Just Accepted by International Journal of Neuroscience

Paraneoplastic Neuromyelitis Optica Spectrum Disorders: Three New Cases and A Review of the Literature Gang Cai, Dian He, Lan Chu, Qingqing Dai, Zhu Xu, Yifan Zhang doi:10.3109/00207454.2015.1054481

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Abstract Neuromyelitis optica spectrum disorders (NMOSD) occasionally develop in patients with tumor in relation to aquaporin-4 IgG (AQP4-IgG), representing a new paraneoplastic phenomenon. We reported three patients with paraneoplastic NMOSD and provided a comprehensive review of the literature. A total of 34 cases with paraneoplastic NMOSD were identified from our own case database (n D 3) and the previous literature (n D 31). The median age at NMOSD-related symptom onset was 50.5 years, and 91% of the cases were female. 11 (32%) cases had breast carcinoma. In 15 (44%) cases, NMOSD-related symptoms preceded tumor detection (median, 3 [range 1–180] months), and in 19 (56%) cases, symptoms followed tumor detection (median, 11 [range 1–96] months). 5/14 (36%) cases had hiccups and vomiting as the initial symptoms, with the involvement of medulla oblongata. In 10/14 (71%) cases, cervical spinal cord was involved. In contrast to idiopathic NMO, NMOSD is more likely to be paraneoplastic than in patients aged over 50 years at the onset of symptoms, especially for female patients. Breast carcinoma is the most common tumor associated with paraneoplastic NMOSD, accounting for nearly a third of all types of tumors. Paraneoplastic NMOSD usually involves medulla oblongata and cervical spinal cord. We recommend adding AQP4-IgG as an onconeural antibody, but its clinical utility warrants further investigations.

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Publisher: Taylor & Francis Journal: Journal of Nuclear Science and Technology DOI: http://dx.doi.org/10.3109/00207454.2015.1054481

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Paraneoplastic Neuromyelitis Optica Spectrum Disorders: Three New Cases and A Review of the Literature

Gang Cai 1, Dian He 1*, Lan Chu 1, Qingqing Dai 1, Zhu Xu 1, Yifan Zhang 1

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Department of Neurology, Affiliated Hospital of Guiyang Medical College * Corresponding author. Address: Department of Neurology, Affiliated Hospital of Guiyang Medical College, No. 28, Gui Yi Street, Guiyang, Guizhou Province, 550004, China. Tel & Fax: +86 851 6812580. Email address: [email protected]

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) occasionally develop in patients with tumor in relation to aquaporin-4 IgG (AQP4-IgG), representing a new paraneoplastic phenomenon. We reported three patients with paraneoplastic NMOSD and provided a comprehensive review of the literature. A total of 34 cases with paraneoplastic NMOSD were identified from our own case database (n = 3) and the previous literature (n =31). The median age at NMOSD-related symptom onset was 50.5 years, and 91% of the cases were female. 11 (32%) cases had breast carcinoma. In 15 (44%) cases, NMOSD-related symptoms preceded tumor detection (median, 3 [range 1-180] months), and in 19 (56%) cases, symptoms followed tumor detection (median, 11 [range 1-96] months). 5/14 (36%) cases had hiccups and vomiting as the initial symptoms, with the involvement of medulla oblongata. In 10/14 (71%) cases, cervical spinal cord was involved. In contrast to idiopathic NMO, NMOSD is more likely to be paraneoplastic than in patients aged over 50 years at the onset of symptoms, especially for female patients. Breast carcinoma is the most common tumor associated with paraneoplastic NMOSD, accounting for nearly a third of all types of tumors. Paraneoplastic NMOSD usually involves medulla oblongata and cervical spinal cord. We recommend adding AQP4-IgG as an onconeural antibody, but its clinical utility warrants further investigations.

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Keywords: neuromyelitis optica spectrum disorders, longitudinally extensive transverse myelitis, optic neuritis, paraneoplastic syndrome, AQP4-IgG, NMO-IgG

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Introduction Neuromyelitis optica (NMO) is an immune-mediated inflammatory demyelinating

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disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord. This disease is clinically characterized by optic neuritis (ON)

seropositivity for anti-aquaporin-4 IgG (AQP4-IgG/NMO-IgG). The term NMO

spectrum disorders (NMOSD) is used to include AQP4-IgG-associated disorders,

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consisting of NMO, limited forms of NMO (idiopathic single or recurrent events of longitudinally extensive myelitis ( ≥ 3 vertebral segment spinal cord lesion seen on magnetic resonance imaging (MRI)), recurrent or simultaneous bilateral ON), asian optic-spinal multiple sclerosis (MS), ON or longitudinally extensive myelitis

associated with systemic autoimmune, and ON or myelitis associated with brain lesions typical of NMO [1]. NMO spectrum disorders occasionally develop in patients with tumor in relation to AQP4-IgG, representing a new paraneoplastic phenomenon.

