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November 12, 2019; 93 (20) Article

Amphiphysin-IgG autoimmune neuropathy

A recognizable clinicopathologic syndrome

Divyanshu Dubey, View ORCID ProfileJiraporn Jitprapaikulsan, Hongyan Bi, Rocio Vazquez Do Campo, Andrew McKeon, Sean J. Pittock, Janean K. Engelstad, John R. Mills, View ORCID ProfileChristopher J. Klein
First published October 17, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008472
Divyanshu Dubey
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Jiraporn Jitprapaikulsan
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Hongyan Bi
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Rocio Vazquez Do Campo
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Andrew McKeon
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Sean J. Pittock
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Janean K. Engelstad
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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John R. Mills
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Christopher J. Klein
From the Department of Neurology (D.D., J.J., H.B., R.V.D.C., A.M., S.J.P., J.K.E., C.J.K.), Laboratory Medicine and Pathology (D.D., J.J., A.M., S.J.P., J.R.M., C.J.K.), Center for MS and Autoimmune Neurology (S.J.P.), Mayo Clinic, Rochester, MN; Beijing Friendship Hospital (H.B.), Capital Medical University, China; and Siriraj Hospital, Mahidol University (J.J.), Bangkok, Thailand.
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Amphiphysin-IgG autoimmune neuropathy
A recognizable clinicopathologic syndrome
Divyanshu Dubey, Jiraporn Jitprapaikulsan, Hongyan Bi, Rocio Vazquez Do Campo, Andrew McKeon, Sean J. Pittock, Janean K. Engelstad, John R. Mills, Christopher J. Klein
Neurology Nov 2019, 93 (20) e1873-e1880; DOI: 10.1212/WNL.0000000000008472

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Abstract

Objective To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)–mediated neuropathy.

Methods Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)–IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves.

Results Fifty-three amphiphysin-IgG–positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve.

Conclusion Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.

Glossary

ANNA1=
antineuronal nuclear antibody type 1;
CRMP5=
collapsin response-mediator protein-5;
IgG=
immunoglobulin G;
IIF=
indirect immunofluorescence;
mRS=
modified Rankin Scale;
PBS=
phosphate-buffered saline;
RT=
room temperature

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • Received April 15, 2019.
  • Accepted in final form June 4, 2019.
  • © 2019 American Academy of Neurology
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