Abstract
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.
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References
Vincent A, Palace J, Hilton-Jones D (2001) Myasthenia gravis. Lancet 357:2122–2128
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
Stoica E, Enulescu O (1992) Deficiency of sympathetic nervous system function in myasthenia. J Auton Nerv Syst 38:69–76
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
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
Vernino S, Lennon VA (2004) Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 10:7270–7275
Vernino S, Hopkins S, Wang Z (2009) Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy. Auton Neurosci 146:3–7
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
Lauriola L, Ranelletti F, Maggiano N et al (2005) Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 64:536–538
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
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
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
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
Gibson TC (1975) The heart in myasthenia gravis. Am Heart J 90:389–396
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
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
Gunal DI, Afsar N, Tanridag T, Aktan S (2002) Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters. Eur Neurol 48:1–5
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
Miglis MG, Racela R, Kaufmann H (2011) Seropositive myasthenia and autoimmune autonomic ganglionopathy: cross reactivity or subclinical disease? Auton Neurosci 164:87–88
Burden SJ, Yumoto N, Zhang W (2013) The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harb Perspect Biol 5:a009167
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
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
Cohen NA, Kaufmann WE, Worley PF, Rupp F (1997) Expression of agrin in the developing and adult rat brain. Neuroscience 76:581–596
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
McAvoy M, Smith MA, Fujii JT (1996) Agrin mRNA expression in the developing chick Edinger-Westphal nucleus. Vis Neurosci 13:293–301
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
Gasperi C, Melms A, Schoser B et al (2014) Anti-agrin autoantibodies in myasthenia gravis. Neurology. doi:10.1212/WNL.0000000000000478
Weatherbee SD, Anderson KV, Niswander LA (2006) LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133:4993–5000
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
Vernino S, Sandroni P, Singer W, Low PA (2008) Autonomic ganglia: target and novel therapeutic tool. Neurology 70:1926–1932
Singer W, Sandroni P, Opfer-Gehrking TL et al (2006) Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 63:513–518
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This study was supported by the Ministry of Science of the Republic of Serbia (grant #175083).
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The authors declare that they have no conflict of interest.
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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.
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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). https://doi.org/10.1007/s00415-014-7465-x
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DOI: https://doi.org/10.1007/s00415-014-7465-x