Clinical Analysis of NMOSD with Area Postrema Syndrome as Initial Symptom

Objective: Patients with neuromyelitis optica spectrum disease (NMOSD) with the initial manifestation of area postrema syndrome (APS) often have unexplained nausea and vomiting and are easily misdiagnosed for the NMOSD. The purpose of this study was to report and discuss clinical analysis, including diagnosis and treatment of 4 cases of NMOSD with APS as the rst symptom. Methods: Four patients with intractable nausea and vomiting were selected for the analysis and nally the cases were conrmed for the NMOSD. All of these patients started with misdiagnosis and mismanagement initially. Results: Among the 4 patients included in this study, 3 were admitted to the department of gastroenterology at the onset of the disease, and 2 of them were not correctly diagnosed and treated on time due to misdiagnosis. Therefore, their symptoms worsened, and they needed to be transferred to ICU for life support. No obvious early medulla lesions were found in one patient. One patient was treated with intravenous immunoglobulin, methylprednisolone, and plasma exchange but there was no signicant clinical improvement, and then the disease was relapsed during the treatment with low-dose rituximab. Conclusion: The clinical manifestations of NMOSD are complex and diverse, and the initial symptoms, onset age of the patient, and MRI ndings can all inuence the clinicians' judgment of the disease. Early identication of the APS and timely therapy can prevent visual and physical disabilities, even respiratory failure and cardiac arrest. Therefore, it is necessary to identify specic and sensitive serum and imaging markers for predicting the prognosis and recurrence of the disease.


Introduction
Neuromyelitis optic spectrum disease(NMOSD) is an immune-mediated in ammatory demyelinating disease of the central nervous system. The typical clinical manifestations are mainly Optic neuritis(ON) and Longitudinally extensive transverse myelitis(LETM). Area postrema syndrome(APS) is relatively rare among the clinical symptoms of NMOSD, and is often presented as nausea and vomiting of unknown cause, which is easy to be misdiagnosed clinically. We retrospectively analyzed the clinical data of 4 patients with NMOSD with the onset of area postrema syndrome, and discussed the pathogenesis, clinical characteristics, diagnosis and treatment of NMOSD, in order to improve clinicians' understanding of this disease and reduce misdiagnosis and mistreatment of patients.

Study population
The current 4 cases are among the 54 patients with AQP4-IgG-positive NMOSD diagnosed in our hospital between 2018 and 2021. We found 5 patients initially presenting with APS, but excluded 1 patient with incomplete medical records. 4 patients included in the study met the 2015 international diagnostic criteria. These diagnoses were made independently by three experienced neurologists. All 4 patients agreed to the publication of their anonymized clinical data.

Data collection
We reviewed the patients' medical records, collecting data including demographic, clinical, laboratory, and magnetic resonance imaging (MRI) data, As well as INVH duration, department of rst visit, time interval from INVH to the development of core NMOSD syndrome, and other core NMOSD features such as acute diencephalon, acute brainstem, symptomatic brain syndrome, and optic neuritis and acute myelitis.

