Accepted Manuscript

ANNA-1/Anti-Hu associated opsoclonus myoclonus and epilepsia partialis continua:

Case report and literature review

Michael Sweeney, MD, Matthew Sweney, MD, M. Mateo Paz Soldán, MD, PhD,
Stacey L. Clardy, MD, PhD

PII: S0887-8994(16)30406-4
DOI: 10.1016/j.pediatrneurol.2016.08.024
Reference: PNU 8981

To appear in: Pediatric Neurology

Received Date: 6 June 2016

Revised Date: 20 August 2016
Accepted Date: 25 August 2016

Please cite this article as: Sweeney M, Sweney M, Paz Soldán MM, Clardy SL, ANNA-1/Anti-Hu
associated opsoclonus myoclonus and epilepsia partialis continua: Case report and literature review,
Pediatric Neurology (2016), doi: 10.1016/j.pediatrneurol.2016.08.024.

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Title: ANNA-1/Anti-Hu associated opsoclonus myoclonus and epilepsia partialis continua: Case report

and literature review

1. Authors: Michael Sweeney MD1, Matthew Sweney MD2, M. Mateo Paz Soldán MD, PhD1, and

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Stacey L. Clardy MD, PhD1Department of Neurology, University of Utah, Salt Lake City, UT

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2. Division of Neurology, Primary Children’s Hospital, Salt Lake City, UT

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Contact Information: michael.sweeney.1@louisville.edu, matthew.sweney@hsc.utah.edu,

mateo.pazsoldan@hsc.utah.edu, stacey.clardy@hsc.utah.edu

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Corresponding Author:

Michael Sweeney, MD, 601 S. Floyd St. Suite 500, Louisville, KY 40202
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Abstract:

Background: Opsoclonus-myoclonus syndrome is a rare clinical condition that has been associated with

neuroblastoma. There are few reported cases of the presence of ANNA-1/anti-Hu antibodies in children

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with neuroblastoma and opsoclonus-myoclonus, all in children less than 3 years of age.

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Methods: We report the new onset of focal seizures without alteration of consciousness and

opsoclonus-myoclonus in an 11-year-old girl with ANNA-1/anti-Hu positivity and a paraspinal

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ganglioneuroblastoma. A systematic review of the literature searching for pediatric cases of ANNA-

1/anti-Hu positivity and malignancy was also performed.

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Results: There were 14 cases identified, 8 of which had opsoclonus-myoclonus. While epilepsia partialis
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continua has been reported in association with several neuronal autoantibodies, association with ANNA-

1/anti-Hu has not been reported.

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Conclusions: This is the first report of epilepsia partialis continua in a pediatric patient with ANNA-
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1/anti-Hu antibodies and neuroblastoma. Testing for anti-neuronal antibodies should be considered in

children presenting with either opsoclonus-myoclonus or atypical epilepsy suggestive of epilepsia

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partialis continua.
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Keywords: opsoclonus-myoclonus, epilepsia partialis continua, antineuronal nuclear antibody, type 1

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(ANNA-1), anti-Hu, neuroblastoma

Abstract Word Count: 155

Article Word Count: 1402

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Introduction

Opsoclonus-myoclonus syndrome is a clinical syndrome consisting of involuntary, chaotic eye

movements, myoclonus of the limbs, and ataxia. Opsoclonus-myoclonus can be associated with an

underlying tumor: in a series of 105 pediatric patients, 42% were found to have an underlying

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neuroblastoma or ganglioneuroblastoma.1 Neuroblastoma typically occurs in children before age 2 with

more than 97% of cases occurring before age 10.2 Of all children diagnosed with neuroblastoma, only 2-

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3% experience associated opsoclonus-myoclonus syndrome.3

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There are few reported cases of the presence of ANNA-1 (anti-Hu) antibodies in children with

neuroblastoma and opsoclonus-myoclonus syndrome. In a series of 64 children with neuroblastoma, 16

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had opsoclonus-myoclonus, 4 of whom had ANNA-1 antibodies detected in serum.4 Another case series
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of 59 children with opsoclonus-myoclonus syndrome showed that 18 children with neuroblastoma were

sero-negative for ANNA-1, ANNA-2, and PCA-1 antibodies.5

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ANNA-1 positivity in children is very rare and has been described in differing clinical scenarios.
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There is one reported case of a 9 year old male who developed limbic encephalitis with intractable

epilepsy in the setting of ANNA-1 antibodies without the presence of a detectable neoplasm.6 In a case
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series of 10 pediatric patients with limbic encephalitis, a 3 year old female had positive ANNA-1
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antibodies without detected neoplasm.7 There are 4 cases published of children with gastrointestinal

dysmotility symptoms in the setting of ANNA-1 positivity.

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Herein we describe a case of an 11-year-old female with intractable localization-related epilepsy

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and opsoclonus-myoclonus, in the context of a ganglioneuroblastoma and ANNA-1 positivity.

