RESUMEN
The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.
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Fármacos Antiobesidad , Reacción de Prevención , Receptor del Péptido 1 Similar al Glucagón , Vías Nerviosas , Rombencéfalo , Respuesta de Saciedad , Animales , Femenino , Masculino , Ratones , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/farmacología , Área Postrema/metabolismo , Área Postrema/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones Endogámicos C57BL , Vías Nerviosas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/efectos de los fármacos , Obesidad/metabolismo , Rombencéfalo/citología , Rombencéfalo/efectos de los fármacos , Rombencéfalo/metabolismo , Rombencéfalo/fisiología , Respuesta de Saciedad/efectos de los fármacos , Respuesta de Saciedad/fisiología , Núcleo Solitario/citología , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiología , AlimentosRESUMEN
Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders1. The Bezold-Jarisch reflex (BJR), first described2,3 in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing4 to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses-hypotension, bradycardia and suppressed respiration-and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push-pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.
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Corazón , Reflejo , Células Receptoras Sensoriales , Síncope , Nervio Vago , Humanos , Área Postrema , Bradicardia/complicaciones , Bradicardia/fisiopatología , Gasto Cardíaco Bajo/complicaciones , Gasto Cardíaco Bajo/fisiopatología , Ecocardiografía , Corazón/fisiología , Frecuencia Cardíaca , Hipotensión/complicaciones , Hipotensión/fisiopatología , Flujometría por Láser-Doppler , Red Nerviosa , Reflejo/fisiología , Células Receptoras Sensoriales/fisiología , Análisis de Expresión Génica de una Sola Célula , Síncope/complicaciones , Síncope/etiología , Nervio Vago/citología , Nervio Vago/fisiologíaRESUMEN
Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2-4. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS-AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS-AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.
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Tronco Encefálico , Conducta de Enfermedad , Neuronas , Animales , Anorexia/complicaciones , Área Postrema/citología , Área Postrema/metabolismo , Tronco Encefálico/citología , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/fisiología , Conducta de Enfermedad/efectos de los fármacos , Letargia/complicaciones , Lipopolisacáridos/farmacología , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleo Solitario/citología , Núcleo Solitario/metabolismoRESUMEN
The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1- and pyruvate kinase-dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.
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Área Postrema , Transportador de Glucosa de Tipo 1 , Glucosa , Piruvato Quinasa , Animales , Ratas , Área Postrema/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Núcleo Solitario/metabolismo , Piruvato Quinasa/metabolismo , Técnicas de Silenciamiento del Gen , Lentivirus/metabolismo , Ácido Pirúvico/metabolismo , Masculino , Dieta Alta en GrasaRESUMEN
BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory autoimmune disease with high risk of recurrence and disability, the treatment goal is a recurrence free state. Area postrema (AP) is one of the most common involved area of NMOSD, which may have a particular significance in the pathogenesis of NMOSD and clinical heterogeneity. Our study is to investigate the clinical and recurrent characteristics AP onset NMOSD patients. METHODS: A retrospective study was done in a cohort of 166 AQP4-IgG seropositive NMOSD patients which were identified by the 2015 IPND criteria. The patients were divided into AP onset (APO-NMOSD) group and non-AP onset (NAPO-NMOSD) group based on the initial episode location. Clinical features and recurrence differences of two groups were compared. RESULTS: The APO-NMOSD group and NAPO-NMOSD group had a population ratio of 24:142. APO-NMOSD patients were younger (34.6y VS 42.3y, P = 0.013), had lower EDSS at first episode (0.7 VS 4.2, p = 0.028) and last follow up (1.9 VS 3.3, p = 0.001), more likely to have multi-core lesions at the first attack (33.3% VS 9.2%, P = 0.001). Also, they had a higher annual recurrence rate (0.4 ± 0.28 VS 0.19 ± 0.25, P = 0.012). In natural course NMOSD patients without immunotherapy, APO-NMSOD had a shorter time of first relapse (P < 0.001) and higher annual recurrence rate (0.31 ± 0.22 VS 0.16 ± 0.26, P = 0.038) than NAPO-NMOSD. APO-NMOSD group also have a higher risk of having the first relapsing compared to optic neuritis onset-NMOSD (HR 2.641, 95% CI 1.427-4.887, p = 0.002) and myelitis onset-NMOSD group (HR 3.593, 95% CI 1.736-7.438, p = 0.001). Compared to NAPO-NMOSD, APO-NMOSD has a higher likelihood of brainstem recurrence (28.6% vs. 4.7%, p<0.001) during the first recurrence, while NAPO-NMOSD is more susceptible to optic nerve involvement (10.7% vs. 41.1%, p = 0.01). CONCLUSION: AQP4-IgG seropositive NMOSD patients with AP onset are youngers and have higher risk of recurrence. Clinicians should pay attention to AP damage in NMOSD, as it indicates a potential risk of recurrence. TRIAL REGISTRATION: Retrospectively registered.
