Pulmonary Medicine

Neuromuscular Disorders Affecting the Thorax: Lambert-Eaton Myasthenia Syndrome

What every physician needs to know

Lambert-Eaton myasthenia syndrome (LEMS) is an uncommon disorder characterized by skeletal muscle weakness that results from impaired release of acetylcholine from presynaptic terminals. The syndrome arises in the setting of related conditions that include small-cell lung cancer (3%), in which LEMS may be a presenting symptom; Hodgkin's lymphoma; atypical carcinoid; malignant thymoma; and autoimmune diseases (e.g., type I diabetes mellitus and autoimmune thyroid disorders). The diagnosis is based on clinical grounds supported by the presence of specific antibodies and characteristic findings on electrodiagnostic tests.

Classification:

Not applicable.

Are you sure the patient has Lambert-Eaton myasthenia syndrome? What should you expect to find?

A number of clinical features characterize LEMS. The majority of patients present with slow, progressive, proximal muscle weakness unaccompanied by significant muscle atrophy. Deep tendon reflexes are diminished or absent. Weakness worsens with sustained muscle activity (i.e., is "fatigable") and is always symmetric. Limb and girdle muscles are predominantly involved, respiratory muscle weakness is common, and although respiratory failure is infrequent, it may be the initial presenting symptom.

Occasionally, subacute or acute presentations are seen, particularly when LEMS occurs as a paraneoplastic syndrome in conjunction with small-cell lung cancer (SCLC).

Autonomic dysfunction, cranial nerve findings (including ptosis, the most common occular sign), and sensory findings (including numbness and paresthesias) may be noted. Low back pain is sometimes observed, and weight loss, perhaps attributable to the underlying disorder, may be noted. Some patients have a history of a preceding viral-type illness.

Beware: there are other diseases that mimic Lambert-Eaton myasthenia syndrome.

A number of disorders may mimic LEMS, including inflammatory muscle diseases, limb-girdle muscular dystrophy, myasthenia gravis, and a variety of myopathies and neuropathies.

How and/or why did the patient develop Lambert-Eaton myasthenia syndrome?

The pathophysiology of LEMS is based on development of antibodies directed against voltage-gated calcium channels (VGCC) in muscle, leading to interruption of the normal calcium flux necessary for acetylcholine (ACh) release. The decrease in ACh release occurs despite normal ACh vesicle numbers, presynaptic concentrations of ACh, and postsynaptic receptor concentrations. Postsynaptic sensitivity to acetylcholine is normal.

Which individuals are at greatest risk of developing Lambert-Eaton myasthenia syndrome?

The incidence of LEMS is unknown, although the disorder is less frequent than myasthenia gravis. Half of cases are associated with malignancy.

The incidence of LEMS in SCLC is 3 percent. Hodgkin's lymphoma is also associated with LEMS, and an increased incidence of autoimmune disease has been noted in both paraneoplastic and non-paraneoplastic forms of LEMS.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

In the proper clinical context, antibodies directed against VGCC should be assayed. A positive result is confirmatory in those with clinical symptoms and signs although the presence of antibody alone is not diagnostic of LEMS.

What imaging studies will be helpful in making or excluding the diagnosis of Lamber-Eaton myasthenia syndrom?

Not applicable.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of Lambert-Eaton myasthenia syndrome?

Noninvasive pulmonary diagnostic studies are not helpful in establishing the diagnosis.

What diagnostic procedures will be helpful in making or excluding the diagnosis of Lambert-Eaton myasthenia syndrome?

In addition to testing for antibodies against VGCC, a bedside test for post-exercise ("postactivation") facilitation of isometric contraction of muscle--that is, a temporary restoration of reduced contractility--may be useful. Electrodiagnostic testing includes assessment of the compound muscle action potential (CMAP) in resting muscle, which is reduced in LEMS.

High-frequency repetitive nerve stimulation or brief maximal isometric stimulation results in an increasein CMAP, and the percent increase may be used as a basis of diagnosis; a 60 percent increase may be considered diagnostic if LEMS is clinically suspected, but the usual response is a change of 100 percent or more. In normal muscles, no change in CMAP may be seen, and patients with myasthenia gravis may show a progressive decline in CMAP with repeated nerve stimulation.

A thorough search for underlying malignancy should be pursued.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of Lambert-Eaton myasthenia syndrome?

The diagnosis of Lambert-Eaton Syndrome does not rest primarily on pathologic, cytologic, or genetic studies.

If you decide the patient has Lambert-Eaton myasthenia syndrome, how should the patient be managed?

Management of LEMS focuses on an evaluation for underlying malignancy while specific therapy is undertaken. Specific therapies include guanidine, which facilitates an increase the presynaptic release of acetylcholine by inhibiting potassium-gated voltage channels. Guanidine therapy is used in conjunction with pyridostigmine. Side effects of guanidine include bone marrow suppression and renal toxicity.

