Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune-mediated neurological disorder that manifests as muscle fatigue, diminished tendon reflexes, with symptoms of cholinergic overactivity. It can be associated with certain neoplastic conditions, the most common being small cell lung carcinoma (SCLC). The basic pathophysiology involved is antibody-mediated targeting of voltage-gated calcium channels (VGCC), which decreases the release of acetylcholine in the synaptic junction. Multiple treatment options have been introduced in the past and, recently, a new drug, amifampridine, has been approved by the Food and Drug Administration (FDA) for the treatment of weakness associated with these patients. We summarize this newly introduced drug with a brief description of other treatment options available.
Introduction & Background
A revolutionary article was published in the Journal of the American Medical Association (JAMA) in 1956, briefing about the syndrome with the neuromuscular transmission defect discovered by Eaton and Lambert, which was the basis for the coined name of the disease, Lambert-Eaton Myasthenic Syndrome (LEMS) . LEMS is an autoimmune disorder of the neuromuscular junction caused by antibodies produced against the voltage-gated calcium channels (VGCC) on the presynaptic nerve terminals, thus inhibiting the release of the neurotransmitter acetylcholine (ACh) . The clinical manifestation of the disease is muscle fatigue, which principally affects the proximal parts of extremities. The tendon reflexes are absent or diminished in these patients . LEMS is also accompanied by symptoms that are representative of cholinergic dysautonomias such as decreased salivation, sweating, constipation, and impotence. Oculobulbar involvement, presenting as ptosis or diplopia, is seen more in myasthenia gravis (MG) as compared to LEMS . LEMS is classified as paraneoplastic or idiopathic. A large fraction of LEMS cases have an underlying tumor, primarily small cell lung carcinoma (SCLC). The occurrence of MG is 46 times more than LEMS. LEMS has a male predominance in 60%-75% of patients in contrast to MG where most cases are seen in females. The age of onset in patients with non-paraneoplastic LEMS is the same as in MG, which is usually around 35 years of age. In contradiction, paraneoplastic LEMS peaks at around 58 years. Seventy-three percent of SCLC individuals are also confirmed as having LEMS .
LEMS is elicited by auto-antibodies that form against the VGCC present in the cell membrane of neurons. These anti-VGCC antibodies are highly sensitive, as they can be detected in 85% of affected individuals. Most frequently, the VGCC autoantibodies detected in such patients' serum are formed against the alpha1 subunit of presynaptic receptors and bind with the alpha1 subunit or, rarely, the beta3 subunit. Therefore, various parts of the presynaptic VGCC complex are potential targets for antibodies [6-7].
It is also reported that non-paraneoplastic LEMS patients are associated with underlying immune-mediated diseases. Wirtz et al. concluded that 27% of non-paraneoplastic LEMS patients and 11% of paraneoplastic LEMS had underlying immune disorders, including type 1 diabetes and thyroid disease . Titulaer et al. showed, in a small case series of paraneoplastic LEMS patients, a persistent affiliation with human leukocyte antigen (HLA)-B8 in class l and HLA-DQ2 and HLA-DR3 in class ll. Around 65% of non-paraneoplastic LEMS patients were found to be HLA-B8 positive, and 50% were HLA-A1 positive while the same frequency existed for HLA-DQ2 and HLA-DR3 .
In both the paraneoplastic and idiopathic forms of LEMS, clinical symptoms are due to an antibody-mediated reduction of VGCC in the presynaptic terminal of the neuromuscular junction (NMJ). Reduction in VGCC leads to a decrease in Ca2+ influx, which is required for presynaptic vesicle fusion and neurotransmitter release. This neurotransmitter, acetylcholine (Ach), is required for postsynaptic muscle contraction. Although in LEMS, NMJ compensates for VGCC, but this compensation is not sufficient to restore the normal amount of neurotransmitter release and thus muscle contraction .