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Área Postrema , Neuromielitis Óptica , Recurrencia , Humanos , Neuromielitis Óptica/epidemiología , Neuromielitis Óptica/diagnóstico , Femenino , Estudios Retrospectivos , Adulto , Masculino , Persona de Mediana Edad , Área Postrema/patología , Adulto Joven , Estudios de Cohortes , Acuaporina 4/inmunologíaRESUMEN
BACKGROUND: Glial fibrillary acidic protein (GFAP) astrocytopathy, a novel autoimmune disease of the nervous system, was first defined in 2016. To our knowledge, area postrema syndrome (APS) with linear enhancement along the surface of the brainstem and fourth ventricle is extremely rare in this disorder. CASE PRESENTATION: A Chinese woman presented with intractable nausea and vomiting after onset of flu-like symptoms. Brain magnetic resonance imaging (MRI) disclosed abnormal signal intensities in the dorsal medulla oblongata including area postrema. Besides, linear enhancement surrounding the surface of the brainstem and fourth ventricle was visualized after gadolinium injection. Cerebrospinal fluid (CSF) analysis showed increased cell count and protein. A cell-based assay was positive for anti-GFAP IgG in CSF. She was diagnosed with autoimmune GFAP astrocytopathy and treated with high-dose glucocorticoid. The patient received a quick recovery with entire resolution of the initial abnormalities. CONCLUSIONS: Isolated APS can be the initial manifestation of autoimmune GFAP astrocytopathy. Linear enhancement surrounding the surface of the brainstem and fourth ventricle is another neuroradiological hallmark.
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Área Postrema , Cuarto Ventrículo , Femenino , Humanos , Cuarto Ventrículo/diagnóstico por imagen , Proteína Ácida Fibrilar de la Glía , Tronco Encefálico , EncéfaloRESUMEN
Objective: To investigate the misdiagnosis of area postrema syndrome (APS) manifesting as intractable nausea, vomiting and hiccups in neuromyelitis optic spectrum disease (NMOSD) and reduce the risk of misdiagnosis. Methods: We retrospectively analyzed data from NMOSD patients attending the Department of Neurology at the First Medical Center of PLA General Hospital between January 2019 and July 2021. SPSS25.0 was then used to analyze the manifestations, misdiagnosis, and mistreatment of APS. Results: A total of 207 patients with NMOSD were included, including 21 males and 186 females. The mean age of onset was 39±15 years (range: 5-72 years). The proportion of patients who were positive for serum aquaporin 4 antibody was 82.6% (171/207). In total, 35.7% (74/207) of the NMOSD patients experienced APS during the disease course; of these patients, 70.3% (52/74) had APS as the first symptom and 29.7% (22/74) had APS as a secondary symptom. The misdiagnosis rates for these conditions were 90.4% (47/52) and 50.0% (11/22), respectively. As the first symptom, 19.2% (10/52) of patients during APS presented only with intractable nausea, vomiting and hiccups; 80.8% (42/52) of patients experienced other neurological symptoms. The Departments of Gastroenterology and General Medicine were the departments that most frequently made the first diagnosis of APS, accounting for 54.1% and 17.6% of patients, respectively. The most common misdiagnoses related to diseases of the digestive system and the median duration of misdiagnosis was 37 days. Conclusions: APS is a common symptom of NMOSD and is associated with a high rate of misdiagnosis. Other concomitant symptoms often occur with APS. Gaining an increased awareness of this disease/syndrome, obtaining a detailed patient history, and performing physical examinations are essential if we are to reduce and avoid misdiagnosis.