Case records
Case1 A 31-year-old female patient developed nausea and vomiting of unknown cause more than a month before admission. She was hospitalized in three hospitals, and was diagnosed as "re ux esophagitis and chronic gastritis" by gastroscopy, but the antiemetic treatment was ineffective. Fever and psychiatric symptoms occurred during the period. After taking antipsychotics 4 days before admission, she developed unconsciousness without convulsions, which lasted for more than 10 hours. After waking up, she felt numbness and weakness in limbs, unable to lift, dyspnea, urination and defecation di culties. After being transferred to ICU of our hospital, MRI plain scan of brain and neck showed multiple abnormal signals in the spinal cord from the medulla oblongata to L1 level, and scattered abnormal signals in bilateral hypothalamus, dorsal pons and medulla oblongata (Fig 1). The serum AQP4-IgG was positive for the rst time and was diagnosed as NMOSD. She accepted Intravenous methylprednisolone (IVMP) was treated with Intravenous immunoglobulin (IVIg) after the rst dose reduction, followed by 3 plasma exchange. One month after admission, the patient received continuous 4 weeks of low-dose rituximab treatment. Before the end of the treatment course, the patient developed worsening limb weakness, accompanied by nausea, blurred vision and diplopia. Relapse was considered, and IVIg was given to improve the condition and discharge.
Caes 2 A 62-year-old female patient developed nausea, vomiting, numbness and weakness of the right limb, dizziness and headache 1 month ago after catching cold. She went to our hospital 1 day ago and MRI showed abnormal signals in the right thalamus, paraventricular region and left occipital lobe (Fig 1).
She was diagnosed as cerebral infarction and discharged after treatment. One month later, the patient came to the hospital again due to dizziness and headache, MRI showed that the original lesion was larger than before, but oligoclonal band were negative, and she was discharged from the hospital. Subsequently, she went to the doctor for 2 times due to recurrent nausea and vomiting. In this time, considering the possible presence of APS, the improved AQP4-IgG test in cerebrospinal uid was found to be positive and diagnosed as NMOSD. She was discharged after accepted IVMP. She's been taking mycophenolate mofetil out of the hospital ever since. Case 3 A 23-year-old male presented with intractable nausea and vomiting 1 month ago and was discharged from hospital after treatment for chronic gastritis. One month later, the patient went to the department of Gastroenterology again due to nausea and vomiting. 3 days after admission, nausea and vomiting became worse, accompanied by limb weakness, dizziness, headache and ataxia. MRI of the cervical spine and thoracic spine showed multiple abnormal signal changes in the medulla oblongata, upper cervical medulla (C1-2 vertebral level), and thoracic medulla (T1-2 vertebral level) (Fig 1). The patient was transferred to the Department of Neurology considering neurological diseases. Improved AQP4-IgG test in cerebrospinal uid was found to be positive and diagnosed as NMOSD. 3 days later, the patient suddenly developed disturbance of consciousness, decreased oxyhemoglobin saturation and decreased blood pressure. He was immediately given oral trachea cannula and breathing machine assisted breathing, and then transferred to ICU for treatment. He was discharged after accepted IVMP and IVIg. Two years later, the patient was admitted with diplopia and brain MRI showed a medulla oblongata lesion extending to the right cerebellum. Consider disease relapse and accept IVMP discharged after treatment.
Case 4 A 30-year-old woman was diagnosed with re ux esophagitis in the department of Gastroenterology at another hospital after repeated vomiting for 2 months. Two months later, the patient was admitted to the neurology department due to numbness and weakness of the right limb. MRI of the cervical spine demonstrates abnormal signals at the medulla oblongata to C2 level (Fig 1). The possibility of central nervous system demyelination disease is considered, the patient was treated with IVMP and discharged. 3 years later, the patient reappeared with weakness, Improved AQP4-IgG test in serum was positive. She was discharged after accepted IVMP. She's been taking mycophenolate mofetil out of the hospital ever since.

Patient demographics and clinical characteristics
Among the above 4 cases, 3 were female and 1 was male. The onset age ranged from 23 to 62 years, with an average onset age of 36.5 years. All patients developed intractable nausea, vomiting, or hiccups, and these symptoms were excluded from the combination of other systemic diseases. 3 patients had acute myelitis, 2 had optic neuritis and 3 had acute brainstem syndrome, 2 patients had acute diencephalic syndrome and 2 patients had cerebral syndrome. All 4 patients had typical relapses, and 2 of them still had persistent nausea, vomiting, or hiccups.

Laboratory ndings
Patient laboratory test data is summarized in Table 1-2. Serum AQP4-IgG was positive in all 4 patients.
Two of the three patients tested for AQP4-IgG in CSF were positive. Recurrent hyponatremia occurred in 2 patients, thyroid peroxidase antibody was elevated in all patients, and rheumatoid factor was positive in 2 patients. In the antinuclear antibody test of 4 patients, 2 patients were positive for anti-SSA antibody and anti-Ro52 antibody. PANCA-IgG antibody were found in 1 patients.

MRI ndings
The MRI ndings of the 4 patients in the study are summarized in Table 2. MRI of all patients showed abnormal signals of the dorsolateral medulla oblongata, no obvious early medulla lesions in 1 patient, and, 2 patients had medulla oblongata lesions connected to the cervical spinal cord. During follow-up, progression of cerebellar lesions to the medulla oblongata in 1 patient. MRI showed abnormal signals in diencephalon in 2 patients, and abnormal signals in cerebral hemisphere in 2 patients.

