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

Abstract

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.

Figure 1. Frequency of APS in patients with NMOSD stratified according to ethnicity

Frequency of APS, total number of attacks (A, B), either isolated APS (C, D) or along with other neurologic disorders (APS-plus: APS with optic neuritis and/or transverse myelitis and/or cerebral lesions [E, F]) during initial attack or subsequent relapses based on ethnicity in a multicenter international NMOSD database from 3 different countries (Japan [69 Asian descent patients], United Kingdom [118 Caucasian, 23 African descent, 16 Asian patients], and United States [122 Caucasian, 33 African descent, 19 Asian]). Note that details of APS on some patients included in this database may have been published in the context of single-center case series. APS = area postrema syndrome; NMOSD = neuromyelitis optica spectrum disorder.

Figure 2. MRI abnormalities in AQP4-IgG–seropositive neuromyelitis optica spectrum disorder patients with APS

MRI head demonstrates a hyperintense lesion in the area postrema adjacent to the 4th ventricle on axial fluid-attenuated inversion recovery (A, arrow) in a patient with APS. In a separate patient, an enhancing lesion is noted the same region on axial T1-weighted head MRI postgadolinium administration (B, arrow). In a third patient a T2-hyperintense lesion in the area postrema is best seen on sagittal T2-weighted MRI of the cervical spine MRI (C, arrow). In a fourth patient, enhancement in the area postrema is demonstrated on sagittal T1-weighted cervical spine MRI post gadolinium (D, arrow). APS = area postrema syndrome; AQP4-IgG = aquaporin-4–immunoglobulin G.

Figure 3. APSS scores at nadir, and post therapy

Change in APSS scores after symptomatic and immunosuppressant therapies for 20 patients with both nadir and posttherapy scores. APSS = Area Postrema Severity Scale.