YEXNR-11754; No. of pages: 6; 4C: Experimental Neurology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr

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Article history: Received 2 April 2014 Revised 29 May 2014 Accepted 1 June 2014 Available online xxxx

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Keywords: Voltage gated potassium channels Leucine-rich glioma inactivated 1 Axonal excitability Neuromyotonia Limbic encephalitis

Institute of Neurology, University College London, United Kingdom Prince of Wales Clinical School & Neuroscience Research Australia, University of New South Wales, Australia School of Medical Sciences, University of New South Wales, Australia d Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom e Brain and Mind Research Institute, University of Sydney, Australia b c

a b s t r a c t

Objective: Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) and acquired neuromyotonia (aNMT), the role of these antibodies in disease pathophysiology has not been elucidated. The present study investigated axonal function across the spectrum of VGKC–complex antibody associated disorders. Methods: Peripheral axonal excitability studies were undertaken in a cohort of patients with LE (N = 6) and aNMT (N = 11), compared to healthy controls (HC; N = 20). Results: Patients with LE demonstrated prominent abnormalities in peripheral axonal excitability during the acute phase, with reduced threshold change in threshold electrotonus (depolarizing 10–20 LE: 58.5 ± 3.1%; HC: 67.4 ± 0.9%; P b .005; S2 accommodation LE: 17.2 ± 1.4%; HC: 22.2 ± 0.6%; P ≤ .005) and in recovery cycle parameters (superexcitability LE: − 16.0 ± 0.9%; HC: −23.4 ± 1.1%; P b .01; subexcitability LE: 8.5 ± 1.2%; HC: 13.8 ± 0.7%; P ≤ .005). The pattern of change in LE patients was dissimilar to the effects of antiepileptic medications, suggesting that these factors did not underlie excitability changes in LE. Normalization of excitability parameters was associated with recovery (TEd peak correlation coefficient = .868; P = .002), suggesting that peripheral excitability studies may provide a marker associated with clinical improvement. In contrast, patients with aNMT demonstrated no significant changes at the site of stimulation. Conclusions: The lack of prominent excitability abnormalities in patients with aNMT likely reflects a distal origin of hyperexcitability, expected to be at the motor nerve terminal, while the prominent changes observed in patients with LE likely represent a complex disturbance at the level of the axonal membrane, combined with electrolyte imbalance and adaptive change. © 2014 Published by Elsevier Inc.

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et al., 1997; Newsom-Davis and Mills, 1993; Vincent et al., 2004). However, these disorders have a broad clinical spectrum, with varying degrees of central nervous system (CNS) and peripheral nervous system (PNS) involvement. Limbic encephalitis (LE) is characterized by CNS-predominant symptoms including memory disturbance, hallucinations, and seizures, coupled with evidence of inflammation in the mesial temporal lobes or hippocampi (Vincent et al., 2004; Zuliani et al., 2012). By contrast, acquired autoimmune neuromyotonia (aNMT) is characterized by predominantly PNS involvement, including spontaneous muscle twitching, cramps and fatigue (Hart et al., 1997; Isaacs, 1961; Newsom-Davis and Mills, 1993), although many patients also exhibit some CNS disturbance (Hart et al., 2002). Some of this clinical heterogeneity may be explained by recent findings identifying specific antigenic targets in patients with VGKCassociated autoantibodies. Specifically, antibodies against leucine-rich

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Susanna B. Park a,b, Cindy S.-Y. Lin c, Arun V. Krishnan c, Neil G. Simon b, Hugh Bostock a,d, Angela Vincent d, Matthew C. Kiernan e,⁎

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Axonal dysfunction with voltage gated potassium channel complex antibodies

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Regular Article

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Introduction

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Voltage-gated potassium channels (VGKCs) are critical in modulating neuronal excitability through stabilizing membrane potential, repolarizing the nodal membrane and limiting repetitive discharges (Kiernan et al., 2001; Miller et al., 1995; Vucic et al., 2010). A number of autoimmune conditions have been linked to the production of antibodies targeting VGKC-complex components, including neuromyotonia, Morvan's syndrome, limbic encephalitis and forms of epilepsy (Hart

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Abbreviations: aNMT, acquired autoimmune neuromyotonia; CASPR2, contactin associated protein 2; CMAP, compound muscle action potential; EMG, electromyography; HC, healthy controls; LE, limbic encephalitis; LGI1, leucine rich inactivated glioma 1; TE, threshold electrotonus; VGKC, voltage gated potassium channel. ⁎ Corresponding author at: Brain and Mind Research Institute, 94 Mallett Street, Camperdown Sydney, NSW 2050, Australia. Fax: +61 2 9114 4254. E-mail address: [email protected] (M.C. Kiernan).

http://dx.doi.org/10.1016/j.expneurol.2014.06.002 0014-4886/© 2014 Published by Elsevier Inc.

Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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S.B. Park et al. / Experimental Neurology xxx (2014) xxx–xxx

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Methods

findings are discussed in the results. Threshold electrotonus parameters are described in terms of the direction: depolarising (TEd) or hyperpolarizing (TEh), and the timing after onset of the current pulse (i.e. 10–20 ms, or 40–60 ms). In addition TEd peak referred to the maximal threshold change (%) after onset of the depolarizing current pulse and S2 accommodation referred to the change in threshold between TEd peak and the TEd 90–100 ms. TEh overshoot and TEd undershoot were the peak threshold changes after the cessation of the polarizing current in both the hyperpolarizing and depolarizing directions. Superexcitability was the greatest threshold decrease in the recovery cycle of excitability, while subexcitability was the greatest threshold increase after an interstimulus interval of 10 ms. Strength duration time constant was measured as the relationship between stimulus width and stimulus strength, and calculated offline according to Weiss' law (Kiernan et al., 2000).

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Patient selection

Mathematical model of motor axonal excitability

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Excitability simulations using a mathematical model of human motor axonal excitability were undertaken. The two-compartment model, composed of a single node and internode, was implemented by MEMFIT software (Bostock, 2006) (described by Howells et al., 2012). Briefly, iterative alterations to reduce the discrepancy between the model and experimental data were undertaken using a least squares method (Howells et al., 2012).

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Immunological studies

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Serum samples from all patients were assessed by a standardized immunoprecipitation assay with 125I-α-dendrotoxin-labeled rabbit brain extract designed to detect antibodies to Kv1.1, Kv1.2 and Kv1.6 channels, or proteins complexed with these channels, as reported previously (Irani et al., 2010). VGKC antibody titres were considered positive if greater than 100 pmol/L. Some of the patient cohort (2 of 6 LE patients; 9 of 11 aNMT patients) also underwent testing for specialized antigenic targets (LGI1, CASPR2, or contactin-2 antibodies Irani et al., 2011).

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Statistical analysis

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Neurophysiological studies

Data are presented as mean ± SEM. Independent T-tests were used to compare patient and healthy control results. Correlations were undertaken using Pearson product-moment correlation coefficients. Linear regression analysis was used to examine relationships between VGKC-complex antibody titres, serum electrolytes and excitability parameters and results are presented as coefficients of determination. In light of the multiple comparisons, a P value of b 0.01 was considered significant (Kiernan et al., 2001). QTrac and SPSS (version 19, IBM, New York, NY) software packages were used for analysis.

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Patients with LE were identified following their acute admission for seizures, short term memory loss and behavioral changes. The study was approved by South Eastern Sydney Area Health Service (Eastern Section) Human Research Ethics Committee and University of New South Wales Human Research Ethics Committee. Participants or family members provided written informed consent in accordance with the declaration of Helsinki. Patients were diagnosed with LE determined by positive VGKCcomplex antibody assays, MRI evidence of signal abnormalities or PET evidence of increased glucose metabolism in the medial temporal lobe. At the time of nerve excitability testing, all acute phase patients were receiving antiepileptic drugs — all patients were receiving sodium valproate (600 mg–1500 mg), and in addition two patients were receiving levetiracetam (1.5–2 g) and one patient carbamazepine (400 mg). During the 26 month follow-up period, LE patient 1 continued to be treated with sodium valproate and levetiracetam on all nerve excitability testing occasions. LE patients 5 and 6 were not receiving antiepileptic drugs at the time of excitability testing. Results from LE patients were contrasted to studies in patients with a diagnosis of acquired autoimmune neuromyotonia (aNMT) according to previously established clinical criteria, with all patients displaying symptoms of muscle twitching or cramps in two or more skeletal muscle regions (Hart et al., 2002). In addition, EMG criteria were applied, including the presence of doublet, triplet or multiplet neuromyotonic discharges or fasciculations (Maddison et al., 1999). At the time of testing, five patients were receiving immunomodulatory treatment with IVIg, plasmapheresis, azathioprine or prednisone, four were receiving symptomatic relief with amitryptiline, two with gabapentin, two with carbamazepine and one with pregabalin.

