Objective To determine the clinical, demographic and imaging characteristics of a Turkish cohort with aquaporin-4-antibody positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) from a single center. Background NA. Design/Methods 35 patients seen between January-2008 and December-2020 with a diagnosis of AQP4-IgG+NMOSD who could be studied in detail were included in the study. Inclusion criteria for patients with NMOSD diagnosis was defined according to International Consensus Diagnostic Criteria (Wingerchuk et al.2015) and all patients were confirmed for AQP4-IgG positive serology at least once by Euroimmune transfected cells assay (EU90). Demographic, clinical and MRI data were obtained retrospectively. Results The female-to-male ratio was 16.5: 1. The mean age of disease onset was 26,16±10,96 years for patients with optic neuritis onset (n:12), and 43.17±11,95 for the subgroup that started with transverse myelitis (TM) (n:16), confirming a significant difference of age at onset according to the first attack type (p < 0.001). The mean age at onset in 5 patients with area postrema syndrome was 35,74±16,83. Half of the total attacks occurred within the first year of disease onset (98/196). The mean time to diagnosis was 2,98±5,78 years after the initial attack. Disease duration was 10,06±9,76 years. Cerebrospinal fluid oligoclonal bands were studied in 24 and were positive in 25%. An autoimmune rheumatologic disease comorbidity was present in 34.5% of the patients. In patients with MRI disclosing = 2 McDonald dissemination in space criteria (spinal included) was more common in TM group and correlated with a higher disability (EDSS) score. Conclusions Turkish AQP4-IgG+NMOSD patients whose disease start with optic neuritis have an earlier age of onset compared to the ones with TM onset. Half of the total attacks occur within the first year of disease onset. Patients with = 2 McDonald MRI dissemination in space criteria were more common in the TM group and had a higher disability (EDSS) score.

Objective To assess the prevalence of dual positive NMOSD and outline its clinical phenotype. Background Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune syndrome that is frequently positive for Aquaporin 4 (AQP4) IgG or Myelin Oligodendrocyte Glycoproteins (MOG) IgG. However, dual positivity to both is rare. Design/Methods This is a retrospective cross-sectional study conducted at a tertiary healthcare center in South Asia between August 2018 and November 2021. The serum and/or CSF samples of suspected cases of NMOSD were tested for both AQP4-IgG and MOG-IgG using an Indirect immunofluorescence test on transfected cells. Results During the study period, 1935 cases of NMOSD were tested for both antibodies- 65 patients (3.36%; 57 females and 8 males) tested positive for AQP4-IgG, 217 patients (11.23%; 122 females and 95 males) tested positive for MOG-IgG and 3 patients (0.15%; 2 females and 1 male) showed dual positivity. There was a strong female preponderance in all three groups (87.69%, 56.22% and 66.66% respectively). This study identified 3 patients with dual positivity. The first patient (42 years, Male) presented with area postrema syndrome initially and subsequently relapsed by developing right-sided numbness of the temporal area and limbs during which he tested dual positive. The second patient (27 years, Female) presented with bilateral optic neuritis (left >right) initially and subsequently relapsed following an episode of a seizure with left-sided hemiplegia and right-sided facial deviation. The third patient (25 years, Female) initially presented with acute bilateral optic neuritis and later developed left-sided hemiplegia post-recovery at which point she tested dual positive. Management using methylprednisolone was ineffective for all three patients, however, plasmapheresis and/or periodic rituximab injections produced an excellent response. Conclusions Our study reports that the prevalence of dual positive NMOSD is 0.15% and its clinical phenotype is more similar to NMO rather than MOG- associated disease.

