Continuing Education Activity

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder which may present as a paraneoplastic phenomenon or a primary autoimmune disorder. More than half of the cases are associated with small cell lung cancer (SCLC). The primary clinical manifestation is muscle weakness. The pathology is due to the generation of antibodies against voltage-gated calcium channels (VGCC) on presynaptic nerve terminals leading to a decrease in the neurotransmitter acetylcholine (ACh). This topic will review the pathogenesis, diagnostic testing, and treatment of Lambert-Eaton myasthenic syndrome. This activity reviews the pathophysiology of Lambert-Eaton syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the cause of Lambert-Eaton syndrome.
• Describe the pathophysiology of Lambert-Eaton myasthenic syndrome.
• Summarize the treatment of Lambert-Eaton myasthenic syndrome.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by Lambert-Eaton syndrome.

Introduction

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder which may present as a paraneoplastic phenomenon or a primary autoimmune disorder. More than half of the cases are associated with small cell lung cancer (SCLC). The primary clinical manifestation is muscle weakness. The pathology is due to the generation of antibodies against voltage-gated calcium channels (VGCC) on presynaptic nerve terminals leading to a decrease in the neurotransmitter acetylcholine (ACh). This topic will review the pathogenesis, diagnostic testing, and treatment of Lambert-Eaton myasthenic syndrome.[1][2][3][4][5]

Etiology

Lambert-Eaton myasthenic syndrome is classified as paraneoplastic or non-paraneoplastic, also referred to as non-tumor Lambert-Eaton myasthenic syndrome (NT-LEMS). NT- LEMS occurs in the absence of malignancy. Sixty percent of patients with Lambert-Eaton myasthenic syndrome have an underlying tumor. Paraneoplastic Lambert-Eaton myasthenic syndrome is typically associated with small cell lung cancer (SCLC). Other malignancies that have been associated with Lambert-Eaton myasthenic syndrome include non-small cell and mixed lung carcinoma, prostate cancer, thymoma and lymphoproliferative disorders. Studies have indicated that the diagnosis of Lambert-Eaton myasthenic syndrome can precede a diagnosis of small cell lung cancer, ranging from up to 5 to 6 years. History of smoking is also considered a risk factor. The genetic association with HLA–B8–DR 3 haplotype is present in about 65% of young patients with NT–L EMS.

Epidemiology

Lambert-Eaton myasthenic syndrome is a rare neuromuscular disorder,  which is 46 times less prevalent than Myasthenia Gravis (MG). However, the annual incidence of Lambert-Eaton myasthenic syndrome was only 10 to 14 times lower than MG. The increased prevalence of MG compared to Lambert-Eaton myasthenic syndrome speaks to the poor prognosis and survival of Lambert-Eaton myasthenic syndrome specifically when associated with SCLC.

Sixty percent to 75% of the patients with Lambert-Eaton myasthenic syndrome were male compared to the female predilection seen in MG. The mean age of presentation associated with paraneoplastic Lambert-Eaton myasthenic syndrome was 58 years. In Lambert-Eaton myasthenic syndrome that was not associated with malignancy. The age and sex distribution were similar to that of MG, with a peak age of onset of 35 years and a second larger peak at 60 years. The Lambert-Eaton myasthenic syndrome without malignancy has a near-normal survival rate.[6][7][8]

Pathophysiology

Lambert-Eaton myasthenic syndrome is a disorder of reduced acetylcholine release from the presynaptic nerve terminals due to antibodies to voltage-gated calcium channels in the presynaptic neuronal cell membrane.

The following is the normal mechanism of ACh release and interaction:

1. ACh is synthesized and stored in vesicles at the motor nerve terminal. 
2. Upon stimulation by an action potential which travels down the motor nerve, ACh is released into the nerve terminal. The release of ACh is dependent on the influx of calcium ions via the voltage-gated calcium channel (VGCC).
3. ACh then binds to the ACh receptors on the postsynaptic neuron, leading to the rapid entry of cations which produces depolarization at the end plate region of the muscle fiber and generating an action potential and subsequent muscle contraction.
4. Acetylcholine within the synaptic cleft is rapidly broken down by the enzyme acetylcholinesterase. 

