Lambert-Eaton Myasthenic Syndrome

Etiology

LEMS is categorized as either paraneoplastic or non-paraneoplastic, the latter being referred to as non-tumor LEMS (NT-LEMS). NT-LEMS is characterized by its absence of association with malignancies. Approximately 60% of LEMS patients have an underlying tumor, with the paraneoplastic form predominantly associated with SCLC.[1]

LEMS is also associated with other malignancies, such as non-SCLC, mixed lung carcinoma, prostate cancer, thymoma, and lymphoproliferative disorders. Research has shown that the diagnosis of LEMS can precede the diagnosis of SCLC by 5 to 6 years. Furthermore, a significant risk factor for LEMS is having a history of smoking. The genetic association with HLA–B8–DR3 haplotype is present in about 65% of young patients with NT–LEMS.[7]

Epidemiology

LEMS is a rare neuromuscular disorder with a prevalence 46 times lower than myasthenia gravis (MG). However, the annual incidence of LEMS is only 10 to 14 times less than that of MG. This contrast in prevalence underscores the challenging prognosis and survival rates of LEMS, particularly when associated with SCLC.

Approximately 60% to 75% of LEMS patients are male, whereas MG has a female predilection. The mean age at presentation for paraneoplastic LEMS in individuals is around age 58. On the other hand, in cases of LEMS not associated with an underlying malignancy, the age and gender distribution resemble that of MG. The onset age peaks at 35, with a larger peak at 60. LEMS not associated with malignancy exhibits a near-normal survival rate, providing a more favorable prognosis.[8][9][10]

Pathophysiology

LEMS is characterized by a reduction in Ach release from presynaptic nerve terminals, which arises from antibodies targeting VGCCs within the presynaptic neuronal cell membrane.

The standard process of ACh release and interaction in the neuromuscular junction are listed below.

1. ACh is synthesized and stored within synaptic vesicles at the motor nerve terminal. 
2. As an action potential propagates down the motor axon, it triggers the opening of VGCCs on the presynaptic nerve terminal, leading to the influx of calcium ions into the terminal. This calcium influx through VGCCs then triggers the quantal release of ACh into the neuromuscular junction.
3. ACh molecules bind to ACh receptors located on the postsynaptic neuron, causing a rapid influx of cations that leads to depolarization at the muscle fiber's end plate. This depolarization, in turn, initiates an action potential, ultimately triggering muscle contraction. 
4. The enzyme acetylcholinesterase rapidly hydrolyzes the ACh molecules present in the synaptic cleft. 

VGCC is a large transmembrane protein facilitating calcium ion influx into nerve terminals via multiple subunits. In LEMS, the functionality of VGCC is compromised due to the cross-linking of these channels mediated by IgG antibodies. More specifically, these antibodies specifically target the P/Q subtype of VGCC. Notably, 85% of patients with LEMS exhibit antibodies against the P/Q-type VGCC. In malignancy-associated LEMS, antibodies against the N-type VGCC have been sporadically identified. 

Autoimmunity within the context of LEMS associated with SCLC follows a distinct mechanism. In these instances, the tumor tissue expresses VGCC. This antigenic expression within the tumor cells triggers autoantibody production. These autoantibodies exhibit cross-reactivity with presynaptic VGCC antigens. 

Non-tumor LEMS has a genetic predisposition associated with specific HLA alleles, including HLA-B8 (HLA class I), HLA-DR3, and HLA-DQ2 (HLA class II). These HLA alleles have also been identified in individuals with other autoimmune conditions, including MG. However, it is noteworthy that this genetic association is not observed in LEMS cases linked to SCLC.

LEMS is a B-cell–mediated autoimmune neurological disorder specifically targeting the cell surface antigen (VGCC). The VGCC-IgG antibody is central to this disorder and directly contributes to its pathogenesis, leading to compromised neuromuscular transmission and manifesting as observable muscle weakness. Profoundly diminished deep tendon reflexes serve as a distinctive hallmark.

In addition to muscle-related symptoms, the effects extend to the release of ACh—a neurotransmitter also relevant to autonomic ganglia. Consequently, this disruption results in clinical manifestations of autonomic involvement, including constipation and atypical pupillary responses to light stimuli.

