AQP4‐IgG positive paraneoplastic NMOSD: A case report and review

Abstract Introduction Neuromyelitis optica spectrum disorder (NMOSD; also known as Devic syndrome) is a clinical syndrome of central nervous system characterized by immune mediated attacks of acute optic neuritis and myelitis. Paraneoplastic neurological syndrome is a group of nervous system disorders resulting from the remote immune effects of malignant neoplasm. NMOSD occurs mostly in young people, and tumor is not a common cause, especially recurrent tumor. Methods We reported a case of a 59‐year‐old man who developed anti‐aquaporin‐4 IgG positive longitudinally extensive myelitis. We also summarized and analyzed previously reported cases of paraneoplastic NMOSD. Results Among these 43 patients, 88.4% patients are female. The largest number of patients is between 60 and 69 years old. Breast cancer and lung cancer are the most common types. The most common lesions were located in the cervicothoracic region with patchy gadolinium enhancement. The existing treatment can only delay rather than stop the progress of the disease. Conclusion It is necessary to perform tumor screening in patients with NMOSD, especially patients over 50 years.


INTRODUCTION
In 1894, Devic and Gault pioneeringly described the clinical characteristics of neuromyelitis optica (derived from neuro-myélite optique aiguë)-optic neuritis (ON) and acute transverse myelitis, which makes it also known as Devic syndrome (Devic, 1894). With further understanding of clinical, radiological, and immunological characteristics of neuromyelitis optica spectrum disorder (NMOSD), especially aquaporin-4 (AQP4) antibody, NMOSD as an independent central nervous system disease has attracted more and more attention (Lennon et al., 2004). Longitudinally extensive myelitis (LETM), ON, and/or peripheral or central nervous system and in different forms (Yi & Park, 2020). With the increase of AQP4-positive paraneoplastic NMOSD cases being reported, whether the occurrence of NMOSD is related to the origin of tumor, and whether cancer screening is needed when NMOSD is suspected have become the concern of clinicians. The central theory of autoimmunity postulates that "onconeural antigen(s)" expressed by tumor have the same characteristics as the antigens expressed by neurons. This allows antibodies produced against tumor surface antigens to attack neurons, leading to paraneoplastic neurological symptoms. However, some studies have shown that these "onconeural antigen(s)" only have a weak immune effect on the central nervous system, which is not enough to cause serious damage, so the underlying mechanism of paraneoplastic neurological diseases still remain poorly understood (Dropcho, 2005). However, the early diagnosis of paraneoplastic NMOSD is of great significance for the prognosis of the disease. Herein, we reported a case of AQP4-positive paraneoplastic NMOSD with recurrent rectal cancer and performed a retrospective analysis of previously reported cases and review articles.

CASE PRESENTATION
A 59-year-old male patient presented to hospital with recurrent parox- analysis and the results were given in Table 1 for 3 days, 500 mg for 3 days, 240 mg for 3 days, and 120 mg for 3 days).
After these series of treatment, the serum AQP4 antibody was still positive, but the titer was significantly lower than before. When the patient was discharged, the muscle strength of both upper extremities was grade 5, the left lower extremity was grade 3, and the right lower extremity was grade 0, which was better than the most serious condition but the patient was still unable to live without the wheelchair. Our study was approved by the Ethics Committee of The First Hospital of Jilin University.

METHODS
Two independent reviewers conducted an independent search about the paraneoplastic NMOSDs up to November 2020 on PubMed databases using predefined medical subject headings (MeSH), such as paraneoplastic, cancer, and NMOSD. All studies reporting cases of AQP4 positive paraneoplastic NMOSD were included in Table S1 and used for the quantitative analysis (Table 2

RESULTS
In our analysis, 43 AQP4-positive paraneoplastic NMOSD patients have been included and reported in Tables 2 and S1. The median age is 50 years old. Among these 43 patients, 38 (38/43, 88.4%) patients are female and five (5/43,11.6%) patients are male. The largest number of patients was between 60 and 69 years ( Figure 3).
By analyzing the types of tumors in these patients, 19 kinds of tumors were found, involving almost all systems of the human body.
One person was reported with three kinds of tumors (Pittock & Lennon, 2008 still had NMOSD after tumor surgery (Beauchemin et al., 2018;Bernard-Valnet et al., 2019;Cai et al., 2016;Etemadifar et al., 2019;Figueroa et al., 2014;Yang et al., 2014;Yuan et al., 2019) and three showed tumor recurrence or metastasis with 3 or 4 years interval between tumor therapy and NOMSD. (Figueroa et al., 2014;Yang et al., 2014;Yuan et al., 2019; Table 3). Two of these six patients relapsed after the first course of NOMSD, and both were with a history of thymoma (Beauchemin et al., 2018;Yang et al., 2014; Table 3). The existing treatment can only delay rather than stop the progress of the disease.