Since AQP4-IgG was incidentally indentified in serum from patients who were initially suspected to be paraneoplastic subacute multifocal neurological disorders in 2004 [2],

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and acute myelitis occurring simultaneously or consecutively, usually with

patients with NMOSD in a paraneoplastic context have been increasingly concerned. Herein, we report three cases with paraneoplastic NMOSD and provide a comprehensive review of the literature.

Patients and Methods NMO spectrum disorders were defined according to the proposal of Wingerchuk, et al.

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in 2007 [1]. The diagnosis of tumor was confirmed by pathology. All AQP4-IgG-positive cases with NMOSD coexisting with tumor were included. Cases

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were seen between 2011 and 2014 in our own case database. Further cases were identified by searches of PubMed for articles published from January 2004 to February 2015 using the term “(neuromyelitis OR Devic OR myelitis OR optic neuritis) AND

disease characteristics, tumor type, cerebrospinal fluid (CSF) findings, MRI findings,

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coexisting autoimmunity, treatment, and outcomes.

Results

A total of 34 cases with NMOSD were identified, three (9%) from our own case database and 31 (91%) from the existing English language literature. An overview of all patients’ clinical, serological, CSF and MRI findings are shown in Table 1. The

three cases were reported below. All patients signed written informed consent.

Case report

Case 1: A 17-year-old girl with no history of prior neurological disease initially

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paraneoplastic”. We extracted data from the eligible case reports on demographic and

presented a sudden onset of nausea-vomiting episodes and visited a gastroenterology clinic. Disease progressed gradually with the occurrence of bilateral blurred vision, dysarthria, dysphagia, limb weakness, and muscle cramps in the following month. MRI of brain and spinal cord revealed a longitudinally extensive T2 lesion extending from the medulla to the upper cervical spinal cord with no enhancement (Figure 1A).

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Visual evoked potential (VEP) evaluation showed bilateral slowing of conduction referred to a demyelinating process. Pertinent laboratory findings showed a decreased

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serum total triiodothyronine (T3) level and seropositivity for AQP4-IgG (Table 1). She was diagnosed with NMO. After treatment with a 5-day course of intravenous

methylprednisolone 1g daily, followed by oral prednisone 1mg/kg·d, the clinical status

About two weeks later, she returned to the hospital because of recurrence of muscle

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cramps in upper limbs. MRI of cervical spinal cord showed a focal

gadolinium–enhanced lesion at the cervicomedullary junction. Thyroid function was tested again and the total and free T3 were in low levels. Ultrasonography revealed a nodule with calcification in the right thyroid lobe. Following biopsy, papillary thyroid carcinoma was confirmed. She was re-treated with oral prednisone 1mg/kg·d followed by a 2-month taper. During the treatment, she underwent unilateral lobectomy plus isthmectomy with dissection of lymph node in neck central area. Eight months after tapering prednisone, she relapsed with limb weakness and muscle cramps. MRI of the cervical spinal cord revealed multiple focal T2 lesions within upper cervical segments.

After treatment with high-dose intravenous methylprednisolone followed oral

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improved remarkably. However, she discontinued prednisone instead of tapering.

prednisone with slow tapering, the symptoms improved gradually. Low-dose prednisone 20mg daily was administered as maintenance therapy.

Case 2: A 35-year-old man had sudden-onset bilateral visual loss and by day 3 became completely blind. Four years ago, he underwent iodine-131 therapy for

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hyperthyroidism, and the thyroid function was normalized. Ten months ago he was diagnosed with acute myeloid leukemia (AML) subtype M2 and underwent

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chemotherapy (acytarabine, pirarubicin and etoposide) at regular intervals. On ocular examination, his visual acuities were no light perception in both eyes, with a relative afferent pupillary defect. Fundus examinations of the optic disc and retina were

nerves (Figure 1B). Cerebrospinal fluid analysis showed a normal level of white blood

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cells and protein. A bone marrow aspirate disclosed an abnormal immunophenotype

cells of 33.9%. Serum AQP4-IgG was tested and the result was positive (Table 1). He

was diagnosed with bilateral ON associated with recurrence of AML and received a 5-day course of 1g/day intravenous methylprednisolone, followed by a 2-month prednisolone taper, as well as chemotherapy. His vision in the left eye recovered to 0.01, whereas the right eye was unchanged. Six months later, he relapsed with vision deterioration in his left eye to no light perception. Following administration of intravenous methylprednisolone 1g daily for five days, the vision in his left eye recovered to counting finger (CF)/50cm. He was discharged on low-dose prednisone 30mg daily, along with regular chemotherapy as prophylaxis.