Microglia are involved in neuroinflammatory processes during diverse pathophysiological conditions. To date, the possible contribution of these cells to deoxynivalenol (DON)-induced brain inflammation and anorexia has not yet been evaluated. DON, one of the most abundant trichothecenes found in cereals, has been implicated in mycotoxicosis in both humans and farm animals. DON-induced toxicity is characterized by reduced food intake, weight gain, and immunological effects. We previously showed that exposure to DON induces an inflammatory response within the hypothalamus and dorsal vagal complex (DVC) which contributes to DON-induced anorexia. Here, in response to anorectic DON doses, we reported microglial activation within two circumventricular organs (CVOs), the area postrema (AP) and median eminence (ME) located in the DVC and the hypothalamus, respectively. Interestingly, this microglial activation was observed while DON-induced anorexia was ongoing (i.e., 3 and 6 h after DON administration). Next, we took advantage of pharmacological microglia deletion using PLX3397, a colony-stimulating factor 1 receptor (CSF1R)-inhibitor. Surprisingly, microglia-depleted mice exhibited an increased sensitivity to DON since non-anorectic DON doses reduced food intake in PLX3397-treated mice. Moreover, low DON doses induced c-Fos expression within feeding behavior-associated structures in PLX3397-treated mice but not in control mice. In parallel, we have highlighted heterogeneity in the phenotype of microglial cells present in and around the AP and ME of control animals. In these areas, microglial subpopulations expressed IBA1, TMEM119, CD11b and CD68 to varying degrees. In addition, a CD68 positive subpopulation showed, under resting conditions, a noticeable phagocytotic/endocytotic activity. We observed that DON strongly reduced CD68 in the hypothalamus and DVC. Finally, inactivation of constitutively active microglia by intraperitoneal administration of minocycline resulted in anorexia with a DON dose ineffective in control mice. Taken together, these results strongly suggest that various populations of microglial cells residing in and around the CVOs are maintained in a functionally active state even under physiological conditions. We propose that these microglial cell populations are attempting to protect the brain parenchyma from hazardous molecules coming from the blood. This study could contribute to a better understanding of how microglia respond to environmental contaminants.

A high-protein diet has become a popular way to lose weight. Calcium-sensing receptor (CaSR) is activated by amino acids in addition to calcium ions. CaSR shows dense expression in the area postrema (AP), which participates in feeding regulation. The effect of CaSR in the AP on food intake and the potential mechanism involved is investigated. Male C57BL/6 mice are used to observe the effect of R568 (agonist of CaSR) on food intake. Enzyme-linked immunosorbent assay, immunofluorescence staining, and chemogenetics are used to explore the neural signaling involved. CaSR activation in the AP inhibited acute feeding; R568 increases the content of glutamate and γ-aminobutyric acid (GABA) in the AP, whereas only glutamatergic neurons mediate the effect of R568. GABA-A receptor and ionic glutamate receptor (N-methyl-D-aspartate receptor [NMDAR]) in the paraventricular nucleus of hypothalamus (PVN) are involved in the effect of R568. Promotion of oxytocin (OT) synthesis in the PVN also participates in the effect of R568, and this mechanism is mediated by NMDAR in the PVN. CaSR activation in the AP suppresses feeding, and AP-PVN glutamatergic and GABAergic signaling pathways are involved.

Updates on clinical, investigatory, and therapeutic aspects of neuromyelitis optica (NMO) spectrum disorders are rapidly evolving. Recently published international consensus diagnostic criteria (ICDC) allowed clinicians to rapidly diagnose the expanding spectrum of NMO spectrum disorders more accurately. The aim of the study was to retrospectively analyze 36 consecutive cases of comprehensively evaluated NMO spectrum disorders using the ICDC. We retrospectively collected 36 cases of NMO spectrum disorders who attended our unit between August 2012 andOctober 2016 and fulfilled the ICDC. All patients underwent magnetic resonance imaging (MRI) of the brain and whole spine with contrast, anti-aquaporin 4 antibody, and detailed blood investigations to rule out systemic vasculitis and other alternate diagnoses. Female-to-male ratio was 6.2:1; 50% of the cases were in the 20-40-year age group. Six patients (16.67%) had combined optic neuritis and myelitis.Nine patients (25%) had pure longitudinally extending transverse myelitis LETM with positive anti aquaporin 4 antibody AQ4Ab. Fourteen patients (38.9%) had myelitis and optic neuritis separately. Nine patients (25%) had area postrema syndrome. Two patients (5.6%) had acute brainstem syndrome and one (2.8%) had hypothalamic syndrome. LETM was commonly found in the cervical level (69.4%).Four patients (11.1%) had no spinal cord involvement. Anti-aquaporin 4 antibody was positive only in 23 cases (63.9%). Initial presentation of NMO spectrum disorder is often due to brain lesions. The ICDC criteria have enhanced clinician's ability to diagnose NMO spectrum disorder in the early stages. In our study, ICDC criteria helped us to diagnose 33% additional cases that would have been missed if the old 2006 revised criteria was applied.

