J Neurol (2015) 262:418–424 DOI 10.1007/s00415-014-7588-0
An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre S. Huda • S. H. Wong • P. Pettingill • D. O’Connell • A. Vincent • M. Steiger
Received: 26 August 2014 / Revised: 14 November 2014 / Accepted: 15 November 2014 / Published online: 27 November 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan’s syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immunemediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies ([100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres [100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres [400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres \400 pM were seen with PNH (n = 15/22; 68 %) but also a heterogeneous range of central and/or peripheral nervous system disorders. Electromyography was supportive of PNH in 65 % of cases and symptomatic treatment was beneficial in 46 % of
S. Huda D. O’Connell M. Steiger Department of Neurology, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazarkerley, Liverpool L9 7LJ, UK S. Huda (&) P. Pettingill A. Vincent Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Level 6 West Wing, Oxford OX3 9DU, UK e-mail: [email protected] S. H. Wong Department of Neuro-ophthalmology, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK
patients. Irrespective of titre, the rate of malignancy in patients with VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97–44.0 p\0.0001). Clinical phenotyping and antibody titres [400 pM can help determine VGKCcomplex antibody relevance. Antibody titres \400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre. Keywords Voltage-gated potassium channel complex Antibody Limbic encephalitis Peripheral nerve hyperexcitability Autoimmunity
Introduction Voltage-gated potassium channels (VGKC) play an important role in the regulation of membrane excitability. Acquired diseases classically associated with VGKCcomplex antibodies include neuromyotonia/peripheral nerve hyperexcitability (PNH), Morvan’s syndrome, limbic encephalitis (LE), and epilepsy. These disorders are the autoimmune equivalent of the inherited potassium channelopathies, which include neuromyotonia, epilepsy, and episodic ataxia [1–3]. The antibodies are directed against proteins of the voltage-gated potassium channel complex (VGKC-complex) which include Leucine-rich Glioma inactivated 1 (LGI1), Contactin-associated protein-2 (CASPR2), and Contactin-2 [4, 5]. Whilst the recognition of these specific targets has clarified some of the phenotypic variation seen in the associated diseases, VGKC-complex antibodies have
J Neurol (2015) 262:418–424
VGKC-complex antibody titre [400 pM 17/57 (30 %) patients had VGKC-complex antibody titres [400 pM. The median age of presentation was 59 years (27–77) with a male to female preponderance of 3:1 (Table 1). Sixteen of 17 (94.1 %) patients presented with a classic VGKC-complex channelopathy (LE; n = 8, PNH; n = 6, LE/PNH; n = 1, and Morvan’s syndrome; n = 1). This was higher than the proportion of patients with a classic VGKC-complex channelopathy [18/40 (45 %)] with VGKC-complex antibody titres \400 pM (Table 1; Fig. 2; p \ 0.0004). Patients in the [400 pM group were
We retrospectively analysed all patients referred to our institution between 2001 and 2011 who had positive VGKC-complex antibodies (titres [100 pM) reported. VGKC-complex antibodies had been requested by neurologists on the basis of primary clinical presentation, sent to the Oxford Neuroimmunology group for testing by radioimmunoprecipitation assay and identified through a computerised laboratory database . Sera still available (n = 19) were subsequently tested by cell-based assays (CBA) for antibodies to the VGKC-complex proteins LGI1, CASPR2, and Contactin-2; these tests were not available at the time of initial sampling. CBAs were performed using human embryonic kidney cells transfected with cDNAs for the individual proteins . Data were extracted through review of written and computerised records and included clinical presentation, treatment response, malignancy, neurophysiology, cerebrospinal fluid (CSF), sodium levels, brain imaging, sleep and autonomic disturbance. To the extent possible, missing data were obtained from referring hospitals. Neuromyotonia/peripheral nerve hyperexcitability, Morvan’s syndrome, limbic encephalitis, and epilepsy were regarded as classic VGKC-complex channelopathies. Data were also analysed with a VGKC-complex antibody titre of 400 pM as a cutoff value. This has previously been suggested as titres below this value were found in an elderly control group [6, 8]. The study was approved by the local institutional clinical governance and audit board and performed in accordance with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Statistical analysis was carried out using GraphPad Prism Version 6.0A. We compared demographic, clinical, and serological data using student’s t test, Kolmogorov– Smirnov test, or Fisher’s exact test. In the absence of normality, a non-parametric Mann–Whitney test was performed. Statistical significance was defined as a two-sided p value less than 0.05. Comparison of cancer incidence rates was performed using odds ratios in age-matched data from the United Kingdom in 2011 and reported with 95 % confidence intervals .
