seizures leading to the emergence of a new group of epilepsy, so called ‘autoimmune epilepsy’ (Bien and Scheffer, 2011, Granerod et al., 2010, Irani et al., 2011, Leypoldt et al., 2015, Khawaja et al., 2016) The current recognized clinical syndromes related to serum antibodies to proteins in the central nervous system are limbic encephalitis/encephalopathies or faciobrachial dystonic seizures (FBDS) with antibodies against voltage-gated potassium channel (VGKC)-complex, N-Methyl-D-Aspartate receptor (NMDA-R), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), gamma aminobutyric acid B receptor (GABAB-R) glutamic acid decarboxylase (GAD) and glycine receptors (GLY-Rs) (Brenner et al., 2013, Irani et al., 2008, Irani et al., 2010, Irani et al., 2011, Liimatainen et al., 2010, Majoie et al., 2006, McKnight et al., 2005, Onugoren et al., 2014, Thieben et al., 2004, Vincent et al., 2004). Two recent studies which presented two large unselected cohorts of a new onset epilepsy or epilepsy with a chronic course also showed different types of the above mentioned antibodies (Brenner et al., 2013, Ekizoglu et al., 2014). Brenner and colleagues (Brenner et al., 2013) demonstrated that 11% of patients with established or newly diagnosed generalized or focal epilepsy were seropositive for at least one of the antibodies to VGKC-complex, NMDA-R, GAD or GLY-Rs. Ekizoğlu and colleagues (Ekizoglu et al., 2014) reported the presence of (GLY-Rs), contactin-associated protein 2 (CASPR-2), NMDA-R, and VGKC-complex in 13.0% of patients with focal epilepsy of unknown cause and in the group with mesial temporal lobe epilepsy with hippocampal sclerosis.

Therefore, the role of autoimmunity has been proposed in the etiology of both new onset and chronic epilepsies. Furthermore, a relationship between autoimmune etiology and antiepileptic drug (AED) resistance has been reported, in which case immunomodulatory or immunosuppressive drugs may show some benefits (Sunwoo, 2016, McKnight et al., 2005, Quek et al., 2012, Dubey and Samudra, 2015).

In our study, we aimed (i) to analyse and confirm the presence of autoantibodies in focal epilepsy patients with unknown cause, (ii) to determine the clinical findings associated with these antibodies and (iii) to investigate the effectiveness of immunosuppression in controlling seizures in seropositive patients.