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| Lambert-Eaton Myasthenic Syndrome (LEMS) |
Etiology
There is a strong association with small-cell lung carcinoma (SCLC). Other autoimmune disorders such as type-1 diabetes mellitus have also been associated with LEMS.Pathophysiology
Calcium plays an important role in the release of ACh from its vesicles within the presynaptic membrane of the neuromuscular junction.In LEMS, antibodies are created against the voltage-gated calcium channels that mediate the release of ACh. This blocks the normal flow of calcium, thereby preventing the release of ACh from its vesicles. There is little to no ACh entering the synaptic cleft. Therefore, there will be minimal to no muscle contraction.
In contrast to myasthenia gravis, continuous or repeated contractions result in improvement of strength. This is termed as post-exercise or post-activation facilitation.
In contrast to myasthenia gravis, continuous or repeated contractions result in improvement of strength. This is termed as post-exercise or post-activation facilitation.
It occurs due to an increased influx of calcium in the presynaptic membrane, by repetitive muscle contractions. This calcium buildup facilitates the release of ACh by binding with multiple vesicles. In time, the excess calcium is cleared off by mitochondria. Thus, this effect is temporary.
Weakness - It is commonly seen in proximal lower limbs muscles. Gradually, weakness progresses from proximal to distal muscle groups and in the cranial direction. Thus, the upper limbs are gradually involved with the oculobulbar region being affected at last. Muscle weakness in LEMS is usually associated with a high level of disability. The clinician can elicit the "Lambert's Sign", wherein the grip becomes more powerful on repeated evaluation of strength. Weakness is exacerbated by heat and exhaustion.
Hyporeflexia - Depressed or absent deep tendon reflexes are a common sign. However, the patient may present with normoreflexia after exercise.
Autonomic Dysfunction - Common features include blurry vision, dry mouth, orthostatic hypotension, impaired sweating and constipation.
Bulbar Involvement - It is rare and may present as ptosis, diplopia or dysphagia. In contrast to MG, ptosis and ophthalmoplegia are very mild in LEMS.
Respiratory Failure - It is extremely rare and occurs very late into the disease. It is associated with increased mortality.
Clinical Features
The patient will usually be an adult male over the age of 50, presenting with either of the following:Weakness - It is commonly seen in proximal lower limbs muscles. Gradually, weakness progresses from proximal to distal muscle groups and in the cranial direction. Thus, the upper limbs are gradually involved with the oculobulbar region being affected at last. Muscle weakness in LEMS is usually associated with a high level of disability. The clinician can elicit the "Lambert's Sign", wherein the grip becomes more powerful on repeated evaluation of strength. Weakness is exacerbated by heat and exhaustion.
Hyporeflexia - Depressed or absent deep tendon reflexes are a common sign. However, the patient may present with normoreflexia after exercise.
Autonomic Dysfunction - Common features include blurry vision, dry mouth, orthostatic hypotension, impaired sweating and constipation.
Bulbar Involvement - It is rare and may present as ptosis, diplopia or dysphagia. In contrast to MG, ptosis and ophthalmoplegia are very mild in LEMS.
Respiratory Failure - It is extremely rare and occurs very late into the disease. It is associated with increased mortality.
Diagnosis
Electrophysiological testing is able to reliably confirm the diagnosis of LEMS. On nerve conduction studies, the latencies and conduction velocities are normal while the CMAP is reduced.Repetitive nerve stimulation (RNS) is the study of choice to detect LEMS.
There will be an initial decrement in the CMAP which is similar to myasthenia gravis. However, on brief exercise, there will be a steady rise in the CMAP. This will be seen for up to 30 seconds.
Although the single-fiber EMG examination is more sensitive, it requires exceptional technical prowess. It will exhibit an increased jitter, signifying a pathology at the neuromuscular junction. Unfortunately, it is unable to differentiate between MG and LEMS.
In EMG-confirmed cases of LEMS, most patients will demonstrate antibodies to voltage-gated calcium channels on serological testing. Secondary laboratory tests (such as creatine kinase, thyroid function test) may assist in reaffirming the diagnosis.
On confirmed diagnosis of LEMS, the clinician may suggest a CT or MRI scan to screen for tumours (especially lung carcinoma).
Pharmacotherapy
Potassium channel blockers such as guanidine and aminopyridine increase intracellular calcium levels by inhibiting mitochondrial activity.
Acetylcholinesterase inhibitors like pyridostigmine prevent the destruction of ACh, allowing ACh to accumulate in the synaptic cleft. This leads to prolonged and repeated stimulation of postsynaptic ACh receptors.
Chemotherapy regimens target the associated tumour.
Immunotherapy
Immunomodulating treatments including plasmapheresis and the administration of intravenous immunoglobulins are effective in the early stages of the disease.
Immunosuppression by corticosteroid therapy may benefit some patients.
Surgery
Some cases may necessitate the surgical removal of the tumour.
In EMG-confirmed cases of LEMS, most patients will demonstrate antibodies to voltage-gated calcium channels on serological testing. Secondary laboratory tests (such as creatine kinase, thyroid function test) may assist in reaffirming the diagnosis.
On confirmed diagnosis of LEMS, the clinician may suggest a CT or MRI scan to screen for tumours (especially lung carcinoma).
Medical Management
Medical management is strictly symptomatic, as there is no "cure" yet. The common medical interventions include the following:Pharmacotherapy
Potassium channel blockers such as guanidine and aminopyridine increase intracellular calcium levels by inhibiting mitochondrial activity.
Acetylcholinesterase inhibitors like pyridostigmine prevent the destruction of ACh, allowing ACh to accumulate in the synaptic cleft. This leads to prolonged and repeated stimulation of postsynaptic ACh receptors.
Chemotherapy regimens target the associated tumour.
Immunotherapy
Immunomodulating treatments including plasmapheresis and the administration of intravenous immunoglobulins are effective in the early stages of the disease.
Immunosuppression by corticosteroid therapy may benefit some patients.
Surgery
Some cases may necessitate the surgical removal of the tumour.
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