Skip to main content

Seronegative autoimmune autonomic neuropathy: a distinct clinical entity

Abstract

Purpose

Autoimmune autonomic ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with autoimmune autonomic failure lacking this antibody.

Methods

Retrospective chart review.

Results

Six patients presented with subacute autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids.

Conclusion

In these cases of autoimmune autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Suarez GA, Fealey RD, Camilleri M, Low PA (1994) Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 44(9):1675–1682

    CAS  Article  PubMed  Google Scholar 

  2. Klein CM, Vernino S, Lennon VA, Sandroni P, Fealey RD, Benrud-Larson L, Sletten D, Low PA (2003) The spectrum of autoimmune autonomic neuropathies. Ann Neurol 53(6):752–758. https://doi.org/10.1002/ana.10556

    Article  PubMed  Google Scholar 

  3. Vernino S (2008) Autoimmune and paraneoplastic autonomic neuropathies. In: Low PABE (ed) Clinical autonomic disorders, 3rd edn. Lippincott Williams & Wilkins, Baltimore, pp 441–454

    Google Scholar 

  4. Vernino S, Adamski J, Kryzer TJ, Fealey RD, Lennon VA (1998) Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 50(6):1806–1813

    CAS  Article  PubMed  Google Scholar 

  5. Vernino S, Ermilov LG, Sha L, Szurszewski JH, Low PA, Lennon VA (2004) Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci 24(32):7037–7042. https://doi.org/10.1523/jneurosci.1485-04.2004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA (2000) Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 343(12):847–855. https://doi.org/10.1056/nejm200009213431204

    CAS  Article  PubMed  Google Scholar 

  7. Gibbons CH, Freeman R (2009) Antibody titers predict clinical features of autoimmune autonomic ganglionopathy. Auton Neurosci 146(1–2):8–12. https://doi.org/10.1016/j.autneu.2008.11.013

    CAS  Article  PubMed  Google Scholar 

  8. Gibbons CH, Vernino SA, Freeman R (2008) Combined immunomodulatory therapy in autoimmune autonomic ganglionopathy. Arch Neurol 65(2):213–217. https://doi.org/10.1001/archneurol.2007.60

    Article  PubMed  Google Scholar 

  9. Iodice V, Kimpinski K, Vernino S, Sandroni P, Fealey RD, Low PA (2009) Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy. Neurology 72(23):2002–2008. https://doi.org/10.1212/WNL.0b013e3181a92b52

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Iodice V, Kimpinski K, Vernino S, Sandroni P, Low PA (2009) Immunotherapy for autoimmune autonomic ganglionopathy. Auton Neurosci 146(1–2):22–25. https://doi.org/10.1016/j.autneu.2008.11.001

    CAS  Article  PubMed  Google Scholar 

  11. Sandroni P, Vernino S, Klein CM, Lennon VA, Benrud-Larson L, Sletten D, Low PA (2004) Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 61(1):44–48. https://doi.org/10.1001/archneur.61.1.44

    Article  PubMed  Google Scholar 

  12. Muppidi S, Scribner M, Gibbons CH, Adams-Huet B, Spaeth EB, Vernino S (2012) A unique manifestation of pupillary fatigue in autoimmune autonomic ganglionopathy. Arch Neurol 69(5):644–648. https://doi.org/10.1001/archneurol.2011.2143

    Article  PubMed  PubMed Central  Google Scholar 

  13. Goldstein DS, Holmes C, Sullivan P, Donadio V, Isonaka R, Zhong E, Pourier B, Vernino S, Kopin IJ, Sharabi Y (2017) Autoimmunity-associated autonomic failure with sympathetic denervation. Clin Auton Res 27(1):57–62. https://doi.org/10.1007/s10286-016-0388-0

    Article  PubMed  Google Scholar 

  14. Low PA, Tomalia VA, Park K-J (2013) Autonomic function tests: some clinical applications. J Clin Neurol 9(1):1–8

    Article  PubMed  PubMed Central  Google Scholar 

  15. Low PA (1993) Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 68(8):748–752

    CAS  Article  PubMed  Google Scholar 

  16. Koike H, Atsuta N, Adachi H, Iijima M, Katsuno M, Yasuda T, Fukada Y, Yasui K, Nakashima K, Horiuchi M, Shiomi K, Fukui K, Takashima S, Morita Y, Kuniyoshi K, Hasegawa Y, Toribe Y, Kajiura M, Takeshita S, Mukai E, Sobue G (2010) Clinicopathological features of acute autonomic and sensory neuropathy. Brain 133(10):2881–2896. https://doi.org/10.1093/brain/awq214

