Version May 2024
INTRODUCTION — Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon disorder of neuromuscular junction transmission with the primary clinical manifestation of muscle weakness. Knowledge of subtle clinical features and laboratory abnormalities that accompany LEMS permits the early identification of the disorder. Early recognition of LEMS is particularly important because of its strong association with small cell lung cancer (SCLC). Although LEMS can occur at any point in the course of SCLC, it may serve as a marker for early disease and thus allow more effective treatment of this malignancy.
This topic will review treatment for LEMS. The clinical features and diagnosis of this disorder are discussed separately. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)
EVALUATION FOR MALIGNANCY — The first priority in the management of LEMS is to evaluate for a primary underlying malignancy. Treatment of the underlying malignancy may be the only intervention necessary to produce improvement in neurologic symptoms.
Small cell lung cancer — Small cell lung cancer (SCLC) is the most common associated tumor in patients with LEMS. Suspicion for lung cancer is particularly high among patients with a history of smoking who are ≥50 years of age [1]. Population studies have consistently shown that approximately one-half of LEMS cases are associated with a malignancy, which is usually SCLC. In a clinical series that included 50 patients with LEMS, SCLC was present in 21 of 25 patients (84 percent) with cancer [2]. From the perspective of patients who have SCLC, the incidence and prevalence of LEMS are estimated to be approximately 3 percent each [3-5]. (See "Pathobiology and staging of small cell carcinoma of the lung".)
Other malignancies — The other malignancies most convincingly associated with LEMS are lymphoproliferative disorders, including Hodgkin lymphoma [6-8]. LEMS has been rarely associated with atypical carcinoid [9], Merkel cell carcinoma [10], thymic neuroendocrine carcinoma [11], malignant thymoma [12], thymic small cell carcinoma [13], and neuroblastoma [8].
Initial evaluation — For all patients with newly diagnosed LEMS and no known cancer, we recommend initial malignancy evaluation with computed tomography (CT) of the chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) of the brain and/or spinal cord should also be obtained if there are focal neurologic symptoms or signs suggesting involvement of the central nervous system (CNS).
Some experts suggest performing 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) as part of the initial screening for malignancy if the CT scans are nondiagnostic [14]. We recommend FDG-PET imaging for all high-risk patients, such as those with a Dutch-English LEMS Tumor Association Prediction (DELTA-P) score ≥3 (table 1), who have negative CT imaging. The DELTA-P score is described below. (See 'DELTA-P score' below.)
We also suggest testing for SOX antibodies (see 'SOX and other antineuronal antibodies' below) for any patient with suspected LEMS without a known SCLC and suggest FDG-PET imaging for patients of any age or smoking history who have elevated SOX antibodies and nondiagnostic CT imaging.
A general overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer is provided elsewhere. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer".)
Follow up surveillance when initial evaluation is negative — If the initial malignancy evaluation is negative in patients with LEMS, we recommend repeating the chest CT scan at three months for high-risk patients (eg, a DELTA-P score ≥3) and patients with elevated SOX antibody titers and at six months for low-risk patients. This is followed by screening at least every six months up until at least two years if testing remains unrevealing [15]. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)
DELTA-P score — The Dutch-English LEMS Tumor Association Prediction (DELTA-P) score (table 1) may be useful to identify patients at low and high risk for SCLC and thereby guide the extent of testing for SCLC. In a cohort study of Dutch and English patients with LEMS, clinical factors within the first three months from LEMS onset that independently predicted the presence of SCLC were age ≥50 years, history of smoking at diagnosis, weight loss ≥5 percent, bulbar involvement, erectile dysfunction in men, and Karnofsky Performance Status (table 2) score <70 [16]. Using these factors, the investigators derived the DELTA-P score (table 1). A DELTA-P score of 0 or 1 was associated with an SCLC probability of 0 and 3 percent, respectively. DELTA-P scores of 4, 5, and 6 were associated with an SCLC probability of 94, 97, and 100 percent, respectively.
