Clinical, Pathophysiological and Electrodiagnostic Aspects of Lambert-Eaton Myasthenic Syndrome

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is characterized by an autoimmune disorder of the neuromuscular junction, which, through a reduction in nerve terminal acetylcholine release mediated by antibodies against functional voltage-gated calcium channels (VGCCs) of the P/Q in presynaptic nerve terminals, leads to proximal muscle weakness, in addition to autonomic dysfunction and areflexia, constituting the classic triad of symptoms. The syndrome presents itself in two forms: the paraneoplastic form—resulting mainly from small cell lung carcinoma—and the underlying autoimmune form. With clinical suspicion of the disease, the diagnosis can be made through serological and electrophysiological tests, which present typical findings and reflect the existence of a presynaptic transmission defect. Treatment is based on early screening and removal of the etiological agent, which in the most common case is the treatment of the underlying cancer. In patients whose symptoms affect their daily activities, some medications can intervene in the search for a better quality of life, such as amifampridine, pyridostigmine and 3,4-diaminopyridine (3,4-DAP). It must be remembered, however, that LEMS has a significant impact on the patient’s quality of life and ability to perform daily activities and therefore warrants timely diagnosis and adequate treatment in itself.

1. Introduction

Lambert-Eaton myasthenic syndrome (LEMS) is characterized as an uncommon disorder of the neuromuscular junction, in which a considerable percentage of cases present as a paraneoplastic form (P-LEMS) associated, in most cases, with lung carcinoma of small cells (CPPC). Another portion of the disorders is associated with underlying autoimmune pathologies (A-LEMS) [1].

LEMS is characterized by the presence of antibodies against presynaptic voltage-gated calcium channels (VGCCs) of the P/Q type, which provide a decrease in the levels of acetylcholine (ACh) that are released in the nerve terminal, providing one of the main symptoms encountered, such as weakness and fatigue. Some clinical symptoms of LEMS overlap with those of other myasthenic syndromes, most commonly myasthenia gravis (MG), which can contribute to misdiagnosis or delay in diagnosis [1].

In addition, LEMS is a disorder in which the pathophysiological, clinical, electrophysiological and laboratory characteristics are distinct, with the presence of common clinical findings among other pathologies, such as autonomic dysfunction and areflexia [1].

Despite being an uncommon disorder in a population sample, among the conditions involving neuromuscular transmission, knowledge about the disease is common, in which the clinical presentation, mainly associated with neoplasia, requires the neurologist to have knowledge about its presentation, diagnosis and treatment [2].

The prognosis of the disease is related to the presence of cancer and the severity/distribution of muscle weakness, in which the cause of death in these patients is mainly due to tumor progression. LEMS is a clinically important early indicator of possible cancer; therefore, a diagnosis of LEMS should immediately prompt rigorous oncologic screening and surveillance [1, 2].

2. Material and methods

This respective chapter is a non-systematic review. All articles used were searched in PubMed, Medline, ScienceDirect, SciELO and Cochrane public databases. The search process for these articles was carried out by searching for terms related to Lambert-Eaton syndrome, selecting the most relevant articles available in English or Portuguese. Additional literature not present in these databases was used to complement the general understanding of the conditions, specific classifications, previous treatments and also to illustrate historical descriptions of the disease.

3. Epidemiology

LEMS is considered a rare disease, which is difficult to diagnose and somewhat underdiagnosed, with an annual incidence corresponding to one-tenth of cases of MG—the main disease in the group of neuromuscular junction disorders [3]. Sanders [4], in a large North American epidemiological study, estimated that the prevalence was 1 in 100,000 of confirmed and probable cases, respectively, being more frequently presented in males and in the older population.

When we refer to the approximate duration of disease prior to the diagnosis of the case, we have approximately 11 months and it was significantly lower among patients with paraneoplastic etiology than those with the autoimmune portion [5]. In addition, in P-LEMS, the average age of onset was 60 years, with 65–75% of patients being male, as previously mentioned [6].

