Neuronal Voltage-Gated Potassium Channel

Complex Autoimmunity in ChildrenRadhika Dhamija, MD†, Deborah L. Renaud, MD†, Sean J. Pittock, MD†‡,

Andrew McKeon, MD†‡, Daniel H. Lachance, MD†‡, Katherine C. Nickels, MD†,Elaine C. Wirrell, MD†, Nancy L. Kuntz, MD†, Mary D. King, MD§,

and Vanda A. Lennon, MD, PhD*†‡

Autoimmunity targeting voltage-gated potassiumchannel complexes have not been systematically docu-mented in children. Identified in the Neuroimmunol-ogy Laboratory records of Mayo Clinic were 12seropositive children, 7 among 252 Mayo Clinic pedi-atric patients tested on a service basis for serologic ev-idence of neurologic autoimmunity (June 2008-April2010), 4 during the assay’s preimplementation valida-tion (before June 2008) and 1 non-Mayo patient withavailable clinical information. Neurologic manifesta-tions were subacute and multifocal. Three had globaldevelopmental regression, 6 movement disorders, 4dysarthria, 3 seizures, 1 Satoyoshi syndrome, 1 painfulred feet, 2 insomnia, 2 gastrointestinal dysmotility, and2 small fiber neuropathy. Neoplasia was found in 1child. Treating physicians recorded improvement inall 7 children who received immunotherapy. Neuro-logic symptom relapse occurred in 3 of 6 children af-ter ceasing immunotherapy. These findings highlighta diverse clinical spectrum of neuronal potassiumchannel complex autoimmunity in children, and theyillustrate benefit from early initiated immunotherapy,with a tendency to relapse when therapy ceases. Diag-nosis is generally delayed in the process of eliminatingneurodegenerative causes. Currently 2.7% of pediat-ric sera evaluated for neurologic autoimmunity arepositive for neuronal potassium channel complex-reactive immunoglobulin G. The frequency and fullspectrum of neurologic accompaniments remainsto be determined. � 2011 Elsevier Inc. All rightsreserved.

From the Departments of *Immunology, †Neurology, and ‡LaboratoryMedicine and Pathology, Mayo Clinic, Rochester, Minnesota, and§Children’s University Hospital, Temple Street, Dublin, Ireland.

� 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.pediatrneurol.2010.10.015 � 0887-8994/$ - see front matter

Dhamija R, Renaud DL, Pittock SJ, McKeon A, LachanceDH, Nickels KC, Wirrell EC, Kuntz NL, King MD,Lennon VA. Neuronal voltage-gated potassium channelcomplex autoimmunity in children. Pediatr Neurol 2011;44:275-281.

Introduction

Voltage-gated potassium channels (VGKC) are tetra-meric signaling proteins containing 6–transmembrane do-main alpha subunits (S1–6) encoded by approximately 50genes in humans. Each includes a voltage-sensitive fourthdomain [1]. VGKCs in neurons of both the central and pe-ripheral nervous systems play an important role in mem-brane repolarization, axonal conduction, and synaptictransmission [1,2]. Autoantibodies targeting VGKCs wereinitially reported in patients with acquired neuromyotonia,a disorder of peripheral nerve hyperexcitability (also calledIsaac syndrome) [3,4], and subsequently in patients witha continuum of autoimmune neuromuscular hyperexcitabilitydisorders with and without central nervous systemaccompaniments (Morvan syndrome, cramp-fasciculationsyndrome, rippling muscle disease) [5-7], rapid eyemovement sleep disorders, intractable epilepsy [8,9], andpotentially reversible encephalopathies [10-12]. Recentreports suggest that the autoantibodies identified byimmunoprecipitation of VGKCs complexed with 125I-a-dendrotoxin (a ligand that binds with high affinity toKv1.1, 1.2, and 1.6 channels) target neuronal proteins thatcoprecipitate with solubilized potassium channels. Two

Communication should be addressed to:Dr. Lennon; Neuroimmunology Laboratory; Mayo Clinic; 200 First StSW; Rochester, MN 55905.E-mail: lennon.vanda@mayo.eduReceived August 31, 2010; accepted October 20, 2010.

Dhamija et al: VGKC Neurologic Autoimmune Spectrum 275

Table 1. Clinical characteristics of 12 children

Patient

No.