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Hipo , Neuromielitis Óptica , Masculino , Femenino , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/diagnóstico , Área Postrema , Estudios Retrospectivos , Hipo/etiología , Hipo/complicaciones , Vómitos/diagnóstico , Vómitos/etiología , Náusea/diagnóstico , Náusea/etiología , Inflamación , Síndrome , Autoanticuerpos , Errores Diagnósticos , Acuaporina 4RESUMEN
Primary central nervous system (CNS) histiocytic sarcoma is a rare hematolymphoid malignancy with features of mature histiocytes and carries a poor prognosis. We describe a unique case in which a 50-year-old woman presented with recurrent acute brainstem syndrome, area postrema syndrome, and myelitis with corresponding magnetic resonance imaging (MRI) lesions meeting diagnostic criteria for seronegative neuromyelitis optica spectrum disorder (NMOSD). Despite initial improvement with steroids and plasma exchange, she experienced recurrent symptoms over 10 months referable to new and persistently enhancing lesions. At autopsy, neuropathology revealed a diffusely infiltrative primary CNS histiocytic sarcoma. This case represents a rare clinicoradiologic mimic of NMOSD, underscoring the importance of evaluation for infiltrative diseases in cases of atypical seronegative NMOSD.
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Neoplasias del Sistema Nervioso Central , Sarcoma Histiocítico , Área Postrema , Diagnóstico Diferencial , Femenino , Sarcoma Histiocítico/diagnóstico , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Neuromielitis Óptica/diagnóstico por imagenRESUMEN
INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described steroid-responsive meningoencephalomyelitis positive for cerebrospinal fluid (CSF) anti-GFAP antibody. Area postrema syndrome (APS) involves intractable hiccups, nausea, and vomiting, which is caused by medulla oblongata (MO) impairment. APS is a characteristic symptom of aquaporin-4 (AQP4) autoimmunity, and it helps to differentiate between AQP4 and GFAP autoimmunity. Conversely, although 6 cases of autoimmune GFAP astrocytopathy with APS and MO lesions have been reported, the association between GFAP autoimmunity and APS is unclear. We report the case of a patient with autoimmune GFAP astrocytopathy presenting with APS-like symptoms without MO lesions and discuss the mechanisms underlying the symptoms. METHODS: CSF anti-GFAP antibody was detected using cell-based assays and immunohistochemical assays. RESULTS: A 54-year-old Japanese man developed persistent hiccups, intermittent vomiting, fever, anorexia, and inattention. Brain magnetic resonance imaging (MRI) showed periventricular lesions with radial linear periventricular enhancement, suggesting autoimmune GFAP astrocytopathy. However, no obvious MO lesions were identified on thin-slice images. Spinal cord MRI revealed hazy lesions with patchy enhancement along the cervical and thoracic cord. CSF analysis demonstrated inflammation, with positive results for anti-GFAP antibodies. Anti-AQP4 antibodies in the serum and CSF were negative. Esophagogastroduodenoscopy revealed gastroparesis and gastroesophageal reflux disease, and vonoprazan, mosapride, and rikkunshito were effective only against persistent hiccups. Steroid therapy was initiated, allowing clinical and radiological improvements. Repeated MRIs demonstrated no obvious MO lesions. CONCLUSION: This report suggests that autoimmune GFAP astrocytopathy presents with APS-like symptoms without obvious MO lesions. The possible causes of hiccups were gastroparesis and cervical cord lesions. Gastroesophageal reflux disease was not considered a major cause of the hiccups. Intermittent vomiting appeared to be associated with gastroparesis, cervical cord lesions, and viral-like symptoms. Testing for anti-GFAP antibodies should be considered in patients with APS-like symptoms in the context of typical clinical-MRI features of autoimmune GFAP astrocytopathy.