Elrington et al., in a prospective study, demonstrated that LEMS has a higher incidence in males, ranging from 60% to 75% of patients, which differs from MG, where most of the conditions present in women. Another factor to be noted is the age of onset, in which the patient with the presence of a non-paraneoplastic form, the age is similar to that of MG, ranging around 35 years. In contrast, in paraneoplastic LEMS, the peak incidence generally remains at 58 years of age. When we compare the prevalence of MG compared to LEMS, the occurrence of the first disease is 46 times higher.

4. Immunophysiology

Under physiological conditions, it would be normal for the depolarization of the presynaptic neuronal membrane to induce the opening of voltage-gated calcium channels (VGCC), which would cause the influx of calcium to the nerve terminal, which would act in muscle contraction. Through the neuromuscular junction. ACh—neurotransmitter active in this process—diffuses through the synapse to bind to its receptors on the postsynaptic membrane of the motor endplate, and this binding opens postsynaptic sodium and potassium channels, promoting depolarization of the endplate motor. After reaching the depolarization threshold, there is an action potential and muscle contraction [7].

Calcium ions play a key role in neurotransmission, where they not only play a role in the performance of vesicular exocytosis that are anchored on the cytoplasmic side of the presynaptic membrane (ready to be released), but also play a role in short-term synaptic plasticity and, probably influence the mechanisms that restore the RRP after presynaptic activation [7].

Figure 1 succinctly illustrates the most relevant stages of neuromuscular transmission, in which first (1) we have the active depolarization of a motor axon promoted by the opening of Na⁺ channels and, in addition, the membrane contains dependent K⁺ and Ca⁺² channels voltage (2). The opening of calcium channels (3) located in the active zones allows the entrance of this, generating an increase in the intra-concentration. Approximately four or five calcium ions bind to its receptor, which triggers the rapid and synchronous release of ACh (4). Subsequently, the empty active zones are replenished by a recycling pool^®, which is believed to be mediated by the intraterminal concentration of calcium ions (5).

Figure 1.

Stages of neuromuscular transmission.

In Lambert-Eaton syndrome, the body produces autoantibodies to the presynaptic VGCC, which therefore results in a reduction of Ach released in the presynaptic nerve terminal [8]. Given this, by altering the release of Ach, the entire cascade of neurotransmission and channel opening mentioned above end up reducing as well. A decreased amount of Ach translates into an underactivation of sodium and potassium channels in the postsynaptic membrane and reduces the action potential in the endplate [7]. Therefore, the action potential ends up not occurring and, consequently, affects muscle contraction, which explains one of the main symptoms of the disease, muscle weakness.

4.1 Tumor association

Association with tumor is reported in about 60% of patients with LEMS [9], in which the majority is due to smoking-related SCLC with neuroendocrine characteristics, but other malignant neoplasms are described in the literature, such as small cell lung carcinomas. Non-small and mixed, prostate carcinoma, thymoma and lymphoproliferative disorders [10, 11]. Studies indicate that the diagnosis of LEMS can precede the diagnosis of neoplasia by a variability of 5–6, in addition to having an extreme relationship with the smoker, which is presented as a risk factor. Titulaer et al. [16] observed that an SCLC diagnosis preceded LEMS identification in only 6% of P-LEMS cases. SCLCs were identified in 92% of these patients within 3 months and in 96% within a year.

Descriptions in the literature show assumptions about the initial human autoimmune response in patients with LEMS being generated against the antigens of the VGCC subunit in lung carcinoma [12], and the paraneoplastic form expresses VGCC of the N, L or P type, in addition to the P/Q subtypes and possibly N are targets of IgG-mediated autoimmunity in LEMS [13] (P/Q are involved in Ach release from motor nerve terminals and N-type in peripheral autonomic terminals [14]).

5. Clinical manifestations

The clinical presentation of LEMS is variable and has an insidious onset, with a slowly progressive clinical course, but occasionally it can be subacute. Presenting symptoms are lower limb weakness (60%) or generalized weakness (18%), muscle pain or stiffness (5%), dry mouth (5%), upper limb weakness (4%), diplopia (4%) and dysarthria (2%). In this aspect, there is a classic triad that can further characterize the disease, with proximal muscle weakness, autonomic characteristics and areflexia [9, 11].

