Anti-Neuronal Autoantibodies in Both Drug Responsive and Resistant Focal Seizures with Unknown Cause☆
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.
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Participants
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 at Epilepsy outpatient clinic of Istanbul University, Cerrahpasa School of Medicine, Department of Neurology. Only patients that gave their consent and were available for follow-up visits were recruited. Healthy controls were included only for assessment of the validity of antibody assays since false
Clinical and demographic findings
There were 39 (41.4%) female patients in the epilepsy group and 22 (44%) women among healthy subjects (not significant). The mean ages (±standard deviation) of the epilepsy group and healthy subjects were 37.5 ± 15.0 and 30.1 ± 11.8 years, respectively. The mean age at the onset of epilepsy and the mean duration of epilepsy were 27 ± 16.3 years (between 4 months to 84 years) and 10.5 ± 9.6 (between 1 month to 51 years), respectively (Table 1).
Autoantibody findings and clinical associations
In the patient group, 13 (13.8%) patients were
Discussion
The first clinical studies of autoimmune epilepsy began with three suspected cases diagnosed as non-infectious encephalitis by Bickerstaff in 1950. Afterwards, the presence of autoantibodies were established in cases with limbic encephalitis (Bien and Scheffer, 2011, Buckley et al., 2001, Thieben et al., 2004, Graus et al., 2008, Vincent et al., 2004) and faciobrachial dystonic seizures (Irani et al., 2011) Later on, it became evident that these neuronal antibodies are not only related to
Conclusion
In conclusion, our results showed that immunity may play a role in focal seizures with unknown etiology, some seropositive patients may benefit from immunotherapy and antibody screening might be beneficial in treatment-resistant focal epilepsy patients. A minority of antibody positive focal seizure patients might actually be autoimmune encephalitis patients presenting with limited or monosymptomatic forms of limbic encephalitis. Thus, autoimmune etiology should be considered in the
Funding
This study was supported by the scientific research grants from Istanbul University and by an unconditional grant from Dem Pharma and Berk Pharma, Turkey.
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The manuscript was presented at the 31st International Epilepsy Congress in 2015.