VGCC, a large transmembrane protein with multiple subunits has an important role as it mediates the influx of calcium into the nerve terminal. In Lambert-Eaton myasthenic syndrome, VGCC is reduced due to the IgG antibody-mediated cross-linking of the channels. More specifically, antibodies are directed towards the P/Q subtype of VGCC.  85% of patients with Lambert-Eaton myasthenic syndrome demonstrate antibodies against the P/Q type VGCC. Rarely, antibodies against the N-type VGCC has been found in malignancy-associated Lambert-Eaton myasthenic syndrome. 

Autoimmunity with SCLC: In patients with Lambert-Eaton myasthenic syndrome associated with SCLC, the tumor tissue expresses VGCC. This expression of antigens on the tumor cells induces the autoantibody production, and the autoantibodies cross-react with presynaptic VGCC antigens. 

Genetic predisposition: Non-tumor Lambert-Eaton myasthenic syndrome is associated with HLA-B8 (HLA - class I) and HLA -DR3 and -DQ2 (HLA class II). These HLA genotypes have also been associated with other autoimmune conditions including myasthenia gravis. Conversely, it is not seen in Lambert-Eaton myasthenic syndrome associated with SCLC. 

History and Physical

The most frequent clinical manifestations of Lambert-Eaton myasthenic syndrome are proximal muscle weakness, autonomic dysfunction, and absent deep tendon reflexes. Symptoms are usually insidious in onset and progress more rapidly in SCLC-LEMS. 

• Muscle weakness: As it typically involves proximal leg, patients complain of difficulty arising from a seated position. Muscle involvement is usually symmetrical, and the pattern of progression has been described to be proximal to distal, and caudal to cranial, finally reaching the oculobulbar region. Patients also describe a dull aching or stiffness. On examination, areflexia is present in the absence of significant muscle atrophy.
• Postexercise or post-activation facilitation which is characterized by the return of tendon reflexes and muscle strength with repeated muscle contraction is associated with Lambert-Eaton myasthenic syndrome. The exam is more evident if tested after the patient rests for a brief period. 
• Oculobulbar weakness: Cranial nerve involvement may be seen in up to 70% of patients with Lambert-Eaton myasthenic syndrome. Ocular symptoms, particularly ptosis and diplopia, are the most common cranial nerve manifestations of Lambert-Eaton myasthenic syndrome. Dysphagia and dysarthria also are seen. These symptoms typically appear in later stages of the disease.
• Autonomic dysfunction is reported in 80% to 96% of the patients. Dry mouth is the most commonly reported symptom. Other symptoms are erectile dysfunction in men, constipation, orthostatic dysfunction, and altered perspiration. 
• Respiratory failure infrequently occurs in the later stages of a patient with Lambert-Eaton myasthenic syndrome.

Evaluation

The presence of clinical features such as proximal muscle weakness associated with areflexia and autonomic dysfunction should prompt an evaluation for Lambert-Eaton myasthenic syndrome. The diagnosis of Lambert-Eaton myasthenic syndrome can be confirmed by the presence of P/Q-type VGCC along with electrodiagnostic studies.

Serology

Antibodies against the P/Q-type VGCC detected in a radioimmunoassay are present in approximately 85% to 95% of patients with Lambert-Eaton myasthenic syndrome. However, the presence of P/Q- type VGCC is not specific to Lambert-Eaton myasthenic syndrome as it has been associated with a number of neurological conditions and other autoimmune disorders. Less frequently (30% to 40%), antibodies against N-type VGCC are seen in Lambert-Eaton myasthenic syndrome. In addition, 64% of Lambert-Eaton myasthenic syndrome patients with SCLC also were found to have antibodies against SOX1, an immunogenic tumor antigen in SCLC with a 95% specificity.

