What is Lambert Eaton myasthenic syndrome (LEMS)?
Lambert Eaton myasthenic syndrome (LEMS) is a disorder of the neuromuscular junction (the interface between motor neurons and their target muscle cells). Damage to this region impairs the transmission of impulses between motor neurons and their target muscle, resulting in clinical symptoms such as muscle weakness and motor dysfunction [1].
Symptoms of Lambert Eaton syndrome
Many of the symptoms of Lambert Eaton relate to disruptions in muscle function. Symptoms of Lambert Eaton myasthenic syndrome include [2]:
- Muscle weakness, which worsens progressively
- Muscle aches
- Chronic fatigue
- Difficulty walking or climbing stairs
- Difficulty lifting objects or raising arms
- Drooping eyelids, dry eyes, blurred vision
- Difficulty swallowing (dysphagia)
- Constipation
- Erectile dysfunction
- Impaired reflex responses
Causes of Lambert Eaton syndrome
Lambert Eaton syndrome is caused by an autoimmune response against voltage-gated calcium channels (VGCCs), which are abundant on the membrane of presynaptic nerve terminals [1]. VGCCs are essential for the release of the neurotransmitter acetylcholine (ACh), which binds to receptors on the target muscle and induces the process of muscle contraction. Specifically, action potentials propagated from upstream neurons trigger membrane depolarization at the neuronal terminal, leading to VGCC opening, calcium influx, and release of ACh into the neuromuscular junction. When VGCCs are damaged via autoimmunity, calcium influx into the presynaptic neuron is inhibited and thus the release of ACh is blocked [1]. This explains why difficulties in muscle contraction occur in patients with Lambert Eaton syndrome.
Why are voltage-gated calcium channels damaged in Lambert Eaton syndrome?
Patients with Lambert Eaton syndrome possess IgG autoantibodies against voltage-gated calcium channels; these autoantibodies bind to VGCCs and form crosslinks, thereby inhibiting receptor function [1]. Lambert Eaton syndrome often occurs comorbidly with small cell lung cancer (SCLC), which helps explain the origin of anti-VGCC antibodies. In patients with Lambert Eaton and SCLC, tumour cells express the VGCC antigen on their surface (along with other cancer-associated and immunogenic peptides). Immune recognition of VGCC on tumour tissue triggers the production of autoantibodies, which target not only the tumour cells, but other VGCC-expressing cells, as well—including motor neurons [1].
In patients without SCLC, the cause of autoantibody production is less clear. Certain HLA alleles (both class I and class II) have been associated with Lambert Eaton syndrome, including HLA-B8, HLA-DR3, and HLA-DQ2 [1]. These alleles have also been implicated in other autoimmune conditions, suggesting a redundant or general role in mediating autoimmune reactions [1].
Diagnosis and treatment
Diagnosing Lambert Eaton syndrome
Lambert Eaton syndrome is typically diagnosed using a combination of assessments [1, 2].
Blood testing
Usually, the first step in diagnosing Lambert Eaton syndrome is to perform a blood test. Serum isolation and immunoassay may reveal the presence of anti-VGCC IgGs, which are present in 85-95% of patients with Lambert Eaton [1]. However, these autoantibodies are not exclusive to Lambert Eaton syndrome and can occur in other autoimmune or neurological disorders; therefore, blood tests do not provide definitive diagnoses.
Electrodiagnostic testing.
If anti-VGCC IgG is detected, electrodiagnostic tests may be performed in order to help confirm a diagnosis of Lambert Eaton syndrome. Electrodiagnostic tests include nerve conduction studies (NCS) and electromyography (EMG).These tests aim to measure the transmission of neural signals to the muscles [2].
Cancer screening.
As mentioned, Lambert Eaton syndrome often co-occurs with small cell lung cancer (SCLC). As such, physicians may recommend cancer screening if they suspect that a patient has Lambert Eaton syndrome. Screening methods typically include computational tomography (CT) or magnetic resonance imaging (MRI) of the chest. If findings from CT scan are negative, positron emission tomography (PET) may be subsequently performed [1]. While Lambert Eaton syndrome can occur in the absence of SCLC, the significant correlation between the two diseases makes cancer screening useful in confirmatory diagnosis. Moreover, such screening can reveal undiagnosed cancers and thereby facilitate appropriate treatment.
Treatment of Lambert Eaton syndrome
How is Lambert Eaton syndrome treated?
If Lambert Eaton syndrome is the result of SCLC, the ultimate priority is to treat the underlying malignancy using chemotherapy, radiation, surgery, or some combination therein. Beyond cancer treatment, most treatments for Lambert Eaton syndrome focus on symptom management via medication [1]. There are several pharmacological agents used to treat Lambert Eaton syndrome, most of which focus on boosting acetylcholine release from the presynaptic terminals of motor neurons.
