Update on Amifampridine as a Drug of Choice in Lambert-Eaton Myasthenic Syndrome

US Neurology, 2014;10(2):ePub ahead of print


Lambert-Eaton myasthenic syndrome (LEMS) is a disabling autoimmune disorder involving impairment of neuromuscular transmission and producing serious muscle weakness, for which few effective medications are currently available. 3,4-diaminopyridine (3,4-DAP, INN/USAN: amifampridine) is the leading treatment for LEMS and has been available for over 25 years as an unapproved drug under treatment and expanded access protocols filed with the US Food and Drug Administration (FDA) or from compounding pharmacies in the US. Administering the correct dose of 3,4-DAP is critical—overdosing can increase the risk for seizures and other adverse events, while underdosing can result in a substantial loss of efficacy or even treatment failure. Two recent studies have shown a wide variation in the 3,4-DAP content of compounded preparations. A tablet formulation of 3,4-DAP phosphate salt (FIRDAPSETM) has been licenced in Europe with orphan medicinal product status since 2009 and appears to be as efficacious as the base in relieving the symptoms of LEMS. The product has also received orphan drug status in the US and is currently being evaluated in a multicenter, double-blind, placebo-controlled phase III trial to support New Drug Application (NDA) approval in the US. A recent safety trial in healthy volunteers using doses at and above normal levels has shown no effect on QT intervals, heart rate, or cardiac depolarization. Based on available clinical trial data, amifampridine phosphate was recently given Breakthrough Therapy designation by the FDA, which may enable fast-track NDA approval, thus increasing the potential for more patients with LEMS to receive an effective therapy.

Keywords: Amifampridine/3,4-diaminopyridine/3,4-DAP, Lambert-Eaton myasthenic syndrome, potassium ion channel blockers, compounded drugs clinical trial evidence, treatment, expanded access protocols
Disclosure: Shin J Oh, MD, has no conflicts of interest to declare. Jörn Peter Sieb, MD, has received honoraria or consultation fees from BioMarin, Temmler, and Valeant.
Acknowledgments: Editorial assistance was provided by James Gilbart, PhD, and Katrina Mountfort, PhD, at Touch Medical Media.
Received: April 10, 2014 Accepted April 15, 2014
Correspondence: Shin J Oh, MD, Department of Neurology, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294, US. E: shinjoh@uab.edu
Support: The publication of this article was supported by Catalyst. The views and opinions expressed are those of the authors and not necessarily those of Catalyst.

Lambert-Eaton myasthenic syndrome (LEMS) is a uncommon, but debilitating, neuromuscular disorder that is estimated to affect 2.32 people per million in Europe1 with a prevalence of up to 3,000 cases in the US.2 The disease has an autoimmune etiology in which autoantibodies bind to P/Q-type voltage-gated calcium channels (VGCCs) and decrease the release of acetylcholine at the synapses affecting peripheral cholinergic neurotransmission.3 The impaired function of the VGCCs decreases the secretion of acetylcholine and disrupts synaptic transmission at neuromuscular junctions and certain autonomic nerve terminals leading to muscular weakness and symptoms of autonomic dysfunction.2,4–6

More than half the patients with LEMS, particularly male smokers aged over 50 years, present with an underlying malignancy, usually small cell lung cancer (SCLC).7,8 However, there are also case reports on a wide variety of lung and non-lung malignancies observed in LEMS patients. The peak age of onset of non-tumor LEMS is 35 years with a second peak at 60 years, whereas paraneoplastic LEMS occurs primarily in middle-aged and older adults, with a median age of onset of 58 years.9 Non-paraneoplastic LEMS can be associated with other organic-specific autoimmune disorders.10 Paraneoplastic cerebellar degeneration can also occur in cancer-associated LEMS cases.11

The diagnosis of LEMS can be challenging since the clinical presentation of sub-acute progressive fatigue and weakness is unspecific. As a result, diagnosis is often delayed from many months up to even decades.10 Clinical suspicion is the key for the diagnosis of LEMS. The symptoms of LEMS are frequently mistaken for those of myasthenia gravis (MG). In contrast to MG, oculo-bulbar paresis is rare and reflexes are reduced or absent in LEMS.