DISCUSSION
In our case, the patient was mainly clinically characterized by myelitis.
MRI showed myelitis of more than three spinal segments, and serum  We observed refractory hyponatremia in our patient. Hyponatremia is a common electrolyte disorder in patients with neurological disorders and has also been reported in patients with NMOSD (Pu et al., 2015). In NMOSD patients, syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia, accounting for about 14.6%-16% (Iorio et al., 2011;Pu et al., 2015).The hypothalamus is the area of high expression of AQP4. Immune-mediated hypothalamic supraventricular nucleus and paraventricular nucleus lesions can lead to abnormal secretion of antidiuretic hormone (ADH), thus causing SIADH. Circumventricular organs (CVOs) that are located around the third and fourth ventricles with abundant AQP4 expression are the target of NMOSD.
It plays a number of important functions through its connections with the hypothalamus and brainstem, including the regulation of sodium and water, so CVOs lesion in patients with NMOSD may lead to SIADH. Another cause of hyponatremia is known as cerebral salt wasting syndrome (CSWS), which is caused by neurological disorders that lead to decreased sympathetic nerve signals to the kidneys or increased brain natriuretic peptide in the blood, resulting in excessive sodium excretion from normal functioning kidneys.
Spinal cord injury, a common lesion in NMOSD, can lead to autonomic nervous system damage-sympathetic dysfunction of blood vessels, leading to hypovolemia and hypotension, which promotes the secretion of antidiuretic hormone and increase renal water retention. Retention of renal fluid leads to dilutional hyponatremia.
Furthermore, spinal cord injury can cause damage to descending renal sympathetic nerve pathways that impair renal sodium preservation and water excretion. Therefore, spinal cord injury can lead to the reduction of kidney to retain sodium ions, resulting in CSWS.
In our case, the patient had immunologic spinal cord injury and no abnormality was found in brain MRI. Therefore, the cause of hyponatremia was considered to be spinal CSWS. With the recovery of spinal cord injury, hyponatremia can recover spontaneously, so only supportive treatment was given to this patient. Intractable hyponatremia was corrected 1 month later with the partial recovery of the spinal cord lesion. For the treatment of hyponatremia associated with nervous system diseases, the most important thing is to identify the cause and symptomatic treatment.
AQP4 is an aquaporin protein expressed on the end feet of astrocytes in the brain, spinal cord, and optic nerve, especially in the areas adjacent to the CSF (Rash et al., 1998). As one of the possible mechanisms of morbidity, AQP4-Ab-mediated humoral immunity is gradually accepted by people. As an aquaporin, AQP4 is not only widely expressed in the central nervous system, but also in nonnervous tissues, including skeletal muscle cells, lung airway cells, gut epithelium, gastric parietal cells, kidney collecting duct cells, placenta, glioblastomas, olfactory epithelial cells, and so on (Verkman et al., 2014). AQP4 was found to be highly expressed in a variety of tumor cells including lung cancer and breast cancer and can promote tumor progression, invasion, and metastasis (Li et al., 2016;Warth et al., 2011).
The expression of AQP4 was low in breast cancer and gastric cancer, but high in lung cancer, meningiomas, and thyroid carcinoma (Papadopoulos & Saadoun, 2015). Paradoxically, in our analysis, breast cancer and lung cancer are the most common tumor types in patients with AQP4-positive paraneoplastic NMOSD, which may be associated with their high incidence. In a 10-year retrospective Mayo study of AQP4-positive paraneoplastic NMOSD, 93% of AQP4 -positive patients had symptoms of NMOSD (Pittock & Lennon, 2008). A study from Cleveland Clinic showed the presence of concurrent tumors in 15% of patients with AQP4-positive NMOSD (Ontaneda & Fox, 2014).
Another study showed that 27% of patients with AQP4-positive neuromyelitis optica were diagnosed with cancer shortly before and after diagnosis (Pittock & Lennon, 2008). Also, in this study, two patients with seropositive NMO-IgG antibodies did not show symptoms of NMOSD, but were found to have tumors (one with breast cancer and one with lung cancer; Pittock & Lennon, 2008). In our analysis, 11 patients (Annus et al., 2018;Baik et al., 2018;Beauchemin et al., 2018;Bernard-Valnet et al., 2019;Figueroa et al., 2014;Jin et al., 2019;Kon et al., 2017;Verschuur et al., 2015) performed AQP4 test in tumor tissue and seven of them are positive (7/11, 63.6%; Baik et al., 2018;Beauchemin et al., 2018;Bernard-Valnet et al., 2019;Figueroa et al., 2014;Jin et al., 2019), four of them are negative (4/11, 36.3%; Annus et al., 2018;Kon et al., 2017;Verschuur et al., 2015). The relatively high negative rate could be related to the limited size of tumor tissue sample. It is worth noticing that 74.4% (32/43) of serum AQP4-positive patients did not perform tumor tissue AQP4 test, which should be improved in our future diagnosis process. We believe that the detection of AQP4 antibody in tumor tissue is the most direct method to confirm the origin of serum AQP4 antibody and the etiology of NMOSD. If the serum AQP4 is positive, it is best to do further AQP4 immunostaining of tumor tissue. In NMOSD, the damage caused by AQP4 antibody often occurs around blood vessels, first man-ifested by complement-mediated loss of a large number of astrocytes, followed by the damage of oligodendrocytes and neurons, ultimately lead to demyelination and severe neuronal damage (Jarius et al., 2020).
