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Management/Treatment of Lambert-Eaton Myasthenic Syndrome

  • Neuromuscular Disorders (C Fournier, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of review

This article reviews the current treatment strategies for patients with Lambert-Eaton myasthenic syndrome (LEMS) including potassium channel blockers, immunosuppressant therapies, and management of dysautonomia.

Recent findings

Since the first report in 1983, 3,4-diaminopyridine (amifampridine) has been used as a symptomatic treatment for LEMS. The biggest recent development in LEMS treatment is the approval of two amifampridine drugs in 2018 by the Food and Drug Administration (FDA). Amifampridine phosphate (Firdapse®) is a salt form that was approved for adult patients with LEMS. Amifampridine (Ruzurgi®) was approved for children aged 6 to 17 years old.

Summary

The primary treatment option for LEMS remains amifampridine, and the efficacy of both FDA-approved formulations has been demonstrated in high-quality clinical trials. Other immunosuppressant treatments, such as corticosteroids, azathioprine, mycophenolate mofetil, and rituximab, can be used when amifampridine is unavailable, are contraindicated, or do not fully control patient symptoms. For the management of acute exacerbations or severe disease, IVIg or plasma exchange can be considered. High-quality evidence supporting the use of immunosuppressive and immunomodulatory treatments in LEMS patients is generally lacking. Treatment response can be monitored by bedside exams and the Triple Timed Up-and-Go test.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Sanders DB, Juel VC, Harati Y, et al. 3,4-Diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia. Muscle Nerve 2018;57:561–568. A randomized double-blind placebo-controlled withdrawal study that showed the efficacy of amifampridine in patients with LEMS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. Journal of neuromuscular diseases. 2015;2:73–85.

    Article  PubMed  Google Scholar 

  3. Abenroth DC, Smith AG, Greenlee JE, Austin SD, Clardy SL. Lambert-Eaton myasthenic syndrome: epidemiology and therapeutic response in the national veterans affairs population. Muscle Nerve. 2017;56:421–6.

    Article  PubMed  Google Scholar 

  4. Wirtz PW, van Dijk JG, van Doorn PA, et al. The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology. 2004;63:397–8.

    Article  CAS  PubMed  Google Scholar 

  5. • Kesner VG, Oh SJ, Dimachkie MM, Barohn RJ. Lambert-Eaton myasthenic syndrome. Neurol Clin 2018;36:379–394. A review article discussing the history, epidemiology, clinical features, diagnosis, and management of LEMS.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg. 2002;104:359–63.

    Article  PubMed  Google Scholar 

  7. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111 ( Pt 3):577–596.

  8. EL Lambert EH, Rooke ED. Defect of neuromuscular conduction associated with malignant neoplasms. Am J of Physiol. 1956;187:612–3.

    Google Scholar 

  9. Fukunaga H, Engel AG, Lang B, Newsom-Davis J, Vincent A. Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones. Proc Natl Acad Sci USA. 1983;80:7636–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fukuoka T, Engel AG, Lang B, Newsom-Davis J, Prior C, Wray DW. Lambert-Eaton myasthenic syndrome: I. Early morphological effects of IgG on the presynaptic membrane active zones. Ann Neurol 1987;22:193–199.

  11. Lennon VA, Kryzer TJ, Griesmann GE, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med. 1995;332:1467–74.

    Article  CAS  PubMed  Google Scholar 

  12. Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10:1098–107.

    Article  PubMed  Google Scholar 

  13. Pellkofer HL, Armbruster L, Linke R, Schumm F, Voltz R. Managing non-paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics in 25 German patients. J Neuroimmunol. 2009;217:90–4.

    Article  CAS  PubMed  Google Scholar 

  14. Titulaer MJ, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: tumor versus nontumor forms. Ann N Y Acad Sci. 2008;1132:129–34.

    Article  PubMed  Google Scholar 

  15. Young JD, Leavitt JA. Lambert-Eaton myasthenic syndrome: ocular signs and symptoms. J Neuroophthalmol. 2016;36:20–2.

    Article  PubMed  Google Scholar 

  16. AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome. Muscle Nerve. 2001; 24(9):1239-47. https://doi.org/10.1002/mus.1140

  17. Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci. 1997;147:35–42.