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Patients underwent nerve conduction studies using a Medelec synergy system (Oxford Instruments, Oxfordshire, UK). Nerve excitability studies were performed on the median nerve, stimulating at the wrist and recording compound motor action potentials (CMAPs) from the abductor pollicis brevis. Standard nerve excitability protocols and equipment included the computerized operational system Qtrac (©Institute of Neurology, London UK), with stimulation provided by the DS5 isolated linear bipolar constant current stimulator (Digitimer, Welwyn Garden City, UK). Multiple excitability measures were recorded using threshold tracking techniques (Bostock et al., 1998), following a standardized protocol (strength–duration time constant, threshold electrotonus (TE), and recovery cycle) as described in Kiernan et al. (2000). Patient excitability results were compared to a healthy control group (N = 20; 53.4 ± 3.5 years), matched by age and temperature. A complete excitability profile was recorded for each participant, although only significant

Results

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Clinical features and antigenic specificity

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Patients with LE all demonstrated confusion, seizures and evidence of hyponatremia (due to syndrome of inappropriate antidiuretic hormone secretion; Table 1). A positive VGKC-complex antibody titre (N100 pM) was identified in each of the LE patients. Two LE patients who underwent testing for LGI1 antibodies (Irani et al., 2011) were found to be positive (patients 1 and 3). The other LE patients were unable to be tested for specialized antigenic targets due to unavailability of the testing at the time of presentation. Five of the LE patients received three days of pulse intravenous methylprednisolone, which produced a reduction in seizures, associated with improvements in memory and normalization of hyponatremia. Treatment was associated with

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glioma inactivated 1 (LGI1) have been identified in LE patients (Irani et al., 2010, 2011; Lai et al., 2010) and contactin-associated protein-2 (CASPR2) antibodies in some patients with aNMT and Morvan's syndrome (Irani et al., 2010, 2012; Vincent and Irani, 2010). Both LGI1 and CASPR2 are VGKC-complex associated proteins rather than components of the channel itself (Irani et al., 2010; Poliak et al., 1999). Accordingly, the role of direct VGKC dysfunction in the pathophysiology of these disorders remains unclear, although IgG preparations obtained from clinically affected patients have been reported to interfere with VGKC function and suppress fast K+ currents in vitro (Lalic et al., 2011; Shillito et al., 1995). The aim of the present study was to investigate axonal membrane ion channel function across the spectrum of VGKC-complex antibody associated disorders in vivo.

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Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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S.B. Park et al. / Experimental Neurology xxx (2014) xxx–xxx t1:1 t1:2

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Table 1 Characteristics of patients with limbic encephalitis. Patient number

Age at onset

Initial VGKC titre (pM)

Amnesia/ confusion

Seizures

Active tumor

Sleep disorder

Hypo-natremia

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Serum Na+ level (mmol) at NES

Nadir serum Na+ level (mmol)

t1:4 t1:5 t1:6 t1:7 t1:8 t1:9

1 2 3 4 5 6

44 59 63 73 75 54

4437* 1208 1030* 156 3110 180

Y Y Y Y Y Y

Y Y Y Y Y Y

– – – Y – –

Y Y Y – Y –

Y Y Y Y Y –

129 135 131 139 141 140

125 133 128 121 122 137

t1:10 t1:11

Clinical characteristics of patients with limbic encephalitis demonstrating clinical symptoms, VGKC-complex antibody titre, and serum Na+ level at nadir and at the time of nerve excitability testing. NES Nerve excitability study * Confirmed LGI1 antibodies.

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significant reductions in antibody titres in two patients in whom followup antibody testing was performed (patients 1 and 3). LE patients had normal nerve conduction studies, indicating the absence of neuropathy. In patient 1, EMG demonstrated fasciculations in the absence of denervation. In the other patients, EMG demonstrated minor increased insertional activity or occasional simple fasciculations with no neurogenic features. In prior studies of LE patients, 7–17% of patients have displayed signs of peripheral nerve hyperexcitability (Klein et al., 2013; Vincent et al., 2004). Positive VGKC-complex antibody titres were identified in 45% of the aNMT cohort. As in other studies, the antibody titre was greater in the LE group than in the antibody-positive aNMT cohort (Table 2; LE 1687 ± 704 pM; aNMT 218 ± 31 pM; P ≤ .05). All five antibody positive aNMT patients underwent specialized antigenic target testing — two aNMT patients were positive for CASPR2 antibodies, one for LGI1 antibodies, one had both and one had contactin-2 antibodies. No specific antigenic targets were identified in VGKC–complex antibody negative aNMT patients. Muscle twitching was the most prominent symptom, with exercise or activity a major factor in exacerbating clinical symptoms. The most common EMG abnormalities were fasciculations (82%), with multiplet discharges identified in 64% of patients (Table 3).

