DEFINITION
Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of neuromuscular transmission. It is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired, causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes.
EPIDEMIOLOGY
Lambert-Eaton syndrome may be associated with cancers such as small-cell lung cancer and autoimmune disorders. It can be found, in patients affected by LEMS, an increased incidence of alleles HLA-B8 e-DR3.
The true incidence of Lambert-Eaton myasthenic syndrome is unknown. Approximately 3% of patients with small-cell lung cancer (SCLC) are believed to be affected. Most figures estimate that between 50% and 70% of patients with Lambert-Eaton myasthenic syndrome have an identifiable cancer, with the overwhelming majority associated with SCLC. However, many different malignancies may be involved. A partial list includes non–small-cell lung cancer; neuroendocrine carcinomas; lymphosarcoma; malignant thymoma; cancers of the breast, stomach, colon, prostate, bladder, kidney, gallbladder, and rectum; basal cell carcinoma; leukemia; lymphoproliferative disorders such Castleman syndrome; and Hodgkin lymphoma. Some figures estimate approximately 400 cases in the United States at any one time. This estimate does not consider the number of patients with Lambert-Eaton myasthenic syndrome who do not have small-cell lung carcinoma or any identifiable malignancy.
Current reports note almost equal frequency in men and women. LEMS is primarily a disease of middle-aged and older people. However, at least 7 children younger than 17 years have been reported to have had LEMS. The most common age for the appearance of symptoms is 60 years.
SYMPTOMS
The main symptoms in this syndrome are:
•Weakness or loss of movement that varies in severity
•Swallowing difficulty, gagging, or choking
•Vision changes
Additional symptoms that may be associated with this disease:
•Blood pressure changes
•Dizziness upon standing
•Dry mouth
DIAGNOSIS
A physical examination shows weakness or paralysis that gets slightly better with activity. Reflexes may be decreased. There may be loss of muscle tissue.
Tests to help diagnose and confirm the condition may include:
Laboratory Studies
•She basic tests would include the following:
- CBC (Complete Blood Count)
- Basic chemistry
- Pulse oximetry
Imaging Studies
•Chest radiography
•Chest computed tomography (CT) if chest malignancy is suspected: Screening strategies may help to detect SCLC in patients with newly diagnosed LEMS and therefore offer a better approach to treatment.
Procedures
•Tensilon test
- This test may be used to help differentiate LEMS and myasthenia gravis. However, the test is highly subjective, and it is of little value in the diagnosis of LEMS.
- The test may produce an improvement in strength but rarely is the response in patients with LEMS as noticeable as the typical response in patients with myasthenia gravis.
•The only true methods of differentiating myasthenia gravis and LEMS are the detection of ACh receptor antibodies and the presence of underlying malignancy.
•Electrodiagnostic studies are critical to the clinical diagnosis. Criteria that are characteristic of LEMS include the following:
- Low-amplitude CMAP after a single, supramaximal stimulus
- Postexercise potentiation of CMAP
- Rapid disappearance of postexercise increment
- Decremental response at lower rates of stimulation after repetitive nerve stimulation and incremental response at higher rates of stimulation
- An example of repetitive nerve stimulation is shown below.
Characteristic responses to repetitive nerve stimulation in a patient with Lambert-Eaton myasthenic syndrome (LEMS). A: Responses elicited from a hand muscle by stimulation of the nerve at 3 Hz. Amplitude of the initial response is less than normal and the response is decremental. B: Responses as in A, immediately after voluntary activation of the muscle for 10 seconds. Amplitude has increased. C: Responses in a hand muscle elicited by 20-Hz stimulation of the nerve for 10 seconds. Response amplitude is less than normal initially, falls further during the first few stimuli, then increases and ultimately becomes more than twice the initial value.
PATHOGENESIS
Lambert-Eaton myasthenic syndrome results from an autoimmune attack directed against the voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal. Recent results suggests that the main pathogenic factors are antibodies specific for P/Q calcium channels. Channels type P/Q are essential in the mechanism of release of Ach.