Titulaer et al. [15] (Table 1) described the spread of weakness in patients with A-LEMS and P-LEMS, which is more characterized by spreading from proximal to distal, affecting feet and hands, from caudal to cranial and, finally, reaching the oculobulbar region. Analyzing and comparing with MG, LEMS presents a different presentation. In addition, the speed of propagation is more pronounced in the paraneoplastic form, in which generalized weakness can already be noticed in the first 3 months [16].

	Lambert-Eaton	Myasthenia Gravis
Typical first symptom	Difficulty getting up	Diplopia
Autonomic symptom	Dry mouth	None
Weaker musculature	Proximal muscle weakness	Extraocular
Deep tendon reflexes	Reduced	Normal
Involvement of autoantibodies	Presynaptic VGCC	Postsynaptic ACh receptor
High frequency RNS	>60% increase in muscle action potential	<60%

Table 1.

Comparison of symptoms and characteristics of LEMS and MG.

In the study conducted by Burns et al. [17], oculobulbar symptoms/signs were present in 78% of patients with the disease. In addition, another retrospective review at the Mayo Clinic in Minnesota evaluated 176 patients, who described the following findings: 23% of patients had ptosis, 20.5% diplopia, 14% decreased visual acuity, in addition to 8, 5% alteration in the extrinsic ocular musculature. In a general context, oculobulbar symptoms present in a more severe and prolonged course of the disease [18].

Autonomic dysfunction is reported in 80–96% of patients, and the most common complaint is dry mouth, in addition to other symptoms such as erectile dysfunction, constipation, orthostatic dysfunction and difficulty urinating [15, 16].

Decreased tendon reflexes or areflexia are common signs we find, which should be tested after a period of rest, as the phenomenon of post-exercise facilitation can mask this characteristic finding since they can be amplified after muscle contraction. Cerebellar ataxia, sensory neuropathy and limbic encephalitis are extremely uncommon findings that are almost completely associated with the paraneoplastic form [16, 19].

6. Diagnostic

As previously seen, LEMS is initially suspected based on the patient’s clinical condition, in which the presence of clinical signs and symptoms should be noted, demonstrating the classic triad of proximal muscle weakness, diminished tendon reflexes and autonomic dysfunction. Based on this principle and having a clinical basis for the diagnosis, there are different electrophysiological studies, such as electromyography (EMG) and nerve conduction studies (NCS) that can contribute to confirming the diagnostic doubt [15].

The diagnosis of LEMS is by combining clinical suspicion with confirmation through electrophysiology and antibody testing against the P/Q-type VGCC IgG antibody (VGCC). The first analysis is through EMG that confirms the presence of a presynaptic disorder, which the physiopathology will be explained in “Electrophysiology” chapter [1, 2].

The importance of antibody research is to predict cancer development, due to half of LEMS patients having associated SCLC15. Nearly 90% of LEMS cases are seropositive for P/Q- type VGCC antibodies, once the disease acts impairing the release of ACh at active zones [20].

Besides, there are several different neuronal VGCC subtypes that also remained highly sensitive and specific for SCLC in all LEMS patients compared to NT-LEMS collaborating for early diagnosis, as N-type VGCCs (reportedly in 33–49% of LEMS)1, anti-Sry-like High Mobility Group Box (SOX), HuD and GABAb [21].

In previous reports, it was found that the presence of either N-type VGCC, SOX2 or GABAb antibodies was 84% sensitive and 87% specific for the SCLC detection [22]. Antibodies against SOX are considered malignant neoplasm-related onconeural autoabs, due to the association with SCLC. Sun et al. found among the 110 anti-SOX1-abs-positive, LEMS (30.0%, n = 33) was the most common paraneoplastic neurological syndrome in patients with cancer.

Autoimmunity with SCLC: In patients with LEMS associated with SCLC, the tumor tissue expresses VGCC, which induces the production of autoantibodies, which ultimately cross-react with presynaptic VGCC antigens [23].

Genetic predisposition: Non-tumor LEMS is more associated with class I HLA-B8 and class II HLA-DR3 and DQ2. These genotypes have been associated with other autoimmunity conditions, which include MG. However, this association does not appear when we have LEMS due to SCLC [23].

