Characteristics of recurrence in area postrema-onset NMO spectrum disorder - a retrospective cohort study.

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.

Isolated Area Postrema Syndrome Preceding the Diagnosis of Giant Cell Arteritis: A Case Report.

OBJECTIVE: We report a case of biopsy-proven giant cell arteritis after an initial presentation of area postrema syndrome. METHODS: A 65-year-old man was evaluated using MRI, temporal artery biopsy, and ultrasound. RESULTS: The patient presented with refractory nausea, vomiting, and hiccups that caused weight loss without any other neurologic or clinical symptoms. His MRI scan 15 days later revealed a hyperintense sign on the area postrema with no abnormal diffusion or contrast enhancement, compatible with isolated area postrema syndrome. An extensive workup for inflammation and other etiologies including neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody disorder, and multiple sclerosis (MS) showed negative results. The patient responded to treatment with methylprednisolone. Two months after the initial clinical manifestation, the patient developed fatigue, headache, and scalp tenderness. He was diagnosed with giant cell arteritis after ultrasonography and biopsy were performed. He responded well to oral glucocorticoids and had only 1 relapse during tapering. He has not had arteritic ischemic optic neuropathy or any new episodes of area postrema syndrome. DISCUSSION: This case demonstrates the importance of expanding the differential diagnosis in patients with area postrema syndrome and no other signs of NMOSD.

Clinical analysis of neuromyelitis optica spectrum disease with area postrema syndrome as the initial symptom.

OBJECTIVE: The objective of this study was to report and discuss clinical analysis, including the diagnosis and treatment of 4 cases of neuromyelitis optica spectrum disease (NMOSD) with area postrema syndrome (APS) as the first symptom. METHODS: Four patients with intractable nausea, vomiting, and confirmed NMOSD were included in the final analysis. All of these patients were initially misdiagnosed and mismanaged. RESULTS: Among the 4 patients, 3 were admitted to the department of gastroenterology at the onset of the disease, and 2 were not correctly diagnosed and treated promptly due to misdiagnosis. Therefore, their symptoms worsened, and they were transferred to Intensive Care Unit (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, after which the disease 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 magnetic resonance imaging (MRI) findings can influence the final diagnosis. Early identification of the APS and timely therapy can prevent visual and physical disabilities, even respiratory failure, coma, 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.

Area postrema syndrome caused by medullary infarction.

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.

Symptomatic care of late-onset Alexander disease presenting with area postrema-like syndrome with prednisolone; a case report.

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.

Neurenteric cyst of the area postrema causing intractable nausea and vomiting.

Neurenteric cysts are rare, benign congenital lesions of the central nervous system. We present a case of a 59-year-old woman with intractable daily nausea and vomiting with a fourth ventricular cyst adjacent to the area postrema. This was surgically resected leading to complete symptom resolution.

Area Postrema: Fetal Maturation, Tumors, Vomiting Center, Growth, Role in Neuromyelitis Optica.

INTRODUCTION: The area postrema in the caudal fourth ventricular floor is highly vascular without blood-brain or blood-cerebrospinal fluid barrier. In addition to its function as vomiting center, several others are part of the circumventricular organs for vasomotor/angiotensin II regulation, role in neuromyelitis optica related to aquaporin-4, and somatic growth and appetite regulation. Functions are immature at birth. The purpose was to demonstrate neuronal, synaptic, glial, or ependymal maturation in the area postrema of normal fetuses. We describe three area postrema tumors. METHODS: Sections of caudal fourth ventricle of 12 normal human fetal brains at autopsy aged six to 40 weeks and three infants aged three to 18 months were examined. Immunocytochemical neuronal and glial markers were applied to paraffin sections. Two infants with area postrema tumors and another with neurocutaneous melanocytosis and pernicious vomiting also studied. RESULTS: Area postrema neurons exhibited cytologic maturity and synaptic circuitry by 14 weeks'. Astrocytes coexpressed vimentin, glial fibrillary acidic protein, and S-100ß protein. The ependyma is thin over area postrema, with fetal ependymocytic basal processes. A glial layer separates area postrema from medullary tegmentum. Melanocytes infiltrated area postrema in the toddler with pernicious vomiting; two children had primary area postrema pilocytic astrocytomas. CONCLUSIONS: Although area postrema is cytologically mature by 14 weeks, growth increases and functions mature during postnatal months. We recommend neuroimaging for patients with unexplained vomiting and that area postrema neuropathology includes synaptophysin and microtubule-associated protein-2 in patients with suspected dysfunction.

Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD.

OBJECTIVE: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS). METHODS: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers. RESULTS: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort. CONCLUSION: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.

[The clinical analyses of neuromyelitis optica spectrum disorder initially presenting with area postrema syndrome in 14 patients].

Objective: To explore the clinical characteristics of the neuromyelitis optica spectrum disorders (NMOSD) with the area postrema syndrome as the initial symptom. Methods: A total of 14 cases were enrolled in the study with the diagnose of NMOSD and the area postrema syndrome as the initial symptom. All the clinical data and imaging profiles by the contrasted magnetic resonance imaging (MRI) of the head and spinal cord were collected and analyzed. Results: The median age of onset was (38.1±17.0) years old and the gender ratio of female to male was 10∶4. The serum aquaporin-4(AQP4)-IgG was positive in 11 subjects and several autoimmune antibodies was positive in 7 subjects. The lesions revealed by MRI of the head mainly located in the area postrema and ependymal periphery which often presented as the linear medullary lesion, while linear lesions over three pieces of vertebra were shown by MRI of the spinal cord which mainly in the grey matter and with a"H" shape around the spinal central canal. Misdiagnose happened in 11 subjects with seven of gastroesophageal reflux disease, two of neurogenic vomiting, one of spinal cord tuberculosis and one of stroke. Conclusions: NMOSD should be considered in patients with unexplained intractable nausea, vomiting and/or hiccups lasted for 48 hours or above, especially in those with positive nervous signs. Contrasted MRI and serum AQP4-IgG need to be performed in the suspected patients. Early detection is crucial for patients with NMOSD.