Electrodiagnostic Testing

The initial findings on electrodiagnostic testing described by Eaton and Lambert were a low CMAP (compound muscle action potential) amplitude at rest, a decremental response at low rates of repetitive nerve stimulation (RNS), and an incremental response at high-rate stimulation. These findings have largely been reproducible however varying findings have also been described. 

Following high-frequency RNS or post-exercise, a significant incremental response up to greater than 100% in CMAP amplitude is seen, however up to a 60% to 99 % increase is considered diagnostic. 

Needle EMG can demonstrate unstable action potentials. 

Single fiber electromyography (SFEMG) often shows significant jitter and transmission blocking that is characteristically improved at higher firing rates. SFEMG is more sensitive than RNS. However, RNS is more widely available and is useful in distinguishing between myasthenia graves and Lambert-Eaton myasthenic syndrome by demonstrating the post-exercise facilitation. 

Screening for Malignancy

Due to the strong affiliation with malignancy, the diagnosis of Lambert-Eaton myasthenic syndrome should prompt an immediate and extensive search for underlying malignancy. A CT or MRI of the chest is the initial recommended imaging study. PET scan is also used for initial screening if CT  is negative. If the initial evaluation is negative, screening for cancer should continue every 3 to 6 months for at least 2 years. Screening every 3 months is indicated for those patients who are at high risk whose DELTA-P score greater than 2 or with positive SOX antibodies which are associated with SCLC-LEMS. The Dutch-English LEMS Tumor Association Prediction (DELTA-P) score consists of variables such as the age of diagnosis and smoking history and is used to risk stratify the association with SCLC in patients with Lambert-Eaton myasthenic syndrome and guide the screening for underlying malignancy.

Treatment / Management

Lambert-Eaton myasthenic syndrome associated with SCLC involves treatment of the underlying malignancy.[1][9][10]

The initial treatment for the symptomatic management of Lambert-Eaton myasthenic syndrome with or without malignancy is geared towards increasing the levels of acetylcholine. Acetylcholinesterase inhibitors such as pyridostigmine (30 to 120 mg every 3 to 6 hours) are used for the treatment of weakness. However, the effects are not as marked as with patients with myasthenia gravis. Another therapeutic option is 3,4 -diaminopyridine (3,4- DAP). 3,4-DAP binds to VGCCs that lead to prolongation of depolarization of the action potential increase the open time of the VGCCs which leads to an increased presynaptic influx of calcium and increased ACh release. 

For patients with refractory weakness, immunosuppression with IVIG as the first-line agent is recommended. Other suggested alternatives include prednisone, rituximab, azathioprine, or plasma exchange.

Differential Diagnosis

Differential Diagnosis of Lambert-Eaton myasthenic syndrome includes MG. The distinguishing features include areflexia, autonomic dysfunction and the phenomena of post-exercise facilitation present in Lambert-Eaton myasthenic syndrome. Myopathies remain an important differential in the diagnosis of Lambert-Eaton myasthenic syndrome. The absence of sensory symptoms helps to rule out polyneuropathy or polyradiculopathies.

Enhancing Healthcare Team Outcomes

The diagnosis and management of patients with Lambert Eaton myasthenia syndrome requires an interprofessional team because of the diverse presentation. The disorder is usually seen in the presence of a malignancy and hence the team should include an oncologist, surgeon, hematologist, ophthalmologist, neurologist, primary care provider and nurse practitioner. The initial treatment for the symptomatic management of Lambert-Eaton myasthenic syndrome with or without malignancy is geared towards increasing the levels of acetylcholine.  For patients with refractory weakness, immunosuppression with IVIG as the first-line agent is recommended. Other suggested alternatives include prednisone, rituximab, azathioprine, or plasma exchange.

The prognosis for patients with this syndrome depends on the primary malignancy. With advanced cases, the prognosis is poor. However, if the primary malignancy is controlled, symptomatic improvement does occur over time but often full recovery is not possible.[11][12] (Level V)