Age at

Onset/Sex

Age at

Diagnosis

Duration of

Follow-up from

Diagnosis

VGKC

(nmol/L)

Neurologic

Manifestations

Antecedent

Event (1-4 wk) MRI Brain

1 5 yr/M 5 yr 3 mo 0.05 Motor tics — Increased T2 signal,

left thalamus

2 3 yr/M 6.5 yr 1.5 yr 0.06 Global regression,

seizures and chorea

Salmonella

gastroenteritis

Normal

3 10 mo/F 3 yr 6 mo 0.11 Symptomatic

generalized

epilepsy,

developmental

delay

— Bilateral increased

T2 signal,

mesial temporal

lobes

4 7 yr/M 9 yr 3 mo 0.13 Painful red feet, cramps,

hypohidrosis

— —

5 8 mo/M 2 yr 1 yr 0.15 Episodic flushing and

overheating, hypohidrosis

— —

6 6 yr/F 6.5 yr 2 mo 0.19 Acute disseminated

encephalomyelitis,

migraine headaches,

tremor

Influenza Symmetric areas of

signal abnormality,

white matter of both

cerebral hemispheres

7 14 yr/M 15 yr 8 yr 0.20 Continuous muscle

fiber activity

(Satoyoshi

syndrome)

— —

8 9 yr/F 15 yr 3 yr 0.25 Dysarthria

(worse when

dysmotility is

worse)

Viral illness Normal

9 8 yr/F 9 yr 2 yr 0.43 Developmental regression,

myoclonus, dystonia,

hyperkinetic dysarthria

— Normal

10 8 yr/F 8 yr 7 yr 0.95 Limbic encephalitis

(insomnia, seizures),

chorea, hyperkinetic

dysarthria

Viral illness Increased T2 signal,

amygdala and mesial

temporal lobes

11 29 mo/F 5 yr 1 yr 1.42 Global developmental

regression, autism,

insomnia

Influenza

vaccine

Normal

12* 9 yr/F 9 yr 6 mo 0.54 Cerebellar ataxia,

intermittent

perioral

myoclonus,

dysarthria

— Normal

* Patient not seen at Mayo Clinic

Abbreviations:

CSF = Cerebrospinal fluid

hpf = High-power field

MRI = Magnetic resonance imaging

VGKC = Voltage-gated potassium channels

276 PEDIATRIC NEUROLOGY Vol. 44 No. 4

Gastrointestinal

Symptoms CSF Findings Immunotherapy

Immunotherapy

Response

Other Clinical

Manifestation or

Autoantibodies

Family History of

Autoimmunity

— — None — — —

— Cell 1/hpf, glucose

73 mg/dL,

protein

25 mg/dL

Yes, IV corticosteroids,

IV immune globulin,

Plasma exchange,

Cyclophosphamide

Mild improvement in

seizure frequency

Eosinophilia Diabetes mellitus,

lupus

— Cell 1/hpf, glucose

59 mg/dL,

protein

32 mg/dL

Yes, Prednisone, IV

immune globulin

Moderate improvement

in seizure frequency,

relapsed after IV

immune globulin,

stopped

Striational

antibody

(1:240)

Rheumatoid

arthritis

— — None — — Hypothyroidism,

psoriasis

Diarrhea — None — No Hashimoto thyroiditis,

Graves disease

— Cell 0/hpf,

glucose

55 mg/dL,

protein

16 mg/dL

None — Antinuclear

antibody

Type 1 diabetes

mellitus, Connective

tissue

disease

— — Yes, Prednisone, IV

immune globulin

Mild improvement in

muscle spasms

Alopecia,

joint pain,

antinuclear

antibody,

striational

antibody

(1:120)

—

Dysmotility — Yes, IV

immune globulin

Moderate recovery in

dysmotility and

dysarthria, relapsed

after, IV

immune globulin,

stopped

Hypothyroidism,

lupus

— Cell 1/hpf, glucose

54 mg/dL,

protein 45 mg/dL

None — No Hypothyroidism,

type 1 diabetes

mellitus

— Cell 1/hpf, glucose

73 mg/dL,

protein 25 mg/dL

Yes, IV corticosteroids,

plasma exchange,

6-mercaptopurine

Marked, complete

recovery

— —

— — Yes, Prednisone, IV

immune globulin,

mycophenolate

mofetil

Moderate recovery

with better eye

contact and

communication,

relapsed after IV

immune globulin

stopped

— —

— Cells 4/hpf, glucose

61 mg/dL,

protein, 232 mg/dL

Oral corticosteroids,

tumor removal

Marked complete

recovery

Neuroblastoma,

antineuronal

nuclear

autoantibody

type 1

(1:3,840)

—

Dhamija et al: VGKC Neurologic Autoimmune Spectrum 277

Figure 1. Magnetic resonance image of the brain of patient 10. Arrowsindicate amygdala and mesial temporal lobes. Note increased T2 signal(A) and resolution after treatment (B).

major antigens identified to date are the leucine-rich, gli-oma inactivated 1 protein (Lgi1), bound by immune globu-lin (Ig) G in serum of patients with limbic encephalitis, anda neurexin, contactin-associated protein 2 (Caspr2), boundby IgG in serum of some patients with neuromuscularhyperexcitability [13,14].

