Syndrome myasthénique de Lambert-Eaton

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

Pathogenèse

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 (SCCL). It is thought that antibodies are produced against the tumour VGCCs but are then also responsible for the resulting attack on non-cancerous cells and their sequelae. This is supported by animal studies.²

Épidémiologie³

It is a rare condition:

• The worldwide prevalence is estimated to be between 1/250,000-1/333,300.

• Males typically have outnumbered females by 2:1 but more recent reports show almost equal incidence. This reflects trends in diagnosis of lung cancer.⁴

• It is usually a condition of later adulthood but does present occasionally in childhood.

Facteurs de risque

• Cancer - typically SCCL is present when weakness begins, or is later found in approximately 50% of patients.⁵In most cases the cancer is found within two years after the onset of LEMS; within four 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 - eg, a patient aged <50 years, who does not have a cancer discovered in the first two years after diagnosis, is unlikely to have an underlying cancer. But, a long-term smoker with onset of LEMS after the age of 50 years, probably has underlying lung cancer.⁶

Présentation

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.

Symptômes

• 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.

Signes

• 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 have been reported (23% and 20.5% respectively in one study).⁷

• Occasionally there may be difficulty in chewing, speech or swallowing.

• Strength may improve initially on exercise but then lessens as exercise is sustained.⁸

• Deep tendon reflexes are reduced or absent. Sensory examination is normal, unless there is a coincident peripheral neuropathy associated with an underlying cancer.

Diagnostic différentiel

• Myasthénie grave.

• Acute or chronic inflammatory demyelinating polyradiculopathy.

• Dermatomyositis/polymyositis.

• Inclusion body myositis.

• Atrophie musculaire spinale.

Enquêtes

• The traditional methods of differentiating myasthenia gravis and LEMS are the detection of ACh receptor antibodies characteristic of myasthenia gravis, or discovering the presence of underlying malignancy. However, studies have shown that electrophysiology using 50 Hz repetitive nerve stimulation has a sensitivity of 97% for the diagnosis of LEMS and a specificity of 99% in excluding myasthenia gravis.⁹

• A serum test for voltage-gated calcium-channel antibodies is now available. Antibodies have been reported in more than 90% of patients with LEMS.⁵

• CT or MRI scanning of the chest to exclude chest malignancy.

• ACh receptor antibodies are occasionally found in low titres in patients with LEMS.

• Bronchoscopy may be necessary if imaging studies are normal but risk of SCCL is high.

Screening for underlying malignancy is recommended for two years after diagnosis.¹⁰

Maladies associées

Cancer is found in 16-40% of patients with LEMS, usually SCCL.¹¹LEMS has also been associated with:

• Lymphosarcoma.

• Malignant thymoma.

• Cancer of the breast, stomach, colon, prostate, bladder, kidney or gallbladder. (Clinical signs usually precede cancer identification.)

Gestion¹¹

Principes généraux

• When LEMS diagnosis is made initially, an extensive search for any underlying cancer should be made.

• Initial therapy should be aimed at treating any neoplasm. Effective treatment of the underlying tumour frequently produces marked improvement in strength.

Pharmacologique¹²¹³

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

• The mainstay of treatment is 3,4-diaminopyridine (amifampridine) which significantly improves muscle strength.¹⁴

• Immunosuppression is recommended for severe cases. This usually involves prednisolone and a steroid-sparing agent such as azathioprine, mycophenolate mofetil, ciclosporin, or methotrexate.

• Randomised trials also support the use of intravenous (IV) immunoglobulin.

• Plasma exchange is another option but has less of an evidence base.

• 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 double-blind, placebo-controlled, cross-over study found no effect of pyridostigmine. Guanidine is more effective but its side-effects of bone marrow depression and renal toxicity preclude its widespread use.

• Research is ongoing to develop specific immunotherapy .

Chirurgical

This depends on the nature of any malignancy discovered.

Complications

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

• Cachexia.

• Paraneoplastic neuropathy.

Pronostic

• 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 SCCL, so patients with LEMS and SCCL often have a better prognosis. When LEMS has been symptomatic for two 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 - eg, anaesthetic.

• Most patients find therapy may help to relieve symptoms partially; however, usually symptoms progress over time.