LEMS is first suspected based on clinical signs and symptoms showing the classic triad of proximal muscle weakness, decreased tendon reflexes, and autonomic dysfunction . The clinical findings need to be confirmed by different electrophysiological studies, such as electromyography (EMG) and nerve conduction studies (NCS). Motor and sensory nerve conduction studies show that the compound muscle action potential (CMAP) amplitude of resting muscle in LEMS patients is lower than the standard . The choice of test for diagnosis is repetitive nerve stimulation (RNS) where a low-frequency stimulation of 2-5 Hz shows a decremental response . A reproducible increase in the CMAP amplitude of 100% or more, with a high-frequency stimulation of 50 Hz (post-activation stimulation), or after vigorous stimulation of muscle for 10s (post-exercise stimulation) confirms LEMS . Needle EMG shows erratic changes in motor unit action potential as low and short during the voluntary action potential. This can be followed by single-fiber EMG measurements of jitter. The increase in jittering shows transmission-blocking and corresponds with the severity of the disease .
A blood test to detect antibodies against VGCC on the nerve side of the NMJ is present in 85%-90% of patients with LEMS . The test alone is not confirmatory of the disease, but it is a sensitive test along with clinical signs. The presence of antibodies to VGCC does not correspond with the severity of the disease, but as the patient is started on immunosuppressive therapy, sensitivity to this test is decreased, as antibody production is reduced, and is effective when performed before the start of treatment . VGCC has two types of antibodies targeted towards them and P/Q type antibodies are most commonly seen in LEMS but a very small percentage has also shown type-N antibodies with an increased incidence of SCLC in them .
There are multiple treatment options available for the symptomatic treatment of LEMS and the most effective ones are those that increase acetylcholine release from the presynaptic membranes. If LEMS and malignancy are present, the primary concern is cancer therapy as successful tumor therapy in LEMS patients also helps reduce the symptoms of LEMS [16-17]. The treatment option can be characterized depending upon its therapeutic impact on improving weakness in patients.
In patients with mild weakness, regular follow-up is advised and patients are treated if any concomitant malignancy is present . The following are some drug options explained along with recent advances to treat moderate to severe and refractory weakness.
The main therapeutic focus in LEMS is to improve neuromuscular transmission. Many symptomatic treatments have been experimented in the past few decades, including pyridostigmine, guanidine, 4-aminopyridine, and 3,4-Diaminopyridine(3,4-DAP), with the last one proving to be the most efficacious . 3,4-DAP binds to the VGCC, causing them to remain open for a longer duration by blocking presynaptic potassium channels. These potassium channels prolong the depolarization at the nerve endings, thus increasing the calcium influx with the subsequent release of ACh from motor nerve terminals improving LEMS-related muscle weakness .
Many trials were conducted in the recent past that have successfully shown the drug’s efficacy and improvement in the Quantitative Myasthenia Gravis (QMG) score. The side effects of the normal therapeutic range are mild, including perioral and extremity paresthesias, nausea, vomiting, and elevated liver enzymes. The side effects of more severity, such as seizures, have a low risk of occurrence because of the drugs low penetration in the CNS, but as it is dose-dependent, it can occur at doses greater than 100 mg per day. 3,4-DAP was first approved in Europe in December 2009 and later, in 2010, it was recommended as a first-line symptomatic treatment for LEMS . Amifampridine phosphate is the salt form of the 3-4-DAP base and it is more stable . The starting dose of amifampridine prescribed for adults is 15-30 mg orally three times a day. The maximum approved daily dose is 80 mg a day. The US Foods and Drug Administration (FDA) approved the use of amifampridine in November 2018 for adults (Firdapse) .
Table 1 summarizes the trials showing the efficacy of amifampridine in patients suffering from LEMS.
Guanidine was approved as the first-line agent in the treatment of LEMS but because of multiple side effects, its usage has been limited . Apparently, guanidine functions by increasing the release of acetylcholine after a nerve impulse. It can also slow down muscle cell membrane depolarization and repolarization rates . If amifampridine is not available or tolerated, then guanidine can be advised with or without pyridostigmine in low doses (1000 mg/day) because of its toxicity profile. It is associated with multiple side effects, such as renal toxicity, and gastrointestinal disturbances such as anorexia, diarrhea, gastric irritation, and bone marrow suppression .