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unremarkable. MRI of optic nerves showed swelling and enlargement of bilateral optic

Case 3: A 43-year-old woman with no history of prior neurological disease initially presented to a gastroenterology clinic with intractable hiccup, nausea and vomiting. Within a week of presentation she successively developed diplopia, dizziness, gait ataxia and right-sided facial palsy. Brain MRI revealed a focal T2 lesion at the

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tegmental part of pons. Pertinent laboratory findings revealed seropositivity for AQP4-IgG (Table 1). She was diagnosed with brainstem encephalitis associated with

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AQP4-IgG. Following treatment with intravenous methylprednisolone 1g daily for three days, the above symptoms improved markedly but she developed dysarthria. A subsequent gadolinium-enhanced MRI scan of brain showed a band-like lesion

continued to receive intravenous methylprednisolone 1g daily for two days, followed

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by a 2-month prednisone taper. During the treatment, a painless mass was palpated in her right breast, with axillary enlarged lymph nodes. Following mammography and biopsy, breast carcinoma was confirmed. She subsequently underwent radical mastectomy plus axillary lymph node dissection and chemotherapy (epirubicin,

paclitaxel and cyclophosphamide), and made an excellent recovery within the next few weeks. After tapering of prednisone, no prophylactic treatment was given. She was relapse-free during 3 years of follow-up.

Clinical data

Thirty-one of 34 (91%) cases were female, corresponding to a female: male ratio of

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extending from the ventral mesencephalon to the ventral medulla (Figure 1C). She

10:1. All cases were seropositive for AQP4-IgG. 21 cases met the revised diagnostic criteria for NMO [3], 12 experienced episodes of LETM and one had bilateral ON. Neurological deficits were severe for most cases. The median age at the onset of NMOSD-related symptoms was 50.5 years (range 17-87 years). In 15 (44%) cases,

NMOSD-related symptoms preceded tumor detection (median, 3 [range 1-180]

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months), and in 19 (56%) patients, symptoms followed tumor detection (median, 11

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[range 1-96] months), in four cases, the time interval was not reported by the authors.

Tumor types

Twenty-one patients had carcinoma (11 breast (32%) (present case 3) [4-7], 3 lung (9%)

cervical (6%) [4, 7] and 1 prostate (3%) [11]), 4 had lymphoma (12%)[ 4,7,12], 3 had

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carcinoid tumor (9%) [4, 13, 14], 2 had monoclonal gammopathy (6%) [4], 2 had

ovarian teratoma (6%) [15, 16], 1 had pituitary somatotropinoma (3%) [4], and 1 had acute myeloid leukemia (3%) (present case 2).

CSF findings

CSF data were available in 14 cases, 6 (43%) of whom had a normal protein level and 8 (57%) had an increased level (median, 79 [range 49-125] mg/dL). 12 (86%) had a

normal white blood cell count, and 2 (14%) had pleocytosis. 3 (23%) of 13 patients were positive for oligoclonal bands (OBs).

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[4, 8, 9], 2 thymic (6%) [4, 10], 2 thyroid (6%) (present case 1) [4] and 2 uterine

Brain and spinal MRI findings 31 (91%) of 34 cases experienced LETM. MRI data were available in 14 patients.

Among them, 10 (71%) patients had T2 or gadolinium-enhanced lesions in cervical spinal cord, and 5 (36%) patients presented hiccups and vomiting as the initial symptoms, with the involvement of medulla oblongata. Affected optic nerves usually exhibited swelling and gadolinium-enhancement on MRI.

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Co-existing autoimmunity

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A total of eight cases underwent a screening for the classical anti-neuronal antibodies, one case showed seropositive for type 1 antineuronal nuclear antibody (ANNA-1/ anti-Hu) [10], and one was seropositive for anti-N-methyl-D-aspartate receptor

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anti-nuclear antibodies (ANA).