History and Physical

The predominant clinical features of LEMS include proximal muscle weakness, autonomic dysfunction, and impaired deep tendon reflexes. The symptoms of LEMS typically have an insidious onset and progress more rapidly in cases of SCLC-LEMS. 

• Muscle weakness predominantly involves the proximal lower extremities, leading to difficulties transitioning from a seated posture. The pattern of muscle involvement is usually symmetrical and characterized by progression from proximal to distal and caudal to cranial regions, eventually reaching the oculobulbar area. Patients often report sensations of dull aching or stiffness. Upon clinical assessment, significant hyporeflexia or areflexia is evident with limited muscle atrophy.

• A characteristic feature of LEMS is post-exercise or post-activation facilitation, characterized by enhanced deep tendon reflexes and muscle strength after repeated muscle contractions. This effect becomes particularly pronounced when evaluated after a brief rest period.

• Oculobulbar weakness is a prominent feature of LEMS, with cranial nerve involvement observed in approximately 70% of patients. The most common cranial nerve manifestations include ocular symptoms such as ptosis and diplopia. Furthermore, dysphagia and dysarthria may manifest, typically appearing in the advanced stages of the disease.

• Autonomic dysfunction is a prevailing concern in LEMS, affecting a significant proportion of patients, with a prevalence ranging from 80% to 96%. The most frequently reported symptom is a dry mouth. Other associated symptoms include erectile dysfunction in men, constipation, orthostatic dysfunction, and altered perspiration. 

• Respiratory failure is a relatively rare occurrence in the advanced stages of LEMS.

Evaluation

Clinical features such as proximal muscle weakness associated with areflexia and autonomic dysfunction should raise suspicion and prompt an evaluation for LEMS. This diagnosis can be confirmed through P/Q-type VGCC and electrodiagnostic studies (EDS).

Serology

Antibodies directed against P/Q-type VGCC, as detected in a radioimmunoassay, are present in approximately 85% to 95% of individuals with LEMS. However, it is noteworthy that P/Q-type VGCCs are not exclusive to LEMS, as they have also been linked to various other neurological conditions and autoimmune disorders.

In LEMS, antibodies targeting N-type VGCC are observed less frequently, accounting for only 30% to 40% of cases. In addition, 64% of patients with LEMS and SCLC also were found to have antibodies against SOX1—an immunogenic tumor antigen in SCLC with a 95% specificity.[11]

Electrodiagnostic Testing

When clinical suspicion arises regarding LEMS, EDS provides valuable assistance in confirming the diagnosis. EDS typically begins with nerve conduction studies (NCS) and electromyography (EMG). Sensory studies conducted as part of NCS typically show normal results, with unaffected nerve conduction velocities. In contrast, motor unit amplitudes are generally significantly reduced.

Repetitive nerve stimulation (RNS) is an essential component of EDS, which commonly reveals a decremental response during low-frequency repetitive nerve stimulation and an incremental response at high-rate stimulation. Although these findings are generally consistent and reproducible, varying results have also been reported. 

Following high-frequency RNS or post-exercise testing, a significant incremental response becomes evident, often exceeding 100% in compound muscle action potential (CMAP) amplitude. Notably, a diagnostic threshold is typically reached with an increase ranging from 60% to 99%. Furthermore, needle EMG can reveal the presence of unstable action potentials. 

Single-fiber EMG (SFEMG) is the most sensitive test for neuromuscular junction disorders. In LEMS, this test often shows a significant increase in jitter and transmission block (jitter block), which is characteristically improved at higher firing rates. Although SFEMG is more sensitive than RNS, RNS remains widely available and notably valuable. RNS aids in differentiating between MG and LEMS, accomplishing this differentiation by highlighting post-exercise facilitation in LEMS as opposed to decrement in MG. 

Screening for Malignancy

Due to the strong association with malignancy, a diagnosis of LEMS warrants an immediate and extensive investigation for an underlying malignancy. The initial recommended imaging study is a computed tomography (CT) or magnetic resonance imaging (MRI) chest scan. A positron emission tomography (PET) scan is also used for initial screening if CT is negative. If the initial evaluation does not reveal any malignancy, it is recommended to continue cancer screening every 3 to 6 months for a minimum of 2 years.