    Article  CAS  PubMed  Google Scholar 

  18. Harper CM, Lennon VA. Lambert-Eaton syndrome. Myasthenia Gravis and Related Disorders: Springer; 2018. p. 221–37.

    Google Scholar 

  19. Lundh H, Nilsson O, Rosén I. Novel drug of choice in Eaton-Lambert syndrome. J Neurol Neurosurg Psychiatry. 1983;46:684–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McEvoy KM, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med. 1989;321:1567–71.

    Article  CAS  PubMed  Google Scholar 

  21. Sanders DB, Massey JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology. 2000;54:603–7.

    Article  CAS  PubMed  Google Scholar 

  22. Oh SJ, Claussen GG, Hatanaka Y, Morgan MB. 3,4-Diaminopyridine is more effective than placebo in a randomized, double-blind, cross-over drug study in LEMS. Muscle Nerve. 2009;40:795–800.

    Article  CAS  PubMed  Google Scholar 

  23. Oh SJ, Shcherbakova N, Kostera-Pruszczyk A, et al. Amifampridine phosphate (Firdapse(®)) is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve. 2016;53:717–25.

    Article  CAS  PubMed  Google Scholar 

  24. •• Shieh P, Sharma K, Kohrman B, Oh SJ. Amifampridine phosphate (Firdapse) is effective in a confirmatory phase 3 clinical trial in LEMS. J Clin Neuromuscul Dis 2019;20:111–119. A recent randomized, double-blind withdrawal trial demonstrating the efficacy of amifampridine phosphate for symptomatic treatment in LEMS.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17:893–902.

    Article  CAS  PubMed  Google Scholar 

  26. FIRDAPSE® (amifampridine). CoralGables, FL Catalyst Pharmaceuticals, Inc. U.S. Food and Drug Administration. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208078s000lbl.pdf. Accessed 20 Aug 2021

  27. RUZURGI® (amifampridine). Plainsboro, NJ. Jacobus Pharmaceutical Company, Inc. U.S. Food and Drug Administration. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209321s000lbl.pdf. Accessed 20 Aug 2021

  28. Sanders DB. Lambert-Eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci. 2003;998:500–8.

    Article  PubMed  Google Scholar 

  29. Wirtz PW, Verschuuren JJ, van Dijk JG, et al. Efficacy of 3,4-diaminopyridine and pyridostigmine in the treatment of Lambert-Eaton myasthenic syndrome: a randomized, double-blind, placebo-controlled, crossover study. Clin Pharmacol Ther. 2009;86:44–8.

    Article  CAS  PubMed  Google Scholar 

  30. Takano H, Tanaka M, Koike R, Nagai H, Arakawa M, Tsuji S. Effect of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome with small-cell lung cancer: correlation with the titer of anti-voltage-gated calcium channel antibody. Muscle Nerve. 1994;17:1073–5.

    Article  CAS  PubMed  Google Scholar 

  31. Peterlin BL, Flood W, Kothari MJ. Use of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome. J Am Osteopath Assoc. 2002;102:682–4.

    PubMed  Google Scholar 

  32. Bird SJ. Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology. 1992;42:1422–3.

    Article  CAS  PubMed  Google Scholar 

  33. Muchnik S, Losavio AS, Vidal A, Cura L, Mazia C. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve. 1997;20:674–8.

    Article  CAS  PubMed  Google Scholar 

  34. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47:678–83.

    Article  CAS  PubMed  Google Scholar 

  35. Lang B, Newsom-Davis J, Wray D, Vincent A, Murray N. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet (London, England). 1981;2:224–6.

    Article  CAS  Google Scholar 

  36. Newsom-Davis J, Murray NM. Plasma exchange and immunosuppressive drug treatment in the Lambert-Eaton myasthenic syndrome. Neurology. 1984;34:480–5.