Treatments

Information about treatment was available in 14 patients, 13 of whom underwent anti-tumor therapies, involving surgical resection, chemotherapy, and radiotherapy. Corticosteroids were the most frequently used medications in treatment of NMOSD. Common practice was to administer high dose methylprednisolone (1g/d) for 5 days, followed by oral steroids with slow tapering. Symptoms were alleviated after treatment with corticosteroids in most patients. Other treatment options included plasma exchange and intravenous immunoglobulin. Azathioprine, cyclophosphamide, cyclosporine A and rituximab were used to prevent relapses.

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(anti-NMDAR) antibodies [16]. In addition, 4 (25%) of 16 cases were seropositive for

Outcomes NMOSD-related symptoms markedly improved after treatment with corticosteroids in patients with breast carcinoma [5, 6], carcinoid [13, 14], ovarian teratoma [15,16], as well as in Case 3. All these patients had a good prognosis after radical treatment,

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except for one patient at advanced stage of breast carcinoma [5]. Disease started or reoccurred with the recurrence or metastasis of tumors in four previous cases [5, 8, 10,

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13], as well as in Case 2. NMOSD-related symptoms reoccurred after removal of tumor in one earlier case [16] and also in Case 1. Three previous cases [13-15], along with Case 3, got relapse-free after radical cure of tumors. Serum AQP4-IgG level

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Discussion

Case 1 had recurrent LETM, as well as simultaneous bilateral ON supported by the results of visual evoked potential. Case 2 had simultaneous bilateral ON and experienced a relapse, leading to a severe residual visual loss. Case 3 presented brainstem encephalitis on a MRI scan at the early stage of the disease and after corticosteroid treatment. Tests for the serum AQP4-IgG resulted positive in all cases. On the basis of these presentations, all patients fulfilled the diagnostic criteria for NMOSD. Of interest, a tumor was detected prior to or after the onset of NMOSD-related symptoms. The presence or recurrence of the tumor and the evidence

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normalized [6] or reduced [12] after immunotherapies and anti-tumor therapies.

of serum AQP4-IgG raised suspicion of paraneoplastic NMOSD. There have been case reports about APQ4-IgG-positive patients with NMOSD associated with breast carcinoma or thyroid carcinoma [4-7], but to our knowledge, the association of acute leukemia with paraneoplastic NMOSD has previously not been reported.

Compared to the sex ratio for idiopathic NMO (female:male 9:1) [1], female

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preponderance is more prominent for paraneoplastic NMOSD. Such preponderance may be attributed to the predominance of breast carcinoma, which accounts for nearly

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a third of all types of tumors. The median age at the onset of NMOSD-related symptom was 50.5 years, by contrast, the median onset age for idiopathic NMO was 39 years [1]. Half of patients with paraneoplastic NMOSD were older than age 50 years, compared

contrast to idiopathic NMO, is more likely to be paraneoplastic in patients aged over

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50 years at the onset of symptoms.

It is reported that the incidence of tumor in patients with NMOSD associated with AQP4-IgG is about 5% [4]. A recent study has shown a higher incidence of 15% [7]. Tumor was seen in 20% of patients aged over 50 years who were AQP4-IgG-positive [7]. By contrast, tumor incidence in patients with multiple sclerosis and clinically

isolated syndrome was much lower (0.8% [18] and 2.9% [19]). There is a similar positive incidence (23%) of OBs in CSF in paraneoplastic NMOSD, compared with idiopathic NMO (15-30%) [1]. Over half of patients with paraneoplastic NMOSD had an increased protein level in CSF, representing a mild inflammatory process. As with

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with only 16% for patients with idiopathic NMO [17]. This suggests that NMOSD, in

idiopathic NMO, paraneoplastic NMOSD usually involves medulla oblongata, presenting hiccups and vomiting as the initial symptoms. An early study revealed aquaporin-4-rich area postrema may be a first point of attack in NMO [20], leading to intractable hiccups and vomiting. Such patients often initially experience a gastroenterologic evaluation.

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Paraneoplastic NMOSD, in relation to AQP4-IgG, is immune-mediated erroneous

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attacks on optic nerves and spinal cord, directed originally against the tumor itself. AQP4 is not only expressed in normal tissues, such CNS, kidney (collecting duct), the stomach (parietal cells), airways, glands, and skeletal muscle [21], but also expressed

microarray analyses have revealed AQP4 protein expression was detected in 3% of

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tumors, involving lung cancer, endometrial cancer, renal cancer and glioma [22].

