The Clinicopathologic Features of Amphiphysin-IgG Autoimmune Neuropathy

Amphiphysin-immunoglobulin G (IgG)-mediated autoimmunity is an important clinical entity characterized by neuropathy, good clinical response to immunotherapy, and increased prevalence of breast cancer, according to study results published in Neurology.

Amphiphysin-IgG autoimmunity was first reported in stiff-person syndrome with breast cancer, and later reports revealed an association with lung cancer. As there is limited information on involvement with the peripheral nervous system, researchers aimed to explore the clinicopathologic features of amphiphysin-IgG-mediated neuropathy.

The study included patients from the Mayo Clinic in Rochester, Minnesota, with evidence of amphiphysin-IgG antibodies on immunofluorescence and Western blot.  Amphiphysin-IgG phenotypes were compared with patients with coexisting autoantibodies and collapsin response-mediator protein-5 (CRMP5)-IgG-isolated neuropathy or cases of anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity.

Of 53 study patients with amphiphysin-IgG-positive, 33 (60%) had neuropathy, including 21 with isolated amphiphysin-IgG, 8 with amphiphysin-IgG and ANNA1-IgG antibodies, 2 with amphiphysin-IgG and CRMP5-IgG antibodies, and 2 patients with all 3 autoantibodies.

In patients with isolated amphiphysin-IgG (19 women; median age 65 years), polyradiculoneuropathy was the most common neuropathy phenotypic presentation (62%), followed by diffuse sensory neuronopathy (35%), and facial neuropathy and gastric dysmotility (3%).

Breast cancer was the most common malignancy documented in patients with isolated amphiphysin-IgG (63%), followed by large cell lung cancer (5.5%) and lung adenocarcinoma (5.5%). In most cases (76%) the diagnosis of neuropathy preceded cancer detection. Pain was a common feature (80%), as was central nervous system involvement (45%).

In amphiphysin-IgG cases with coexisting paraneoplastic antibodies, sensory neuronopathy was the most common phenotypic presentation. In this group, small cell cancer was the most common malignancy (75%), with a single case of breast cancer.

Nerve biopsies in isolated amphiphysin-IgG alone cases (n=6) had markedly reduced axonal fiber loss with subperineurial edema in 4 and large epineurial perivascular inflammation in 2 patients.

Immunotherapy was used for management of neuropathy in 15 patients, with a favorable outcome — defined as ≥1 improvement on modified Rankin Scale (mRS) during follow-up — evident in 58% of patients. Furthermore, there was a significantly higher change in mRS compared with patients treated with only cancer treatment or symptomatic treatment (P =.042). 

A significantly higher percentage of patients with amphiphysin-IgG neuropathy had a favorable outcome (44% vs 16%; odds ratio 4.2; 95% CI, 1.1-15.5; P =.028). Only 1/9 patients (11%) with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had an immunotherapy response.

The researchers acknowledged several study limitations, including the small study sample, retrospective design, and variable immunotherapy regimens used.

“This work facilitates understanding of peripheral nerve involvement in amphiphysin-IgG autoimmunity,” concluded the researchers.

Reference

Dubey D, Jitprapaikulsan J, Bi H, et al. Amphiphysin-IgG autoimmune neuropathy: a recognizable clinicopathologic syndrome [published online October 17, 2019]. Neurology. doi:10.1212/WNL.0000000000008472