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Reflujo Gastroesofágico , Gastroparesia , Hipo , Masculino , Humanos , Persona de Mediana Edad , Proteína Ácida Fibrilar de la Glía , Área Postrema/metabolismo , Hipo/etiología , Hipo/patología , Gastroparesia/patología , Astrocitos/metabolismo , Acuaporina 4/metabolismo , Vómitos/patología , Reflujo Gastroesofágico/patología , AutoanticuerposRESUMEN
BACKGROUND: Area postrema syndrome (APS) as the isolated manifestation in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy has been rarely reported. CASE PRESENTATION: A 61-year-old male patient presented with intractable hiccup. He was first admitted to the department of Gastroenterology because he had no symptoms other than hiccup. Then he was diagnosed with possible digestive system disease and started on treatment. 2 weeks later, his symptom didn't improve at all. After consultation, the patient was referred to our department. Cerebrospinal fluid (CSF) analysis revealed lymphocytes pleocytosis, elevated protein level. Cell-based assays demonstrated GFAP antibodies in blood and CSF. His symptom improved with steroid pulse therapy (methylprednisolone, 1 g for 5 days), followed by a gradual tapering of oral prednisolone. Three months after the initial presentation, he showed no relapses. CONCLUSIONS: We report atypical manifestation of autoimmune GFAP astrocytopathy which presented as APS, suggesting that autoimmune GFAP astrocytopathy should be added to the list of possible cause of APS.
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Área Postrema , Hipo , Astrocitos , Proteína Ácida Fibrilar de la Glía , Hipo/etiología , Humanos , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana EdadRESUMEN
BACKGROUND: Alexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone. CASE PRESENTATION: A normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting. CONCLUSIONS: This study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.
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Enfermedad de Alexander , Enfermedad de Alexander/genética , Enfermedad de Alexander/patología , Área Postrema/patología , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Masculino , Prednisolona/uso terapéutico , Convulsiones , Vómitos , Pérdida de PesoRESUMEN
In the present study, we report a case of persistent intractable nausea and vomiting after a medullary infarction. Area postrema syndrome due to ischemic stroke is very rare. In this case, brain magnetic resonance imaging revealed an ischemic lesion in the lateral medulla extending caudally and dorsomedially. The patient presented with sustained nausea, vomiting, and poor oral intake over one month after the index stroke, even after resolution of dizziness and disappearance of nystagmus. She did not respond to intravenous metoclopramide with ondansetron. However, their intractable nausea and vomiting eventually resolved with concomitant use of domperidone and itopride orally in addition to intravenous metoclopramide with ondansetron.
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Área Postrema , Ondansetrón , Área Postrema/diagnóstico por imagen , Área Postrema/patología , Femenino , Humanos , Infarto/patología , Metoclopramida/uso terapéutico , Náusea/etiología , Síndrome , Vómitos/complicacionesRESUMEN
BACKGROUND: Area postrema syndrome (APS) is recognized as a core feature in neuromyelitis optica (NMO) diagnosis. Isolated APS can occur at NMO onset and frequently results in a delay of diagnosis, along with devastating secondary neurologic deficits. To date, few studies have characterized APS-onset neuromyelitis optica spectrum disorder (APSO-NMOSD). OBJECTIVE: We aimed to describe the clinical and radiologic features of patients with APSO-NMOSD who are initially misdiagnosed in a cohort of patients from Zhengzhou, China. MATERIALS AND METHODS: We identified 15 patients who presented with APS as an initial manifestation, based on the 2015 international consensus diagnostic criteria for NMOSD, and reviewed their demographic, clinical, laboratory, and magnetic resonance imaging (MRI) data. RESULT: Fifteen patients (3 men, 12 women) aged 14-50 years old were included in our study. All patients presented with APS that included intractable nausea, vomiting, or hiccups (INVH) as the initial manifestation; many experienced a delay in diagnosis. Serum AQP4 was positive in eleven patients and myelin oligodendrocyte glycoprotein (MOG) in one patient. All patients had a linear medullary lesion or a linear medulla-spinal lesion on sagittal MRI. An "inverted V sign" on axial medulla oblongata images, representing a lesion involving the area postrema, was noted in seven patients in this study. CONCLUSIONS: APS can occur as a sole and initial manifestation of NMOSD, often leading to misdiagnosis in the early process of disease. Identifying patients with an "inverted V" sign and a linear medullary lesion upon MRI examination can help to quickly identify APS patients and avoid further diagnostic delays.
