Lambert-Eaton Myasthenic Syndrome

It is a rare condition.

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

• Cancer - typically small cell carcinoma of the lung (SCLC) is present when weakness begins, or is later found in 40% of patients.² In most cases the cancer is found within 2 years after the onset of 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 SCLC have a history of long-term smoking. Only half of patients with auto-immune LEMS are long-term smokers. e.g. a patient < 50years, 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 LEMS onset after age 50years, probably has underlying lung cancer.

Symptoms

• Symptoms usually begin insidiously, with many patients undiagnosed for months, or years.
• Weakness is a major symptom. Usually 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, postural hypotension may be seen.

Signs

• Reduced strength in proximal muscles of arms and legs, producing waddling gait and difficulty raising arms.
• Eyelid ptosis and mild diplopia is found in 25% of patients.
• Occasionally there may be difficulty in chewing, speech or swallowing.
• Approximately 50% 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.

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

• The only methods of differentiating myasthenia gravis and LEMS are the detection of ACh receptor antibodies, or discovering the presence of underlying malignancy.
• A serum test for voltage-gated calcium channel antibodies is now available.² 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 e.g. SLE or rheumatoid arthritis).³
• CT or MRI of the chest to exclude chest malignancy.
• ACh receptor antibodies are occasionally found in low titres in LEMS patients.
• Electrophysiological testing shows a small compound muscle action potential and facilitation with exercise or 20 Hz repetitive stimulation.⁴
• Bronchoscopy may be necessary if imaging studies are normal, but risk of SCLC is high.

Cancer is found in 40% of patients with LEMS, usually small cell cancer of the lung. It is thought that antibodies that have been produced to attack the cancer cells, attack the calcium channels by mistake.³LEMS has also been associated with:

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

General principles

• When LEMS diagnosis made initially, an extensive search for any underlying cancer should be made.
• Initial therapy should be aimed at treating any neoplasm.⁵ 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.⁶ Other therapies aim to deplete the serum autoantibodies or to suppress the immune system.

• The limited evidence from randomised controlled trials (RCT) show either 3,4 -diaminopyridine or IV immunoglobulin (dose 2 g/kg)⁷ improve muscle strength. ^8,9 There is insufficient data to quantify the effect.¹⁰
• Other treatments e.g. plasma exchange, steroids and immunosuppressive agents (e.g. prednisolone or azathioprine) have not been tested in RCT.
• 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.

• 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

• This depends mainly on the presence and nature of any underlying malignancy, or the severity of any associated autoimmune disease.
• LEMS often leads to the early detection of SCLC, so patients with LEMS and SCLC 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, but usually symptoms progress over time.

,