Aquaporin-4 immunoreactivity has additionally been found to express on tumor cells of breast carcinoma [6], lung carcinoma [9], carcinoid [13], ovarian teratoma [15], and thymoma [23]. AQP4 autoantibodies from serum and CSF of NMO patients bound to AQP4 expressed on cell membrane of thymoma [23] and lung adenocarcinoma [9]. In addition, there are some other evidence to suggest an association of AQP4-IgG with tumors, such as occurrence or reoccurrence of NMOSD accompanying the recurrence or metastasis of tumors [5, 8, 10, 13], freedom from relapse after radical cure of tumors

[13-15], and reduction in serum AQP4-IgG after immunotherapies and anti-tumor therapies [6,12].

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on tumor cells by mature neurons, glia, or muscle as onconeural antigens [4]. Tissue

Tumor-directed immune responses initiated by AQP4 expressing on tumor cells have the potential to target AQP4 in CNS. Disease in CNS could start with the movement of AQP4-IgG from the periphery into the circumventricular organs, where blood–brain barriers might lack, such as the area postrema [20] and the posterior hypothalamus [24],

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or where blood–brain barriers might not be fully developed, such as the prelaminar portion of optic nerve [25] and root entry zones in the spinal cord [26]. Once in the

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CNS, AQP4-IgG causes astrocyte cytotoxicity, initially by complement activation and then by a cascade of inflammatory events such as granulocyte infiltration and then macrophage infiltration, then causes further disruption of the blood–brain barrier,

altered immune status by secreting cytokines, such as interleukin 6 [28], leading to

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patients more susceptible to immune attack.

In general, the prognosis depended crucially on the type and stage of tumors. NMOSD-related symptoms markedly improved after treatment with corticosteroids in patients with benign tumors. Such patients always got an optimal prognosis after surgical resection. In addition, corticosteroids were consistently effective in acute treatment for NMOSD related to breast carcinoma, and those at early stage who had radical treatment could achieve a good outcome.

Of note, there are three kinds of paraneoplastic neurological syndromes mimicking

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oligodendrocyte death, and ultimately neuronal cell death [27]. Moreover, tumor

NMOSD: optic neuropathy and myelopathy associated with collapsin response-mediator protein 5 (CRMP5/anti-CV2) antibodies, myelopathy associated with amphiphysin antibodies, and myelopathy associated with ANNA-1/ anti-Hu. CRMP5 /anti-CV2 antibodies are usually associated with small cell lung carcinoma, thymoma, prostate carcinoma, thyroid papillary carcinoma and renal cancer. The

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relevant case reports were reviewed elsewhere [29], among the patients, serum AQP4-IgG was tested in two cases and the result was negative [29, 30]. Amphiphysin

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antibodies are more likely to present in patients with breast and lung carcinoma [31]. ANNA-1/anti-Hu is recognized as an IgG marker for small-cell lung carcinoma, but also presents in patients with thymoma [10, 32]. Intriguingly, Yang et al. reported a

for both AQP4-IgG and ANNA-1 [10]. In addition, Zoccarato et al. reported a case

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who developed limbic encephalitis followed by NMO, whose serum harbored

anti-NMDAR antibodies and AQP4-IgG [16]. These cases represent a phenomenon of paraneoplastic overlapping syndromes.

Conclusion

In contrast to idiopathic NMO, NMOSD is more likely to be paraneoplastic in patients aged over 50 years at the onset of symptoms, especially for female patients. Breast carcinoma is the most common tumor associated with paraneoplastic NMOSD, accounting for nearly a third of all types of tumors. Paraneoplastic NMOSD usually involves medulla oblongata and cervical spinal cord. We recommend adding

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case of paraneoplastic NMO in the setting of invasive thymoma, who was seropositive

AQP4-IgG as an onconeural antibody, but its clinical utility warrants further investigations.

Acknowledgments We would like to thank Hongyu Zhou and Hongxi Chen, Department of Neurology, West China Hospital, Sichuan University, for their technical assistance.

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Funding

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This work was supported by Guiyang Medical College and funded by Department of Science and Technology of Guizhou Province, China (No. LH [2014] 7134).

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The authors report no conflicts of interest.