Cushing's syndrome is due to increased glucocorticoid levels in the body, and it is characterized by several clinical alterations which concern both vegetative and behavioral functions. The anatomical correlates of these effects remain largely unknown. Apart from peripheral effects induced by corticosteroids as counter-insular hormones, only a few reports are available concerning the neurobiology of glucocorticoid-induced vegetative and behavioral alterations. In the present study, C57 Black mice were administered daily a chronic treatment with corticosterone in drinking water. This treatment produces a significant and selective increase of TH-positive neurons within two nuclei placed in the lateral column of the brainstem reticular formation. These alterations significantly correlate with selective domains of Cushing's syndrome. Specifically, the increase of TH neurons within area postrema significantly correlates with the development of glucose intolerance, which is in line with the selective control by area postrema of vagal neurons innervating the pancreas. The other nucleus corresponds to the retrorubral field, which is involved in the behavioral activity. In detail, the retrorubral field is likely to modulate anxiety and mood disorders, which frequently occur following chronic exposure to glucocorticoids. To our knowledge, this is the first study that provides the neuroanatomical basis underlying specific symptoms occurring in Cushing's syndrome.

The development of a novel antioxidant-based antiemetic drug to improve quality of life during anticancer therapy

The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease-modifying therapies may result in permanent neurological disability. Standardized 3-Tesla 3-dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross-sectionally and longitudinally. An ideal introverted planar triangle threshold separating groups with NMOSD and MS was accomplished using the highest Youden's J statistic. For the classification of NMOSD, out-of-sample and in-sample measurements of the following were acquired: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The study cohort included 60 people with NMOSD, 100 people with MS, 12 with other neurological diseases, and five healthy controls. Significantly higher cross-sectional median introverted triangle counts were observed when the NMOSD (median [interquartile range]: 100 [23.5]) group was compared to MS (65 [20.25]; p<.0001) and other neurological diseases (66 [13.75]; p<.0001). Distinct spatial dissemination patterns of triangles extending craniocaudally at the region of interest within the dorsal medulla was also seen between groups with NMOSD and MS (p<.0001). For the identification of NMOSD, out-of-sample sensitivity (83%), specificity (100%), PPV (100%), and NPV (60%) were achieved. Cross-sectional and longitudinal dorsal medulla surface texture differences within selective regions of vulnerability differentiate NMOSD from MS.

Background and ObjectivesTo report the frequency of area postrema syndrome (APS) in glial fibrillary acidic protein-immunoglobulin G (GFAP-IgG)–positive patients and emphasize the importance of APS among the phenotypes in autoimmune GFAP astrocytopathy.MethodsEight GFAP-IgG–positive cases with APS were retrospectively identified during 2015–2021. The APS phenotypes were described. A literature review of 8 previously reported cases was also included in analysis.ResultsA total of 8 patients (11%) (1 woman, 7 men; mean age: 52.4 ± 18.4 years) presented with APS in a cohort of 74 GFAP-IgG–positive patients, 3 of whom (4%) had disease onset with APS. All patients had hiccups, and hiccups was the unique symptom of APS in 5 patients. The median time from disease onset to APS occurrence was 2 days (range 0–20), and the mean duration of APS episodes was 23.6 ± 11.4 days. No patient had isolated APS attack. All episodes were completely resolved with a mean duration of 9.3 ± 5.4 days after immunotherapy. APS manifestations of 8 cases in previous studies showed similar features with our cases. In total, coexisting aquaporin-4-IgG was only detected in one of the 16 cases.DiscussionAPS could be an early, but not isolated clinical manifestation of autoimmune GFAP astrocytopathy. Hiccups was the predominant symptom of APS in this disorder. APS attacks of autoimmune GFAP astrocytopathy have good response to immunotherapy.