Another therapy is the use of aminopyridines, such as dalfampridine, which prolong nerve terminal membrane depolarization, leading to increased calcium entry and subsequent increased ACh release. However, they are limited in use because of side effects (seizures). The agent is not approved in the United States.

Acetylcholinesterase inhibitors, including pyridostigmine, are better tolerated than other agents; however, they are not particularly effective.

Plasmapheresis in LEMS provides results that are not as rapid as those observed in myasthenia gravis. Generally, five exchanges over seven to fourteen days are suggested. Plasmapheresis may be used in combination with an oral immunosuppressive agent.

Intravenous immunoglobulin (IVIG) leads to clinical improvement and decreases in VGCC antibodies; the benefit of IVIG peaks in two to four weeks.

Oral immunosuppressive therapy includes prednisone alone or in combination with azathioprine; prednisone may also be given in combination with plasmapheresis.

If the patient presents with respiratory failure, airway protection and implementation of mechanical ventilation are critical.

What is the prognosis for patients managed in the recommended ways?

The presence of antibodies directed at VGCC in LEMS is associated with longer survival, and treatment of underlying SCLC often leads to remission of LEMS. Plasmapheresis does not lead to rapid relief of symptoms and provides only short-term benefit; similarly, improvement in weakness following use of IVIG typically lasts only four to eight weeks.

What other considerations exist for patients with Lambert-Eaton myasthenia syndrome?

No additional considerations are relevant.

What's the evidence?

Nicolle, MW, Stewart, DJ, Remtulla, H, Chen, R, Bolton, CF. "Lambert-Eaton myasthenic syndrome presenting with severe respiratory failure". Muscle Nerve. vol. 19. 1996. pp. 1328-33.

(This paper examines two cases of LEMS that presented with primary respiratory failure. The diagnosis was made through clinical suspicion and electrophysiologic testing. With treatment, the severe respiratory failure was reversed.)

Oh, SJ. "Diverse electrophysiological spectrum of the Lambert-Eaton myasthenic syndrome". Muscle Nerve. vol. 12. 1989. pp. 464-9.

(Thirteen patients with LEMS were studied and found to have three different patterns on the repetitive nerve stimulation test that likely represented different degrees of blocking in LEMS. Two of these patterns could be misinterpreted as myasthenia gravis patterns.)

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. vol. 54. 1991. pp. 764-7.

(One hundred and fifty patients with small cell lung cancer were studied, and 44 percent were found to have neuromuscular or autonomic deficits. The overall prevalence of LEMS in small-cell lung cancer was 3 percent in this study.)

Maddison, P, Lang, B, Mills, K, Newsom-Davis, J. "Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer". J Neurol Neurosurg Psychiatry. vol. 70. 2001. pp. 212-7.

(Forty-seven patients with LEMS without small-cell lung cancer were retrospectively evaluated. The prognosis was found to be favorable, but substantial immunotherapy was required to maintain clinical stability. Initial clinical muscle strength, but not anti-VGCC antibody titres or electrophysiological scores, were predictive of outcomes.)

Kamenskaya, MA, Elmqvist, D, Thesleff, S. Arch Neurol. vol. 32. 1975. pp. 505-9.

(This animal study demonstrated the ability of guanidine to increase the amount of acetylcholine released by a motor neuron.)

Oh, SJ, Kim, DS, Head, TC, Claussen, GC. "Low-dose guanidine and pyridostigmine: a relatively safe and effective long-term symptomatic therapy in Lambert-Eaton myasthenic syndrome". Muscle Nerve. vol. 20. 1997. pp. 1146-52.

(Low-dose guanidine and pyridostigmine was used in nine patients with LEMS and was shown to improve clinical status in all patients without any serious side effects from the guanidine.)

Dau, PC, Denys, EH. "Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert syndrome". Ann Neurol. vol. 11. 1982. pp. 570-5.

(Five patients with LEMS were first treated by plasmapheresis alone, followed plasmapheresis along with prednisone and azathioprine. The greatest improvement was seen with treatment with plasmapheresis with prednisone and azathioprine.)

Bain, PG, Motomura, M, Newsom-Davis, J, Misbah, SA, Chapel, HM, Lee, ML. "Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome". Neurology. vol. 47. 1996. pp. 678-83.

(A randomized, double-blind, placebo-controlled crossover trial that evaluated the effect of IVIG on nine patients with LEMS. Improvement in muscle function peaked at two to four weeks and declined by eight weeks.)

Streib, EW, Rothner, AD. "Eaton-Lambert myasthenic syndrome: long-term treatment of three patients with prednisone". Ann Neurol. vol. 10. 1981. pp. 448-53.

(Three patients with LEMS were treated with prednisone for six months, twelve months, and three years, respectively, resulting in increased muscle strength and electromyographic improvement in all patients. Decreased doses of prednisone led to deterioration in all patients.)
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