A Rare, Autoimmune Cause of Intractable Nausea and Vomiting

Some cases of unexplained, intractable vomiting are caused by an autoimmune disorder in which patients develop antibodies against the brain protein astrocytic aquaporin-4 (AQP4), according to the March issue of Clinical Gastroenterology and Hepatology.

AQP4 is a water channel in the central nervous system. Antibodies against AQP4 cause neuromyelitis optica spectrum disorders (NMOSDs)—relapsing inflammatory demyelinating disorders of the central nervous system. NMOSDs primarily affect the optic nerves and spinal cord, but AQP4 is also present in the brainstem area postrema, which controls vomiting. NMOSDs can therefore cause intractable nausea, vomiting, and hiccups.

Patients with NMOSDs commonly undergo extensive evaluations that do not lead to a diagnosis, because many physicians are unaware of this emerging neurologic entity.

Raffaele Iorio et al. analyzed data from a total of 139 patients who tested positive for antibodies against AQP4 at the Mayo Clinic, and found that 13% came to their doctors with intractable nausea and vomiting as their initial symptoms.

“We observed that a significant proportion of patients seem to complain of intractable vomiting nausea, with or without hiccups, preceding the onset of their optic neuritis or transverse myelitis,” said Sean Pittock, the study’s senior author, in a video abstract.

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Pittock added that the vomiting lasted from 1 to 90 days, and preceded the development of the neurologic symptoms by up to 720 weeks.

The authors found that 70% of the patients initially presented to a gastroenterologist or an internist, and that extensive investigation revealed no gastroenterological explanation for their symptoms.

The NMOSD can be confirmed by magnetic resonance imaging analysis, to identify lesions in the area postrema— a structure in the brain’s medulla that controls vomiting and contains high levels of AQP4.

Early diagnosis is important, so patients can receive immunosuppressive therapy; 50% of untreated patients become blind in 1 or both eyes or confined to a wheelchair within 5 years of disease onset.

How do these antibodies cause this disorder? AQP4 is present on the pasma membrane of astroglial cells in area postrema, where it is accessible to circulating antibodies. Binding of antibodies leads to cross-linking and internalization of AQP4 and its membrane partner molecules. Iorio et al. propose that antibody-induced down-regulation of AQP4 disrupts water or neurotransmitter homeostasis to activate area postrema neurons, and vomiting ensues.

“If you see a patient that has intractable vomiting of unclear etiology, in which there does not appear to be a gastroenterologic cause, consider the possibility of AQP4 autoimmunity,” Pittock says in the video abstract.

However, NMOSDs are rare (an estimated prevalence of 0.5–4.4 per 100,000 people). When the authors analyzed data from control patients who presented with idiopathic nausea or vomiting (318 with gastroparesis and 117 without gastroparesis), none were seropositive for antibodies against AQP4.

Nevertheless, AQP4 autoimmunity can be added to diagnosable central causes of intractable nausea and vomiting in patients with no evidence for gastroparesis.

Read the article online.
Iorio R, Lucchinetti CF, Lennon VA, et al. Intractable nausea and vomiting from autoantibodies against a brain water channel. Clin Gastroenterol Hepatol 2013;240–245.

1 Comment

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    Lee Ann Lutz-Badders March 12, 2013

    Could there be a connection to Cyclic Vomiting Syndrome?

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