ABSTRACTWhile rotavirus diarrhea has been considered to occur only due to intrinsic intestinal effects within the enteric nervous system, we provide evidence for central nervous system control underlying the clinical symptomology. Our data visualize infection by large-scale three-dimensional (3D) volumetric tissue imaging of a mouse model and demonstrate that rotavirus infection disrupts the homeostasis of the autonomous system by downregulating tyrosine hydroxylase in the noradrenergic sympathetic nervous system in ileum, concomitant with increased intestinal transit. Interestingly, the nervous response was found to occur before the onset of clinical symptoms. In adult infected animals, we found increased pS6 immunoreactivity in the area postrema of the brain stem and decreased phosphorylated STAT5-immunoreactive neurons in the bed nucleus of the stria terminalis, which has been associated with autonomic control, including stress response. Our observations contribute to knowledge of how rotavirus infection induces gut-nerve-brain interaction early in the disease.

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.

Many potential causes of optic nerve inflammation exist, including typical and atypical causes, which require different management strategies. The objective of this study is to identify red flags that help differentiate typical from atypical optic neuritis (ON). This prospective study included 66 patients (100 eyes) with immune-mediated ON from January 2016 to June 2019, carefully excluding the nonimmune causes. The clinico-radiological features, investigations, therapy, and outcome were analyzed. We evaluated 33 cases each of typical and atypical ON. The typical group included 29 idiopathic ON and four associated with multiple sclerosis. Atypical ON included 19 neuromyelitis optica (NMO), seven MOG-associated ON (MOG-ON), and others due to Sjogren's syndrome, granulomatous polyangiitis, sarcoidosis, and IgG4 disease. Atypical ON occurred significantly and more frequently with extremes of ages (<10 or >70 years), bilateral simultaneous or severe vision loss with early disc pallor, multiple attacks, symptoms/neuro-imaging indicating non-MS disease e.g., long segment ON/myelitis, large confluent lesions, the involvement of optic tract, chiasma, area postrema or diencephalon, and (pachy) meningitis. Systemic involvement and poor outcomes despite steroids and second-line immunosuppression were observed more often in the atypical ON. The red flags indicating atypical ON are onset at extremes of age, multiple attacks, bilateral simultaneous or severe to very severe vision loss, early disc pallor, neurological symptoms, or imaging abnormalities suggesting non-MS disease, systemic involvement, and poor steroid responsiveness. The awareness might help the clinician promptly identify and escalate therapy to ensure a better outcome.

Acute optic neuritis (ON) is caused by variety of complex disorders that can be differentiated with the help of history, radiology, and serology. Identification of nonneurological symptoms that occur before the demyelinating event aids in timely diagnosis and prevention of further neurological attacks. We describe a case of unilateral ON with a history of intractable hiccups, nausea, and vomiting, wherein the possibility of area postrema syndrome (APS) was overlooked until the development of visual symptoms. APS recently identified as a hallmark of neuromyelitis optica spectrum disorder is a rare neurologic cause of gastrointestinal symptoms. This atypical presentation of APS results from autoantibodies directed against the aquaporin-4 rich sites, such as area postrema. This case brings to light the importance of eliciting history of intractable hiccups, nausea, and vomiting in a patient with ON. Despite being a commonly encountered symptom, it may rarely raise a suspicion for neuromyelitis optica.

The prevalence, incidence, and clinical assessment of neuromyelitis optica spectrum disorder in patients with demyelinating diseases

BackgroundArea postrema syndrome (APS) as the isolated manifestation in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy has been rarely reported.Case presentationA 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.ConclusionsWe 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.

