Antibodies to voltage-gated potassium and calcium channels in epilepsy

doi:10.1016/j.eplepsyres.2006.06.003

Epilepsy Research

Volume 71, Issues 2–3, October 2006, Pages 135-141

https://doi.org/10.1016/j.eplepsyres.2006.06.003 Get rights and content

Abstract

Objective

To determine the prevalence of antibodies to ion channels in patients with long standing epilepsy.

Background

Although the CNS is thought to be protected from circulating antibodies by the blood brain barrier, glutamate receptor antibodies have been reported in Rasmussen's encephalitis, glutamic acid decarboxylase (GAD) antibodies have been found in a few patients with epilepsy, and antibodies to voltage-gated potassium channels (VGKC) have been found in a non-paraneoplastic form of limbic encephalitis (with amnesia and seizures) that responds to immunosuppressive therapy.

Methods

We retrospectively screened sera from female epilepsy patients (n = 106) for autoantibodies to VGKC (Kv 1.1, 1.2 or 1.6), voltage-gated calcium channels (VGCC) (P/Q-type), and GAD. All positive results, based on the values of control data [McKnight, K., Jiang, Y., et al. (2005). Serum antibodies in epilepsy and seizure-associated disorders. Neurology 65, 1730–1735], were retested at lower serum concentrations, and results compared with previously published control data. Demographics, medical history, and epilepsy related information was gathered.

Results

The studied group consisted predominantly of patients with long standing drug resistant epilepsy. VGKC antibodies were raised (>100 pM) in six patients. VGCC antibodies (>45 pM) were slightly raised in only one patient. GAD antibodies were <3 U/ml in all patients. The clinical features of the patients with VGKC antibodies differed from previously described patients with limbic encephalitis-like syndrome, and were not different with respect to seizure type, age at first seizure, duration of epilepsy, or use of anti-epileptic drugs from the VGKC antibody negative patients.

Conclusion

The results demonstrate that antibodies to VGKC are present in 6% of patients with typical long-standing epilepsy, but whether these antibodies are pathogenic or secondary to the primary disease process needs to be determined.

Introduction

The incidence of auto-immune diseases in the general population is 5–7% (female predominance 9:1). Although the CNS is thought to be protected by the blood brain barrier against circulating antibodies, potentially pathogenic serum autoantibodies in CNS diseases such as Rasmussen encephalitis have been described, and a neuroimmunological dysfunction has been suggested in unexplained malignant childhood epilepsies (van Engelen et al., 1995). Other autoantibodies, such as those to glutamic acid decarboxylase (GAD), and antibodies to paraneoplastic antigens (Dalmau et al., 1999), are probably not primary mediators of the associated diseases, but are useful secondary markers for immune-mediated neurological diseases.

In the last few years the role of channelopathies in acute or transient neurological disorders has been recognized, usually in relation to genetic mutations in hereditary disease. In humans, mutations in the VGKC have been implicated in both benign familial neonatal convulsions and partial epilepsy with episodic ataxia type1. Mutations in the genes encoding α1 subunits of the VGCC CACNL1A4 have been implicated in several human disorders such as familial hemiplegic migraine, episodic ataxia type 2 and spinocerebellar ataxia type 6. Mutations in the equivalent mouse gene are also responsible for the tottering (tg) and leaner (tg^la) phenotypes, which exhibit severe ataxia and epileptic seizures (Moulard et al., 2001, Ptacek and Fu, 2001, Avanzini and Ptacek, 2002, Chang and Lowenstein, 2003). We hypothesised that autoantibodies directed at the same channels may produce a phenotypically similar disorder. More recently, evidence has accumulated that antibodies to potassium channels (VGKC) are involved in certain limbic syndromes (Vincent et al., 2004), and in some patients with subacute onset of unexplained epilepsy (McKnight et al., 2005). Other studies suggest the presence of glutamic acid decarboxylase antibodies in drug resistant epilepsy (Peltola et al., 2000).

The aim of the present study was to look for autoantibodies against VGKC, VGCC and GAD in female patients with epilepsy of age 14–45 years, since autoimmunity is particularly common in females of this age range. Furthermore, we aim to describe the clinical profile of the patients with positive antibodies.

Section snippets

Patients and methods

Sera from a consecutive series of female epilepsy patients (age 14–45 years, n = 106) were tested. All patients visited the outpatient clinic of a tertiary referral clinic (Epilepsy Centre Kempenhaeghe). The majority of these patients had long standing intractable epilepsy, using more than one anti-epileptic drug. Clinical records of the patients were reviewed for age, medication, age at onset and duration of epilepsy, type of epilepsy syndrome, seizure type and frequency, etiologic factors and

Results

Out of the 106 patients tested, seven were positive. VGKC antibodies were raised (>100 pM) in six patients compared to the previously-reported controls which consisted of multiple sclerosis (n = 50), stroke (n = 62), other neurologic diseases (n = 19) and healthy individuals (n = 19); only one patient with stroke had a slightly elevated anti-VGKC titre (McKnight et al., 2005). The patient with the highest VGKC antibody titre (1406 pM) also had an equivocal GAD antibody (1 U/ml). This patient, a

Discussion

In the present study antibodies to VGCC, VGKC or GAD were found in 6.7% of female adult patients with long standing epilepsy. The expected incidence of any type of autoantibody in a female population is 9–12.5% (Song and Leonard, 2000), but the antibodies to ion-channel proteins measured in this study have been shown to be very infrequent (0.5%) in healthy controls or patients with other neurological diseases (n = 150) (McKnight et al., 2005).

Reports of elevated GAD antibodies have been recorded

Acknowledgments

The study was approved by the Medical Ethics Committee. The first author is grateful to Dr. J. Hulsman for his support during this study, to Ad Schellekens and Mario Loosen for preparing the samples, and to Linda Clover and Annael Galati for doing the VGKC and GAD antibody assessments.

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After an initial selection of 1656 articles, only six retrospective observational studies with a level of evidence between 2+ and 3 and a SIGN B recommendation degree remained. The total number of patients examined was 139. The estimated efficacy of AEDs with AE was 10.7%. There was response to AEDs in 18% of seronegative patients, 11% in VGKC positives and in 8% with GAD65. Seventy-three percent of responders to AEDs were in treatment with Na+ channel blockers in monotherapy or in combination.
The efficacy of AEDs in AE was low, although this may be in part due to a selection bias. Nevertheless, patients could benefit from these drugs even after immunotherapy failure. Seronegative patients seemed to have a better response to AEDs.
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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).
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Antibodies to voltage-gated potassium and calcium channels in epilepsy

Abstract

Objective

Background

Methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgments

Lancet

J. Allergy Clin. Immunol.

Brain Res. Brain Res. Rev.

J. Allergy Clin. Immunol.

Rheum. Dis. Clin. N. Am.

Potassium channel antibodies in two patients with reversible limbic encephalitis

Ann. Neurol.

Epilepsy

N. Engl. J. Med.

Hashimoto encephalopathy: syndrome or myth?

Arch. Neurol.

Proposal for revised clinical and electroencephalographic classification of epileptic seizures

Epilepsia

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Epilepsia

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Brain Pathol.