Skip to main content


Log in

The presence of dysautonomia in different subgroups of myasthenia gravis patients

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript


To analyze the presence of autonomic dysfunction in different subgroups of myasthenia gravis (MG) patients. Standard cardiovascular reflex tests according to Ewing, spectral and time domain analysis of heart rate variability (HRV) at rest were assessed in 27 patients with thymoma-associated acetylcholine receptor (AChR)-positive MG, 25 AChR-positive MG patients without thymoma and 23 patients with muscle-specific tyrosine kinase (MuSK) MG. All patients were compared to the healthy controls, matched for sex and age. In the group of AChR-positive MG patients with thymoma, hand grip (p < 0.05), orthostasis (p < 0.05), breathing test (p < 0.05) and Valsalva maneuver (p < 0.01) were more often pathological than in the controls. Analysis of the spectral domain of HRV showed increased low-frequency (p < 0.05) and decreased high-frequency component (p < 0.05). Time domain parameters of HRV and baroreflex sensitivity (BRS) at rest were significantly reduced (p < 0.01). In the patients with AChR MG without thymoma, Valsalva maneuver test was more often pathological (p < 0.05) and higher rate of supraventricular extrasystoles (p < 0.01) was registered than in the healthy controls. In the patients with MuSK-positive MG, hand grip and Valsalva maneuver tests were more often pathological than in the controls (p < 0.05). Low-frequency component of the spectral domain of HRV (p < 0.05) and the frequency of cardiac arrhythmia were increased. BRS at rest was significantly lower in patients compared to the controls (p < 0.01). We determined the presence of autonomic failure in all subgroups of MG patients. Since autonomic dysfunction can lead to cardiac arrhythmias and even sudden death, it is of major importance to be aware of this association and to properly diagnose and treat these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others


  1. Vincent A, Palace J, Hilton-Jones D (2001) Myasthenia gravis. Lancet 357:2122–2128

    Article  CAS  PubMed  Google Scholar 

  2. Evoli A, Padua L, Monaco ML, Scuderi F, Batocchi AP, Marino M, Bartoccioni E (2003) Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 126:2304–2311

    Article  PubMed  Google Scholar 

  3. Stoica E, Enulescu O (1992) Deficiency of sympathetic nervous system function in myasthenia. J Auton Nerv Syst 38:69–76

    Article  CAS  PubMed  Google Scholar 

  4. Lechin F, van der Dijs B, Pardey-Maldonado B et al (2000) Enhancement of noradrenergic neural transmission: an effective therapy of myasthenia gravis: a report on 52 consecutive patients. J Med 31:333–361

    CAS  PubMed  Google Scholar 

  5. Peric S, Rakocevic Stojanovic V, Nisic T et al (2011) Cardiac autonomic control in patients with myasthenia gravis and thymoma. J Neurol Sci 307:30–33

    Article  CAS  PubMed  Google Scholar 

  6. Vernino S, Lennon VA (2004) Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 10:7270–7275

    Article  CAS  PubMed  Google Scholar 

  7. Vernino S, Hopkins S, Wang Z (2009) Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy. Auton Neurosci 146:3–7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Lavrnic D, Losen M, Vujic A et al (2005) The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiatry 76:1099–1102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Lauriola L, Ranelletti F, Maggiano N et al (2005) Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 64:536–538

    Article  CAS  PubMed  Google Scholar 

  10. Leite MI, Strobel P, Jones M et al (2005) Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 57:444–448

    Article  PubMed  Google Scholar 

  11. Jeretzki A 3rd, Barohn RJ, Ernstoff RM et al (2000) Myasthenia gravis: recommendations for clinical research standards. Task force of the Medical Scientific Advisory Board of the Myasthenia gravis Foundation of America (review). Neurology 55:16–23

    Article  Google Scholar 

  12. Ewing D (1992) Analysis of heart rate variability and other non-invasive tests with special reference to diabetes mellitus. In: Mathias C, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 3rd edn. Oxford University Press, London, pp 312–333