SOX and other antineuronal antibodies — SOX (SRY-related high mobility group [HMG] box) antibodies are common in SCLC. In one report, SOX antibodies were detected in 29 of 43 patients (67 percent) with LEMS associated with SCLC and only 2 of 43 patients (5 percent) with nontumor LEMS [17]. Additionally, the presence of GABAb and N-type voltage-gated calcium channel antibodies predict a significantly higher risk of tumor-associated LEMS. The presence of antineuronal antibodies can also improve the detection of cancer in LEMS patients with low DELTA-P scores of 1 to 2 [18].
INITIAL SYMPTOMATIC THERAPY — Several medications increase the amount of acetylcholine available at the postsynaptic membrane. The most effective agents increase the presynaptic release of acetylcholine and thereby reverse the underlying physiologic deficit present in LEMS. If adequate to induce stable functional muscle strength, no further treatment may be needed.
Mild weakness, no functional impact — Patients with LEMS who have mild weakness that does not interfere with function can be monitored without the use of symptomatic or immunologic therapy (algorithm 1).
Moderate to severe weakness — For patients with moderate or severe weakness that does interfere with function, we suggest initiating amifampridine. If amifampridine is not tolerated or is unavailable, pyridostigmine could be considered.
Amifampridine (3,4-diaminopyridine) — The aminopyridines are beneficial in patients with LEMS. The mechanism of action is potassium channel blockade that significantly prolongs the presynaptic nerve terminal membrane depolarization, which enhances calcium entry and thereby improves the release of acetylcholine.
3,4-diaminopyridine (3,4-DAP) is the best-tolerated aminopyridine due to its limited central nervous system (CNS) penetration. Dalfampridine (4-aminopyridine) was the first aminopyridine to be recognized as having beneficial effects in LEMS. However, clinical use was limited by frequent toxicity in the therapeutic range (including generalized seizures), which required much higher doses than those now used in patients with multiple sclerosis, for example [19]. 3,4-DAP has the same mechanism of action and considerably less CNS penetration than dalfampridine, making it the clear preference in LEMS.
3,4-DAP was initially studied and developed as a base (3,4-DAP base), which was available in the United States through a compassionate use program from compounding pharmacies, and later formulated as an oral tablet. Amifampridine phosphate (Firdapse) was approved by the US Food and Drug Administration (FDA) in 2018 for use in adults and in 2022 for children age 6 years and older [20,21].
The effectiveness of 3,4-DAP compared with placebo for improving motor and autonomic symptoms in LEMS has been demonstrated in multiple small randomized controlled trials [22-28]. In these trials, 3,4-DAP improved muscle strength in patients with LEMS, making it the most effective symptomatic treatment for LEMS [26]. In the largest individual trial, 38 patients (≥18 years of age) with LEMS completed an open-label run-in phase of amifampridine and were then entered into a blinded two-week discontinuation phase in which they were randomly assigned to continued amifampridine or placebo (which included a seven-day taper off active drug) [27]. By day 14, the patients in the amifampridine group had superior quantitative myasthenia gravis (QMG) scores (mean difference 1.7 points, 95% CI 0.0-3.4) and were less likely to experience clinically significant disease progression (6 versus 59 percent at day 8 and 12.5 versus 38 percent at 14 days). There were no statistically significant differences in timed walk testing or compound muscle action potential (CMAP) amplitudes.
The recommended starting dose of amifampridine for adults and children weighing 45 kg or more is 15 to 30 mg daily taken orally in three to four divided doses [21,29]. The dose can be titrated upwards based on effect and tolerability by 5 mg daily every three to four days. The maximum single dose is 20 mg and the maximum approved daily dose is 80 mg. However, 3,4-DAP base doses up to 100 mg/day have been widely used [24]. For children less than 45 kg, the recommended starting dose is 5 to 15 mg divided three to four times daily with increases as needed in 2.5 to 5 mg increments every three to four days with a maximal daily dose of 10 mg per dose or 40 mg daily. The recommended starting dose of amifampridine for patients with kidney or liver impairment is the lowest recommended initial dose based on body weight and age category.