The most common clinical presentation of LEMS is proximal muscle weakness (more pronounced in the hip girdle than in the shoulder girdle) and easy fatigability. The classic triad of LEMS includes proximal leg weakness, hyporeflexia or areflexia, and cholingergic dysautonomia (dry mouth, impotence, and orthostatic hypotension).12 Tendon reflexes are reduced or absent, but it is important to note that they may be preserved early in the course of the illness. Cranial muscles may also be involved with symptoms such as ptosis, facial weakness, dysphagia, dysarthria, and difficulty chewing. Cranial muscle weakness is usually milder and rarer than in MG and it occurs after the onset of limb-girdle weakness. Additional symptoms of autonomic dysfunction include reduced salivation, erectile dysfunction, dryness of the eyes, and reduced sweating.13 The presence of an annoying dry mouth in patients with unexplained muscular fatigability is characteristic of LEMS. A transient improvement in muscle strength and reflexes immediately after brief exercise is classically observed in LEMS patients and is pathognomonic of LEMS.14

Diagnosis of LEMS is based on an assessment of clinical symptoms in conjunction with electrophysiologic parameters and antibody testing. Repetitive nerve stimulation (RNS) test is the electrophysiologic study of choice for the diagnosis of LEMS. RNS test demonstrates the characteristic so-called ‘LEMS triad’, including (see Figure 1):

  • Low Compound Muscles Action Potential (CMAP) amplitude.
  • Decremental responses in the low-rate (2–5 Hz) stimulation.
  • Marked incremental responses (facilitation) of the CMAP amplitudes in the high-rate stimulation (HRS) (50 Hz) in the RNS test or after voluntary muscle contraction over a brief (10 second) period of time.12

For the brief exercise test, 10-second exercise is critical.15 A more than 100 % increase in the CMAP in the HRS or after brief exercise is almost pathognomonic of LEMS. A recent study showed that a more than 60 % increment after brief exercise or during HRS is sufficient for the diagnosis of LEMS.12 The diagnosis of LEMS may be confirmed by radioimmunoassay of VGCC antibodies, which are believed to be the main pathogenic factors in LEMS,16 and P/Q VGCC antibodies are detected in 85 % of patients with clinically and electrophysiologically defined LEMS.17,18 In seronegative LEMS patients, without detectable VGCC antibodies, the electrophysiologic findings are less pronounced.19

Because of the high prevalence of SCLC in LEMS, it is mandatory to perform a careful tumor screening, especially in patients with a history of smoking. SCLC is usually identified within 2 years of the diagnosis of LEMS. Computed tomography (CT)-thorax scans detected most of the tumors found and was far more sensitive than chest X-rays.20 [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) may have an additive value in tumor screening in selected cases.

The Advent of an Effective Treatment
Symptomatic Treatment
A range of medications have been tried with varying success as treatments for LEMS, but due to the rarity of the condition, few randomized controlled trials (RCTs) have been conducted apart from 3,4-diaminopyridine (3,4-DAP), which has been more thoroughly investigated and is discussed in the next section.