Therapy and EDSS score
Table3-therapy and EDSS score before treatment 4 Discussion Current epidemiological survey data show that the rst onset of NMOSD is mostly in young and middleaged people, mostly in women, and the incidence of NMOSD is higher in African, Asian and Latin American populations than in white populations. Due to the small sample size and different AQP4 antibody detection techniques, the incidence of NMOSD in different regions is still controversial. It is worth a rming that with the maturity of detection technology and the improvement of people's understanding of the disease, the incidence of the disease in various regions of the world is increasing year by year [1,2,3,4]. One study showed that in 100 patients with APS onset NMOSD, women were still more common, and the epidemiological data were similar to other NMOSD patients [5]. NMOSD has the characteristics of high recurrence rate and high disability rate in the course of disease, but the pathogenesis and recurrence factors are not completely clear. Multi-center studies have shown that NMOSD is related to genetics, environment, autoimmune, infection, climate and other factors, and its pathogenesis remains to be further explored [6,7].
In addition to the common optic neuritis and acute myelitis, patients with area postrema syndrome are often prone to missed diagnosis and misdiagnosis. APS can appear as an isolated clinical symptom in the early stage of the disease, often presenting as intractable nausea and vomiting. Therefore, APS is often seen in other departments other than neurology [8]. Among the 4 patients included this time, 3 were admitted to the Department of Gastroenterology at the onset of the disease, and 2 of them were not correct diagnosed and treated in time due to misdiagnosis, so their symptoms worsened and they needed to be transferred to ICU for life support. Therefore, it is of great importance to improve clinicians' understanding of the disease. The pathogenesis of APS is mainly related to aquaporin 4 antibody (AQP4-IgG). AQP4 is highly expressed in the nervous system, such as thalamus, hypothalamus, corpus callosum, periventricular, spinal cord, optic nerve and area postrema. The area postrema serves as the nausea, vomiting and hiccup center, and vomiting-related chemical stimuli can cause nausea and vomiting by stimulating chemoreceptors in the area postrema [9,10]. In this paper, case 2 was misdiagnosed as cerebral infarction for many times and failed to receive timely diagnosis and treatment for a long time. A multi-center retrospective study in South Korea divided patients into early-onset NMOSD (EONMOSD, age of rst onset ≤50 years) and late-onset NMOSD (LONMOSD) according to their age of onset. The results showed that age of onset was an important factor affecting the course of disease and clinical prognosis. In this study, 62.2% of LONMOSD patients presented with transverse myelitis and 37.2% presented with optic neuritis. Other clinical manifestations were rare [11]. Another study also supports this view, LONMOSD has fewer lesions around the fourth ventricle and more lesions in the cerebral hemisphere than EONMOSD [12]. By comparing 12 male LONMOSD patients and 64 female LONMOSD patients, other scholars found that the onset of transverse myelitis was less in males, the time from onset to diagnosis was shorter than that in females, and the EDSS score was lower [13]. Clinical diagnosis of NMOSD is often confused by gender, age of onset and atypical clinical manifestations. Some patients may have monoplegia or hemiplegia due to different lesion location, which needs to be differentiated from ischemic cerebrovascular disease.
In order to improve the diagnosis rate of APS, experts at home and abroad have reached a consensus on the diagnostic criteria of APS. Clinical acute or subacute intractable nausea, vomiting and/or hiccup, symptoms lasting more than 48 hours and excluding other causes, APS should be highly suspected, and the diagnosis can be con rmed after the improvement of AQP4 antibody test [5,14]. In recent years, some scholars for AQP4 antibody negative serum myelin oligodendrocytes glycoprotein (MOG) antibody positive patients study found that compared with the NMOSD AQP4 antibody positive patients, two kinds of antibody negative and MOG antibody positive patients rarely serious clinical symptoms, the prognosis is good, the APS MOG antibody positive patients rarely appear, This is consistent with our data [15,16]. There are markers in the imaging of APS patients, and the occurrence of "inverted V sign" in medulla oblongata segment on axial MRI has high speci city for the diagnosis of NMOSD. In addition, sagittal MRI of most APS patients also showed "linear sign", but "linear sign" were also seen in other diseases besides NMOSD [17,18]. Case 2 underwent cranial MRI procedures several times before the diagnosis, but no obvious lesions on the dorsolateral medulla oblongata were identi ed. These observations caution clinicians to consider the patients with intractable nausea and vomiting without apparent medulla oblongata lesions on the imaging for the diagnosis of central nervous system demyelinating diseases.
NMOSD patients are often associated with other autoimmune diseases, such as systemic lupus erythematosus and sjogren's syndrome [19]. Studies have found thymus degeneration in NMOSD patients, which may be an important cause of systemic immune dysfunction [20]. The positive antinuclear antibody was not signi cantly correlated with the course and severity of NMOSD, but the positive antinuclear antibody was more likely to be accompanied by the increase of other antibodies than the negative antinuclear antibody [21]. So far, no large sample studies have demonstrated the existence of speci c autoimmune diseases among NMOSD patients with different clinical symptom onset.
The symptoms of most NMOSD patients improved after shock therapy with high dose steroid (HDS) [14], but a small number of patients were still insensitive to HDS. Patients who are not sensitive to HDS therapy during the acute attacks may be treated with intravenous immunoglobulin (IVIg), which reduces disability and prolongates the time to relapse [22]. In addition to IVIg, Immune adsorption (IA) and Plasma exchange (PE) have been suggested to be equally effective in the acute attacks [23]. Compared with IVMP alone, HDS combined with IVIg is superior to IVMP alone. Comparing the data of 243 patients with acute onset NMOSD, a study concluded that HDS combined with IVIg was superior to HDS alone in patients with EDSS > 6. However, continued use of IVIg does not improve the outcome of patients who do not respond to HDS treatment [24]. This may explain why case 1 in this study received IVIg and PE after HDS without signi cant clinical improvement.
Rituximab (RTX) is increasingly being used in the treatment of NMOSD by depleting CD20 and thereby suppressing the immune system. A number of studies have con rmed the safety and effectiveness of RTX, and the low incidence of adverse drug safety events and opportunistic infections is more advantageous than other therapeutic drugs [25,26,27]. In China, low-dose RTX is mostly used to prevent the recurrence of NMOSD. RTX can signi cantly reduce the recurrence rate of NMOSD and effectively improve the degree of disability of patients, but there are still a small number of patients with short-term recurrence after RTX application [28,29]. Some scholars believe that it takes time for RTX to eliminate pathogenic antibodies, and peripheral B cells are mainly affected, and a single course of RTX treatment cannot eliminate speci c memory B cells [30,31]. In our study, case 1 did not monitor B cells during the application of low-dose RTX, so the dosage of RTX could not be adjusted, which may be one of the reasons for the short-term recurrence of the disease in the patient. Perhaps adjusting the dose of RTX treatment according to the number of B cells and individualizing the treatment plan are important means to reduce short-term recurrence of RTX treatment in the future.
Older age, shorter time between onset and rst onset, and lack of Immunosuppressive therapy (IST) have been found to be associated with higher mortality, regardless of the severity of the onset [32]. According to the follow-up of 17 patients with NMOSD, 14 of them relapsed after six months of drug withdrawal, suggesting that patients with severe clinical symptoms before IST treatment should be carefully discontinued [33]. A Chinese single-center study also supports the view that more caution is needed when discontinuing IST, regardless of the duration of use [34]. Due to the existence of respiratory and cardiovascular centers in the upper cervical spinal cord and lower brain stem, the progression of medulla oblongata lesions in NMOSD patients is likely to endanger patients' lives. Therefore, NMOSD with area postrema syndrome as initial symptom should undergo careful clinical evaluation before careful discontinuation of drugs.
Clinically assessing whether a patient with NMOSD needs to stop treatment, intensify treatment, or initiate preventive treatment is di cult due to the lack of markers that can be used to predict disease. Levels of serum glial brillary acidic protein (sGFAP) were slightly higher in patients with NMOSD in clinical remission compared with healthy controls, and sGFAP was signi cantly higher in acute attacks compared with remission. SGFAP may be used as a biomarker of disease activity in remission in the future. Higher sNfL levels were also found to indicate shorter onset time [35]. A prospective study in China suggested that sNfL could be used as a biomarker for the severity of NMOSD, and higher levels of TH-2related cytokines (by antagonizing IL-1, IL-4, IL10 and IL-13 receptors) were involved in the process of disease remission [36]. In addition, IL-6, IL-10, C3 and C4 are thought to be involved in the occurrence of diseases and may become potential biomarkers for clinical diagnosis and treatment in the future [37,38,39,40].