The clinical spectrum of VGKC complex autoimmunitycurrently recognized in adult patients includes idiopathicand paraneoplastic disorders of the central and peripheralsomatic, autonomic, and enteric nervous systems [15-18].In a paraneoplastic context, these autoantibodies are mostcommonly associated in adults with adenocarcinomas,small-cell lung carcinoma, thymoma, and hematologicmalignancies [15]. Little information has been reportedconcerning clinical correlations of VGKC complex auto-immunity in children. Here we report manifestations docu-mented in seropositive patients younger than 18 years.

Methods

We identified 12 patients younger than age 18 years whose serum IgG

immunoprecipitated VGKC complexes solubilized from brain tissue.

Seven were among 252 Mayo Clinic patients tested on a service basis

for serologic evidence of neurologic autoimmunity (June 2008 to April

2010), and another 4 were identified during the assay’s preimplementation

validation (before June 2008); we additionally included 1 non–Mayo pa-

tient for whom clinical information was available. Clinical information for

Mayo Clinic patients was obtained by retrospective chart review. The

study was approved by the Mayo institutional review board.

Contemporary evaluation of pediatric patients suspected to have neuro-

logic autoimmunity includes, in the Mayo Neuroimmunology Laboratory,

radioimmunoprecipitation assays to detect cation channel autoantibodies

(voltage-gated calcium channels [P/Q-type and N-type] and a-dendro-

toxin-sensitive potassium channel complexes; nicotinic acetylcholine re-

ceptors [muscle-type and neuronal ganglionic-type]) and glutamic acid

decarboxylase-65; enzyme-linked immunosorbent assay to detect skeletal

muscle striational autoantibodies, and indirect immunofluorescence (com-

posite substrate of mouse tissues) optimized to detect antineuronal nuclear

autoantibody type 1, collapsin response-mediator protein 5 IgG [19,20],

Purkinje cell cytoplasmic autoantibody type 2 [21], N-methyl-D-aspartic

acid receptor, and other autoantibodies reactive with hippocampal or basal

ganglionic synaptic proteins [22].

Autoantibodies reactive with neuronal VGKC complexes are identified

by radioimmunoprecipitation with digitonin-solubilized porcine brain

synaptic membrane proteins ligated with 125I-a-dendrotoxin, which binds

with high affinity to Kv1.1, 1.2, and 1.6 VGKCs [7,15]. The normal value

range is 0.00 to 0.02 nmol/L. False positive binding of 125I-a-dendrotoxin

is excluded [23].

Results

We identified 12 patients younger than age 18 yearswhose autoantibodies bound to VGKC complexes. Eightwere identified through service evaluation for serologicmarkers of neurologic autoimmunity (June 2008-April2010). In none was testing for VGKC autoantibody specif-ically requested by the physician. Four more were identi-fied through additional testing based on clinical suspicionduring the assay’s preimplementation validation. Elevenwere assessed at Mayo Clinic, and clinical informationfor the 12th patient was obtained by contacting the pa-tient’s physician. Before serologic testing was considered,

278 PEDIATRIC NEUROLOGY Vol. 44 No. 4

all children had undergone extensive diagnostic studies, asindicated by the clinical history, to exclude metabolic andgenetic disorders. Demographic and clinical characteristicsof the children are listed in Table 1.

Demographics

Eight of the 12 patients were girls; 11 were Caucasian; 1was Asian. Median age at symptom onset was 7.5 years (8months to 14 years).

Clinical Presentation

Before the onset of neurologic symptoms, 5 patients hada prodrome of fatigue, upper respiratory symptoms, and fe-ver. Neurologic manifestations in all cases were multifocaland subacute in onset (manifesting over weeks). The dura-tion between onset of neurologic symptoms and detectionof VGKC antibodies ranged from <1 month to 6 years. Di-agnosis was delayed because an autoimmune etiology wasnot suspected. Three patients manifested global develop-mental regression, and 1 had autistic features. Six patientshad movement disorders, including chorea (2), dystonia(1), myoclonus (2), tremor (1), motor tics (1), and cerebel-lar ataxia (1). Four patients had dysarthria. Two patientshad prominent insomnia. Three patients had seizures, 1with limbic encephalitis and 2 with new-onset symptom-atic generalized epilepsy. Several patients had evidenceof peripheral or autonomic nervous system involvement:1 peripheral nerve hyperexcitability with painful musclespasms (diagnosis, Satoyoshi syndrome), 1 painful redfeet, 2 gastrointestinal dysmotility, and 2 small fiber neu-ropathy. The only child who had typical symptoms of lim-bic encephalitis was an 8-year-old Caucasian girl (patient10) who experienced subacute onset of seizures, chorea,hyperkinetic dysarthria, and insomnia after a prodromeof sore throat and fever. Serum sodium was low (126mEq/L), suggesting hypothalamic derangement. Magneticresonance imaging of the brain demonstrated increased T2

signal in the amygdala and mesial temporal lobes (Fig 1).