  1. 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.
  2. Sanders DB, Lambert-eaton myasthenic syndrome: diagnosis and treatment, Ann N Y Acad Sci, 2003;998:500–8.
  3. Sakai W, Nakane S, Matsuo H, Autoantibody against the presynaptic P/Q-type voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome, Brain Nerve, 2013;65:441–8.
  4. Lambert EH, Elmqvist D, Quantal components of end-plate potentials in the myasthenic syndrome, Ann N Y Acad Sci, 1971;183:183–99.
  5. Nagel A, Engel AG, Lang B, et al., Lambert-Eaton myasthenic syndrome IgG depletes presynaptic membrane active zone particles by antigenic modulation, Ann Neurol, 1988;24:552–8.
  6. Newsom-Davis J, The emerging diversity of neuromuscular junction disorders, Acta Myol, 2007;26:5–10.
  7. Gutmann L, Phillips LH, 2nd, Gutmann L, Trends in the association of Lambert-Eaton myasthenic syndrome with carcinoma, Neurology, 1992;42:848–50.
  8. O’Neill JH, Murray NM, Newsom-Davis J, The Lambert-Eaton myasthenic syndrome. A review of 50 cases, Brain, 1988;111 (Pt 3):577–96.
  9. Gilhus NE, Lambert-eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy, Autoimmune Dis, 2011;2011:973808.
  10. Pellkofer HL, Armbruster L, Krumbholz M, et al., Lambert-eaton myasthenic syndrome differential reactivity of tumor versus non-tumor patients to subunits of the voltage-gated calcium channel, J Neuroimmunol, 2008;204:136–9.
  11. Mason WP, Graus F, Lang B, et al., Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome, Brain, 1997;120(Pt 8):1279–300.
  12. Oh SJ, Kurokawa K, Claussen GC, et al., Electrophysiological diagnostic criteria of Lambert-Eaton myasthenic syndrome, Muscle Nerve, 2005;32:515–20.
  13. O’Suilleabhain P, Low PA, Lennon VA, Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates, Neurology, 1998;50:88–93.
  14. Odabasi Z, Demirci M, Kim DS, et al., Postexercise facilitation of reflexes is not common in Lambert-Eaton myasthenic syndrome, Neurology, 2002;59:1085–7.
  15. Hatanaka Y, Oh SJ, Ten-second exercise is superior to 30-second exercise for post-exercise facilitation in diagnosing Lambert-Eaton myasthenic syndrome, Muscle Nerve, 2008;37:572–5.
  16. Lennon VA, Serological diagnosis of myasthenia gravis and the Lambert-Eaton myasthenic syndrome, (eds.), Handbook of myasthenia gravis and myasthenic syndromes, New York: Dekker, 1994;149–64.
  17. Motomura M, Johnston I, Lang B, et al., An improved diagnostic assay for Lambert-Eaton myasthenic syndrome, J Neurol Neurosurg Psychiatry, 1995;58:85–7.
  18. Motomura M, Lang B, Johnston I, et al., 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.
  19. Oh SJ, Hatanaka Y, Claussen GC, et al., Electrophysiological differences in seropositive and seronegative Lambert-Eaton myasthenic syndrome, Muscle Nerve, 2007;35:178–83.
  20. Titulaer MJ, Wirtz PW, Willems LN, et al., Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome, J Clin Oncol, 2008;26:4276–81.
  21. 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.
  22. Verschuuren JJ, Wirtz PW, Titulaer MJ, et al., Available treatment options for the management of Lambert-Eaton myasthenic syndrome, Expert Opin Pharmacother, 2006;7:1323–36.
  23. Oh SJ, Kim DS, Head TC, et al., Low-dose guanidine and pyridostigmine: relatively safe and effective long-term symptomatic therapy in Lambert-Eaton myasthenic syndrome, Muscle Nerve, 1997;20:1146–52.
  24. McEvoy KM, Windebank AJ, Daube JR, et al., 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome, N Engl J Med, 1989;321:1567–71.
  25. Sanders DB, Howard JF, Jr, Massey JM, 3,4-Diaminopyridine in Lambert-Eaton myasthenic syndrome and myasthenia gravis, Ann N Y Acad Sci, 1993;681:588–90.
  26. Sanders DB, Massey JM, Sanders LL, et al., A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome, Neurology, 2000;54:603–7.
  27. Lambert EH, Defects of neuromuscular transmission in syndromes other than myasthenia gravis, Ann N Y Acad Sci, 1966;135:367–84.
  28. Lindquist S, Stange IM, Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine, Neuropsychiatr Dis Treat, 2011;7:341–9.
  29. Lundh H, Nilsson O, Rosen I, et al., Practical aspects of 3,4-diaminopyridine treatment of the Lambert-Eaton myasthenic syndrome, Acta Neurol Scand, 1993;88:136–40.
  30. Tarr TB, Malick W, Liang M, et al., Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton myasthenic syndrome, J Neurosci, 2013;33:10559–67.
  31. 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.
  32. Chalk CH, Murray NM, Newsom-Davis J, et al., Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma, Neurology, 1990;40:1552–6.
  33. Pellkofer HL, Voltz R, Kuempfel T, Favorable response to rituximab in a patient with anti-VGCC-positive Lambert-Eaton myasthenic syndrome and cerebellar dysfunction, Muscle Nerve, 2009;40:305–8.
  34. Peterlin BL, Flood W, Kothari MJ, Use of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome, J Am Osteopath Assoc, 2002;102:682–4.