Case Presentation

A previously healthy 11-year-old Hispanic female presented to the emergency department

following a seizure. There was no personal or family history of epilepsy or autoimmunity. Initial routine
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EEG demonstrated focal slowing in the left frontal and right posterior head regions. The following week,

she developed focal jerking of the left face and arm without alteration of consciousness. The face and

arm jerking was initially intermittent but became continuous after a few days, prompting evaluation

with continuous video EEG monitoring. Several brief electrographic seizures originating from the left

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hemisphere were captured. Antiepileptic therapy was initiated with oxcarbazepine. Despite rapid

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titration of oxcarbazepine and addition of levetiracetam, no clinical benefit was achieved.

Her initial evaluation also included brain imaging and spinal fluid analysis. Brain MRI

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demonstrated hyperintense T2/FLAIR signal in the right mesial temporal lobe and left subinsular region

(Figure 1). These abnormal areas did not enhance with contrast administration and there was no

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diffusion restriction. Cerebrospinal fluid analysis demonstrated RBC 0/µL, WBC 17/µL, protein 28 mg/dL,
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and glucose 68 mg/dL. HSV, CMV, EBV, WNV and HHV-6 PCR tests were all negative, as was NMDA

receptor antibody testing.

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The seizures persisted despite one month of antiepileptic therapy with oxcarbazepine and
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levetiracetam. She also developed mild ataxia and opsoclonus. She was again admitted to the hospital,

and additional antiepileptic medications were initiated, including phenytoin (6mg/kg/day) and clobazam
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(1mg/kg/day). A transient improvement in the seizure frequency with the addition of clobazam was
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noted for 2 days, but was not sustained. Repeat cerebrospinal fluid analysis revealed RBC 1/µL, WBC

4/µL, protein 32 mg/dL, glucose 66 mg/dL, 20 unique oligoclonal bands (not initially tested on first
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cerebrospinal fluid examination), and an IgG index of 1.58. While awaiting results of the paraneoplastic
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evaluation, she was treated empirically with prednisone 90 mg PO daily for 2 weeks, followed by a 1

month taper. She was found to have ANNA-1 positivity in the serum (1:7680) and in the CSF (1:1024) on

testing by Mayo Medical Laboratories. Upon completion of the prednisone taper, she was treated with

IVIG (2gm/kg) with some benefit noted in her seizure frequency.

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Following detection of ANNA-1, neoplastic evaluation with spinal MRI showed a nonenhancing

paraspinal mass at the L2-L4 vertebral levels. Biopsy of the mass was consistent with a

ganglioneuroblastoma, nodular subtype (N-MYC not amplified, urine homovanillic acid/vanillylmandelic

acid negative, low mitosis-karyorrhexis index, metaiodobenzylguanidine scintiscan without increased

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uptake). Due to the location of the tumor, full resection was not achieved. She was started on

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chemotherapy (protocol ANBL0532, cyclophosphamide, doxorubicin and vincristine). She subsequently

experienced further decrease in seizure frequency but did not experience full resolution of the epilepsy.

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Despite 6 rounds of chemotherapy, monthly IVIG, and ongoing treatment with 4 antiepileptic therapies,

she suffered persistent focal seizures, primarily involving the left face. Rituximab was added to her

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chemotherapy regimen without clear benefit. After 1 year, she continued with ongoing subtle
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opsoclonus, mild ataxia, dysarthric speech and frequent focal seizures of the left face and hand.
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Review of Reported Cases

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A comprehensive literature search revealed 14 (10 female, 4 male) cases of pediatric patients

with ANNA-1 positivity and associated malignancy, ages ranging from 8 months to 16 years (Table 1). All
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cases were associated with either a neuroblastoma or ganglioneuroblastoma. Of 14 total, 8 experienced

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opsoclonus-myoclonus as part of the clinical syndrome, with only one patient reported to have had a

seizure (not epilepsia partialis continua). Gastrointestinal symptoms were prominent, and were the
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presenting symptom in 4 of the 14 cases.

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Discussion

Opsoclonus-myoclonus syndrome is an immune-mediated neurologic disease, though the

pathophysiology remains unclear. In some patients, it occurs as part of a paraneoplastic syndrome.

Rarely, an anti-neuronal antibody may be detected, most commonly ANNA-1.

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ANNA-1 positivity in children is rare. A study from the French Paraneoplastic Neurologic

Syndrome Reference Center reported 252 cases of ANNA-1 positivity, with only 8 of those cases

occurring in patients less than 18 years old. Six of these subjects presented with a limbic encephalitis in

the absence of a detected neoplasm. The other 2 patients, included in Table 1, presented with

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opsoclonus-myoclonus.8

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In adults, ANNA-1 positivity has been associated most commonly with small cell carcinoma of

the lung.9 In children, ANNA-1 is most frequently associated with neuroblastoma or

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ganglioneuroblastoma. Numerous clinical syndromes involving the central, autonomic and peripheral

nervous systems have been described in association with ANNA-1, commonly including gastrointestinal

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dysmotility, limbic and brainstem encephalitis, sensory neuronopathy and peripheral neuropathy, and
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cerebellar degeneration.10,11 Of the published cases of children with ANNA-1 positivity and tumor, 4 of

the cases reported ileus or severe constipation. These symptoms may predate central nervous system
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symptoms or may occur without evidence of central nervous system involvement. This highlights the
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importance of assessing the autonomic nervous system in patients with possible paraneoplastic disease.