Pyridostigmine has been advised in the treatment of moderate to severe weakness along with guanidine. It has better tolerance as compared to the rest of the acetylcholinesterase inhibitors. The mechanism of action of pyridostigmine is by increasing the concentration of acetylcholine in the synaptic clefts by the reversible inhibition of cholinesterase activity to improve the parasympathetic tone . The dose recommended for treating LEMS is wide and ranges from 30 mg to 180 mg. The dosing intervals depends upon the side effects and clinical response. The side effects associated with pyridostigmine are mild such as nausea, abdominal cramping, and diarrhea .
In patients suffering from refractory weakness and not responding to acetylcholinesterase inhibitors, immunomodulators are used to target the immune system, as it has been central in showing resistance to the treatment.
The following options can also be used in the treatment of LEMS.
Intravenous Immune Globulin
Intravenous immune globulin (IVIG) is considered a first-line treatment option to treat the refractory pattern of weakness seen in patients with LEMS. The mechanism of action of IVIG is unknown, but it is suspected that it works by neutralizing pathogenic autoantibodies and by regulating autoreactive B cells . The total dose of 2 g/kg is effective for the course of two to five days; maintenance therapy for four to 12 weeks with repeat infusion has also been beneficial for patients who initially responded to IVIG treatment. It takes two to four weeks for IVIG to improve weakness, followed by recurrent weakness in the next few weeks . The complications and side effects associated with IVIG are minor and include laboratory changes, rash, headache, and, rarely, deep venous thrombosis .
Table 2 summarizes the immunosuppressive agents used in patients suffering from LEMS.
It is recommended for use when other immunosuppressive agents fail to give sufficient clinical response. Trials [38-39] conducted retrospectively showed the efficacy of these substances in patients suffering from LEMS. It is a monoclonal antibody that works by binding to the CD20 receptor and causing the cytotoxicity of B cell lymphocytes, which results in halting the immune response mediated through this pathway. The standard dose is given to LEMS patients at 375 mg/m2 once weekly for four weeks and then every month for the next two months . The side effects associated with rituximab include cardiac disorders, such as arrhythmias and acute coronary syndrome, and in other systems, anaphylaxis, allergic reactions, nausea, and vomiting .
Patients suffering from the antibody-mediated disorder with a refractory pattern have multiple options, and plasma exchange has shown beneficial effects in them. In patients suffering from LEMS, it has limited advantages, but with concomitant use with another immunosuppressive disorder, it can be beneficial in some patients [42-43]. The recommended protocol for MG is five exchanges over the course of seven to 14 days but no recommendations have been made for LEMS. Therefore, it is suggested to use the same protocol in LEMS, as the pathology is the same between the two disorders .
The major determinant of prognosis in LEMS has been the presence of neoplasm. In patients with SCLC associated with LEMS, longer survival has been observed as compared to patients with SCLC but no associated neurological illness . In patients without any associated neoplasm, survival is normal or near-normal, as seen in a study; in 47 patients with LEMS without SCLC, 10 patients died at a mean age of 70 years unrelated to the LEMS. However, two deaths were possibly related to complications of glucocorticoid therapy .
Table 3 provides a list of take-home messages.
LEMS is a rare autoimmune-mediated neuromuscular disorder caused by a decrease in acetylcholine release from the neuromuscular junction. The prognosis of LEMS depends upon the presence of malignancy, as it can shorten survival in these patients, but near-normal life expectancy has been observed in idiopathic LEMS. The treatment options are primarily focused on the symptomatic improvement of weakness, and these include amifampridine, guanidine, and pyridostigmine. For refractory weakness, patients can go for IVIG, prednisone, or other immunosuppressive agents. Rituximab and plasma exchange have also been proven to be beneficial in some refractory cases.