  35. Tim RW, Massey JM, Sanders DB, Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment, Neurology, 2000;54:2176–8.
  36. Skeie GO, Apostolski S, Evoli A, et al., Guidelines for treatment of autoimmune neuromuscular transmission disorders, Eur J Neurol, 2010;17:893–902.
  37. 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.
  38. Vedeler CA, Antoine JC, Giometto B, et al., Management of paraneoplastic neurological syndromes: report of an EFNS Task Force, Eur J Neurol, 2006;13:682–90.
  39. Maddison P, Newsom-Davis J, Mills KR, et al., Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma, Lancet, 1999;353:117–8.
  40. Titulaer MJ, Verschuuren JJ, Lambert-Eaton myasthenic syndrome: tumor versus nontumor forms, Ann N Y Acad Sci, 2008;1132:129–34.
  41. Lundh H, Nilsson O, Rosen I, Novel drug of choice in Eaton-Lambert syndrome, J Neurol Neurosurg Psychiatry, 1983;46:684–5.
  42. Thomsen RH, Wilson DF, Effects of 4-aminopyridine and 3,4-diaminopyridine on transmitter release at the neuromuscular junction, J Pharmacol Exp Ther, 1983;227:260–5.
  43. Bever CT, Jr, Young D, Anderson PA, et al., The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial, Neurology, 1994;44:1054–9.
  44. Boerma CE, Rommes JH, van Leeuwen RB, et al., Cardiac arrest following an iatrogenic 3,4-diaminopyridine intoxication in a patient with Lambert-Eaton myasthenic syndrome, J Toxicol Clin Toxicol, 1995;33:249–51.
  45. Lundh H, Nilsson O, Rosen I, Treatment of Lambert-Eaton syndrome: 3,4-diaminopyridine and pyridostigmine, Neurology, 1984;34:1324–30.
  46. Sadeh M, River Y, Argov Z, Stimulated single-fiber electromyography in Lambert-Eaton myasthenic syndrome before and after 3,4-diaminopyridine, Muscle Nerve, 1997;20:735–9.
  47. Tim RW, Massey JM, Sanders DB, Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response to therapy in 59 patients, Ann N Y Acad Sci, 1998;841:823–6.
  48. Oh SJ, Claussen GG, Hatanaka Y, et al., 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.
  49. Quartel A, Turbeville S, Lounsbury D, Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment, Curr Med Res Opin, 2010;26:1363–75.
  50. Flet L, Polard E, Guillard O, et al., 3,4-diaminopyridine safety in clinical practice: an observational, retrospective cohort study, J Neurol, 2010;257:937–46.
  51. Keogh M, Sedehizadeh S, Maddison P, Treatment for Lambert-Eaton myasthenic syndrome, Cochrane Database Syst Rev, 2011;CD003279.
  52. Maddison P, Treatment in Lambert-Eaton myasthenic syndrome, Ann N Y Acad Sci, 2012;1275:78–84.
  53. Raust JA, Goulay-Dufay S, Le Hoang MD, et al., Stability studies of ionised and non-ionised 3,4-diaminopyridine: hypothesis of degradation pathways and chemical structure of degradation products, J Pharm Biomed Anal, 2007;43:83–8.
  54. Funck-Bretano C, Relative bioavailability study of 3,4-DAP administered as a salt or a base – DAPSEL study, Clinical study report, 2006;.
  55. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Guidance for industry expedited programs for serious conditions – drugs and biologics – draft guidance, 2013.
  56. McPherson TB, Fontane PE, Jackson KD, et al., Prevalence of compounding in independent community pharmacy practice, J Am Pharm Assoc (2003), 2006;46:568–73.
  57. The Council of the European Communities EEC, Council Directive 751319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products, 1975.
  58. Goldman MP, Sodium tetradecyl sulfate for sclerotherapy treatment of veins: is compounding pharmacy solution safe?, Dermatol Surg, 2004;30:1454–6; discussion 6.
  59. FDA, US Food and Drug Administration, Limited FDA Survey of Compounded Drug Products, 2006;.
  60. Burton JM, Bell CM, Walker SE, et al., 4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis, Neurology, 2008;71:1833–4.
  61. Schwam E, Severe accidental overdose of 4-aminopyridine due to a compounding pharmacy error, J Emerg Med, 2011;41:51–4.
  62. Green DM, Jones AC, Brain KR, Content variability of active drug substance in compounded oral 3,4-diaminopyridine products, J Clin Pharm Ther, 2012;37:53–7.
  63. Active content variability of compounded 3,4-Diaminopyridine in solid oral dosage forms PCR-16., TREAT-NMD Conference, 2011.
  64. US Food and Drug Administration, Aminopyridine Review FDA Compounding Advisory Committee, 1999.
  65. US Government Deartment of Health and Human Services List of bulk drug substances that may be used in pharmacy compounding, 1999;64:996–1003.
  66. Murray NM, Newsom-Davis J, Karni Y, Oral 3,4-diaminopyridine in the treatment of the Lambert-Eaton myasthenic syndrom (LEMS) (Abstract), J Neurol Neurosurg Psychiatry, 1984;47:1052.
Keywords: Amifampridine/3,4-diaminopyridine/3,4-DAP, Lambert-Eaton myasthenic syndrome, potassium ion channel blockers, compounded drugs clinical trial evidence, treatment, expanded access protocols