The initial evaluation of the described patient demonstrated evidence of inflammation within
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the spinal fluid. This included the presence of white blood cells, positive oligoclonal bands, and an
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elevated IgG index. Though not specific, these findings, in the setting of new onset seizures, raise

suspicion for an immune-mediated process such as autoimmune epilepsy, paraneoplastic syndrome, or

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acute disseminated encephalomyelitis12. Additional data from neurodiagnostic studies may also increase
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suspicion. A recent study evaluated imaging and electroencephalographic data in pediatric patients with

autoimmune encephalitis. Of 18 patients identified, 56% demonstrated MRI abnormalities within the

limbic structures. Electroencephalographic data was available for 16 patients and was abnormal in 81%

of them. Abnormal findings included an abnormal background rhythm, generalized slowing, focal

slowing, and focal epileptiform discharges. This study identified patients using a chart review of
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encephalopathic patients, potentially missing cases of immune-mediated encephalitis13. The patient

described here lacked evidence of alteration of consciousness, mood or behavior changes, or memory

concerns. This lack of encephalopathy is atypical in encephalitis and likely speaks to the focal CNS

involvement. As such, this patient may illustrate the center of a clinical spectrum between

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paraneoplastic opsoclonus and immune-mediated encephalitis.

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Paraneoplastic symptoms in children with opsoclonus-myoclonus syndrome and neuroblastoma

can be challenging to treat. In the largest published case series of children with opsoclonus-myoclonus

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syndrome, 41 children had a neuroblastoma, and only 37% of them were reported to improve after

tumor resection. In the rest of the children, 32% remained clinically stable and 32% showed worsening.1

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In our case, complete resection of the tumor was not achieved secondary to anatomical location. The
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significance of the residual tissue, from an immunological standpoint, is unclear.

Our patient presented with several unique clinical features. Epilepsia partialis continua has not
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been described in a pediatric patient with ANNA-1 positivity or opsoclonus-myoclonus. In this case,
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seizures and encephalitis preceded the opsoclonus-myoclonus, demonstrating an immune-mediated

process prior to the onset of opsoclonus-myoclonus. Additionally, our patient was 11-year-old at
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presentation, with all previously described cases of opsoclonus-myoclonus syndrome, neuroblastoma

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and ANNA-1 positivity having occurred in children less than 3 years of age. Testing for anti-neuronal

antibodies should be considered in children presenting with either opsoclonus-myoclonus or atypical

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epilepsy suggestive of epilepsia partialis continua.

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Declaration of Conflicts of Interest

The authors declare no potential conflicts of interest with respect to the research, financial

relationships, authorship, and/or publication of this article.

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Author Contributions

MiS was responsible for literature review and manuscript preparation. MPS, MaS, and SC assisted with

manuscript revision.

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Ethical Approval

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This is a case report submission thus no IRB approval was necessary. All patient identifiers were

removed.

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Figure 1: The coronal FLAIR sequence of the brain MRI shows hyperintense T2/FLAIR signal in the right

mesial temporal lobe and in the left subinsular region. Subsequent resolution of the signal change in the

mesial temporal lobe suggests that this may represent acute changes related to ongoing seizures. The

subinsular changes persisted in subsequent MRI studies.

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Table 1: Published cases of ANNA-1 positivity in children with tumors.
Reported Case Age/Sex Tumor Antibody Clinical Features
Titer (serum)
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Antunes et al. 27mo/F Neuroblastoma (stage III) NR opsoclonus-myoclonus

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17mo/M Neuroblastoma (stage III) opsoclonus-myoclonus
24mo/F Neuroblastoma (stage III) opsoclonus-myoclonus
29mo/F Neuroblastoma (stage I) opsoclonus-myoclonus
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Fisher et al. 20mo/F Neuroblastoma NR opsoclonus-myoclonus, seizures,

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hearing loss
Ketterl et al.15 8mo/F Neuroblastoma (stage IV) 1:10,240 opsoclonus-myoclonus
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8
Honnorat et al. 18mo/F Neuroblastoma NR opsoclonus-myoclonus
12mo/F Neuroblastoma opsoclonus-myoclonus
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Mpofu et al. 27mo/F Neuroblastoma NR Myoclonus, hemiplegia
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Drukker et al. 4y/M Neuroblastoma (stage III) 1:51200 Ileus, dysmotility, peripheral
paresthesias
Wildhaber et 14y/F Ganglioneuroblastoma 1:1280 Ileus
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Schobinger- 16y/F Ganglioneuroblastoma 1:1280 Severe constipation
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Clément et al.
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Van Vuurden et 5y/M Neuroblastoma (stage III) 1:51200 Ileus, sensory neuronopathy
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al.
Allen et al.21 9y/M Neuroblastoma (stage I) 1:3840 Ataxia, dysarthria, excessive
blinking (VGKC+0.45nmol/L)
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Key: NR – not reported, VGKC – voltage-gated potassium channel complex

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