    Article  PubMed  Google Scholar 

  17. Hart RG, Kanter MC (1990) Acute autonomic neuropathy. Two cases and a clinical review. Arch Intern Med 150(11):2373–2376

    CAS  Article  PubMed  Google Scholar 

  18. Low PA, Dyck PJ, Lambert EH, Brimijoin WS, Trautmann JC, Malagelada JR, Fealey RD, Barrett DM (1983) Acute panautonomic neuropathy. Ann Neurol 13(4):412–417. https://doi.org/10.1002/ana.410130407

    CAS  Article  PubMed  Google Scholar 

  19. Mericle RA, Triggs WJ (1997) Treatment of acute pandysautonomia with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 62(5):529–531

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Feldman EL, Bromberg MB, Blaivas M, Junck L (1991) Acute pandysautonomic neuropathy. Neurology 41(5):746–748

    CAS  Article  PubMed  Google Scholar 

  21. Kurokawa K, Noda K, Mimori Y, Watanabe C, Katayama S, Nakamura S, Sannomiya K, Yamamoto S, Tahara E (1998) A case of pandysautonomia with associated sensory ganglionopathy. J Neurol Neurosurg Psychiatry 65(2):278–279

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Fagius J, Westerberg CE, Olsson Y (1983) Acute pandysautonomia and severe sensory deficit with poor recovery. A clinical, neurophysiological and pathological case study. J Neurol Neurosurg Psychiatry 46(8):725–733

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Neville BG, Sladen GE (1984) Acute autonomic neuropathy following primary herpes simplex infection. J Neurol Neurosurg Psychiatry 47(6):648–650

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Kanda F, Uchida T, Jinnai K, Tada K, Shiozawa S, Fujita T, Ohnishi A (1990) Acute autonomic and sensory neuropathy: a case report. J Neurol 237(1):42–44

    CAS  Article  PubMed  Google Scholar 

  25. Bennett JL, Mahalingam R, Wellish MC, Gilden DH (1996) Epstein-Barr virus-associated acute autonomic neuropathy. Ann Neurol 40(3):453–455. https://doi.org/10.1002/ana.410400316

    CAS  Article  PubMed  Google Scholar 

  26. Irioka T, Yamada M, Yamawaki M, Saito Y, Mizusawa H, Yamada M, Miura H (2001) Acute autonomic and sensory neuropathy after interferon alpha-2b therapy for chronic hepatitis C. J Neurol Neurosurg Psychiatry 70(3):408–410

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Colan RV, Snead OC 3rd, Oh SJ, Kashlan MB (1980) Acute autonomic and sensory neuropathy. Ann Neurol 8(4):441–444. https://doi.org/10.1002/ana.410080419

    CAS  Article  PubMed  Google Scholar 

  28. Isonaka R, Holmes C, Cook GA, Sullivan P, Sharabi Y, Goldstein DS (2017) Pure autonomic failure without synucleinopathy. Clin Auton Res 27(2):97–101. https://doi.org/10.1007/s10286-017-0404-z

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Samarpita Sengupta, PhD, for assistance with preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven Vernino.

Ethics declarations

Conflict of interest

Drs. Golden and Bryarly have no conflict of interest to report. Dr. Vernino has served as a consultant for Athena Diagnostics and Lundbeck and on the speaker bureau for Lundbeck.

Ethical approval

This study was approved by the UT Southwestern Institutional Review Board and was therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Subjects gave their informed consent prior to their inclusion in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Golden, E.P., Bryarly, M.A. & Vernino, S. Seronegative autoimmune autonomic neuropathy: a distinct clinical entity. Clin Auton Res 28, 115–123 (2018). https://doi.org/10.1007/s10286-017-0493-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10286-017-0493-8

Keywords

  • Autoimmune autonomic ganglionopathy
  • Orthostatic hypotension
  • Autonomic neuropathy
  • Autonomic testing
  • Immunotherapy