Autoimmune Serology and Family History

The median value for VGKC immunoprecipitation was0.19 nmol/L (range 0.05-1.42 nmol/L; normal range0.00-0.02 nmol/L). None of the patients had a personal his-tory of autoimmune disorders, but 4 had serologic evidenceof autoimmunity: 2 had antinuclear antibody, 1 had anti-neuronal nuclear autoantibody type 1 (positive at end pointdilution 1: 3,840; normal value is negative at 1:240), and 2had striational antibody (positive at 1:120 and 1:240; nor-mal value is negative at 1:60). A family history of autoim-munity was documented in 7 patients (Table 1).

Cerebrospinal Fluid Findings

Cerebrospinal fluid was obtained from 6 patients. Theinterval between onset of neurologic symptoms and perfor-mance of the cerebrospinal fluid tap ranged from 1 monthto 3.5 years (Table 1). Nucleated cell numbers were nor-mal, but protein was elevated in one.

Neoplasia

We found a single neoplasm (neuroblastoma at the liverhilum) in 1 of 5 patients (patient 12) who underwent exten-sive evaluation for malignancy (computed tomographicscan of chest, abdomen, and pelvis; metaiodobenzylguani-dine scan; whole-body positron emission tomography).The patient had cerebellar ataxia, dysarthria, and periodicmyoclonus, and was seropositive for antineuronal nuclearautoantibody type 1.

Treatment

Seven of 12 patients received one or more immunother-apies, including intravenous and oral corticosteroids,intravenous immune globulin, plasma exchange, 6-mercap-topurine, cyclophosphamide, andmycophenolate mofetil. Inall cases, the therapy was acute (6 corticosteroids, 5 intrave-nous immune globulin, and 2 plasma exchange); 5 of 7patients received combination treatment. Corticosteroid-sparing agents were introduced in 3 patients (6-mercaptopu-rine, cyclophosphamide, and mycophenolate mofetil). Thetreating physicians reported mild symptom improvementsin 2 (decreased frequency of seizures in 1; muscle spasmsin 1), moderate in 3 (decreased frequency of seizures in 1;improvement in gastrointestinal motility and dysarthria in1; improved communication skills in 1) and marked in 2(resolution of limbic symptoms in 1; resolution of cerebellarataxia and dysarthria in 1). Neurologic symptoms disap-peared after neuroblastoma resection in the patient whowas positive for antineuronal nuclear autoantibody type 1.Themedian interval between symptom onset and start of im-munotherapy was 2.4 years (range 1 month to 6 years). Im-munotherapy was commenced within 4 weeks of symptomonset in both patients whose symptoms improved markedly.Relapses occurred after cessation of immunotherapy in 3 of6 patients. One patient (patient 10; Table 1) had not re-

sponded to initial plasma exchange (5 treatments), but im-proved remarkably after intermittent high-dose oralcorticosteroid therapy was commenced. Recovery was com-plete 3 months later. In the next 2 years, while receivingmonthly IV corticosteroid maintenance therapy, she experi-enced a single relapse when corticosteroid cessation was at-tempted. Seven years after symptom onset (and aftercorticosteroids had been withdrawn from the patient for 5years), she had no recurrent neurologic problems, and noVGKC complex-reactive autoantibody was detectable. Inpatient 11, the serum antibody level fell progressively duringintravenous immune globulin treatment (from 1.42 to 0.78nmol/L) but, after the family’s decision to stop treatment,it rose (to 2.17 nmol/L), and developmental and social skillsregressed.

Discussion

VGKC complex-reactive autoantibodies are an underap-preciated biomarker of autoimmune neurologic disease.They are at this time the most common of neural autoanti-bodies identified in adult patients evaluated for paraneoplas-tic autoimmunity in the Mayo Clinic NeuroimmunologyLaboratory, being found in 3%of sera submitted for compre-hensive testing [24]. By comparison, the detection frequen-cies of antineuronal nuclear autoantibody type 1 (‘‘anti-Hu’’), collapsin response-mediator protein 5 IgG, andvoltage-gated calcium channel autoantibodies (P/Q-typeandN-type) are 0.3%, 0.3%, and 1%.This study has revealeda similar high frequency ofVGKCcomplex-reactive autoan-tibodies (2.7%) in pediatric patients. Thus the newly recog-nized neurologic entity of VGKC complex autoimmunityseems not to be rare in children. Its clinical spectrum in pe-diatric patients is likely broader than presently recognized.

