First Manifestation of AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder Associated with the COVID-19 mRNA Vaccine BNT162b2

BNT162b2 is one of the effective COVID-19 vaccines. However, some researchers have also reported that the vaccines caused some neurological complications. Here, we present a case of a 52-year-old female who developed aquaporin (AQP) 4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) fourteen days after the first dose of BNT162b2. She experienced pain of the neck, weakness of the left arm and leg, numbness of the left hand, and impaired temperature sensation of the right leg. MRI showed T2WI hyperintense lesions in the area postrema and cervical spinal cord ranging from C1 to C6 level, and Gd-enhanced lesions from C3 to C5 level; especially left lateral column was predominantly enhanced. Cell-based assays showed anti-AQP4 antibody (AQP4Ab) was positive. We diagnosed AQP4-IgG-positive NMOSD. After high-dose glucocorticoid therapy, she is showing improved symptoms. The present case was characterized by the findings that a Gd-enhanced lesion in the cervical cord localized dominantly at the left lateral column, consistent with the side of the shoulder where the vaccine was injected. Many studies suggested that AQP4-IgG-positive NMOSD development has multistep mechanisms following the blood-brain barrier (BBB) breakdown. We suspected that BNT162b2-associated immune responses lead to BBB disruptions. Through the limitedly damaged BBB, the plasma cells producing AQP4Abs might be recruited to CNS, and AQP4Abs might bind to the cervical cord and the area postrema. A large population-based study revealed that BNT162b2-associated complications were less likely to be observed than COVID-19 infectious symptoms. However, considering the present case, neurologists need to observe the conditions following vaccination.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Associated With Area Postrema Syndrome: A Case Report

Glial fibrillary acidic protein astrocytopathy is an immunotherapy-responsive autoimmune disease of the central nervous system with various clinical manifestations; among these, there are few reports about area postrema syndrome (APS). The authors present the case of a female patient admitted to the hospital with intractable nausea and vomiting as the predominant symptom. The patient's cerebrospinal fluid was tested by cell-based assays (CBA) and found positive for the presence of anti-glial fibrillary acidic protein (GFAP) antibody, in addition, serological testing showed elevated levels of thyroglobulin and thyroperoxidase-specific antibodies. Brain and cervical MRI showed abnormally high signal on the T2 sequence in the dorsal medulla oblongata and right pontine arm. Therefore, the patient was diagnosed with autoimmune GFAP astrocytopathy. The symptoms improved rapidly after treatment with corticosteroids, and no recurrence has been observed thus far. APS may be a relatively rare clinical manifestation of GFAP astrocytopathy. Importantly, such presentation is challenging to correctly diagnose without typical MRI imaging findings. However, the detection of antibodies in the cerebrospinal fluid or serum may be valuable. Systemic and neurological autoimmunity often coexist, comprehensive antibody screening should be conducted.

Pediatric Neuromyelitis Optica Spectrum Disorder: Case Series and Literature Review

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray matter. The aquaporin-4 antibody (AQP4-IgG) is specific for NMOSD. Recently, myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been found in a group of AQP4-IgG negative patients. NMOSD is rare among children and adolescents, but early diagnosis is important to start adequate therapy. In this report, we present cases of seven pediatric patients with NMOSD and we review the clinical and neuroimaging characteristics, diagnosis, and treatment of NMOSD in children.

Fibroblast Growth Factor-1 Activates Neurons in the Arcuate Nucleus and Dorsal Vagal Complex

Central administration of fibroblast growth factor-1 (FGF1) results in long-lasting resolution of hyperglycemia in various rodent models, but the pre- and postsynaptic mechanisms mediating the central effects of FGF1 are unknown. Here we utilize electrophysiology recordings from neuronal populations in the arcuate nucleus of the hypothalamus (ARH), nucleus of the solitary tract (NTS), and area postrema (AP) to investigate the mechanisms underlying FGF1 actions. While FGF1 did not alter membrane potential in ARH-NPY-GFP neurons, it reversibly depolarized 83% of ARH-POMC-EGFP neurons and decreased the frequency of inhibitory inputs onto ARH-POMC-EGFP neurons. This depolarizing effect persisted in the presence of FGF receptor (R) blocker FIIN1, but was blocked by pretreatment with the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX). Non-FGF1 subfamilies can activate vascular endothelial growth factor receptors (VEGFR). Surprisingly, the VEGFR inhibitors axitinib and BMS605541 blocked FGF1 effects on ARH-POMC-EGFP neurons. We also demonstrate that FGF1 induces c-Fos in the dorsal vagal complex, activates NTS-NPY-GFP neurons through a FGFR mediated pathway, and requires VGSCs to activate AP neurons. We conclude that FGF1 acts in multiple brain regions independent of FGFRs. These studies present anatomical and mechanistic pathways for the future investigation of the pharmacological and physiological role of FGF1 in metabolic processes.

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 first symptom.Methods: Four patients with intractable nausea and vomiting were selected for the analysis and finally the cases were confirmed 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 significant 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 findings can all influence the clinicians' judgment of the disease. Early identification of the APS and timely therapy can prevent visual and physical disabilities, even respiratory failure and cardiac arrest. Therefore, it is necessary to identify specific and sensitive serum and imaging markers for predicting the prognosis and recurrence of the disease.