- Lorenzoni PJ, Kay CS, Werneck LC, Scola RH: Lambert-Eaton myasthenic syndrome: the 60th anniversary of Eaton and Lambert's pioneering article [Article in English, Portuguese]. Arq Neuropsiquiatr. 2018, 76:124-126. 10.1590/0004-282x20170194
- 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, 1:1467-1475. 10.1056/nejm199506013322203
- Titulaer MJ, Wirtz PW, Kuks JB, et al.: The Lambert-Eaton myasthenic syndrome 1988-2008: a clinical picture in 97 patients. J Neuroimmunol. 2008, 15:153-158. 10.1016/j.jneuroim.2008.05.025
- Jayarangaiah A, Kariyanna PT: Lambert Eaton Myasthenic Syndrome. InStatPearls, Treasure Island (FL), US; 2019.
- Elrington GM, Murray NM, Spiro SG, Newsom-Davis J: Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients. J Neurol Neurosurg Psychiatry. 1991, 54:764-767. 10.1136/jnnp.54.9.764
- Gilhus NE: Lambert-Eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy. Autoimmune Dis. 2011, 2011:973808. 10.4061/2011/973808
- Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J: An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1995, 58:85-87. 10.1136/jnnp.58.1.85
- Wirtz PW, Bradshaw J, Wintzen AR, Verschuuren JJ: Associated autoimmune diseases in patients with the Lambert-Eaton myasthenic syndrome and their families. J Neurol. 2004, 251:1255-1259. 10.1007/s00415-004-0528-7
- Titulaer MJ, Verschuuren JJ: Lambert-Eaton myasthenic syndrome. Tumor versus nontumor forms. Ann N Y Acad Sci. 2008, 1132:129-134. 10.1196/annals.1405.030
- Huelsbrink R, Hashemolhosseini S: Lambert-Eaton myasthenic syndrome - diagnosis, pathogenesis and therapy. Clin Neurophysiol. 2014, 125:2328-2336. 10.1016/j.clinph.2014.06.031
- Titulaer MJ, Lang B, Verschuuren JJ: Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011, 10:1098-1107. 10.1016/s1474-4422(11)70245-9
- Varma S: Electromyography and neuromuscular disorders: clinical‐electrophysiologic correlations, 3rd Edition, edited by David C. Preston and Barbara E. Shapiro, 664 pp., Elsevier Saunders. Muscle Nerve. 2012, 48:308. 10.1002/mus.23894
- Chiou-Tan FY, Tim RW, Gilchrist JM, et al.: Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle Nerve. 2001, 1:1236-1238. 10.1002/mus.1139
- 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, 37:572-575. 10.1002/mus.20979
- Pellkofer HL, Armbruster L, Krumbholz M, Titulaer MJ, Verschuuren JJ, Schumm F, Voltz R: Lambert-Eaton myasthenic syndrome differential reactivity of tumor versus non-tumor patients to subunits of the voltage-gated calcium channel. J Neuroimmunol. 2008, 204:136-139. 10.1016/j.jneuroim.2008.08.002
- Mason WP, Graus F, Lang B, et al.: Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain. 1997, 120:1279-300.
- Wang S, Bruzzi J, Rodriguez-Garza VP, Komaki RR: Lambert-Eaton myasthenic syndrome in a patient with small-cell lung cancer. Clin Lung Cancer. 2006, 7:282-284. 10.3816/CLC.2006.n.008
- Tarr TB, Wipf P, Meriney SD: Synaptic pathophysiology and treatment of Lambert-Eaton myasthenic syndrome. Mol Neurobiol. 2015, 52:456-463. 10.1007/s12035-014-8887-2
- 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, 86:44-48. 10.1038/clpt.2009.35
- 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. 10.1002/mus.26052
- Kesner VG, Oh SJ, Dimachkie MM, Barohn RJ: Lambert-Eaton myasthenic syndrome. Neurol Clin. 2018, 36:379-394. 10.1016/j.ncl.2018.01.008
- Raust JA, Goulay-Dufay S, Le Hoang MD, Pradeau D, Guyon F, Do B: 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, 4:83-8. 10.1016/j.jpba.2006.06.007
- U.S. Food & Drug Administration. FDA approves first treatment for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder. (2018). https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-lambert-eaton-myasthenic-syndrome-ra....
