Autoimmune autonomic neuropathy (AAN)

Timothy C. Hain, MD Page last modified: May 5, 2020
Also see: syncope orthostatic dysautonomia cough syncopePOTs Rehab training for POTs Tilt table testing

Autoimmune autonomic neuropathy is a recently described disorder in which patients report difficulties with maintaining blood pressure, usually combined with gastrointestinal problems and dry eyes/unreactive pupils. It is attributed to antibodies to the ACH receptor ganglionic antibody, called the "G-AChR" antibody (Sandroni and Low, 2009). Note that this is NOT the same antibody as the AcHR antibody used to help with diagnosis of myasthenia gravis -- it has a "G" in front of it to denote that it is the antibody associated with the autonomic ganglion. This topic was recently reviewed by Golden and vernino (2019). See also the syncope page and the orthostatic hypotension pages.

This syndrome, was first clearly described by Harik et al (1977), in a patient with lack of tears and saliva, lack of stomach and bladder motility, absent sweating and hypertension. It would seem a little close to "the Holmes-Adie" syndrome which affects both peripheral nerves and pupils.

Vernino et al (1998) reported on 12 patients with positive blood tests -- both from 12 patients with autonomic neuropathy as well as other 247 neurological disorders, some of which had cancer. About 1/3 of their 12 patients had cancer. None of their 52 healthy subjects had these antibodies. Note that only 5 of the 12 patients they reported had positive blood tests -- thus the "hit rate" for this blood test is about 50-50, in patients who have appropriate findings.

In 2003, Vernino again reported on this in rabbits and suggested that symptoms include ones related to the heart, dry eyes, and dilated pupils, gastroparesis, hypotension, and low plasma catacholamines.

According to Sandroni et al (2004), More than 50% of patients with high levels of ganglionic acetylcholine receptor (AChR -- now called G-AchR) autoantibodies have a combination of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light response, upper gastrointestinal tract symptoms, and neurogenic bladder. Mild versions of most of these symptoms occur in most of patients when they are asked.

So as a summary of the AAN syndrome --it should include dry eyes, abnormal pupils, and cardiac disturbance.

Causes of AAN

Abnormal antibodies are attributed (as usual) to viruses, autoimmune disorders, and occasionally to cancer. There are many case reports. Nakao et al (2016) reported a case following CMV infection. Inamura et al (2020) noted that anti-gAChR antibodies can be found in rheumatologic disorders. Jahngir et al (2018) reported a case report in lymphoma (2018).

Evaluation of AAN

Physical examination should include at a minimum

Routine Laboratory Testing for AAN:

In addition to testing for dysautonomia (see above), the key diagnostic test is to check for G-AChR receptor antibodies. This diagnosis requires a positive blood test for these antibodies. Note that this blood test is positive roughly 50% of the time in patients with subacute autonomic neuropathy, and also is positive about 50% of the time in patients without any autonomic neuropathy at all. Thus it has substantial false positives, and perhaps (it is hard to say lacking a gold standard) also substantial false negatives. Note also that the G-AChR test is not the same as the AChR test for myasthenia gravis. It is important not to get these confused.

Treatment

In persons with positive antibodies, the main treatment effort is directed at reducing the antibodies. Syngle et al (2015) reported that disease modifying anti-rheumatic drugs improved autonomic dysfunction.

Regarding IVIG, Dupond et al (1999) reported treatment with IVIG in 2 cases of autononomic neuropathy (neither one of which was tested for ACH antibodies). Ishitobi also reported recovery after IVIG, again without ACH antibodies. Lukkarinen et al (2010) also reported response to IVIG, again without ACH antibodies. So as a summary, IVIG has helped some patients with similar symptoms.

Regarding plasmapheresis - -as of 2015, there were no papers concerning use of plasmapheresis for autoimmune autonomic neuropathy. It seems reasonable to try however.

Bouxin et al (2019) reported success using rituximab and steroids, after IVIG and plasmapheresis failure.

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