Individuals at higher risk, particularly those with a Dutch-English LEMS Tumor Association Prediction (DELTA-P) score exceeding 2 or positive SOX antibodies associated with SCLC-LEMS, should undergo screening every 3 months as recommended. The DELTA-P score consists of variables such as the age at diagnosis and smoking history to assist in stratifying the risk of SCLC in LEMS patients. This score helps determine the frequency and depth of screening for underlying malignancies.[12]

Treatment / Management

In cases of LEMS associated with SCLC, it is essential to address the root cause by treating the underlying malignancy.[2][13][14] In addition to treating the underlying cancer, managing symptoms is the key approach for LEMS treatment, which includes various options. However, the most effective and theoretically sound interventions focus on improving presynaptic ACh release; some are mentioned below.(B3)

Amifampridine or 3,4-diaminopyridine (3,4-DAP): This medication blocks presynaptic potassium channels, prolonging the action potential duration. This elongation leads to increased presynaptic calcium influx and subsequent ACh release. It is considered the first-line symptomatic treatment. The recommended dosage for adults is 15 to 30 mg, administered 3 times daily.[15]

Acetylcholinesterase inhibitors: Although pyridostigmine is an acetylcholinesterase inhibitor used to address weakness, its effects are generally less pronounced than in the case of patients with MG. The recommended adult dosage for this drug is 30 to 120 mg, administered every 3 to 6 hours.

Guanidine: This compound enhances ACh release following a nerve action potential. Guanidine should be considered only when amifampridine is unavailable due to its significant adverse effects and potential renal toxicity.[16] The recommended adult dosage is 1 g daily.

In cases where patients continue to have an enduring weakness that does not respond to symptomatic treatments, it becomes necessary to consider immunomodulating or immunosuppressive therapies, some of which are mentioned below.

Intravenous immune globulin (IVIG): IVIG is the primary treatment option for refractory cases. Despite its uncertain mechanism of action, it is believed to function by neutralizing autoantibodies and regulating autoreactive B cells. The usual regimen involves administering 2 g/kg over 2 to 5 days. [16]

Steroids and other immunosuppressive agents: Although azathioprine, mycophenolate, and cyclosporine may be considered for specific cases, their efficacy is generally lower than IVIG. In addition, the potential for significant adverse effects often limits their widespread use. 

Rituximab: This monoclonal antibody targets CD20 receptors found on B lymphocytes. Theoretically, it is effective against all B-cell-mediated diseases, including LEMS. Nevertheless, data supporting its more extensive utilization is insufficient.[16]

Plasma exchange: In certain refractory cases, plasma exchange holds the potential to offer benefits.

Differential Diagnosis

The differential diagnosis of LEMS includes MG. The distinguishing features include areflexia, autonomic dysfunction, and the post-exercise facilitation phenomenon specific to LEMS. Myopathies are also substantial considerations in the diagnostic process. The absence of sensory symptoms assists in excluding polyneuropathy or polyradiculopathies.

Prognosis

Patients diagnosed with LEMS often experience a diminished quality of life due to weakness, autonomic involvement, and potential treatment-related adverse effects. However, LEMS typically responds positively to symptomatic and immunosuppressive therapies. Upon diagnosis, approximately 60% of patients maintain their independence in daily activities, and this proportion increases to 85% within a year of treatment.[17]

The life expectancy of LEMS patients depends on whether it is paraneoplastic or non-paraneoplastic (NT-LEMS). Survival for NT-LEMS patients is similar to the general population. Conversely, the prognosis for paraneoplastic LEMS patients depends upon the underlying cancer. Most commonly, SCLC is the associated malignancy. Intriguingly, individuals with LEMS-SCLC exhibit more favorable survival rates than those with non-LEMS SCLC, with an overall median survival of 17 months compared to 7 months (P < .0001).[17]

Complications

Complications associated with LEMS can be categorized into those originating from the condition and resulting from treatment. Issues stemming from LEMS include weakness-related complications such as falls, fractures, and aspiration pneumonia. Autonomic involvement contributes to complications such as dry mouth, constipation, dysphagia, and erectile dysfunction, resulting in weight loss and emaciation.

On the other hand, treatment-related complications encompass adverse effects of medications. Symptoms such as tingling and numbness associated with 3,4-DAP can occur. Furthermore, complications such as cytopenia and infections might develop due to immunosuppressive drugs.