The side effects of 3,4-DAP at typical therapeutic doses are usually mild, mainly perioral and extremity paresthesias in 50 to 60 percent of patients [27]. Headache, nausea, abdominal pain, diarrhea, and elevated liver enzymes can also occur. 3,4-DAP has been associated with seizures, particularly at high doses [30], and the FDA label for amifampridine includes a contraindication in patients with a history of seizure. A history of seizure has been an eligibility exclusion in most trials, and therefore experience is limited in patients with epilepsy. If the balance of risks and benefits is felt to favor use in a patient with symptomatic LEMS and epilepsy, 3,4-DAP should be used cautiously at the lowest dose possible. 3,4-DAP should also be used with caution in patients with severe asthma [24,30].
Pyridostigmine if 3,4-DAP is not available — The acetylcholinesterase inhibitors are, unfortunately, only marginally effective in isolation for the treatment of LEMS and should only be tried in patients who are intolerant of or do not have access to 3,4-DAP. Acetylcholinesterase inhibitors reduce the metabolism of acetylcholine, thereby increasing the amount available for acetylcholine receptor binding. Pyridostigmine is the best tolerated of the acetylcholinesterase inhibitors.
Pyridostigmine has been used as adjunct treatment in patients receiving 3,4-DAP in the hope that this combination, which is well tolerated, confers additional symptomatic benefit. However, the utility of this approach is uncertain and high-quality data are sparse. One randomized controlled crossover trial of nine patients with LEMS compared 3,4-DAP, pyridostigmine, the combination of both drugs, and placebo [22]. There was no benefit for pyridostigmine, either alone or in combination with 3,4-DAP, for the outcomes of muscle strength and CMAP amplitude.
Pyridostigmine is used in a wide dose range between 30 and 180 mg at dosing intervals between three and six hours, depending upon side effects and clinical response. Nausea, abdominal cramping, and diarrhea are adverse effects seen in approximately 5 to 10 percent of patients and can be major limiting factors, but they are dose dependent, being uncommon at low doses and common at high doses. Acetylcholinesterase inhibitors have no major systemic toxicities.
IMMUNOTHERAPY FOR REFRACTORY WEAKNESS — The presence of LEMS is synonymous with the presence of antibodies directed against voltage-gated calcium channels (see "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis", section on 'Pathophysiology'). In patients with significant weakness and a limited response to the symptomatic therapies outlined above, a reduction in this aberrant immune response is often central to successful treatment. Several different strategies have been employed, including a variety of oral agents and immunomodifying treatments.
Our approach to refractory weakness — For patients with LEMS without malignancy or with a treated malignancy who have moderate or severe weakness that interferes with function and does not improve sufficiently with symptomatic therapy, we start immunomodulatory treatment.
●For most patients with refractory LEMS, we suggest initial immunomodulatory treatment with intravenous immunoglobulin (IVIG) (algorithm 1). A typical course of IVIG is 2 g/kg total given over two to five days. (See 'Intravenous immune globulin' below.)
●For patients who do not respond to or tolerate IVIG, we use alternative immunomodulatory options. Prednisone may be as effective as IVIG, has the widest experience, and is cost-effective, but also has the greatest breadth of side effects. Azathioprine, mycophenolate mofetil, and cyclosporine are less toxic than prednisone for long-term use but may not be as effective.
•Our preferred alternative regimen to IVIG is to start prednisone (1 mg/kg per day, or 1 to 1.5 mg/kg every other day) and azathioprine (2 to 3 mg/kg per day) simultaneously, followed later by an attempt to taper or discontinue prednisone in order to reduce long-term prednisone toxicity. Unfortunately, this strategy may not be as successful in patients with LEMS as it is in patients with myasthenia gravis (MG) [31]. Some experts are reluctant to use oral immunosuppressive agents such as azathioprine in patients with cancer because of concerns that such treatment may exacerbate the malignancy. (See 'Prednisone' below and 'Other oral immunosuppressive agents' below.)