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Declaration of Interest

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revealing ovarian teratoma. J Neuroimmunol. 2013; 263:145-7. 16. Zoccarato M, Saddi MV, Serra G, Pelizza MF, Rosellini I, Peddone L,et al. Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis. J Neurol. 2013; 260:3185-7. 17. Collongues N, Marignier R, Zéphir H, Papeix C, Blanc F, Ritleng C, et al. Neuromyelitis optica in France: a multicenter study of 125 patients. Neurology. 2010; 74:736-42. 18. Stich O, Murek C, Rasiah C, Rauer S. Screening for well-characterized paraneoplastic antineuronal antibodies in multiple sclerosis. Int J Neurosci. 2011;121:477-9. 19. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity, socioeconomic status and multiple sclerosis. Mult Scler 2008;14:1091-8. 20. Apiwattanakul M, Popescu BF, Matiello M, Weinshenker BG, Lucchinetti CF, Lennon VA, et al. Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol. 2010; 68:757-61. 21. Verkman AS. Aquaporins in clinical medicine. Annu Rev Med. 2012; 63:303–16. 22. The Human Protein Atlas. Cancer Atlas. http://www.proteinatlas.org/. Accessed December 20, 2014. 23. Chan KH, Kwan JS, Ho PW, Ho SL, Chui WH, Chu AC, et al. Aquaporin-4 water channel expression by thymoma of patients with and without myasthenia gravis. J Neuroimmunol. 2010; 227:178-84. 24. Iorio R, Lucchinetti CF, Lennon VA, et al. Syndrome of inappropriate antidiuresis may herald or accompany neuromyelitis optica. Neurology 2011; 77:1644–46. 25. Hofman P, Hoyng P, vanderWerf F, Vrensen GF, Schlingemann RO. Lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head. Invest Ophthalmol Vis Sci 2001; 42:895–901. 26. Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M. The blood-spinal cord barrier: morphology and clinical implications. Ann Neurol 2011; 70:194–206. 27. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012;11:535-44. 28. Itou J, Tanaka S, Sato F, Akiyama R, Kawakami Y, Toi M. An optical labeling-based proliferation assay system reveals the paracrine effect of interleukin-6 in breast cancer. Biochim Biophys Acta. 2015;1853:27-40. 29. Jarius S, Wandinger KP, Borowski K, Stoecker W, Wildemann B. Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature. Clin Neurol Neurosurg. 2012; 114:331-5. 30. Ducray F, Roos-Weil R, Garcia PY, Slesari J, Heinzlef O, Chatelain D, et al. Devic's syndrome-like phenotype associated with thymoma and anti-CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry. 2007; 78:325-7. 31. Pittock SJ, Lucchinetti CF, Parisi JE, Benarroch EE, Mokri B, Stephan CL, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol. 2005; 58:96-107. 32. Vernino S, Eggenberger ER, Rogers LR, Lennon VA. Paraneoplastic neurological autoimmunity associated with ANNA-1 autoantibody and thymoma. Neurology. 2002; 59:929-32.

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Figure 1. The Findings of Magnetic Resonance Imaging Scan in the Three New Cases. A, Sagittal T2-weighted image of the cervical spinal cord in Case 1. The arrowhead indicates a longitudinally extensive transverse lesion extending from the medulla to the upper cervical spinal cord. B, Horizontal fat-suppressed T2-weighted image of the optic nerves in Case 2. The arrowheads indicate swollen and enlarged optic nerves. C, Sagittal T1 image of the brain postinfusion of gadolinium in Case 3. The arrowheads indicate the area of gadolinium enhancement.

17

Sex

F

M

F

F

F

F

F

Reference

Present case 1

Present case 2

Present case 3

Mueller et al.[5]

Armağan et al.[6]

De Santis et al. [8]

Iorio et al. [9]

72

63

62

63

43

35

Limb weakness and cervical pain

Lumbar and leg pain, followed by bilateral vision loss 3 months later

Nausea and vomiting, followed by band-like chest tightness, weakness and numbness in legs and urinary retention within one month

Paresthesias and leg and arm weakness, followed by a relapse with band-like chest pain, weakness and numbness in legs and urinary retention 15 months later

intractable hiccup and vomiting, followed by diplopia, gait ataxia, facial palsy and dysarthria within 2 weeks

bilateral visual loss progressing to blindness within three days

Neurological Symptoms Age at Onset of NMOSD, y 17 Intractable hiccup and vomiting, followed by blurred vision, dysarthria, limb weakness within one month (+)

(+)

(+)

(+)

(+)

(+)

Brainstem encephalitis

rLETM

LETM

NMO

LETM

Serum AQP4-Ig G (+)

rON

NMO

Neurological Diagnosis

ANA, ANCA, anti-DNA, Smith, SSA, SSB, TPO antibodies (-)

ANA, ANCA, antiDNA, Smith, SSA, SSB, TPO antibodies (-)

ANA, anti-DNA, Smith, SSA, SSB, TPO antibodies (-)

Serum other antibodies

ANA, anti-DNA, ANCA, ENA, ACA, ANNA-1,2, PCA-1, anti- Ma2, CRMP5, amphiphysin(-)