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Neuromielitis Óptica , Adolescente , Adulto , Acuaporina 4 , Área Postrema , Autoanticuerpos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Glicoproteína Mielina-Oligodendrócito , Estudios Retrospectivos , Adulto JovenRESUMEN
The pathways for peripheral-to-central immune communication (P â C I-comm) following sterile lung injury (SLI) are unknown. SLI evokes systemic and central inflammation, which alters central respiratory control and viscerosensory transmission in the nucleus tractus solitarii (nTS). These functional changes coincide with increased interleukin-1 beta (IL-1ß) in the area postrema, a sensory circumventricular organ that connects P â C I-comm to brainstem circuits that control homeostasis. We hypothesize that IL-1ß and its downstream transcriptional target, cyclooxygenase-2 (COX-2), mediate P â C I-comm in the nTS. In a rodent model of SLI induced by intratracheal bleomycin (Bleo), the sigh frequency and duration of post-sigh apnea increased in Bleo- compared to saline- treated rats one week after injury. This SLI-dependent change in respiratory control occurred concurrently with augmented IL-1ß and COX-2 immunoreactivity (IR) in the funiculus separans (FS), a barrier between the AP and the brainstem. At this barrier, increases in IL-1ß and COX-2 IR were confined to processes that stained for glial fibrillary acidic protein (GFAP) and that projected basolaterally to the nTS. Further, FS radial-glia did not express TNF-α or IL-6 following SLI. To test our hypothesis, we blocked central COX-1/2 activity by intracerebroventricular (ICV) infusion of Indomethacin (Ind). Continuous ICV Ind treatment prevented Bleo-dependent increases in GFAP + and IL-1ß + IR, and restored characteristics of sighs that reset the rhythm. These data indicate that changes in sighs following SLI depend partially on activation of a central COX-dependent P â C I-comm via radial-glia of the FS.
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Área Postrema , Lesión Pulmonar , Animales , Bleomicina/toxicidad , Comunicación , Neuroglía , Ratas , Ratas Sprague-DawleyRESUMEN
Anti-Glial fibrillary acidic protein (GFAP) encephalomyelitis is a recently described entity and while the spectrum of this disease has been explored, further research is needed to fully describe its phenotype. Area postrema syndrome (APS) is usually associated with neuromyelitis optica spectrum disorders (NMOSDs), whereas no case of APS has been previously reported with anti-GFAP encephalomyelitis. In this article, we report a case of APS in a 41-year-old woman in the context of anti-GFAP encephalomyelitis. This case was not associated with additional anti-AQP4 IgG and therefore extends the clinico-radiological spectrum of anti-GFAP encephalomyelitis.
