Lambert–Eaton myasthenic syndrome (LEMS)

Version: 3.0
Published: 20 October 2018
Condition for which Ig has an established therapeutic role.

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Specific Conditions
  • Lambert–Eaton myasthenic syndrome
Indication for Ig Use
  • Additional therapy for LEMS patients with disability where symptomatic therapy is insufficient
Level of Evidence Evidence of probable benefit – more research needed (Category 2a)
Description and Diagnostic Criteria Lambert–Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission first recognised clinically in association with lung cancer and subsequently in cases in which no neoplasm was detected.

Patients with LEMS have a presynaptic neuromuscular junction defect. The clinical picture is characterised by proximal muscle weakness with augmentation of strength after exercise, mild oculomotor signs, depressed deep tendon reflexes and autonomic dysfunction (dry mouth, constipation, erectile failure).
 
Diagnosis should be confirmed by the presence of antibodies to Voltage gated calcium channels, electrophysiology consistent with LEMS, or both.
Justification for Evidence Category In the Biotext (2004) review, one systematic review (containing one randomised control trial [RCT] with nine patients) and one case series of seven patients with a crossover design were included. Intravenous immunoglobulin (IVIg) appeared to provide some benefit to patients with LEMS. However, both studies only included a small number of patients.

Expert consensus states that IVIg produces temporary improvement in patients with LEMS. It therefore has a role as second line therapy (Asia–Pacific IVIg Advisory Board 2004). Treatment of LEMS with 3,4DAP and pyridostigmine has been shown to be efficacious in an RCT (Wirtz 2009) and should be regarded as combined first line therapy. 3,4DAP is not a licensed medication in Australia but can be sourced as an import and used under the Special Access (SASB) scheme.

One submission to the National Blood Authority reported on a RCT that showed significant improvement in strength associated with a decline in the level of pathogenic antibodies (NSW IVIg User Group). IVIG may provide additional benefit.

Immunosuppression with prednisone, azathioprine or cyclosporine has been reported in cases to be beneficial in non-paraneoplastic LEMS however has not been subject to an RCT.

Treatment of paraneoplastic LEMS including with 3,4DAP, pyridostigmine or with IVIG will not treat the underlying neoplasia but may be necessary for symptomatic reasons. Treatment of the underlying neoplasia often helps the LEMS (Newsom-Davis Semin Neurol 2003). Patients with paraneoplastic LEMS due to small cell lung cancer have been associated with a significantly longer mean survival than patients with small cell lung cancer suggesting an immune vs tumour effect. Accordingly immunosuppression (as opposed to IVIg) has not generally been applied in paraneoplastic LEMS.
Diagnosis Requirements

A diagnosis must be made by a Neurologist.
Qualifying Criteria for Ig Therapy
AND
  • Alternative therapies have failed or an insufficient response has been achieved
Intravenous immunoglobulin (IVIg) should be used for a maximum period of four months (induction plus three maintenance cycles) before determining whether the patient has responded. If there is no benefit after this period, IVIg therapy should be abandoned.
 
Review by a neurologist is required within four months of treatment and annually thereafter. Consideration should be given to a trial of weaning at each review.
 
Documentation of clinical effectiveness is necessary for continuation of IVIg therapy.
Review Criteria for Assessing the Effectiveness of Ig Use
Intravenous immunoglobulin (IVIg) should be used for a maximum period of four months (induction plus three maintenance cycles) before determining whether the patient has responded. If there is no benefit after this period, IVIg therapy should be abandoned.
 
Review by a neurologist is required within four months of treatment and annually thereafter. Consideration should be given to a trial of weaning at each review.
 
Documentation of clinical effectiveness is necessary for continuation of IVIg therapy.