Treatments for Lambert Eaton syndrome include [1]:
- Amifampridine or 3,4-diaminopyridine (3,4-DAP): inhibits potassium channels on the presynaptic motor neuron. Preventing potassium influx helps prolong the duration of the action potential and boost calcium influx, which increases the release of acetylcholine into the neuromuscular junction.
- Acetylcholinesterase inhibitors: inhibits the enzymatic breakdown of acetylcholine within the neuromuscular junction, which allows greater persistence of acetylcholine and promotes activation of acetylcholine receptors on the target muscle.
- Guanidine: enhances acetylcholine release from the presynaptic nerve terminal. However, guanidine is not used as a first-line of treatment due to its potential for renal toxicity.
- Intravenous immune globulin (IVIG): typically used in patients who do not respond to other forms of treatment (refractory cases). The pharmacological mechanism of action remains unclear, but it is believed that IVIG may function by neutralizing autoreactive anti-VGCC autoantibodies.
Prognosis for Lambert Eaton syndrome
Although Lambert Eaton syndrome is associated with diminished quality of life, the prognosis is not fatal. Individuals do often experience limitations in activities of daily living due to muscle weakness, autonomic dysregulation, and potential adverse effects of treatment. Nonetheless, the majority of cases respond positively to treatment, resulting in manageable symptoms and capacity for independent living [1].
What is myasthenia gravis (MG)?
Like Lambert Eaton syndrome, myasthenia gravis is an autoimmune condition affecting the neuromuscular junction [3]. As a result of this commonality, the two exhibit overlapping symptoms and clinical presentations. However, myasthenia gravis has a distinct pathophysiology from that of Lambert Eaton syndrome and is diagnosed using different methods.
Symptoms of myasthenia gravis
Symptoms of myasthenia gravis can range in severity, depending on the stage of disease [3]. However, common symptoms include [4]:
- Muscle weakness, which is exacerbated by activity and improves with rest
- Droopy eyelids, which can affect one or both eyes
- Double vision
- Difficulty making facial expressions
- Speaking, swallowing, and breathing difficulties
- Difficulty holding up one’s head
- Difficulty completing physical activities (e.g., lifting objects, climbing stairs, standing up)
- Difficulty walking
- Aching muscles, especially in the arms
Causes of myasthenia gravis
Myasthenia gravis is caused by the production of autoantibodies against the acetylcholine receptor, which is present on the surface of postsynaptic skeletal muscles [3]. These autoantibodies are of the IgG isotype, but may vary in their subtype. IgG1 and IgG3 autoantibodies function by activating one arm of the complement pathway, which culminates in the formation of membrane attack complexes (MACs) [3]. This leads to the destruction of acetylcholine receptors expressed by the skeletal muscle. IgG1 and IgG3 may also reduce acetylcholine signaling by blocking the binding of ACh to its receptor and/or promoting antibody-mediated endocytosis of the receptor [3]. In contrast, IgG4 autoantibodies do not have the capacity to activate the complement system and do not target the ACh receptor directly. Instead, these antibodies bind to a separate complex within the neuromuscular junction composed of the proteins Agrin–LRP4–MuSK [3]. This complex is responsible for the recruitment and clustering of ACh receptors, and its inhibition by IgG4 binding leads to a diminished number of acetylcholine receptors on the skeletal muscle surface. As a result, the acetylcholine released from the presynaptic motor neuron is unable to bind its cognate receptor and thus cannot activate skeletal muscle contraction [3].
Diagnosing myasthenia gravis
Because myasthenia gravis shares symptoms with Lambert Eaton syndrome and various other neurological disorders, accurately diagnosing the syndrome requires a combination of tests in order to rule out differential diagnoses. Some tests used to diagnose myasthenia gravis include [3, 4]:
Blood testing.
Serum isolation and immunoassays can be used to reveal the presence of anti-AChR and/or anti-Agrin–LRP4–MuSK immunoglobulins. These tests are fairly specific and are a fundamental first step in diagnosing myasthenia gravis. However, individuals with myasthenia gravis may be seronegative for both types of immunoglobulin, necessitating further diagnostic assessments.
Electrodiagnostic testing.
This type of testing is often performed in seronegative patients with suspected myasthenia gravis. Electrodiagnostic tests may include repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), which aim to measure delays in nerve conduction to the neuromuscular junction.
Edrophonium test.
If blood tests and electrodiagnostic tests remain inconclusive, physicians may recommend a type of assessment called an edrophonium test. In this test, the medication edrophonium chloride is administered intravenously. This compound inhibits acetylcholinesterase (the enzyme which catalyzes ACh degradation in the neuromuscular junction); therefore, edrophonium administration increases the amount of available acetylcholine within the neuromuscular junction. If muscular symptoms improve temporarily following edrophonium chloride administration, this suggests a diagnosis of myasthenia gravis.