Se ci sono più voci su OMIM usare questo formato di ricerca:
Autism
Patients often present association with small-cell lung cancer (SCLC) and it seems it could give the specific signal for production of autoimmune antibodies, although exists another group of patients who are not affected by tumor. However in both groups it can be found an association with immune disorders. The immune attack results in a loss of functional VGCCs at the motor nerve terminals.
The number of quanta released by a nerve impulse is diminished. However, because presynaptic stores of ACh and the postsynaptic response to ACh remain intact, rapid repetitive stimulation or voluntary activation that aids in the release of quanta will raise the endplate potential above threshold and permit generation of muscle action potential. As neuromuscular transmission is completed at additional neuromuscular junctions, a transient increase will occur in the strength of the muscle. Parasympathetic, sympathetic, and enteric neurons are all affected. Clinically, this phenomenon is noted by the appearance of previously absent tendon reflexes following a short period of strong muscle contraction by the patient.
WARNINGS
- Drugs that may exacerbate weakness in LEMS
- Drugs that compromise neuromuscular transmission frequently exacerbate weakness in LEMS. Competitive neuromuscular blocking agents, such as d-tubocurarine and pancuronium, have an exaggerated and prolonged effect in patients with LEMS.
- Initial signs of possible LEMS include prolonged weakness or apnea following administration of neuromuscular blocking agents during anesthesia.
- Some antibiotics, particularly aminoglycosides, fluoroquinolones (eg, ciprofloxacin), and erythromycin, have significant neuromuscular blocking effects. Some antiarrhythmics (eg, quinine, quinidine, procainamide) and beta-adrenergic blocking drugs also worsen myasthenic weakness.
- Exacerbation of LEMS after administration of any of several other agents, including magnesium and intravenous iodinated radiographic contrast agents, has been reported in isolated cases. In general, patients with LEMS should be observed for clinical worsening after initiating any new medication.
- Unless absolutely necessary, avoid drugs that are known to impair neuromuscular transmission. In such cases, a thorough knowledge of their potential deleterious effects is required.
- Elevated temperature
- Weakness of LEMS may be worse when the ambient temperature increases or when the patient is febrile.
- Patients should avoid hot showers or baths.
- Systemic illness of any sort may cause transient worsening of weakness.
COMPLICATIONS
Possible complications in this pathology are:
- Difficulty breathing
- Difficulty swallowing
MEDICATION
In general, before medical therapy begins, myasthenia gravis must be excluded. If the diagnosis is in any doubt, further workup or therapy for myasthenia gravis should be considered. Medical therapy is tailored for each patient and might include various combinations of the drugs listed below. Therapy is best coordinated with the primary care physician and appropriate consultants.
Typical treatments for the patients with SCLC as the cause of their LEMS would include combination therapy with cisplatin and etoposide. Through both tumor modulation and its direct immunosuppressive properties, chemotherapy does seem to improve the symptoms of LEMS.
Cholinesterase inhibitors
These agents act by inhibiting the breakdown of ACh, which is intended to help compensate for the relative lack of ACh quanta release in LEMS. They usually do not provide a significant improvement; however, a few patients with mild disease may note some difference.
•Pyridostigmine (Mestinon)
•Guanidine hydrochloride).
Potassium channel blockers
Aminopyridines block potassium channels in membranes and facilitate chemical synaptic transmission at autonomic, neuromuscular, and central synapses. Both 4-aminopyridine and 3,4-diaminopyridine4 have been used, but 4-AP is thought to be less effective and is almost twice as toxic, with many neurologic effects reported.
•3,4-diaminopyridine (DAP)
Immunosuppressants
If therapies already described are ineffective, more aggressive immunotherapy may be indicated. Therapy can take the form of plasma exchange or high dose IVIG, with the potential for more long-term immunosuppression, usually with prednisone or azathioprine.
•Prednisone (Deltasone, Orasone, Sterapred)
•Azathioprine (Imuran)
Blood products/immunomodulating agents
Agents in this category may be used to improve clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.
•Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin)
