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Original Investigation |

Frequency of Synaptic Autoantibody Accompaniments and Neurological Manifestations of Thymoma

Anastasia Zekeridou, MD1; Andrew McKeon, MD1,2; Vanda A. Lennon, MD, PhD1,2,3
[+] Author Affiliations
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
2Department of Neurology, Mayo Clinic, Rochester, Minnesota
3Department of Immunology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. 2016;73(7):853-859. doi:10.1001/jamaneurol.2016.0603.
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Importance  Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG–mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma.

Objective  To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma.

Design, Setting, and Participants  We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26).

Main Outcomes and Measures  Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems.

Results  Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG.

Conclusions and Relevance  Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).

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Figure.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–IgG Detected by Indirect Immunofluorescence on Mouse Brain

IgG in serum of patient with thymoma-related paraneoplastic encephalitis binds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in mouse brain tissue.

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