•Other reasonable choices include oral prednisone (1 mg/kg per day, or 1 to 1.5 mg/kg every other day) alone, azathioprine alone at 2 to 3 mg/kg per day, other oral immunosuppressives (cyclosporine and mycophenolate), or plasma exchange given as five or more exchanges (3 to 5 L of plasma each) over 7 to 14 days.
●Plasma exchange is more cumbersome than IVIG and is suggested for special circumstances such as IVIG intolerance or refractory disease in patients with a severe clinical course. (See 'Plasma exchange' below.)
●Rituximab can also be used for patients with disease that is refractory to the other agents listed above.
Intravenous immune globulin — IVIG therapy, a nonspecific immunomodulating therapy, has proven useful in a number of antibody-mediated diseases such as MG. A number of small studies conducted in the mid-1990s suggested benefit in LEMS as well, with both clinical improvement and a reduction in the voltage-gated calcium channel antibodies [26,32-37]. A course of IVIG (total dose of 2 g/kg over two to five days) is often effective, and maintenance therapy with repeat infusions at 4- to 12-week intervals is a reasonable strategy for patients with symptom recurrence who responded to initial IVIG treatment.
The only randomized trial of this therapy for LEMS involved nine patients who were treated in a crossover design with IVIG (1 g/kg per day for two days) or placebo [32]. There was significant improvement in serial measurements of limb, respiratory, and bulbar muscle strength associated with IVIG treatment, and a nonsignificant improvement in the resting compound muscle action potential (CMAP) amplitude.
The benefits of IVIG treatment seem to peak at approximately two to four weeks following the infusion (the half-life is roughly one month), followed by recurrent weakness over the subsequent weeks [32-36]. The use of maintenance IVIG for recurrent weakness has been both feasible and beneficial [33].
Overall, IVIG is well tolerated, but particular problems as well as several idiosyncratic reactions can be induced by the large volume of fluid required and by the increase in serum viscosity that occurs [38]. (See "Overview of intravenous immune globulin (IVIG) therapy".)
Numerous IVIG products are available with different relative toxicities based upon the formulation. Thus, a good working familiarity with these preparations is recommended, particularly when ordering treatment for patients who may be at higher risk of complications from IVIG. This category includes patients with renal insufficiency and a serum creatinine >1.5 mg/dL (>133 micromol/L), cerebrovascular disease, peripheral artery disease, cardiovascular disease, or advanced age.
Prednisone — There are no large-scale treatment trials to guide medication selection, but many smaller studies and case reports have commented upon the efficacy of prednisone alone [39] or combined with azathioprine or plasmapheresis [40-43]. Oral prednisone for LEMS is typically started at a dose of 1 mg/kg per day or 1 to 1.5 mg/kg every other day [39]. This dose is maintained until clinically significant improvement is evident, which may take several months. At that point, a slow tapering of the prednisone dose can begin. Glucocorticoid tapering should be individualized in patients with LEMS, based upon the clinical situation. A reasonable tapering regimen with either a daily or alternate-day glucocorticoid treatment program is to decrease the dose every two weeks by 10 mg/day until the dose is ≤20 mg/day, or ≤30 mg every other day, at which point the dose reduction is slowed to 5 mg/day every two weeks. With doses ≤7.5 mg/day, tapering is often further slowed to 2 to 2.5 mg/day every two weeks.
Attention to symptoms suggestive of adrenal insufficiency is important for patients who have been exposed to daily glucocorticoids for longer than three weeks, particularly those taking the dose equivalent of prednisone ≥10 mg/day. However, adrenal testing is seldom needed.