It was recently established that VGKC proteins per se aregenerally not the antigenic target of these autoantibodies.Nevertheless, radioimmunoprecipitation remains the opti-mal screening assay to detect VGKC complex antibodies.Twomajor proteins that have been identified as primary an-tigens coprecipitate as complexes with 125I-a-dendrotoxin-ligated VGKCs in radioimmunoprecipitation assays. Theseare the secreted leucine-rich, glioma inactivated 1 (Lgi1)protein (associated with limbic encephalitis) andcontactin-associated protein 2 (Caspr2) (associated withneuromuscular hyperexcitability) [13,14]. Lgi1 binds toand bridges presynaptic disintegrin and metalloproteinasedomain-containing protein 23 (ADAM23) and postsynapticADAM22 protein forming a trans-synaptic complex withpresynaptic Kv1.1 channels. Caspr2 colocalizes withKv1.1 and Kv1.2 in paranodal axons and hippocampus.The clinical heterogeneity of VGKC complex autoimmu-nity may reflect different VGKC-associated antigenic tar-gets (such as Lgi1, Caspr2), different epitopes on theseproteins, or as yet unidentified VGKC-complexed proteins.

The spectrum and severity of neurologic manifestationsof VGKC complex autoimmunity remain to be determined.It is conceivable that milder, spontaneously remitting

Dhamija et al: VGKC Neurologic Autoimmune Spectrum 279

phenotypes may exist. Our experience to date documentsa diversity of clinical presentations in children who haveVGKC complex autoimmunity, and it justifies early test-ing for serologic markers of autoimmunity in childrenmanifesting any subacute neurologic disorder of unknowncause. In all but 2 of the presented cases, the diagnosiswas delayed because an autoimmune pathogenesis wasnot considered earlier. Investigation in larger case seriesis needed to ascertain the frequency of the unprecedentedassociations that we noted with developmental delay orregression, autism, and Satoyoshi syndrome. A personalor family history of autoimmunity, seropositivity fororgan-specific or non-organ-specific autoantibodies, ora prodromal ‘‘viral’’ illness should raise a suspicion forneurologic autoimmunity. The young age of the patientsin our study likely explains their lack of a personal historyof autoimmunity. Follow-up through adulthood is neededto establish this association. Neoplasia was detected inonly 1 patient in this initial series of pediatric cases.That patient was additionally seropositive for antineuronalnuclear autoantibody type 1, a recognized marker of neu-roblastoma [25]. The frequency of cancer in children sero-positive for VGKC complex autoantibodies has not yetbeen determined, but in adult patients it is 33% [15].Thus an occult neoplasm should be considered in pediatricpatients.

Conclusion

Treatment was started within 4 weeks of symptom onsetin both of the patients who had greatest recoveries. Promptand aggressive immunomodulatory therapy is therefore ad-vocated, but there is no definitive evidence-based approachto treating VGKC complex autoimmunity. Therapeuticapproaches reported to be beneficial in adult patients in-clude plasmapheresis, corticosteroids (oral and intrave-nous), and intravenous immune globulin in combinationwith corticosteroid-sparing immunosuppressant medica-tions [26]. For initial therapy of adults and children, werecommend pulse corticosteroids in high dose (IV methyl-prednisolone, 1 g or 30-50 mg/kg, for 5 days), and forpatients who cannot tolerate the adverse effects of cortico-steroids, who have diabetes, or who are at risk for diabetes,we recommend intravenous immune globulin (0.4 g/kgdaily for 3-5 days). Plasmapheresis (total of 5-7 exchanges,provided on alternate days) is usually reserved for patientswho cannot tolerate either corticosteroids or intravenousimmune globulin. On the basis of our experience to date,we recommend that the child be re-evaluated for objectiveevidence of improvement after the first 6 weeks of therapy.A favorable response justifies use of a corticosteroid-sparing agent (e.g., oral azathioprine or mycophenolatemofetil). Rituximab or intravenous cyclophosphamidemay be options if these initial approaches are not beneficialor if relapses occur after treatment [26]. Larger studies areneeded to better define the optimal type, dose, and durationof immunotherapy.

280 PEDIATRIC NEUROLOGY Vol. 44 No. 4

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