Conclusion
The clinical manifestations of NMOSD are complex and diverse, and the initial symptoms, onset age and MRI can all affect clinicians' judgment of the disease. Early identi cation of APS and timely therapy can prevent visual and physical disabilities, even respiratory failure and cardiac arrest. Clinical withdrawal of NMOSD patients needs to be evaluated in many aspects. For patients with older onset and APS, the treatment course can be appropriately extended to reduce disease recurrence. It is necessary to strengthen the study of serum and imaging markers for predicting the progression and recurrence of the disease.

Declarations Ethics approval and consent to participate
The studies have approved by The First A liated Hospital of Hainan Medical University Ethics Review Board. Informed consent was obtained from all patients included in the study.

Consent for publication
Not applicable.

Availability of data and materials
Data supporting these ndings are available from the corresponding author upon request. The data cannot be made publicly available because of privacy or ethical restrictions.

Competing interests
All authors declare that they have no con ict of interests. Authors' contributions Ting Liu, Lijuan Li, Lin Ma designed the study. Ting Liu, Binji Liang, Xian Li collected and prepared the patient information. Ting Liu, Lijuan Li, Lin Ma, Binji Liang, Xian Li interpreted the data. Ting Liu, Lijuan Li, Lin Ma drafted the manuscript. All of the authors critically reviewed and revised the manuscript, and nal approval of the version to be published. Figure 1 the MRI of case 1 is A-B, the MRI of case 2 is C-D, the MRI of case 3 is E, the MRI of case 4 is F. Figure A shows medulla oblongata, cervical medulla, and thoracic medulla with hyperintense signal. Figure B shows bilateral hypothalamus with hyperintense signal. Figure C shows hyperintense signal in Page 15/15 paraventricular. Figure D shows hyperintense signal in the medulla oblongata. Figure E shows right cerebellum and brainstem with hyperintense signal. Figure F shows hyperintense signal in the dorsal medulla oblongata.