One thousand six hundred and fourteen VGKC-complex assays were requested for 1,298 patients between 2001 and 2011. VGKC-complex antibody titres [100 pM were detected in 57/1,298 patients (4.4 %), median age 59 years (25–77). Of these n = 17 had VGKC-complex titres [400 pM (17/1298; 1.3 %). There was an increase in the number of requests over this time, particularly after 2005 (Fig. 1), but the proportion of sera with VGKC-complex antibody titres [100 pM or 400 pM did not change appreciably between 2001 and 2005 and 2006–2011. Thirty-four of the 57 (60 %) patients presented with a classic VGKC-complex channelopathy, specifically peripheral nerve hyperexcitability (PNH; 21/57, 36.8 %) and/or limbic encephalitis (LE; 12/57 21 %). One patient had Morvan’s syndrome. The remaining patients (23/57, 40 %) had a wide range of central nervous system (CNS) and peripheral nervous system (PNS) disorders. The number of malignancies detected in patients (median age 59 years) with VGKC-complex antibodies (n = 7/57; 12 %) was significantly higher than the national cancer incidence reported in individuals aged 55–59 years (n = 699.6/100,000, 0.007 %) in the UK in 2011 (OR 19.9, 95 % CI 8.97–44.0 p \ 0.0001) .
Materials and methods
Number of Requests
been reported in some patients without a defined immunemediated syndrome [6–9]. Our institution provides a tertiary neurological service to approximately 3.5 million patients in the North West of England and North Wales but also includes a large number of patients with PNH reflecting the expertise of the late Dr. Ian Hart . The aim of this study was to analyse the clinical relevance of positive VGKC-complex antibodies in patients referred for testing.
Year Fig. 1 Proportion of VGKC-complex antibody results [100 or 400 pM 2001–2011
J Neurol (2015) 262:418–424
also more likely to receive immunotherapy compared to those with antibody titres \400 pM (Table 1; 76.5 vs. 25 % p = 0.0008) and a beneficial response was seen in 12/13 (92.3 %) treated patients. The rates of malignancy, however, did not differ significantly above or below a 400 pM cutoff (Table 1). Nine sera were available for further testing. LGI1 or CASPR2 antibodies were detected in LE (n = 2/3), PNH (n = 1/4), LE/PNH (n = 1/1) but not in the patient with Morvan’s syndrome. Contactin-2 antibodies were not detected in any sera tested. Further clinical details on these patients can be found in Table 2.
Table 1 Clinical and demographic features in patients with VGKCcomplex antibodies VGKC-complex \400 (n = 40) Age at presentation (yrs)
VGKC-complex [400 (n = 17)
20/40 (50 %)
VGKC-complex ab peak (pM)
Classic VGKCcomplex presentation
18/40 (45 %)
13/17 (76.5 %)
10/40 (25 %)
8/10 (80 %)
759 (437–4064) \0.0001c 16/17 (94.1 %)
2/17 (11.8 %)
5/40 (12.5 %)
13/17 (77 %)
12/13 (92.3 %)
Yrs years, ab antibody a
Student’s t test
Fisher’s exact test
VGKC-complex antibody association ***
Number of Patients
Fisher's exact test p =0.0004
30 20 10
VGKC-complex Ab Titre Fig. 2 Utility of VGKC-complex antibody 400 pM cutoff. VGKCcomplex antibody titres [400 pM were associated with classic VGKC-complex channelopathies
40/57 (70 %) patients had VGKC-complex antibody titres \400 pM. The median age of presentation was 54.5 years (25–76) with a male to female ratio of 1:1 (Table 1). Of these patients, 18/40 (45 %) had a classic VGKC-complex channelopathy (PNH; n = 15, LE; n = 3). The remaining patients had a range of CNS and/or PNS disorders detailed in Table 3. Ten out of 40 (25 %) patients were treated with immunotherapy (LE; n = 2, PNH; n = 2, CNS vasculitis; n = 1, Rasmussen’s encephalitis; n = 1, Guillain–Barre syndrome; n = 2, myasthenia gravis; n = 1, chronic inflammatory demyelinating polyneuropathy; n = 1) and 8/10 (80 %) improved, similar to the response rate seen in patients with antibody titres [400 pM (Table 1; 80 vs. 92.3 %, p = 0.56). Ten sera were available for testing by CBAs (LE; n = 2, PNH; n = 5, Rasmussen’s encephalitis; n = 1, multiple system atrophy; n = 1, and narcolepsy; n = 1). Only one patient with PNH and an associated malignant thymoma had CASPR2 antibodies but did not respond to immunotherapy. The remaining sera were negative by CBAs. Further clinical details for these patients can be found in Table 3. Limbic encephalitis The median age of presentation of LE was 63 years (47–77) with a male to female preponderance of 11:1. VGKC-complex antibody titres were between 133 and 4064 pM, mean 990 pM, and 9/12 (75 %) patients with LE had VGKC-complex titres [400 pM. Temporal lobe abnormalities with magnetic resonance imaging were detected in 67 % (8/12), abnormal electroencephalography in 64 % (7/11), hyponatraemia in 50 % (6/12), inflammatory CSF in 58 % (7/12), and sleep disturbance in 100 % (9/9). Of the five patients with a documented description of the seizures (partial seizures with or without secondary generalisation), semiology was not suggestive of faciobrachial dystonic seizures. No cases of LE were associated with malignancy. 11 patients with LE were treated with immunotherapy consisting of different combinations of intravenous methylprednisolone, intravenous immunoglobulin, and plasma exchange. All patients were reported to have improved following immunotherapy. PNH
An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.
Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic ence...