    Google Scholar 

  13. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 17:354–381

    Article  Google Scholar 

  14. Gibson TC (1975) The heart in myasthenia gravis. Am Heart J 90:389–396

    Article  CAS  PubMed  Google Scholar 

  15. Shukla G, Gupta S, Goyal V, Singh S, Srivastava A, Behari M (2013) Abnormal sympathetic hyper-reactivity in patients with myasthenia gravis: a prospective study. Clin Neurol Neurosurg 115:179–186

    Article  PubMed  Google Scholar 

  16. Sivan Puneeth C, Retanaswami Chandra S, Yadav R, Narasappa Sathyaprabha T, Chandran S (2013) Heart rate and blood pressure variability in patients with myasthenia gravis. Ann Indian Acad Neurol 16:329–332

    Article  Google Scholar 

  17. Gunal DI, Afsar N, Tanridag T, Aktan S (2002) Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters. Eur Neurol 48:1–5

    Article  PubMed  Google Scholar 

  18. Lennon V, Ermilov LG, Szurszewski JH, Vernino S (2003) Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J Clin Invest 111:907–913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Miglis MG, Racela R, Kaufmann H (2011) Seropositive myasthenia and autoimmune autonomic ganglionopathy: cross reactivity or subclinical disease? Auton Neurosci 164:87–88

    Article  PubMed  Google Scholar 

  20. Burden SJ, Yumoto N, Zhang W (2013) The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harb Perspect Biol 5:a009167

    Article  PubMed Central  PubMed  Google Scholar 

  21. Amenta AR, Creely HE, Mercado ML et al (2012) Biglycan is an extracellular MuSK binding protein important for synapse stability. J Neurosci 32:2324–2334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Ksiazek I, Burkhardt C, Lin S et al (2007) Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J Neurosci 27:7183–7195

    Article  CAS  PubMed  Google Scholar 

  23. Cohen NA, Kaufmann WE, Worley PF, Rupp F (1997) Expression of agrin in the developing and adult rat brain. Neuroscience 76:581–596

    Article  CAS  PubMed  Google Scholar 

  24. Ma E, Morgan R, Godfrey EW (1995) Agrin mRNA variants are differentially regulated in developing chick embryo spinal cord and sensory ganglia. J Neurobiol 26:585–597

    Article  CAS  PubMed  Google Scholar 

  25. McAvoy M, Smith MA, Fujii JT (1996) Agrin mRNA expression in the developing chick Edinger-Westphal nucleus. Vis Neurosci 13:293–301

    Article  CAS  PubMed  Google Scholar 

  26. Gingras J, Rassadi S, Cooper E, Ferns M (2007) Synaptic transmission is impaired at neuronal autonomic synapses in agrin-null mice. Dev Neurobiol 67:521–534

    Article  CAS  PubMed  Google Scholar 

  27. Gasperi C, Melms A, Schoser B et al (2014) Anti-agrin autoantibodies in myasthenia gravis. Neurology. doi:10.1212/WNL.0000000000000478

    PubMed  Google Scholar 

  28. Weatherbee SD, Anderson KV, Niswander LA (2006) LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133:4993–5000

    Article  CAS  PubMed  Google Scholar 

  29. Zisimopoulou P, Evangelakou P, Tzartos J et al (2013) A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. doi:10.1016/j.jaut.2013.12.004

    PubMed  Google Scholar 

  30. Vernino S, Sandroni P, Singer W, Low PA (2008) Autonomic ganglia: target and novel therapeutic tool. Neurology 70:1926–1932

    Article  PubMed Central  PubMed  Google Scholar 

  31. Singer W, Sandroni P, Opfer-Gehrking TL et al (2006) Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 63:513–518

    Article  PubMed  Google Scholar 

Download references


This study was supported by the Ministry of Science of the Republic of Serbia (grant #175083).

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard

This study has been approved by the Ethics Committee of the School of Medicine, University of Belgrade. Informed consent was obtained from each patient and control included in the study.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Ana Nikolić.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nikolić, A., Perić, S., Nišić, T. et al. The presence of dysautonomia in different subgroups of myasthenia gravis patients. J Neurol 261, 2119–2127 (2014).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: