Intractable hiccups as a brainstem red flag: demyelinating disorders with emphasis on neuromyelitis optica spectrum disorder and area postrema syndrome

Abstract

Persistent and intractable hiccups may indicate brainstem pathology rather than benign gastrointestinal causes. Among inflammatory demyelinating disorders, neuromyelitis optica spectrum disorder (NMOSD) frequently involves the dorsal medulla, particularly the area postrema, a key structure in the hiccup reflex arc. Area postrema syndrome (APS), characterized by otherwise unexplained hiccups, nausea, or vomiting lasting ≥ 48 h, represents a core diagnostic feature of NMOSD. A structured narrative literature review was conducted using PubMed, Scopus, and Web of Science databases from inception to January 2026. Studies addressing persistent or intractable hiccups associated with demyelinating disorders, including NMOSD, multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), were analyzed with emphasis on neuroanatomical, immunopathological, and radiological correlations. NMOSD is the prototypical demyelinating disorder associated with intractable hiccups due to selective astrocytic injury in the area postrema. APS may precede optic neuritis or myelitis and can represent the initial manifestation of disease. Multiple sclerosis and MOGAD may also involve the brainstem but differ in lesion distribution, immunopathology, and treatment implications. Early recognition of dorsal medullary involvement and antibody testing is critical for accurate diagnosis and timely immunotherapy. Intractable hiccups should be recognized as a potential brainstem red flag symptom. Awareness of their association with NMOSD and related demyelinating disorders facilitates early diagnosis, appropriate immunotherapy, and prevention of neurological disability.