+3

-9

Breast carcinoma

Breast carcinoma

A continuous Gd-enhanced lesion extending from the mesencephalon to the medulla

A hyperintese T2 lesion extending from C5 to T10 with patchy Gdenhancement at T6-T9

WBC normal, protein 125 mg/dL, OBs (-)

18

Onconeural antibodies (-)

Mastectomy chemotherapy IV MePDNL , DXM, oral PDN gamma knife surgery

IV MePDNL, oral PDN Mastectomy, chemotherapy

IV MePDNL , oral PDN, chemotherapy

A hyperintense T2 lesion extending from C2 to C6 with patchy Gd-enhancement.

A hyperintense T2 lesion extending from thecervicomedullary junction to T1, without

IV MePDNL , oral steroid, AZP, mastectomy chemotherapy, CTX IV MePDNL , PE, chemotherapy

IV MePDNL, PE, radiotherapy

+2

+3

-3

Breast ductal carcinoma

Non-small cell carcinoma.

Acinar lung adenocarcino ma

PscT rE ip tD

-10

Acute myeloid leukemia (M2)

Swelling and enlargement of bilateral optic nerves

Improvement of limb weakness

No improvement, died after 10 months of diagnosis.

Remarkedly improved. Serum AQP4-IgG normalized

Rapidly improved, no further relapses , but died 6 months after presentation of metastasis

Fully recovered, no further relapses

Slightly improved, relapse 8 months later

Treatments Outcomes Time interval, m* +1 IV MePDNL , oral Partially PDN, thyroidectomy improved, relapse 10 months later

Papillary thyroid carcinoma

Tumors

A hyperintese T2 lesion at the medulla and C1-C2, without enhancement

MRI Findings

ANA, anti-DNA, ANCA, Hyperintense T2 lesions WBC normal, at C5–C6, C7 and T1, protein 65 mg/dL, ANNA-1,2, anti-Ma2, T2, Gd-enhanced lesions CRMP5, PCA-1, OBs (+) at both optic nerves amphiphysin (-)

WBC normal, protein78 mg/dL, IgG index 0.72, OBs(-)

WBC 9/μl, protein ANA, ANNA-1,2,3, 86mg/dL, OBs (-), PCA-1,Tr, anti-AchR, IgG index normal VGCC, CRMP5, amphiphysin(-),

WBC and protein normal

WBC and protein normal

WBC and protein normal

CSF Findings

Table 1. Clinical and Paraclinical Findings in Patients with Paraneoplastic Neuromyelitis Optica Spectrum Disorders

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57

F

F

F

F

F

NakayamaIchiyama et al.[12]

Figueroa et al.[13]

Al-Harbi et al.[14]

Frasquet et al. [15]

Zoccarato et al. [16]

50

42

38

48

87

M

Kitazawa et al.[11]

55

F

Yang et al. [10]

Painless left-sided partial vision loss, followed by bilateral leg weakness, ascending paresthesias, and decreased sensation 3 months later

Progressive paresthesia in the chest and weakness in the lower limbs.

Impaired gait and paraplegia, followed by left-sided visual loss nine months later

Hiccups and vomiting, paresthesia in the upper chest, followed by urinary retention, severe weakness in both legs three weeks later

Severe vomiting, vertigo, blurred vision, diplopia, ataxic gait and left-sided numbness

WBC and protein ANNA-1(+), ANNA-2, normal, OBs(-) PCA-1, anti-AchR, CRMP5, recoverin, anti-DNA, ACA, ANA and ANCA (-)

enhancement

(+)

(+)

(+)

(+)

(+)

(+)

(+)

NMO

NMO

LETM

NMO

NMO

LETM

NMO

No data

ANA, ANCA,anti-SSA, SSB(-)

Small-bowel neuroendocri ne tumor .

A hyperintense T2 lesion extending from C6 to T4 with focal patchy Gdenhancement and cord swelling at T3-T4

-72

+2

+1

-12

Type I gastric carcinoid

Mature cystic ovarian teratoma

Ovarian teratoma

An Gd-enhanced lesion extending from the medulla to C2

A hyperintense T2 lesion extending from the lower brainstem to the conus medullaris with patchy Gdenhancement

Multiple T2 lesions in the pons, hypothalamus, medulla oblongata, and cervical spine

ANA, ANCA, anti-thyroid, onconeuronal and NMDA-R antibodies (-)