Unlike other CNS neuroimmune diseases, NMOSD lacks intrathecal antibody synthesis, and the concentration of AQP4 in plasma is more than 500 times than that in CSF, indicating that AQP4 is formed peripherally and enters the central nervous system (Jarius et al., 2010).
And before the morbidity of NMOSD, there are often incentives such as infection, which may temporarily increase the permeability of the blood-brain barrier in the optic nerve or spinal cord, thus promoting the circulation of AQP4 antibodies into the central nervous system (Papadopoulos & Verkman, 2012). Serum AQP4 in four patients were reexamined after treatment, and three of them were AQP4 negative.
One patient was still positive, but the level of AQP4 was decreased.
Serum AQP4 can be used as a means of follow-up and preventing recurrence.
The clinical management of patients with paraneoplastic syndromes usually involves four aspects: recognition of the disease as a paraneoplastic syndrome, identification of the associated tumor, treatment of the tumor, and suppression of the autoimmune response that causes neurologic damage (Dropcho, 2005). Accordingly, we believe that the management of paraneoplastic NMOSD should also include the above four steps. First, clinical characteristics should meet the diagnostic criteria of NMOSD, then the cause screening should be followed. If the diagnosis of paraneoplastic NMOSD is definite, the core of treatment is about the primary tumor, which avoids further deterioration of the disease and is conducive to recovery. Immunomodulatory therapies are also of great significance in addition to cancer therapy. NMOSD treatment includes two steps: acute attack treatment and long-term maintenance treatment (Kessler et al., 2016).
Acute attacks of NMOSD can lead to varying degrees of inflammatory injuries. The purpose of acute treatment is to alleviate the acute inflammatory attack and minimize CNS damage (Kessler et al., 2016).
IVMP is usually the first choice of treatment in the acute phase, plasma exchange and IVIG are used as an escalatory treatment for those patients with inadequate response to IVMP (Bruscolini et al., 2019;Kessler et al., 2016). Maintenance treatment is aimed at better alleviation of symptoms and prevention of recurrence. The immunotherapy mainly includes immunosuppressive drugs in combination with low-dose corticosteroids (Holmøy et al., 2020 Theoretically, there is a possibility that immunosuppression may lead to tumor progression, but there is no clear evidence, and immunosuppression may have some benefits in improving nervous system damage, so there is no consensus on whether immunosuppressive agents should be used in patients with paraneoplastic NMOSD. Paraneoplastic syndromes-associated antineuronal antigens are divided into two types (Höftberger et al., 2015). One exists in nerve cells, and its toxicity is mediated by cytotoxic T cells, often leading to irreversible cell damage or death. Another kind of antigen is located on the cell surface or synapse, which directly mediates nerve injury through direct antigen-antibody reaction. AQP4 is water channel protein widely expressed in the astrocyte cell plasma membrane. AQP4-positive NMOSD could lead to central or peripheral nerve injury by the binding of AQP4-specific autoantibody to APQ4 on the plasma membrane of astrocytes. Therefore, the most direct therapeutic measure is the blocking therapy, that is, to prevent AQP4-specific autoantibodies from binding to AQP4 on astrocyte membranes. This molecule therapy is something to look forward to.

CONCLUSION
Here, we reported a case of AQP4-positive paraneoplastic NMOSD related with recurrent rectal cancer and perform a retrospective analysis of previously reported cases. NMOSD is a female predominance disease with typical onset age in the third to fourth decades of life. For the elderly, NMOSD could just be the presentation in nervous system, indicating some underlying tumors. For the elderly, people at high risk of cancer and patients with poor treatment response, tumors should be suspected as an underlying cause and screened thoroughly. Paraneoplastic syndromes caused by tumor recurrence and metastasis need to be fully considered in patients with a history of cancer and clinical manifestation of NMOSD. Early detection of underlying tumors and combination of surgery and immunotherapy are critical for a good prognosis. More data are needed to further differentiate the characteristics of NMOSD caused by different types of tumors, so as to achieve more targeted cancer screening.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

FUNDING
This work was supported by a grant from the National Natural Science Foundation of China (82071351).

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2282