6.1 Screening for malignancy

Because of the high association with malignancy, the diagnosis of the myasthenic syndrome should lead to immediate and extensive search and screening for underlying malignant processes. Among them, computed tomography (CT) of the chest or magnetic resonance imaging (MRI) would be the recommended initial imaging study. PET scan can also be used in this evaluation if the first studies are negative. In the face of a first negative analysis, screening should continue and be performed every 3–6 months over a period of at least 2 years, in which case a quarterly assessment should be indicated for those at high risk, whose DELTA-P score is greater than 2 or with positive SOX antibodies associated with SCLC-LEMS [23, 24].

DELTA-P is a simple clinical scoring system based on age, weight loss, smoking, bulbar involvement, erectile dysfunction, and Karnofsky performance status, called the LEMS Tumor Association Prediction Score, which was developed and evaluated in 2011. This scoring system indicates the presence of an SCLC with very high accuracy and therefore helps clinicians to identify high-risk patients and optimize the triage and follow-up process [6].

6.2 Electrophysiology

Among the established criteria and the electrophysiology of LEMS, repetitive nerve stimulation (RNS) is the test of choice, making it possible to analyze characteristic findings that are part of the classic triad in the diagnosis, such as:

1. Decreased compound motor action potentials (CMAPs) in resting NCS (reaching less than 50% of the lower limit of normal), which is a common finding in all disorders of the presynaptic terminal of the neuromuscular junction, in addition, to be observed in approximately 96% of cases of LEMS [23].

2. Decrease in CMAP response at low frequency (2–5 Hz), which produces a successive decline in CMAP amplitude from its normal baseline. A decrease greater than 10% is considered abnormal and this presentation is found in approximately 94–98% of patients with LEMS [23, 24].

3. Increase in response greater than 100% demonstrated immediately after 10–30 seconds of maximum voluntary contraction (post-exercise test), or with high-frequency stimulation (20–50 Hz)—an incremental response has been used as the electrophysiological gold standard for the diagnosis of LEMS [23, 24].

Needle EMG shows erratic changes in motor unit action potential such as low and short during voluntary action potential. This may be due to single-fiber EMG measurements on the jitter, which increased jittering shows transmission blockage and may correspond to disease severity [1, 23, 24].

Fiber EMG usually does not differ between presynaptic and postsynaptic disorders of the neuromuscular junction. It should be noted that early in the clinical course of LEMS, when the initial CMAP amplitude is not yet reduced, the abnormal incremental response may be easier to demonstrate than the more characteristic incremental response. Given this, the combination of a normal CMAP or when it is slightly reduced, in addition to a lack of incremental response, can lead to a misdiagnosis of LEMS or lead to a misdiagnosis of MG¹.

Hatanaka and Oh [25], in a study conducted in 2008, showed that longer exercises can lead to a progressive decrease in the increment, in which the diagnostic sensitivity is greater using a 10-second exercise when compared to a 30-second exercise. The same authors found in later studies that, when comparing negative LEMS VGCC, the positive result of this serology is associated with a lower baseline CMAP and a greater response to the increment. These findings suggest that the RNS pattern is more drastically altered in positive VGCC and thus becomes more indicative of LEMS. Therefore, this study contributed even more with the use of the 60% increment criterion, which is quite critical for the diagnosis of seronegative LEMS. Finally, the authors also conclude that the effect of exhaustion after exercise on the RNS has no diagnostic value [26].

7. Treatment

The treatment itself for the onset of the disease is based on the underlying etiology, requiring monitoring and treatment of the cancer, if it has a neoplastic etiology. However, there are drugs that can act directly on the synaptic terminal, improving quality of life and reducing symptoms. Among them, we have amifampridine, which is an oral medication that acts on voltage-dependent potassium channels in the presynaptic terminal, blocking them, thus preventing the efflux of potassium ions and prolonging depolarization. In this mechanism, there is an increase in the release of Ach through the prolongation of the influx of calcium ions, which will promote an improvement in the neuromuscular function. This medication has been approved in the USA as intended to be first-line therapy in the treatment of the syndrome by the Food and Drug Administration (FDA) (Table 2) [27].

