Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission caused by impaired presynaptic release of acetylcholine (ACh).

It was first described by Lee McKendre Eaton (1905-1958), an American neurologist, with Edward H Lambert and E D Rooke.¹

Pathogenesis

Lambert-Eaton myasthenic syndrome (LEMS) results from an autoimmune attack directed against the P/Q subtype of voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal. These channels are also found in high numbers in the tumour cells associated with LEMS (small-cell cancer of the lung). It is thought that antibodies are produced against the tumour VGCCs but are then also responsible for the resulting attack on noncancerous cells and their sequelae.^2,3

Epidemiology

It is a rare condition:

• Rates for UK population are equivalent to that of myasthenia gravis, i.e. 0.4 per 100,000.
• Males typically have outnumbered females by 2:1, but more recent reports show almost equal incidence. This reflects trends in diagnosis of lung cancer.
• It is usually a condition of later adulthood, but does present occasionally in childhood.

Risk factors

• Cancer - typically small-cell carcinoma of the lung (SCCL) is present when weakness begins, or is later found in approximately 50% of patients.⁴ In most cases the cancer is found within 2 years after the onset of Lambert-Eaton myasthenic syndrome (LEMS); within 4 years in virtually all cases.
• Smoking and age at onset are major risk factors for cancer in LEMS. All patients with associated SCCL have a history of long-term smoking. Only half of patients with autoimmune LEMS are long-term smokers, e.g. a patient aged <50 years, who does not have a cancer discovered in the first 2 years after diagnosis, is unlikely to have an underlying carcinoma. But, a long-term smoker with onset of LEMS after the age of 50 years, probably has underlying lung cancer.

Presentation

Lambert-Eaton myasthenic syndrome (LEMS) causes proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes. The initial presentation can be similar to that of myasthenia gravis, although the course of the two diseases may be very different.

Symptoms

• Symptoms usually begin insidiously, with many patients undiagnosed for months, or years.
• Weakness is a major symptom. Usually, in the proximal muscles of lower limb. Gait is affected.
• Muscles may ache and be tender. Oropharyngeal and ocular muscles are mildly affected.
• Bulbar and respiratory muscles are usually spared.
• Autonomic symptoms - dry mouth, impotence in males, and postural hypotension may be seen.

Signs

• Reduced strength in the proximal muscles of the arms and legs, producing a waddling gait and difficulty with raising the arms.
• Eyelid ptosis and mild diplopia is found in 25% of patients.
• Occasionally there may be difficulty in chewing, speech or swallowing.
• Approximately 50% of patients may find strength improves initially on exercise, but then lessens as exercise is sustained.
• Deep tendon reflexes are reduced or absent. Sensory examination is normal, unless there is a coincident peripheral neuropathy associated with an underlying cancer.

Differential diagnosis

• Myasthenia gravis.
• Acute or chronic inflammatory demyelinating polyradiculopathy.
• Dermatomyositis/polymyositis.
• Inclusion body myositis.
• Spinal muscular atrophy.

Investigations

• The only methods of differentiating myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS) are the detection of acetylcholine (ACh) receptor antibodies, or discovering the presence of underlying malignancy.
• A serum test for voltage-gated calcium-channel antibodies is now available.⁴ Antibodies have been reported in 75-100% of patients with LEMS and underlying cancer, and 90% of patients without. (They are found in <5% of patients with myasthenia gravis and up to 25% in patients with antibody levels secondary to, for example, systemic lupus erythematosus (SLE) or rheumatoid arthritis.)²
• CT or MRI scanning of the chest to exclude chest malignancy.
• ACh receptor antibodies are occasionally found in low titres in patients with LEMS.
• Electrophysiological testing shows a small compound muscle action potential and facilitation with exercise or 20 Hz repetitive stimulation.⁵
• Bronchoscopy may be necessary if imaging studies are normal, but risk of small-cell carcinoma of the lung (SCCL) is high.

Screening for underlying malignancy is recommended for two years after diagnosis.⁶

Associated diseases

Cancer is found in 40% of patients with LEMS, usually small-cell carcinoma of the lung (SCCL). LEMS has also been associated with:

• Lymphosarcoma.
• Malignant thymoma.
• Carcinoma of breast, stomach, colon, prostate, bladder, kidney or gallbladder. (Clinical signs usually precede cancer identification.)