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Axonal excitability in limbic encephalitis

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Patients with LE in the acute phase had prominent abnormalities in peripheral axonal excitability, with reduced threshold change in threshold electrotonus (Table 4; TEd 10–20 ms P b .005; TEd peak P b .005; S2 accommodation P ≤ .005) and reduced threshold change in recovery cycle parameters (superexcitability P b .01; subexcitability P ≤ .005) compared to healthy controls (Fig. 1A). Subsequently, LE patients assessed during recovery phase demonstrated normal axonal excitability. A representative LE patient (patient 1) was followed with serial axonal excitability studies to determine the pattern of changes during the recovery period. Comparison of recordings from the initial hospitalization to the follow-up recording 26 months later demonstrated gradual normalization of excitability traces (Fig. 2). Recovery in excitability parameters in patient 1 was significantly correlated with improvements in serum Na+ level

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Table 2 Clinical characteristics of VGKC cohort.

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Number of patients Mean age at diagnosis (range) % male Positive VGKC antibodies (%) Mean positive VGKC titre (pmol/L) Positive titre range (pmol/L) Antigenic specificity

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Comparison with anticonvulsant medications

Limbic encephalitis

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6 61 ± 5 (44–75) 67% 100% 1687 ± 704

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156–4437 2 LGI1

150–304 2 CASPR2, 1 LGI1, 1 CASPR2/LGI1, 1 Contactin-2

Comparison of limbic encephalitis and acquired autoimmune neuromyotonia patients with regard to age, sex, and VGKC-complex antibody titre.

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A further series of studies were undertaken to determine whether anticonvulsant medications exerted an effect on the axonal excitability profile observed in LE patients. Specifically, studies were undertaken in two separate patient cohorts receiving comparable doses of singleagent, steady-state sodium valproate (N = 7; dose range 400– 2000 mg) and carbamazepine (N = 8; dose range 400–1000 mg). LE patients demonstrated significant differences compared to both cohorts, with significantly reduced superexcitability (LE − 16 ± .9%; sodium valproate −24 ± 2%; P b .01; carbamazepine −24 ± 1%; P b .01) and altered threshold electrotonus (TEd peak LE 58 ± 3%; sodium valproate 69 ± 2%; P b .05; TEh overshoot LE 10 ± 2%; carbamazepine 18 ± 2%; P b .05), suggesting that the results in LE patients could not be explained on the basis of an effect of anticonvulsant therapy mediated through Na+ conductances.

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Comparison with acquired autoimmune neuromyotonia

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To further delineate the changes observed in LE, a series of studies 252 were undertaken in aNMT patients. In contrast to patients with LE, 253 there were no significant differences in nerve excitability measures 254 t3:1 t3:2

Table 3 Clinical characteristics of acquired neuromyotonia cohort. Percentage of patients (%)

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(Fig. 3A; TEd 10–20 ms correlation coefficient = .860; P b .005; Ted 40–60 ms correlation coefficient = 0.828; P b .01; TEd peak correlation coefficient = 0.868; P b .005). In order to explain these changes, mathematical modeling of axonal properties was undertaken to determine the single parameters which could maximally reduce the error in fitting results of the baseline recording to healthy control values. The maximum discrepancy reduction by changing single parameters was obtained by a reduction in the percentage of persistent Na+ channels (79.9% error reduction with a reduction of 87% of persistent Na+ channels) followed by reduction in external Na+ concentration (72.5% error reduction with a reduction in external Na+ concentration by 34%).

Clinical symptoms Muscle twitching Muscle cramps Stiffness Fatigue Weakness Sensory symptoms EMG findings Fasciculations Spontaneous activity Multiplet discharges Neurogenic changes Polyphasic motor units

100% 82% 45% 64% 55% 36%

82% 45% 64% 64% 55%

Clinical characteristics of the acquired neuromyotonia cohort including clinical symptoms and EMG findings.

Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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Excitability parameters in patients with acute phase limbic encephalitis compared to healthy controls. Parameters from threshold electrotonus recordings are demonstrated including the maximum threshold change during a 100 ms depolarizing pulse (TEd peak), the threshold change following 10–20 ms of a depolarizing pulse (TEd 10– 20 ms) and the accommodation to a 100 ms depolarizing pulse (S2 accommodation). Parameters from the recovery cycle of excitability are demonstrated including the maximum threshold reduction (superexcitability) and the maximum threshold increase after an interstimulus interval of 10 ms (subexcitability).

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between the aNMT patients and the healthy control subjects. Specifically, there were no differences in threshold electrotonus measures [S2 accommodation (aNMT 20.8 ± 1.0%; HC 22.2 ± 0.6; NS), TE depolarizing undershoot (aNMT −16.3 ± 1.0; HC −18.0 ± 0.8%; NS) or TE hyperpolarizing overshoot (aNMT 15.0 ± 1.1%; HC 15.7 ± 0.9% NS)] or in subexcitability (aNMT 13.5 ± 1.4% HC 13.8 ± 0.7% NS). There were also no significant differences in strength duration time constant as compared to healthy controls (aNMT 0.46 ± 0.02 ms; HC 0.44 ± 0.02 ms; NS).

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Findings from the present series have established a complex evolution of axonal abnormalities in patients with VGKC-complex associated antibodies. Perhaps counterintuitively, greater changes were identified in patients with LE, a CNS-predominant phenotype in whom antibody titres were significantly higher, when compared to aNMT patients. LE patients demonstrated coherent excitability abnormalities associated with longitudinal changes observed during clinical recovery. In contrast, excitability changes in patients with aNMT were not suggestive of generalized axonal hyperexcitability.

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Altered excitability and limbic encephalitis

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LE patients demonstrated prominent changes in peripheral axonal excitability, which normalized over the course of clinical recovery. LGI1 is expressed, albeit at a low level, in the PNS (Ogawa et al., 2010), and therefore could be directly affected, especially given the extremely high titres of antibodies in the periphery (Irani et al., 2011). Mouse models of inactivated LGI1 demonstrate evidence of neuromuscular

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TEd peak (%) 53.2 60.8 60.4 TEd 10–20 ms (%) 52.4 61.5 61.7 S2 accommodation (%) 14.5 19.4 17.6 Superexcitability (%) −14.1 −17.7 −17.3 Subexcitability (%) 7.0 10.2 11.1

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dysfunction and hypomyelination, also indicating PNS involvement (Silva et al., 2010). Further, sera from a patient with LGI1-associated LE demonstrated altered excitability in hippocampal synapses, effects which were mimicked by K+ channel blockers, suggesting functional disruption of VGKC by LGI1 antibodies (Lalic et al., 2011). However, axonal excitability changes in LE patients did not match the excitability profile predicted simply by blockade or dysfunction of fast VGKC channels. Recordings from patients with episodic ataxia type 1, leading to reduced Kv1.1 channel function, demonstrated prominent excitability abnormalities opposite to those observed in LE (Tomlinson et al., 2010). Similarly, blockade of fast K+ current with 4-AP leads to reduced accommodation in threshold electrotonus, with increased superexcitability (Baker et al., 1987). Mathematical modeling of the recordings obtained from the present cohort raise the possibility that LE excitability changes were linked in part to reductions in persistent Na+ current or potentially extracellular Na+ concentration. While the excitability changes identified in LE patients were dissimilar to patients on antiepileptic drugs, arguing against a global effect of antiepileptic drugs on axonal function, changes in axonal excitability may be adaptive, acting to reduce the potential for hyperexcitability and repetitive activity. Of relevance, minor adaptive changes were identified in an earlier study of patients with aNMT and thought to reflect increased slow K+ channel function as a compensatory measure to reduce hyperexcitability produced by fast K+ channel dysfunction (Kiernan et al., 2001). However, excitability in LE patients did not match expected changes with upregulation of a slow K+ current (Kiernan et al., 2001; Sittl et al., 2010). An alternative explanation for the generalized reduction in both threshold electrotonus and recovery cycle could be reduced peripheral membrane excitability, similar to patients with mutations in Na+ channel SCN1β subunits (Kiernan et al., 2005), which could also act to reduce hyperexcitability via stabilization of the axonal membrane. Further, alteration in ionic fluxes at the axonal membrane level may contribute to the underlying changes. In the present study, changes in peripheral excitability measures during recovery matched with normalization of serum Na+ fluctuations. Separately, previous studies have demonstrated that fluctuation in serum K+ (within an overall normal range) may induce excitability changes in healthy subjects (Kuwabara et al., 2007), and induce excitability changes in patients with chronic renal failure (Krishnan et al., 2005). Finally, it remains possible that another as yet unidentified factor associated with both clinical recovery and serum Na+ levels may underlie the observed changes in excitability. However, while reductions in extracellular Na+ concentration have been experimentally demonstrated to reduce excitability in animal preparations, typically a larger reduction in concentration is required to substantially affect excitability. Donnelly et al. (1998) demonstrated that a 20% reduction in external sodium produced a 5% reduction in

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Fig. 1. A. Comparison of threshold electrotonus (left) and recovery cycle (right) curves between LE patients (white) and healthy controls (black).

Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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excitability in rat chemoreceptor afferents, representing an equivalent drop in serum Na+ levels from 140 to 112 mmol/L. They determined that this would produce a shift in the Nernst potential for Na+ of 6 mV and be unlikely to affect the electrochemical driving force for Na+. Further Grossmann and Jurna (1974) demonstrated that a reduction in external Na+ from 154 to 77 mmol/L produced a reduction in membrane potential of only 2.7 mV in rat sensory nerve fiber bundles.

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Fig. 2. A. Changes in VGKC-complex antibody titre (top) and serum Na+ concentration (below) in LE patient 1 over 26 months in relation to immunomodulatory treatments and clinical recovery. B. Recovery of excitability profile in patient 1 demonstrated at initial recording (white) and 26 months later (black) in threshold electrotonus (left) and recovery cycle (right).

Fig. 3. A. Correlation of serum Na+ levels with excitability parameter TEd peak recorded in LE patient 1 on nine occasions over 26 months of clinical recovery.

In contrast, in our study, the increase in serum Na+ level in patient 1 from nadir to complete recovery was only 12% (from 125 to 140 mmol/L), and this corresponded to N 300% increase in the excitability parameter superexcitability in the same time frame. Given the dramatic reductions in Na+ required to produce relatively modest changes in excitability in animal models, it seems that the extent of hyponatremia in our cohort may not have been extensive enough to produce the extent of changes in peripheral excitability.

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Spontaneous activity in aNMT is likely to originate at the motor nerve terminals where VGKCs and associated proteins are unprotected by myelin or the blood nerve barrier and as such, remain susceptible to antibody-mediated attack (Deymeer et al., 1998; Hart et al., 2002; Maddison et al., 1999). A number of lines of evidence support the view that the most prominent abnormality in patients with aNMT is distal and thus would not be observable at a more proximal site of stimulation, as undertaken in the present study (Arimura et al., 2005; Deymeer et al., 1998; Hart et al., 2002; Isaacs, 1961; Kiernan et al., 2001; Maddison et al., 1999; Vucic et al., 2010). In addition, a previous study of nerve excitability profile in aNMT patients did not find evidence of global disturbance in axonal excitability, consistent with findings from the present cohort, despite clinical evidence of fasciculations and

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Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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Acknowledgments

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SBP is a recipient of a RG Menzies Foundation/National Health and Medical Research Council of Australia (NHMRC) Training Fellowship [# 1016446]. Support through NHMRC [ForeFront Program Grant # 1037746] is also gratefully acknowledged. The authors thank colleagues who referred patients for assessment.

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Axonal excitability studies provide evidence for prominent excitability alterations in the peripheral nerve of LE patients, which follow a similar time course to clinical recovery. However, patients with aNMT did not demonstrate prominent excitability abnormalities, potentially reflecting a distal origin of hyperexcitability at the motor nerve terminal. In contrast to aNMT, the changes in LE patients may reflect a generalized excitability disturbance at the level of the axonal membrane, and as such, excitability studies may provide a marker associated with clinical improvement in LE associated with VGKC-complex antibodies.

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neuromyotonia, although minor adaptive changes were identified (Kiernan et al., 2001). A less likely explanation has suggested that ectopic activity in aNMT arises at the level of the anterior horn cell, in association with CNS dysfunction secondary to binding of anti-VGKC antibodies to central neurons (Hart et al., 1997). Perhaps arguing against such a possibility is the finding of normal cortical excitability in aNMT patients (Vucic et al., 2010), providing further indirect support that ectopic activity in aNMT arises predominantly at a distal level.

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Please cite this article as: Park, S.B., et al., Axonal dysfunction with voltage gated potassium channel complex antibodies, Exp. Neurol. (2014), http://dx.doi.org/10.1016/j.expneurol.2014.06.002

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Axonal dysfunction with voltage gated potassium channel complex antibodies.

Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) a...
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