Imaging tests.
Occasionally, myasthenia gravis occurs co-morbidly with thymic cancer (thymoma). If an individual has been diagnosed with myasthenia gravis, computed tomography (CT) or magnetic resonance imaging (MRI) of the chest may therefore be recommended to screen for thymoma.
Treatment of myasthenia gravis
How is myasthenia gravis treated?
There is currently no cure for myasthenia gravis. However, medications and lifestyle changes can help manage chronic symptoms. Treatment recommendations for myasthenia gravis include [3, 4]:
- Acetylcholinesterase inhibitors: include drugs such as pyridostigmine bromide, neostigmine, and ambenonium chloride. These compounds inhibit the action of acetylcholinesterase, which elevates the amount of acetylcholine available within the neuromuscular junction and boosts transmission of nervous signals. These drugs tend to work better in those with autoantibodies against AChR than those with autoantibodies against Agrin–LRP4–MuSK [3].
- Immunosuppressive treatment: for patients who do not respond to acetylcholinesterase inhibitors, immunosuppressants may be prescribed. Glucocorticoid steroids, such as prednisone, prednisolone, and methylprednisolone, may be used to blunt the autoimmune response and diminish the progression of disease.
- Intravenous immunoglobulins (IVIG): neutralizing antibodies which target anti-AChR and/or anti-Agrin–LRP4–MuSK autoantibodies and prevent them from triggering autoimmunity.
- Avoiding triggers: some patients experience a worsening of symptoms in response to certain triggers. Avoiding stressors which tend to exacerbate symptoms can be an effective form of lifestyle management. Some common triggers for myasthenia gravis include fatigue, stress, infections, certain medications, and surgical procedures. While these triggers may not be entirely avoidable, they can be mitigated by getting plenty of sleep, working to avoid undue stress, getting flu vaccinations, and honest communication with one’s physician [4].
Prognosis for myasthenia gravis
While myasthenia gravis is currently not curable, it is not a fatal condition. Most patients do not experience significant reductions in life-span as a result of the disorder, although their quality of life may be impacted due to symptoms. Sudden episodes of muscle weakness can, in rare cases, lead to death if an individual is alone and cannot access support (for example, exercising alone) [3]. However, the biggest burden of myasthenia gravis is not mortality but morbidity, which is associated with muscle weakness and adverse effects of some medications [3].
Key differences between Lambert Eaton and myasthenia gravis
Pathophysiology
Lambert Eaton syndrome occurs due to impairments in acetylcholine release from the presynaptic motor neuron. This impairment results from damage to voltage-gated calcium channels (VGCCs) and concomitant disruption of calcium-induced neurotransmitter release. Myasthenia gravis results from damage to acetylcholine receptors and/or accessory protein complexes on the postsynaptic muscle fiber. Acetylcholine release from the presynaptic neuron is unimpaired in myasthenia gravis; instead, the responsiveness of the postsynaptic muscle fiber to acetylcholine is diminished.
Muscle weakness
In Lambert Eaton syndrome, muscle activation tends to improve temporarily following activity or exercise, indicated by deep tendon reflexes and increased rates of muscle contraction [1]. In contrast, exercise or physical activity tends to exacerbate muscle weakness in patients with myasthenia gravis, and strength tends to return following a period of rest or inactivity [3].
Autoantibodies
In Lambert Eaton syndrome, autoantibodies are targeted against voltage-gated calcium channels (VGCCs) within the membrane of presynaptic motor neurons. In myasthenia gravis, autoantibodies target acetylcholine receptors (IgG1 and IgG3) or the associated Agrin–LRP4–MuSK complex (IgG4) located on the postsynaptic target muscle.
Related malignancies
Lambert Eaton syndrome typically co-occurs with cases of small cell lung cancer (SCLC) due to the presence of shared surface antigens. On the other hand, Myasthenia gravis may co-occur with forms of thymic cancer, such as thymoma.
Conclusion
Lambert Eaton syndrome and myasthenia gravis are both autoimmune conditions which result in damage to the neuromuscular junction and lead to impaired muscle contraction. While the two disorders share several symptoms and treatments, they are distinct in their pathophysiological and molecular characteristics. Accurately distinguishing Lambert Eaton syndrome from myasthenia gravis is crucial in order to optimize treatment, and differentiating the two is aided by the use of multiple diagnostic assessments, such as blood testing, electrodiagnostic testing, and CT/MRI scanning. While neither disorder is curable, early intervention and continuous support can help mitigate the syndromes’ adverse impacts.