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Área Postrema , Autoanticuerpos/inmunología , Encefalomielitis/inmunología , Proteína Ácida Fibrilar de la Glía/inmunología , Adulto , Autoantígenos/inmunología , Encefalomielitis/complicaciones , Encefalomielitis/patología , Femenino , Humanos , Náusea/inmunología , Síndrome , Vómitos/inmunologíaRESUMEN
BACKGROUND: Stress cardiomyopathy (Takotsubo cardiomyopathy) is very rare in the central nervous system (CNS) demyelinating disorders. Although this dysfunction of the heart-brain axis has been reported in several case series related to multiple sclerosis (MS), stress cardiomyopathy by neuromyelitis optica (NMO), which is rarer CNS demyelinating disorder than MS, is extremely rare. Herein, we report a case of stress cardiomyopathy associated with a medullary lesion as a presentation of NMO. CASE PRESENTATION: A 30-year-old woman was treated by veno-arterial extracorporeal membrane oxygenation due to catastrophic cardiopulmonary dysfunction after prolonged and unexplained nausea, vomiting, and cough. Myoclonus on the limbs developed afterward. Taken with suspicion of area postrema syndrome (APS), the brain MRI showed a demyelinating lesion in the medulla oblongata. APS and severe heart failure by stress cardiomyopathy were completely resolved by ECMO and hydrocortisone therapy. However, the CNS demyelinating lesion recurred after 1 month. The patient was diagnosed with NMO evident by the presence of aquaporin-4 antibody; Steroid therapy improved her symptoms. CONCLUSION: NMO should be considered as one of the differential diagnoses in patients with APS preceding severe cardiopulmonary distress.
Asunto(s)
Área Postrema , Neuromielitis Óptica/diagnóstico , Cardiomiopatía de Takotsubo/diagnóstico , Adulto , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Bulbo Raquídeo/patología , Recurrencia , SíndromeRESUMEN
BACKGROUND: Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions of GDF15 in mice started on high-fat diet (HFD). METHODS: The actions of GDF15 were inhibited using two methods: (1) Groups of 8 mice under HFD had their endogenous GDF15 neutralised by monoclonal antibody treatment, (2) Groups of 15 mice received AAV-shRNA to knockdown GFRAL at its hypothesised major sites of action, the hindbrain area postrema (AP) and the nucleus of the solitary tract (NTS). Metabolic measurements were determined during both experiments. CONCLUSIONS: Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15-GFRAL axis plays an important role in resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS.
Asunto(s)
Adiposidad , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Factor 15 de Diferenciación de Crecimiento , Rombencéfalo , Adiposidad/genética , Adiposidad/fisiología , Animales , Área Postrema/citología , Área Postrema/metabolismo , Área Postrema/fisiología , Peso Corporal/fisiología , Dieta Alta en Grasa , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/citología , Neuronas/metabolismo , Neuronas/fisiología , Obesidad/metabolismo , Rombencéfalo/citología , Rombencéfalo/metabolismo , Rombencéfalo/fisiología , Núcleo Solitario/citología , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiologíaRESUMEN
Amylin acts in the area postrema (AP) and arcuate nucleus (ARC) to control food intake. Amylin also increases axonal fiber outgrowth from the APânucleus tractus solitarius and from ARCâhypothalamic paraventricular nucleus. More recently, exogenous amylin infusion for 4 wk was shown to increase neurogenesis in adult rats in the AP. Furthermore, amylin has been shown to enhance leptin signaling in the ARC and ventromedial nucleus of the hypothalamus (VMN). Thus, we hypothesized that endogenous amylin could be a critical factor in regulating cell birth in the ARC and AP and that amylin could also be involved in the birth of leptin-sensitive neurons. Amylin+/- dams were injected with BrdU at embryonic day 12 and at postnatalday 2; BrdU+ cells were quantified in wild-type (WT) and amylin knockout (KO) mice. The number of BrdU+HuC/D+ neurons was similar in ARC and AP, but the number of BrdU+Iba1+ microglia was significantly decreased in both nuclei. Five-week-old WT and KO littermates were injected with leptin to test whether amylin is involved in the birth of leptin-sensitive neurons. Although there was no difference in the number of BrdU+c-Fos+ neurons in the ARC and dorsomedial nucleus, an increase in BrdU+c-Fos+ neurons was seen in VMN and lateral hypothalamus (LH) in amylin KO mice. In conclusion, these data suggest that during fetal development, endogenous amylin favors the birth of microglial cells in the ARC and AP and that it decreases the birth of leptin-sensitive neurons in the VMN and LH.