Lambert-Eaton myasthenic syndrome—approach to treatment
Screen for small cell cancer	If cancer is detected then aggressive treatment for malignancy may improve or be curative for LEMS
Amifampridine	Begin 5 mg three times per day and gradually increase every 3–4 days by 5 mg
Pyridostigmine	30–60 mg three to four times per day
If insufficient improvement then add immunosuppressant therapy	Prednisone, azathioprine, mycophenolate, etc.
If severe or refractory weakness the add IVIg/PE Rituximab	IVIg 2 g/kg over 4–5 days then maintenance or plasma exchange

Table 2.

Options for treatment of LEMS include treating the malignancy (if paraneoplastic).

Another medication that can act on the mechanism of Ach release and promote the improvement of neuromuscular function is pyridostigmine, which inhibits acetylcholinesterase and, consequently, increases its concentration in the motor plate synapse [28]. However, this medication is generally not very effective in monotherapy, although benefits have been reported in some patients when associated with 3,4-diaminopyridine (3,4-DAP) [29].

In patients in whom the symptoms of the disease interfere with aspects of the day and limitation of daily activities, 3,4-DAP can be used for symptomatic improvement and is recommended, eventually, even as initial therapy. This medication has as its mechanism of action the blockade of potassium channels, which prolongs the depolarization of the presynaptic nerve terminal and, as a consequence, increases the entry of calcium through the VGCC channels, leading to an increase in the release of ACh. The beneficial effects of 3,4-DAP include improvement in muscle strength, autonomic symptoms and CMAP amplitude [29, 30, 31]. Sanders et al. [32], in their study carried out in 2018, demonstrated the effectiveness of treatment with medication in symptomatic control.

If the neuromuscular disease is refractory to the two aforementioned medications, immunomodulatory therapy may be an option, with intravenous immunoglobulin being the first line, in addition to other alternatives, such as prednisone, rituximab, azathioprine and plasmapheresis [7].

Intravenous immunoglobulin, therefore, has been successfully used for the treatment of several neurological diseases that present immunomediation, and can be used both as induction treatment in symptomatic patients and for maintenance treatment in patients with recurrence of symptoms [33].

In a double-early, randomized, placebo-controlled crossover study, Bain PG et al. demonstrated significant improvements in muscle, respiratory and bulbar strength indices that were associated with a reduction in serum VGCC antibody patterns [34].

8. Prognosis

In evaluating the survival and prognosis of the patient who has a case of LEMS, the main determinant to be considered is the presence or absence of neoplasia, that is, whether we are facing a paraneoplastic LEMS or not. In patients with SCLC associated with LEMS, a longer survival can be noted, when compared to patients with SCLC, but without the neurological pathology together [35]. In patients without associated neoplasia, survival is normal or almost normal, as seen in the study conducted by Maddison et al. [35], in which 47 patients with LEMS without SCLC, 10 died at a mean age of 70 years, unrelated to the LEMS.

9. Conclusion

Despite being a rare disease in the population context, when referring to the clinical practice of neurology, this pathology is one of the main differential diagnoses in the involvement of the neuromuscular junction. Proximal muscle weakness, autonomic disorders and areflexia are the main clinical findings in the range of diseases that involve this group, which, for the correct diagnosis, must take LEMS into account and be involved in the differential diagnosis.

In case of clinical suspicion, tools that help in the diagnosis are accessible in our midst, in addition to clinical and electrophysiological criteria. Early recognition and immediate initiation of treatment improve patient survival and prognosis, in addition to rapid visualization of the underlying etiology, such as treatment of neoplasms, in case this becomes the cause of the syndrome.

Finally, patients with a suspected or confirmed diagnosis should be covered and examined by a multidisciplinary team, which includes, in addition to neurological treatment, the presence of respiratory, oncological, thoracic, pathological and radiological services. In addition, it is important to highlight the importance of oncological screening and evaluation for the diagnosis of the syndrome, since this disease is closely associated with paraneoplastic involvement and, in some situations, may precede the malignant diagnosis itself.

Acknowledgments

We would like to give due recognition to Dr. Felipe Ibiapina for making this work possible and to the University of Joinville for encouraging and opening doors for such a publication.

Conflict of interests

The authors declare no conflict of interest.