Management

General principles

• When Lambert-Eaton myasthenic syndrome (LEMS) diagnosis is made initially, an extensive search for any underlying cancer should be made.
• Initial therapy should be aimed at treating any neoplasm.⁷ Effective treatment of the underlying tumour frequently produces marked improvement in strength.

Pharmacological

Several drugs are available for symptomatic treatment, e.g. guanidine, aminopyridines or acetylcholinesterase inhibitors.⁸ Other therapies aim to deplete the serum autoantibodies or to suppress the immune system.

• The limited evidence from randomised controlled trials (RCTs) shows either 3,4-diaminopyridine or intravenous (IV) immunoglobulin (dose 2 g/kg)⁹ improves muscle strength.^10,11 There are insufficient data to quantify the effect.¹²
• Other treatments, e.g. plasma exchange, steroids and immunosuppressive agents (e.g. prednisolone or azathioprine), have not been tested in RCTs.
• Cholinesterase inhibitors: they work by inhibiting the breakdown of ACh. This is intended to help compensate for the relative lack of ACh release in LEMS. They usually do not provide a significant improvement. A few patients with mild disease may notice the benefit.
• In patients who do not have cancer, aggressive immunotherapy is justified.

Surgical

This depends on the nature of any malignancy discovered.

Complications

• Be aware of medications that can cause deterioration in the patient's condition - including neuromuscular blocking agents, aminoglycosides, magnesium, iodinated IV contrast and calcium-channel blockers.
• Cachexia.
• Paraneoplastic neuropathy.

Prognosis

• This depends mainly on the presence and nature of any underlying malignancy, or the severity of any associated autoimmune disease.
• Lambert-Eaton myasthenic syndrome (LEMS) often leads to the early detection of small-cell carcinoma of the lung (SCCL), so patients with LEMS and SCCL often have a better prognosis. When LEMS has been symptomatic for 2 years and no underlying cancer has been found, the LEMS is most likely to be of autoimmune origin. Prognosis is then based on severity of dysfunction, and the presence and severity of other autoimmune conditions.
• Maximum severity is usually established within months of first symptoms appearing. Exacerbations may occur secondary to intercurrent illness and drugs that affect neuromuscular transmission, e.g. anaesthetic.
• Most patients find therapy may help to relieve symptoms partially; however, usually symptoms progress over time.

Document references

1. Lambert EH, Eaton LM, Rooke ED: defect of neuro-muscular conduction associated with neoplasms. Am.J Physiol 1956;187:612-3 Original descriptive article.
2. 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 Jun 1;332(22):1467-74. [abstract]
3. Honnorat J, Antoine JC; Paraneoplastic neurological syndromes. Orphanet J Rare Dis. 2007 May 4;2:22. [abstract]
4. Mareska M, Gutmann L; Lambert-Eaton myasthenic syndrome. Semin Neurol. 2004 Jun;24(2):149-53. [abstract]
5. Tim RW, Sanders DB; Repetitive nerve stimulation studies in the Lambert-Eaton myasthenic syndrome. Muscle Nerve. 1994 Sep;17(9):995-1001. [abstract]
6. Titulaer MJ, Soffietti R, Dalmau J, et al; Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011 Jan;18(1):19-e3. doi: 10.1111/j.1468-1331.2010.03220.x. Epub [abstract]
7. Newsom-Davis J; Lambert-Eaton myasthenic syndrome. Rev Neurol (Paris). 2004 Feb;160(2):177-80. [abstract]
8. Verschuuren JJ, Wirtz PW, Titulaer MJ, et al; Available treatment options for the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother. 2006 Jul;7(10):1323-36. [abstract]
9. Illa I; IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. 2005 May;252 Suppl 1:I14-8. [abstract]
10. Keogh M, Sedehizadeh S, Maddison P; Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011 Feb 16;2:CD003279. [abstract]
11. McEvoy KM, Windebank AJ, Daube JR, et al; 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med. 1989 Dec 7;321(23):1567-71. [abstract]
12. Clinical guidelines for the use of intravenous immunoglobulin, Dept of Health (November 2007)

Internet and further reading

• Buchwald B, Ahangari R, Weishaupt A, et al; Presynaptic effects of immunoglobulin G from patients with Lambert-Eaton myasthenic syndrome: their neutralization by intravenous immunoglobulins. Muscle Nerve. 2005 Apr;31(4):487-94. [abstract]
• Kleinschmidt P; Lambert-Eaton Myasthenic Syndrome in Emergency Medicine, eMedicine, May 2010

Acknowledgements