    Article  CAS  PubMed  Google Scholar 

  37. Guptill JT, Oakley D, Kuchibhatla M, et al. A retrospective study of complications of therapeutic plasma exchange in myasthenia. Muscle Nerve. 2013;47:170–6.

    Article  PubMed  Google Scholar 

  38. Maddison P, Lang B, Mills K, Newsom-Davis J. Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer. J Neurol Neurosurg Psychiatry. 2001;70:212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. CELLCEPT® (mycophenolate mofetil). Raleigh, NC Genentech USA, Inc. U.S. Food and Drug Administration. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf. Accessed 20 Aug 2021

  40. IMURAN® (azathioprine) San Diego, CA Prometheus Laboratories Inc. U.S. Food and Drug Administration. Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf. Accessed 20 Aug 2021

  41. Maddison P, McConville J, Farrugia ME, et al. The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 2011;82:671–3.

    Article  PubMed  Google Scholar 

  42. van Sonderen A, Wirtz PW, Verschuuren JJ, Titulaer MJ. Paraneoplastic syndromes of the neuromuscular junction: therapeutic options in myasthenia gravis, Lambert-Eaton myasthenic syndrome, and neuromyotonia. Curr Treat Options Neurol. 2013;15:224–39.

    Article  PubMed  Google Scholar 

  43. Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clinical autonomic research: official journal of the Clinical Autonomic Research Society. 2001;11:145–54.

    Article  CAS  Google Scholar 

  44. Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol. 1997;42:147–56.

    Article  CAS  PubMed  Google Scholar 

  45. Maule S, Milazzo V, Maule MM, Di Stefano C, Milan A, Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension. Funct Neurol. 2012;27:101–6.

    PubMed  PubMed Central  Google Scholar 

  46. Gibbons CH, Freeman R. Clinical implications of delayed orthostatic hypotension: a 10-year follow-up study. Neurology. 2015;85:1362–7.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Xin W, Lin Z, Mi S. Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies. Heart (British Cardiac Society). 2014;100:406–13.

    Google Scholar 

  48. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clinical autonomic research: official journal of the Clinical Autonomic Research Society. 2011;21:69–72.

    Article  Google Scholar 

  49. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol. 2017;264:1567–82.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Chobanian AV, Volicer L, Tifft CP, Gavras H, Liang CS, Faxon D. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med. 1979;301:68–73.

    Article  CAS  PubMed  Google Scholar 

  51. Norcliffe-Kaufmann L, Axelrod FB, Kaufmann H. Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens. 2013;27:51–5.

    Article  CAS  PubMed  Google Scholar 

  52. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med. 1993;95:38–48.

    Article  CAS  PubMed  Google Scholar 

  53. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. Jama 1997;277:1046–1051.

  54. Smith W, Wan H, Much D, Robinson AG, Martin P. Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study. Official Journal of the Clinical Autonomic Research Society: J Clin Auton Res. 2016;26:269–77.

    Article  Google Scholar 

  55. Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998;51:120–4.

    Article  CAS  PubMed  Google Scholar 

  56. Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014;83:328–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Elgebaly A, Abdelazeim B, Mattar O, Gadelkarim M, Salah R, Negida A. Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension. Clinical autonomic research: official journal of the Clinical Autonomic Research Society. 2016;26:171–80.

    Article  Google Scholar 

  58. Hauser RA, Biaggioni I, Hewitt LA, Vernino S. Integrated analysis of droxidopa for the treatment of neurogenic orthostatic hypotension in patients with Parkinson disease. Movement disorders clinical practice. 2018;5:627–34.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Biaggioni I, Arthur Hewitt L, Rowse GJ, Kaufmann H. Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension. BMC Neurol. 2017;17:90.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Payne M, Bradbury P, Lang B, et al. Prospective study into the incidence of Lambert Eaton myasthenic syndrome in small cell lung cancer. Official Publication of the International Association for the Study of Lung Cancer: J thoracic oncol. 2010;5:34–8.