Clinical and Prognostic Aspects of Patients With The Neuromyelitis Optic Spectrum Disorder (NMOSD) From a Cohort in Northeast Brazil

Introduction: Neuromyelitis optic spectrum disorders (NMOSD) is a rare inflammatory and demyelinating disease of the central nervous system (CNS) more frequent in women and Afro-descendants. No previous epidemiological or prognostic study has been conducted in the region of the state of Bahia, Brazilian Northeast. Objective: To evaluate clinical and prognostic aspects in patients with NMOSD from a cohort in northeastern Brazil. Material and Methods: A single-center retrospective study was conducted with consecutive patients diagnosed with NMOSD. Clinical and epidemiological characteristics were described. The degree of disability was expressed by the Expanded Disability Status Scale (EDSS). Worsening disability were analyzed through negative binomial regression adjusted for disease duration. Results: Ninety-one patients were included, 72 (79.1%) female and 67 (73.6%) afro descendants. Mean age at onset was 36 (± 14) years and 73.3% were anti-aquaporin-4 antibody positive. Isolated transverse myelitis (32.9%) and isolated optic neuritis (22.4%) were the most frequent initial clinical syndromes. After multivariate analysis, optic neuritis (RR = 0.15; 95% CI=0.03 – 0.59; p = 0.008) and dyslipidemia (RR = 0.07; 95% CI=0.04 – 0.40; p < 0.001) were associated with slower disease progression. Area postrema involvement (RR = 29.69; 95% CI=3.40 – 226.07; p = 0.002) and age at onset (RR = 1.05; 95% CI=1.00 – 1.10; p = 0.037) were associated with faster disease progression. Conclusions: In the first clinical and prognostic study in northeastern Brazil, we identified area postrema involvement, age at onset, optic neuritis at fist syndrome and dyslipidemia as the main prognostic factors associated with disease progression.

Area postrema syndrome in neuromyelitis optica spectrum disorder: diagnostic challenges and descriptive patterns

Background Although area postrema syndrome (APS) is one of the core clinical features of neuromyelitis optic spectrum disorder (NMOSD), it is frequently misdiagnosed as gastrointestinal or systemic disorders. In this study, we describe the diagnostic challenges in NMOSD patients with APS and their characteristic clinical and radiological features. All patients who attended our university hospitals during the period from March 2019 to August 2020 with a diagnosis of NMOSD according to the latest diagnostic criteria were admitted and evaluated clinically, radiologically with gadolinium-enhanced brain and spinal MRI, measures of serum Anti-Aquaporin 4 (Anti-AQP4) and clinical status using the Expanded Disability Status Scale (EDSS) scores. APS was diagnosed if there was a history of intractable nausea, vomiting, or hiccups (INVH) that had lasted longer than 1 week with the exclusion of other etiologies, or less than 48 h if associated with a lesion in the dorsal medulla on MRI scan. Results Twenty out of 90 (22.2%) identified patients with a diagnosis of NMOSD had a history of unexplained intractable nausea, vomiting or hiccoughs lasting an average of 20 days. Seventeen patients were anti-Aquaporin 4 seropositive. Seven patients (35%) presented initially with isolated clinical features of APS and were diagnosed only after subsequent relapse. Patients with APS preceding other core clinical presentations (13 cases, 65%) were diagnosed after development of motor manifestations. All patients developed acute myelitis during the course of illness. Brain and spinal MRI scans showed that 13 had a linear lesion in the dorsal tegmentum of the medulla oblongata adjacent to the fourth ventricle. Otherwise, longitudinally extensive transverse myelitis was found in 80%, while 35% showed extension of the cord lesion to the AP. Conclusions APS as a core clinical characteristic of NMOSD is not a rare presentation as was previously thought and can occur in both AQP4-seropositive and seronegative NMOSD.

Fibroblast Growth Factor 19 Increases the Excitability of Pre-Motor Glutamatergic Dorsal Vagal Complex Neurons From Hyperglycemic Mice

Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output.

Consensus of expert advices on routing, diagnosis, and management of patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune inflammatory disorders accompanied by central nervous system damage, widespread immunemediated demyelination, and axonal damage, involving mainly the optic nerves, spinal cord, and area postrema. The diagnostic capabilities, administration and routing of patients, and therapeutic approaches to this disease need to be improved. During several expert councils held in 2019–2021 in different regions of the Russian Federation, we discussed multiple issues related to various aspects of medical care for patients with NMOSDs. As a result, the experts developed further steps necessary to improve the medical care to these patients: to write and publish clinical guidelines for the diagnosis and treatment of NMOSDs; to consider the possibility of optimizing the NMOSDs diagnostic program including the aquaporin-4 antibodies (AQP4-IgG) testing; to evaluate the implementation of a set of measures aimed at including the corresponding laboratory investigations into the system of state guarantees (together with the institutions of the Ministry of Health of Russia), if there is clinical and economic feasibility; to include the issues of timely NMOSDs evaluation in educational programs initiated by the scientific medical community, in order to raise awareness of primary care neurologists in relation to the clinical and neuroimaging signs of probable NMOSDs; to assess the possibility of introducing routing schemes for patients with NMOSDs at the regional level; to work out a decision on the collection of NMOSDs epidemiological and clinical data in the Russian Federation.