- Sanders DB, Massey JM, Sanders LL, Edwards LJ: A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology. 2000, 54:603. 10.1212/wnl.54.3.603
- McEvoy KM, Windebank AJ, Daube JR, Low PA: 3,4-diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med. 1989, 7:1567-1571. 10.1056/NEJM198912073212303
- 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, 53:717-725. 10.1002/mus.25070
- 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. 10.1002/mus.21422
- Keogh M, Sedehizadeh S, Maddison P: Treatment for Lambert‐Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011, 2011:CD003279. 10.1002/14651858.CD003279.pub3
- 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. 10.1002/mus.26052
- Oh SJ, Kim DS, Head TC, Claussen GC: Low‐dose guanidine and pyridostigmine: relatively safe and effective long‐term symptomatic therapy in Lambert‐Eaton myasthenic syndrome. Muscle Nerve. 1997, 20:1146-1152.
- Kalia J, Swartz KJ: Elucidating the molecular basis of action of a classic drug: guanidine compounds as inhibitors of voltage-gated potassium channels. Mol Pharmacol. 2011, 80:1085-1095. 10.1124/mol.111.074989
- Bayry J, Thirion M, Misra N, et al.: Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Neurol Sci. 2003, 24:217-221. 10.1007/s10072-003-0081-7
- 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, 47:678-683. 10.1212/wnl.47.3.678
- Wittstock M, Benecke R, Zettl UK: Therapy with intravenous immunoglobulins: complications and side-effects. Eur Neurol. 2003, 50:172-175. 10.1159/000073059
- Streib EW, Rothner AD: Eaton‐Lambert myasthenic syndrome: long‐term treatment of three patients with prednisone. Ann Neurol. 1981, 10:448-453. 10.1002/ana.410100507
- Newsom-Davis J: Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003, 23:191-198. 10.1055/s-2003-41135
- Sanders DB: Lambert‐Eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci. 2003, 998:500-508. 10.1196/annals.1254.065
- 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, 82:671-673. 10.1136/jnnp.2009.197632
- Boutin E, Rey C, Romeu M, Pouget J, Franques J: Favourable outcome after treatment with rituximab in a case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome [Article in French, English]. Rev Med Interne. 2013, 34:493-496. 10.1016/j.revmed.2013.04.007
- Weiner GJ: Rituximab: mechanism of action. Semin Hematol. 2010, 47:115-123. 10.1053/j.seminhematol.2010.01.011
- Diaz-Manera J, Martínez-Hernández E, Querol L, et al.: Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012, 17:189-193. 10.1212/WNL.0b013e3182407982
- Dau PC, Denys EH: Plasmapheresis and immunosuppressive drug therapy in the Eaton‐Lambert syndrome. Ann Neurol. 1982, 11:570-575. 10.1002/ana.410110604
- Motomura M, Hamasaki S, Nakane S, Fukuda T, Nakao YK: Apheresis treatment in Lambert‐Eaton myasthenic syndrome. Ther Apher. 2000, 1:287-290. 10.1046/j.1526-0968.2000.004004287.x
- Newsom-Davis J, Murray NM: Plasma exchange and immunosuppressive drug treatment in the Lambert‐Eaton myasthenic syndrome. Neurology. 1984, 34:480. 10.1212/wnl.34.4.480
- Maddison P, Gozzard P, Grainge MJ, Lang B: Long-term survival in paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2017, 88:1334-1339.
- Maddison P, Lang B, Mills K: Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer. J Neurol Neurosurg Psychiatry. 2001, 70:212-217. 10.1136/jnnp.70.2.212
Recent Advances and Therapeutic Options in Lambert-Eaton Myasthenic Syndrome
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Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Cite this article as:
Anwar A, Saleem S, Ahmed M, et al. (August 21, 2019) Recent Advances and Therapeutic Options in Lambert-Eaton Myasthenic Syndrome. Cureus 11(8): e5450. doi:10.7759/cureus.5450
Received by Cureus: August 12, 2019
Peer review began: August 19, 2019
Peer review concluded: August 20, 2019
Published: August 21, 2019
© Copyright 2019
Anwar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.