Chronic pain is more prevalent and reported to be more severe in women. Opioid analgesics are less effective in women and result in stronger nauseant effects. The neurobiological mechanisms underlying these sex differences have yet to be clearly defined, though recent research has suggested neuronal–glial interactions are likely involved. We have previously shown that similar to people, morphine is less effective at reducing pain behaviors in female rats. In this study, we used the immunohistochemical detection of glial fibrillary acidic protein (GFAP) expression to investigate sex differences in astrocyte density and morphology in six medullary regions known to be modulated by pain and/or opioids. Morphine administration had small sex‐dependent effects on overall GFAP expression, but not on astrocyte morphology, in the rostral ventromedial medulla, the subnucleus reticularis dorsalis, and the area postrema. Significant sex differences in the density and morphology of GFAP immunopositive astrocytes were detected in all six regions. In general, GFAP‐positive cells in females showed smaller volumes and reduced complexity than those observed in males. Furthermore, females showed lower overall GFAP expression in all regions except for the area postrema, the critical medullary region responsible for opioid‐induced nausea and emesis. These data support the possibility that differences in astrocyte activity might underlie the sex differences seen in the processing of opioids in the context of chronic neuropathic pain.

BackgroundAlexander 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 presentationA 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.ConclusionsThis 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.

Body weight and adiposity represent biologically controlled parameters that are influenced by a combination of genetic, developmental and environmental variables. Although the hypothalamus plays a crucial role in matching caloric intake with energy expenditure to achieve a stable body weight, it is now recognized that neuronal circuits in the hindbrain not only serve to produce nausea and to terminate feeding in response to food consumption or during pathological states, but also contribute to the long-term control of body weight. Additionally, recent work has identified hindbrain neurons that are capable of suppressing food intake without producing aversive responses like those associated with nausea. Here we review recent advances in our understanding of the hindbrain neurons that control feeding, particularly those located in the area postrema and the nucleus tractus solitarius. We frame this information in the context of new atlases of hindbrain neuronal populations and develop a model of the hindbrain circuits that control food intake and energy balance, suggesting important areas for additional research.

Introduction Neuromyelitis optica spectrum disorders (NMOSD) would disproportionately affect blacks within mixed populations. However, they are rarely reported in black African. The objective of this work was to report the experience of Togo, a West African country in terms of NMOSD. Methods This is a series of six cases diagnosed between 2015 and 2020 in the only three neurology departments in Togo. The diagnosis of NMOSD was made according to the criteria of the International Panel for NMO Diagnosis (2015) and the patients had a minimum clinical follow-up of 6 months after the diagnosis. The search for anti-aquaporin 4 (AQP4) antibodies was performed by immunofluorescence on transfected cells. Results The mean age was 25.33 years and the sex ratio female/male was 5/1. The average time between the first attack and the diagnosis was 122.83 days. Clinically, there was isolated medullary involvement (2/6), simultaneous opticomedullary involvement (3/6), and area postrema syndrome (1/6). Five patients were anti-AQP4 positive. All six patients had extensive longitudinal myelitis. At 6 months of follow-up, there was one case of death and one case of blindness. Conclusion The rarity of NMOSD cases in Togo could be linked to an underestimation. To better characterize the NMOSDs of the black African population, multicenter and multidisciplinary studies are necessary.

Radial glia-like cells in the hypothalamus and dorsal vagal complex are neural precursors (NPs) located near subventricular organs: median eminence and area postrema, respectively. Their strategic position can detect blood-borne nutrients, hormones, and mitogenic signals. Hypothalamic NPs increase their proliferation with a mechanism that involves hemichannel (HC) activity. NPs can originate new neurons in response to a short-term high-fat diet as a compensatory mechanism. The effects of high carbohydrate Western diets on adult neurogenesis are unknown. Although sugars are usually consumed as sucrose, more free fructose is now incorporated into food items. Here, we studied the proliferation of both types of NPs in Sprague Dawley rats exposed to a short-term high sucrose diet (HSD) and a control diet. In tanycyte cultures, we evaluated the effects of glucose and fructose and a mix of both hexoses on HC activity. In rats fed an HSD, we observed an increase in the proliferative state of both precursors. Glucose, either in the presence or absence of fructose, but not fructose alone, induced in vitro HC activity. These results should broaden the understanding of the nutrient monitoring capacity of NPs in reacting to changes in feeding behavior, specifically to high sugar western diets.