Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome | |
---|---|
Other names | Lambert–Eaton syndrome, Eaton–Lambert syndrome, myasthenic syndrome, carcinomatous myopathy |
Specialty | Neurology |
Frequency | 3.4 per million people[1] |
Lambert–Eaton myasthenic syndrome (LEMS) is a rare
Around 60% of those with LEMS have an underlying
If the disease is associated with cancer, direct treatment of the cancer often relieves the symptoms of LEMS. Other treatments often used are
The condition affects about 3.4 per million people.[1] LEMS usually occurs in people over 40 years of age, but may occur at any age.
Signs and symptoms
The weakness from LEMS typically involves the muscles of the proximal arms and legs (the muscles closer to the trunk). In contrast to
Three-quarters of people with LEMS also have disruption of the autonomic nervous system. This may be experienced as a dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension (falls in blood pressure on standing, potentially leading to blackouts). Some report a metallic taste in the mouth.[4]
On neurological examination, the weakness demonstrated with normal testing of power is often less severe than would be expected on the basis of the symptoms. Strength improves further with repeated testing, e.g. improvement of power on repeated hand grip (a phenomenon known as "Lambert's sign"). At rest, reflexes are typically reduced; with muscle use, reflex strength increases. This is a characteristic feature of LEMS. The pupillary light reflex may be sluggish.[4]
In LEMS associated with lung cancer, most have no suggestive symptoms of cancer at the time, such as cough, coughing blood, and unintentional weight loss.[3] LEMS associated with lung cancer may be more severe.[5]
Causes
LEMS is often associated with lung cancer (50–70%), specifically small-cell carcinoma,[4] making LEMS a paraneoplastic syndrome.[5] Of the people with small-cell lung cancer, 1–3% have LEMS.[3] In most of these cases, LEMS is the first symptom of the lung cancer, and it is otherwise asymptomatic.[3]
LEMS may also be associated with
Mechanism
In normal neuromuscular function, a
In LEMS, antibodies against VGCC, particularly the P/Q-type VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be released from the neuromuscular junction. Apart from skeletal muscle, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS.[4][3] P/Q voltage-gated calcium channels are also found in the cerebellum, explaining why some experience problems with coordination.[5][6] The antibodies bind particularly to the part of the receptor known as the "domain III S5–S6 linker peptide".[6] Antibodies may also bind other VGCCs.[6] Some have antibodies that bind synaptotagmin, the protein sensor for calcium-regulated vesicle fusion.[6] Many people with LEMS, both with and without VGCC antibodies, have detectable antibodies against the M1 subtype of the acetylcholine receptor; their presence may participate in a lack of compensation for the weak calcium influx.[6]
Apart from the decreased calcium influx, a disruption of active zone vesicle release sites also occurs, which may also be antibody-dependent, since people with LEMS have antibodies to components of these active zones (including voltage-dependent calcium channels). Together, these abnormalities lead to the decrease in muscle contractility. Repeated stimuli over a period of about 10 seconds eventually lead to sufficient delivery of calcium, and an increase in muscle contraction to normal levels, which can be demonstrated using an electrodiagnostic medicine study called needle electromyography by increasing amplitude of repeated compound muscle action potentials.[4]
The antibodies found in LEMS associated with lung cancer also bind to calcium channels in the cancer cells, and it is presumed that the antibodies originally develop as a reaction to these cells.[4] It has been suggested that the immune reaction to the cancer cells suppresses their growth and improves the prognosis from the cancer.[3][6]
Diagnosis
The diagnosis is usually made with nerve conduction study (NCS) and electromyography (EMG), which is one of the standard tests in the investigation of otherwise unexplained muscle weakness. EMG involves the insertion of small needles into the muscles. NCS involves administering small electrical impulses to the nerves, on the surface of the skin, and measuring the electrical response of the muscle in question. NCS investigation in LEMS primarily involves evaluation of compound motor action potentials (CMAPs) of effected muscles and sometimes EMG single-fiber examination can be used.[4]
CMAPs show small amplitudes but normal latency and conduction velocities. If repeated impulses are administered (2 per second or 2 Hz), it is normal for CMAP amplitudes to become smaller as the acetylcholine in the motor end plate is depleted. In LEMS, this decrease is larger than observed normally. Eventually, stored acetylcholine is made available, and the amplitudes increase again. In LEMS, this remains insufficient to reach a level sufficient for transmission of an impulse from nerve to muscle; all can be attributed to insufficient calcium in the nerve terminal. A similar pattern is witnessed in myasthenia gravis. In LEMS, in response to exercising the muscle, the CMAP amplitude increases greatly (over 200%, often much more). This also occurs on the administration of a rapid burst of electrical stimuli (20 impulses per second for 10 seconds). This is attributed to the influx of calcium in response to these stimuli.[4][3] On single-fiber examination, features may include increased jitter (seen in other diseases of neuromuscular transmission) and blocking.[4]
Blood tests may be performed to exclude other causes of muscle disease (elevated
Treatment
If LEMS is caused by an underlying cancer, treatment of the cancer usually leads to resolution of the symptoms.[4] Treatment usually consists of chemotherapy, with radiation therapy in those with limited disease.[3]
Immunosuppression
Some evidence supports the use of
Other
Three other treatment modalities also aim at improving LEMS symptoms, namely
Tentative evidence supports 3,4-diaminopyridine at least for a few weeks.[8] The 3,4-diaminopyridine base or the water-soluble 3,4-diaminopyridine phosphate may be used.[9] Both 3,4-diaminopyridine formulations delay the repolarization of nerve terminals after a discharge, thereby allowing more calcium to accumulate in the nerve terminal.[4][3]
Pyridostigmine decreases the degradation of acetylcholine after release into the synaptic cleft, and thereby improves muscle contraction. An older agent, guanidine, causes many side effects and is not recommended. 4-Aminopyridine (dalfampridine), an agent related to 3,4-aminopyridine, causes more side effects than 3,4-DAP and is also not recommended.[3]
The FDA approved amifampridine for use in children 6 years and older with LEMS in addition to the prior approval for use in adults with LEMS on November 28, 2018.[10]
History
Anderson and colleagues from St Thomas' Hospital, London, were the first to mention a case with possible clinical findings of LEMS in 1953,[11] but Edward H. Lambert, Lee Eaton, and E.D. Rooke at the Mayo Clinic were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1956.[12][13] In 1972, the clustering of LEMS with other autoimmune diseases led to the hypothesis that it was caused by autoimmunity.[14] Studies in the 1980s confirmed the autoimmune nature,[6] and research in the 1990s demonstrated the link with antibodies against P/Q-type voltage-gated calcium channels.[4][15]
References
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- ^ "vocabulary.com - myasthenic syndrome".
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- ^ PMID 21328260.
- PMID 21822385.
- ^ "Firdapse (amifampridine phosphate) FDA Approval History". Drugs.com. Retrieved February 5, 2019.
- PMID 13110148.
- Who Named It?
- ^ Lambert EH, Eaton LM, Rooke ED (1956). "Defect of neuromuscular conduction associated with malignant neoplasms". Am. J. Physiol. 187: 612–613.
- PMID 4115499.
- PMID 10975475.