Clinical Study When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study B.J. O’Sullivan a , T. Steele a , M.A. Ellul a,b , E. Kirby a , A. Duale a , G. Kier a,c , D. Crooks c , A. Jacob a , T. Solomon a,b,d,1 , B.D. Michael a,b,d,e,⇑,1 a Department of Neuroscience, The Walton Centre NHS Foundation Trust, Liverpool, UK b Department of Clinical Infection, Microbiology and Immunology, The Institute for Infection and Global Health, University of Liverpool, Ronald Ross Building, 8 West Derby Street, Liverpool, UK c Department of Neuropathology, The Walton Centre NHS Foundation Trust Liverpool, UK d NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, UK e Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, USA article info Article history: Received 24 March 2016 Accepted 20 April 2016 Available online xxxx Keywords: Autoimmune Clinical features Diagnosis Encephalitis abstract Patients with voltage-gated potassium channel (VGKC)-complex antibodies are increasingly recognized as having central, peripheral or combined phenotypes. With increasing awareness, more patients are tested and the clinical spectrum is expanding. Consequently, clinicians may be uncertain as to which patients should or should not be tested. Previous studies have identified common clinical features, but none has looked at the usefulness of these in predicting seropositive disease. We conducted a case- control study of patients tested for VGKC-complex antibodies over 10 years at a regional tertiary neurol- ogy centre determining which clinical/biochemical features were associated with antibody-positive dis- ease. We found a marked increase in the numbers tested, although the percentage positive remained low. Antibody titre was highest in central disease (p < 0.001). Time from presentation to testing was shorter in those with VGKC-disease (p = 0.01). Seizures were present in 11 (69%) of those with VGKC-disease versus three (18%) without (odds ratio [OR] 10.3, 95% confidence interval [CI]: 2.0–52.7, p = 0.005). There was an inverse correlation between the antibody titre and serum sodium. A multivariate model selected seizures and hyponatraemia as predictive of VGKC disease (sensitivity 75% and specificity 82%); faciobrachial dys- tonic movements were specific but insensitive. Interestingly serum alkaline phosphatase was higher in those with VGKC-disease (p = 0.016) and highest in those with peripheral disease (p = 0.015). An ALP > 70 u/L was strongly associated with antibody positivity (OR 4.11 95% CI: 1.43–11.8, p = 0.007) with a sensitivity of 74.2%. The presence of seizures, faciobrachial movements, and hyponatraemia should raise suspicion of VGKC-disease; alkaline phosphatase may represent a novel biomarker, particularly in those with peripheral disease. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Voltage-gated potassium channel (VGKC)-complex antibodies were initially identified in association with peripheral nerve hyper-excitability [1–5]. They are now recognised to be associated with clinical syndromes of both the peripheral (PNS) and central (CNS) nervous system, causing neuromyotonia and limbic encephalitis respectively, or a combined phenotype termed Mor- van’s syndrome [6–9]. This variation in clinical phenotypes is attri- butable to different antibody targets on the extracellular domains of neuronal cell membrane proteins, with antibodies directed against contactin-2 associated proteins (CASPR2) causing predom- inantly peripheral disease and those against leucine-rich glioma inactivated 1 (LGI1) associated with central manifestations [10–14]. Regardless of clinical presentation, early intervention is pivotal, particularly as timely immunotherapy can significantly improve outcome in those with CNS disease [15–19]. However, an increasingly diverse clinical picture of VGKC dis- ease is emerging. Several studies have implicated VGKC-complex antibodies in epilepsy, chronic pain, neuropsychiatric presenta- tions and disorders of movement and autonomic function [20–24]. An expanding clinical spectrum, growing awareness and improved availability of serum assays has led to an increase in VGKC-complex antibody testing [25]. However, a positive serum http://dx.doi.org/10.1016/j.jocn.2016.04.021 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +44 7515404533. E-mail address: benmic@liv.ac.uk (B.D. Michael). 1 These authors have contributed equally to the manuscript. Journal of Clinical Neuroscience xxx (2016) xxx–xxx Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn Please cite this article in press as: O’Sullivan BJ et al. When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.04.021