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Área Postrema/metabolismo , Linaje de la Célula , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Microglía/metabolismo , Animales , Animales Recién Nacidos , Núcleo Arqueado del Hipotálamo/embriología , Área Postrema/embriología , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Área Hipotalámica Lateral/embriología , Área Hipotalámica Lateral/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Leptina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Fenotipo , Embarazo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleo Hipotalámico Ventromedial/embriología , Núcleo Hipotalámico Ventromedial/metabolismoRESUMEN
In this topical review, we discuss the history of the area postrema syndrome, with special attention given to early studies aimed at identifying the area postrema and its function, possible early cases of the syndrome and its current relevance in neuroimmunology and demyelinating diseases. In 1896, Retzius named a structure in the posterior medulla oblongata as the area postrema. The work of Borison in the middle of the 20th century led to the elucidation of its function as a "vomiting center." The historical medical literature is filled with excellent examples that could be described as "area postrema syndrome." While severe and bilateral optic neuritis and transverse myelitis still constitute the classic components of neuromyelitis optica spectrum disorder (NMOSD), intractable vomiting and hiccups due to area postrema involvement is now recognized as essentially pathognomonic, indeed a shiny pearl in neuroimmunology and demyelinating diseases.
Asunto(s)
Área Postrema/fisiopatología , Hipo/fisiopatología , Náusea/fisiopatología , Neuromielitis Óptica/fisiopatología , Vómitos/fisiopatología , Hipo/etiología , Hipo/historia , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Náusea/etiología , Náusea/historia , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/historia , Síndrome , Vómitos/etiología , Vómitos/historiaRESUMEN
BACKGROUND: Area postrema syndrome (APS) is considered to be one of the most specific clinical presentations of neuromyelitis optica spectrum disorders (NMOSDs). In sub-Saharan Africa, NMOSDs and even more so those revealed by an APS, are rarely reported. However, studies among mixed populations have shown that NMOSDs disproportionately affect black people with relatively more frequent encephalic involvement. We report a case of APS revealing an NMOSD associated with central nervous system (CNS) tuberculosis in a young Togolese woman residing in Togo (West Africa). CASE PRESENTATION: A 28-year-old Togolese woman was admitted for left hemibody sensory problems with ataxia. These problems were observed while the patient was hospitalized for a few days in the hepato-gastroenterology department for persistent vomiting, abdominal pain and hiccups lasting for about a month. The examination confirmed left hemibody ataxia with nystagmus when looking to the left, pronounced left osteotendinous reflexes, and left hemibody hypoesthesia up to the base of the neck. Encephalic magnetic resonance imaging (MRI) showed a hypersignal lesion in the bulbar more lateralized on the left in the fluid-attenuated inversion recovery sequence, not enhanced after a gadolinium injection. Biological assessment showed the presence of Mycobacterium tuberculosis deoxyribonucleic acid in the cerebrospinal fluid and a sedimentation rate of 120 mm in the 1st hour. The result of the anti-AQP4 antibody test was positive. Two months from the onset of digestive problems with Lhermitte's sign and hand and foot contracture access without vesico-sphincter problems were established. Cervical medullary MRI showed an additional intramedullary hypersignal lesion in the T2 sequence at the C2 level, not enhanced after a gadolinium injection. A second course of intravenous corticosteroids was administered, and anti-tuberculosis treatment was continued. The outcome was favorable. After 8 months of anti-tuberculosis treatment, the patient started immunosuppressive therapy (azathioprine 50 mg twice daily) to limit the risk of recurrence of NMOSD. CONCLUSION: The recognition of an APS is an additional challenge for the diagnosis of NMOSDs, especially in countries with limited resources. CNS tuberculosis must be tested when faced with an NMOSD because it seems to be a major cause.