[Area postrema lesion as a cause of intractable nausea, vomiting and hiccups in neuromyelitis optica spectrum disorders]. / Porazhenie area postrema kak prichina neukrotimoi ikoty, toshnoty i rvoty pri zabolevaniiakh optikomielitnogo spektra (nabliudenie iz praktiki).

Neuromyelitis optica (Devic's disease) is a chronic autoimmune disease associated with the production of anti-bodies to aquaporin-4 (AQP4). Area postrema lesions is the third, after optic neuritis and myelitis, syndrome of opticomyelitis-related disorders. Clinical symptoms of this disorder include intractable nausea, vomiting and hiccups. In many cases, area postrema syndrome manifests as the first clinical symptom of a neuromyelitis optica spectrum disorder that hampers the diagnosis. The authors present a case report of a female patient with area postrema lesions developed several months before the first disabling attack of myelitis.

Effects of +Gz Loads on Structural Organization of Central Autonomic Nuclei.

Structural alterations in the central autonomic nuclei (dorsal vagal complex and intermediolateral nucleus) of the centrifuged random-bred male rats subjected to +Gz loads were examined. Acute exposure to gravitational loads predominantly produced the reactive changes in these nuclei, while persistently repeated regular loads resulted in cumulation of the destructive alterations. The structural perturbations in the central autonomic nuclei can disturb the autonomic regulation of physiological functions. The character of such disturbances is partially determined by the peculiarities in structural organization of these nuclei.

Sudden Infant Death With Area Postrema Lesion Likely Due to Wrong Use of Insecticide.

We report a noteworthy case of a 7-month-old infant who suddenly and unexpectedly died during her sleep. After a complete postmortem examination, review of the clinical history, and detailed death scene investigation, the death remained unexplained, leading to a diagnosis of sudden infant death syndrome. However, an extensive review of the brainstem neuropathology revealed a severe alteration in the area postrema (a highly vascular structure lying at the base of the fourth ventricle outside of the blood-brain barrier). The alteration was likely due to massive and repeated to a common household insecticide in the last few weeks of life. These results provide an explanation for this sudden infant death, allowing a differential diagnosis from sudden infant death syndrome.

Chronic Psychological Distress as an Inducer of Microglial Activation and Leukocyte Recruitment into the Area Postrema.

BACKGROUND: Chronic psychological distress can cause neuroinflammation, but the involvement of leukocytes in this inflammatory response remains unclear. The area postrema (AP) is considered a neural-immune interface because it lacks a blood-brain barrier and a site for leukocyte recruitment in neuroinflammatory conditions induced by immunological insults, but its role in chronic psychological distress has not been explored. OBJECTIVE: To determine leukocyte recruitment to the AP after chronic psychological distress. METHODS: Rats were exposed to cat odor for 5 consecutive days to induce distress, and, on the 6th day, their brains were dissected to perform immunohistofluorescence studies of the AP. Immune cells were identified and quantified with CD45 and CD11b markers. The distribution of neurons and immune cells was determined using TrkA and CD45 markers, respectively. RESULTS: Distress induced a significant increase in CD45(+) and CD11b(+) cells in the AP. Three immunophenotypes were determined in the control and distress groups: CD45(+)/CD11b(-), CD45(+)/CD11b(+) and CD45(-)/CD11b(+). CD expression, morphology and fluorescence intensity enabled the identification of different immune cell types: starting from longitudinal ramified microglia (mainly in the control group) to amoeboid microglia, monocytes and lymphocytes (mostly in the distressed group). TrkA and CD45 expression in the AP revealed the proximity between soma neurons and leukocytes. Interestingly, some CD45(+) cells expressed TrkA, with increased expression in the distressed group. CONCLUSIONS: The identification of microglial activation, leukocyte recruitment and the close proximity between neurons and leukocytes in the AP after chronic psychological distress exposure suggests the AP as a site for distress-induced immune responses and engraftment of leukocytes infiltrating the CNS.

Brain tumors and the area postrema.

Brain tumors can rarely present with symptoms mistaken for anorexia nervosa. We report a patient with a long-standing history of anorexia who developed headaches and was found on brain MRI to have a brain tumor in the area of the fourth ventricle. On admission, the patient presented with a 4 month history of headaches and a 10 year history of "anorexia nervosa". Interestingly, the patient did not endorse the classic sense of an altered self-body image. Her body weight on admission was 37 kg. The patient underwent surgical resection of the tumor. On postoperative day (POD) 1, the patient subjectively reported an increased appetite. On POD 2, we documented that she finished her entire food tray for the first time during her hospital stay. Her peri-operative course was without any complications. She presented for a follow-up clinic visit 2 weeks postoperatively and was noted to have a new body weight of 47 kg (10 kg gain). To our knowledge, this is the first reported occurrence of a sporadic, and third overall occurrence, of a hemangioblastoma that presented with an anorexia nervosa-like syndrome that was ultimately cured with surgical resection. In patients presenting with a history of psychiatric illness, it is important to consider the possibility of underlying, organic pathologies in the central nervous system affecting the relevant neuro-anatomical domains.