19

Hystero-adnexecto my, PE, steroids, AZP

Adnexectomy, IV MePDNL, PE, IVIG , rituximab

IV MePDNL , IVIG, PDNL, AZP, gastric ablation

IV PDNL, PE, artery radioembolization rituximab

Markedly improved

Fully recovered, no further relapses during one-year follow-up

Markedly improved, with no recurrence on prolonged follow up

Myelitis improved, no further episodes of leg weakness during 30-month follow-up

oCord swelling and lesion decreased, Sserum AQP4-IgG level reduced

Followed IV MePDNL, LETM BTM, rituximab, CTX , PDNL, chemotherapy

Myelitis improved, visual acuities deteriorated

Visual acuity improved partly, no improvement in myelitis

Thymectomy, Chemoradiotherapy, IV MePDNL oral PDNL, CYA , AZP

Preceded IV MePDNL NMO

-72

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Mature B-cell lymphoma

Prostate adenocarcinoma

A hyperintense T2 lesion extending from C5 to T4

Gd-enhanced lesions at bilateral optic chiasm and at T6-T10

Invasive thymoma

ANA, ANCA,ACA anti-DNA, SSA, SSB, ANNA-1,2, CRMP5, Ma2, amphiphysin(-)

WBC, IgG index NMDA-R antibody (+), ANNA-1,2, CRMP5, normal, protein 84mg/dL, OBs (-) Ma2, PCA-1, VGCC amphiphysin(-)

WBC normal, protein 80.5 mg/dL, OBs(+)

WBC, protein normal

ANA (+), anti-DNA WBC, protein, IgG index normal, (+), anti- Smith(+), lupus anticoagulant (+), OBs (-) anti-AchR (+), ANNA-1, anti-CRMP5, amphiphysin (-)

WBC 44/μl, protein 49mg/dL, OBs(-)

WBC, IgG index normal, protein 55mg/dL, OBs(-)

A hyperintese T2 lesion extending from T3 to T11 and Gd-enhanced lesions at both optic nerves.

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Progressive bilateral visual loss, followed by a relapse with paraplegia and hiccups 3 months later

Progressive vision loss in the right eye, followed by two relapses with vision loss in the left eye and lower limb weakness and hypesthesia within about 27 months

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F (5)

Ontaneda et al.[7]

30 to 64

18 to70

No data

No data

(+)

No data

No data

NMO

(+)

OBs (+) in one of ANA (+) in three of five three cases cases

cSe pTt eAd CM Can Eu

NMO, LETM, rLETM

LETM

LETM

-96 to +180

-15 to +6 Breast carcinoma (3), et al. ‡

Breast carcinoma (5), et al. † No data

No data

No data

No data

20

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AQP4, anti-aquaporin-4; ANA, anti nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibodies; ACA, anti-cardiolipin antibodies; AchR, acetylcholine receptor; ANNA, anti-neuronal nuclear autoantibody; AZP, azathioprine; BTM, betamethasone; CRMP5, collapsin response mediator protein 5; CTX, cyclophosphamide; CYA, cyclosporine A; DXM, dexamethasone; ENA, extractable nuclear antigen; Gd, gadolinium; IV, intravenous; IVIG , intravenous immunoglobulin; LETM, longitudinally extensive transverse myelitis; MePDNL, methylprednisolone; NMO, neuromyelitis optica; NMOSD, NMO spectrum disorders; NMDA-R , N-methyl-D-aspartate receptor; OBs, oligoclonal bands; PCA, purkinje cell autoantibody; PE, plasma exchange; PDNL, prednisolone; PDN, prednisone; rON, recurrent optic neuritis; rLETM, recurrent LETM; SSA/SSB, Sjoren’s syndrome antigen A or B; TPO, thyroperoxidase; VGCC, voltage gated calcium channel; WBC, white blood cells. * Time interval indicates time from onset of NMO or LETM to tumor detection; negative value indicates tumor was diagnosed first. † Other tumors included: B-cell lymphoma (2), lung carcinoma (1), thymic carcinoma (1), cervical carcinoma (1), thyroid carcinoma (1), carcinoid tumor (1), pituitary somatotropinoma (1), and monoclonal gammopathy (2). ‡ Other tumors included cervical carcinoma (1) and small lymphoctic ymphoma (1).

F(14) M(1)

Pittock et al.[4]

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Paraneoplastic neuromyelitis optica spectrum disorders: three new cases and a review of the literature.

Neuromyelitis optica spectrum disorders (NMOSD) occasionally develop in patients with tumor in relation to aquaporin-4 IgG (AQP4-IgG), representing a ...
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