Clinical effectiveness of Ig therapy may be assessed by:
 

On review of the initial authorisation period

  • Clinically significant improvement in muscle weakness as measured by an increase of at least one point in the Medical Research Council (MRC) sum score compared to the qualifying score
  • OR
  • Clinically significant improvement in the severity of autonomic symptoms compared to the severity of symptoms at the qualifying assessment
  • OR
  • Patient with severe disease continues to report post infusion improvement with end-of-cycle deterioration and additional immunosuppressant agents have been commenced

On review of a continuing authorisation period

  • Stabilised disease as assessed by the Medical Research Council (MRC) sum score that is greater than or equal to the previous review score and greater than the qualifying score
  • OR
  • Patient with severe disease continues to report post infusion improvement with end-of-cycle deterioration and additional immunosuppressant agents have been commenced
  • OR
  • Stability in autonomic symptoms compared to the previous review and sustained improvement compared to symptoms at qualifying
AND
  • A trial of Ig weaning towards cessation of Ig therapy is planned for patients who are clinically stable to identify those in remission or a reason provided as to why a trial is not planned
Dose
  • Induction Dose (IVIg) - 2 g/kg in 2 to 5 divided doses.
  • Maintenance Dose (IVIg) - 0.4–1g/kg, 2–6 weekly. A maximum dose of 2 g/kg may be given in any four week period. This might be by smaller doses more frequently.
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
 
Refer to the current product information sheet for further information on dose, administration and contraindications.
 Dose Calculator
Bibliography
Association of British Neurologists 2005, Guidelines for the use of intravenous immunoglobulin in neurological diseases, The Association, London. Available from: http://www.theabn.org/media/docs/ABN%20publications/IVIg-guidelines-final-July05.pdf
 
Bain, PG, Motomura, M, Newsom-Davis, J, et al 1996, ‘Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome’, Neurology, vol. 47, no. 3, pp. 678–83. https://www.ncbi.nlm.nih.gov/pubmed/8797464
 
Biotext 2004, ‘Summary data on conditions and papers’ in A systematic literature review and report on the efficacy of intravenous immunoglobulin therapy and its risks, commissioned by the National Blood Authority on behalf of all Australian Governments, pp. 184–7. Available from: https://www.blood.gov.au/system/files/A-systematic-literature-review-and-report-on-the-efficacy-of-IVIg-therapy-and-its-risks.pdf
 
Dalakas, MC 2004, ‘The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile’, Pharmacology & Therapeutics, vol. 102, no. 3, pp. 177–93. https://www.ncbi.nlm.nih.gov/pubmed/15246245
 
Kleyweg, RP, van der Meche, FG & Schmitz, PI 1991, ‘Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome’, Muscle Nerve, vol. 14, no. 11, pp. 1103–9. https://www.ncbi.nlm.nih.gov/pubmed/1745285
 
Kornberg, AJ 2004, Bringing consensus to the use of IVIg in neurology. Expert consensus statements on the use of IVIg in neurology, 1st edn. A report for the Asia–Pacific IVIg Advisory Board, Melbourne.
 
Maddison, P & Newsom-Davis, J 2005, ‘Treatment for Lambert-Eaton myasthenic syndrome (Cochrane Review)’, in The Cochrane Library, Issue 2, John Wiley & Sons, Ltd, Chichester, United Kingdom.
 
Medical Research Council. Aids to the examination of the peripheral nervous system, Memorandum no. 45, Her Majesty's Stationery Office, London, 1981. Available from: https://mrc.ukri.org/research/facilities-and-resources-for-researchers/mrc-scales/mrc-muscle-scale/
 
Motomura, M, Bain, PG, et al 1995, ‘Effects of intravenous immunoglobulin treatment on anti-calcium channel antibody titres in the Lambert-Eaton myasthenic syndrome’, Journal of Neurology, vol. 242, pp. S44.
 
Newsom-Davis J 2003, ‘Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome’, Seminars in Neurology, vol. 23, no. 2, pp. 191-8. https://www.thieme-connect.com/DOI/DOI?10.1055/s-2003-41135
 
Skeie, GO, Apostolski,S, Evoli, A, et al 2006, ‘Guidelines for the treatment of autoimmune neuromuscular transmission disorders’, European Journal of Neurology, vol. 13, no.7, pp. 691–9. https://www.ncbi.nlm.nih.gov/pubmed/16834699
 
Wirtz, PW, Verschuuren, JJ, van Dijk, JG, et al 2009, ‘Efficacy of 3,4-Diaminopyridine and Pyridostigmine in the Treatment of Lambert–Eaton Myasthenic Syndrome: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study’, American Society for Clinical Pharmacology and Therapeutics, Vol. 86, issue. 1, pp. 44-48. https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1038/clpt.2009.35