    Article  Google Scholar 

  61. Titulaer MJ, Wirtz PW, Kuks JB, et al. The Lambert-Eaton myasthenic syndrome 1988–2008: a clinical picture in 97 patients. J Neuroimmunol. 2008;201–202:153–8.

    Article  PubMed  CAS  Google Scholar 

  62. Chalk CH, Murray NM, Newsom-Davis J, O’Neill JH, Spiro SG. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology. 1990;40:1552–6.

    Article  CAS  PubMed  Google Scholar 

  63. Wirtz PW, Willcox N, van der Slik AR, et al. HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome. J Neuroimmunol. 2005;159:230–7.

    Article  CAS  PubMed  Google Scholar 

  64. Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2008;70:924–8.

    Article  CAS  PubMed  Google Scholar 

  65. Titulaer MJ, Klooster R, Potman M, et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. Official Journal of the American Society of Clinical Oncology: J clin oncol. 2009;27:4260–7.

    Article  CAS  Google Scholar 

  66. Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet (London, England). 1999;353:117–8.

    Article  CAS  Google Scholar 

  67. Maddison P, Gozzard P, Grainge MJ, Lang B. Long-term survival in paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2017;88:1334–9.

    Article  PubMed  Google Scholar 

  68. • Liu Y, Xi J, Zhou L, et al. Clinical characteristics and long term follow-up of Lambert-Eaton myasthenia syndrome in patients with and without small cell lung cancer. J Clin Neurosci 2019;65:41–45. A retrospective study describing clinical characteristics, treatment response, and long-term follow-up in 50 patients with LEMS with and without small cell lung cancer.

    Article  PubMed  Google Scholar 

  69. Mtinangi BL, Hainsworth R. Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope. Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 1998;8:231–5.

    Article  CAS  Google Scholar 

  70. Baas SJ, Endert E, Fliers E, Prummel MF, Wiersinga WM. Establishment of reference values for endocrine tests. III: Primary aldosteronism. The Netherlands journal of medicine 2003;61:37–43.

  71. Jordan J, Shannon JR, Black BK, et al. The pressor response to water drinking in humans: a sympathetic reflex? Circulation. 2000;101:504–9.

    Article  CAS  PubMed  Google Scholar 

  72. Shannon JR, Diedrich A, Biaggioni I, et al. Water drinking as a treatment for orthostatic syndromes. Am J Med. 2002;112:355–60.

    Article  PubMed  Google Scholar 

  73. May M, Jordan J. The osmopressor response to water drinking. Am J Physiol Regul Integr Comp Physiol. 2011;300:R40-46.

    Article  CAS  PubMed  Google Scholar 

  74. Smit AA, Wieling W, Fujimura J, et al. Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction. Clinical autonomic research: official journal of the Clinical Autonomic Research Society. 2004;14:167–75.

    Article  Google Scholar 

  75. Henry R, Rowe J, O’Mahony D. Haemodynamic analysis of efficacy of compression hosiery in elderly fallers with orthostatic hypotension. Lancet (London, England). 1999;354:45–6.

    Article  CAS  Google Scholar 

  76. • Raja SM, Sanders DB, Juel VC, et al. Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia. Muscle Nerve 2019;60:292–298. A study demonstrating the excellent test-retest reproducibility and inter-rater reliability of Triple Timed Up-and-Go test in patients with LEMS on stable therapy and content and face validity for the assessment of lower extremity dysfunction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sanders DB, Guptill JT, Aleš KL, et al. Reliability of the triple-timed up-and-go test. Muscle Nerve. 2018;57:136–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Neuromuscular Disease, Department of Neurology, Duke University Medical Center, Durham, NC, USA

    Yohei Harada MD & Jeffrey T. Guptill MD MA MHS FAAN

  2. Clinic 1L, DUMC, Box 3403, Durham, NC, 27710, USA

    Jeffrey T. Guptill MD MA MHS FAAN

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  1. Yohei Harada MD
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Harada, Y., Guptill, J.T. Management/Treatment of Lambert-Eaton Myasthenic Syndrome. Curr Treat Options Neurol 23, 34 (2021). https://doi.org/10.1007/s11940-021-00690-4

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