The risk of hypothalamic-pituitary-adrenal axis suppression and adrenal insufficiency due to glucocorticoid therapy and tapering is discussed in detail elsewhere. (See "Pharmacologic use of glucocorticoids" and "Clinical manifestations of adrenal insufficiency in adults".)
Other oral immunosuppressive agents — Azathioprine can be added as a glucocorticoid-sparing medication, typically starting at 50 mg twice a day, and increasing by 50 mg weekly up to a total dose of 2 to 3 mg/kg per day. Azathioprine is often given in divided doses to reduce gastrointestinal side effects, but it can be given as a single daily dose. The most common adverse effect with azathioprine is a reversible flu-like illness with fever, nausea, vomiting, and malaise. Less common serious adverse effects include infection, hepatotoxicity, and dose-related bone marrow suppression with leukopenia and/or thrombocytopenia. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
Mycophenolate mofetil may be substituted in patients who do not tolerate azathioprine [43]. The standard adult dose is 1000 mg twice a day on an empty stomach, but doses up to 1500 mg twice a day are occasionally used. Side effects are generally few with mycophenolate. The most common adverse side effects are gastrointestinal, mostly nausea or diarrhea. Leukopenia can also occur in some patients. All patients should have periodic surveillance laboratory monitoring including blood counts and trough mycophenolate levels for those taking higher doses.
Although efficacy has not been well documented, cyclosporine or the combination of IVIG and an oral immunosuppressive agent would be reasonable in patients with LEMS that is refractory to the more established agents [44]. Hypertension and nephrotoxicity are the most common limiting adverse effects of cyclosporine. Other adverse effects include tremor, nausea, gingival hyperplasia, myalgias and flu-like symptoms, and hypertrichosis. The risk of malignancy, primarily squamous cell skin cancer and lymphoma, may be increased with long-term use.
Rituximab — In retrospective case reports, treatment with intravenous rituximab was associated with improvement in a few patients with LEMS who had previously been treated with multiple other immunosuppressive therapies [45,46]. Rituximab is therefore reserved for patients with disease that is refractory to other immunosuppressive treatments.
Plasma exchange — Plasma exchange (plasmapheresis) is an attractive therapy for a putative antibody-mediated disorder, and benefit was noted in the early 1980s in several small case series [40-42,47]. However, patients with LEMS do not respond as rapidly to plasma exchange as do those with MG. In addition, the benefit of plasma exchange is only short term, due to continued production of the offending antibodies, and repeated treatment is necessary. Nevertheless, combined therapy with plasma exchange and oral immunosuppressive agents remains a beneficial approach for some refractory patients [41,47].
There are inadequate data to determine the best plasma exchange treatment protocol for LEMS. Five exchanges (3 to 5 L of plasma each) over 7 to 14 days is the typical course of treatment for MG, and this represents a reasonable protocol for patients with LEMS, given the pathogenic similarities between the two disorders. On the other hand, anecdotal evidence suggests that more than five exchanges may be necessary to achieve maximum improvement [42].
The utility of plasma exchange is limited for many patients by several factors, including the need for vascular access, the limited availability of the procedure in many geographic areas, and the high cost of treatment.
PROGNOSIS — The prognosis of LEMS differs between paraneoplastic and nonparaneoplastic LEMS.
Paraneoplastic LEMS — Survival is usually shortened in paraneoplastic LEMS due to progression of the underlying neoplasm, which is typically small cell lung cancer (SCLC). The most important prognostic factor in patients with SCLC is the extent of disease (stage) at presentation, as reviewed elsewhere. (See "Overview of the initial treatment and prognosis of lung cancer", section on 'SCLC'.)
There is good evidence that the presence of LEMS is associated with longer survival in patients with SCLC [3,48-51]. As an example, one report found that the median survival was longer for 31 patients with SCLC and LEMS compared with 279 patients who had SCLC without neurologic illness (18 versus 9.5 months; hazard ratio 1.8, 95% CI 1.1-2.7) [49]. The presence of LEMS was an independent predictor of prolonged survival. Among patients who have LEMS with malignancy, those with SCLC had a longer survival than patients with non-SCLC tumors (17 versus 7 months) [51].
With treatment of SCLC, limited evidence suggests that most patients with LEMS experience at least partial remission in the clinical symptoms of LEMS-related muscle weakness [52-54] and the associated electrophysiologic abnormalities [55]. However, weakness can persist after treatment of SCLC. (See "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management" and "Treatment of refractory and relapsed small cell lung cancer".)
Nonparaneoplastic LEMS — Limited data suggest that life expectancy in nonparaneoplastic LEMS is normal [51] or nearly normal [31]. However, a significant minority have physical limitations or are disabled. In a long-term study of 47 patients with LEMS who did not have SCLC, 10 patients died at a mean age of 70 years and after a median symptom duration of 11 years [31]. Most of the deaths were unrelated to LEMS, although two were possibly related to complications of glucocorticoid therapy.
Among 43 patients in the study treated with immunosuppression for over 1 year (median treatment duration 6 years; range 1.3 to 17 years), muscle strength scores were improved in 88 percent [31]. However, among survivors at last follow-up, approximately 30 percent required a wheelchair for mobility either at all times or for moving outside the house.
SUMMARY AND RECOMMENDATIONS
●Evaluation for malignancy – The aggressive search for and treatment of a primary underlying malignancy in patients with any risk factors for small cell lung cancer (SCLC) is central to the management of patients with Lambert-Eaton myasthenic syndrome (LEMS). (See 'Evaluation for malignancy' above.)
●Initial symptomatic therapy with amifampridine – For patients with LEMS with or without a malignancy who have weakness that interferes with function (algorithm 1), we suggest initial symptomatic therapy with amifampridine (Grade 2B). Amifampridine is the phosphate salt of 3,4-diaminopyridine (3,4-DAP) that is approved for use in some regions, including Europe and the United States; compounded 3,4-DAP base may be an option through compassionate use programs if amifampridine is unavailable. (See 'Amifampridine (3,4-diaminopyridine)' above.)
●Immunotherapy for refractory weakness
•IVIG – For patients with LEMS without malignancy or with a treated malignancy who have moderate or severe weakness that interferes with function and does not improve sufficiently with symptomatic therapy (algorithm 1), we suggest initial use of intravenous immune globulin (IVIG) at a dose of 2 g/kg total over two to five days, rather than oral immunosuppressive drugs or plasma exchange (Grade 2C). (See 'Intravenous immune globulin' above.)
For patients with symptom recurrence who respond to initial IVIG treatment, we suggest maintenance therapy with repeat IVIG infusions at 4- to 12-week intervals determined by symptomatic need.
•Alternative and adjunctive options – Our preferred alternative regimen to IVIG is to simultaneously start oral prednisone, 1 mg/kg per day or 1 to 1.5 mg/kg every other day, and azathioprine 2 to 3 mg/kg per day, followed later by an attempt to taper or discontinue prednisone. (See 'Our approach to refractory weakness' above.)
Other reasonable choices would be oral prednisone (1 mg/kg per day or 1 to 1.5 mg/kg every other day) alone, azathioprine alone at 2 to 3 mg/kg per day, other oral immunosuppressives (cyclosporine and mycophenolate), or plasma exchange given as five or more exchanges (3 to 5 L of plasma each) over 7 to 14 days. (See 'Prednisone' above and 'Other oral immunosuppressive agents' above and 'Plasma exchange' above.)
●Prognosis – Survival is usually shortened in paraneoplastic LEMS due to progression of the underlying neoplasm, which is typically SCLC. The most important prognostic factor in patients with SCLC is the extent of disease (stage) at presentation. Limited data suggest that life expectancy in nonparaneoplastic LEMS is normal or nearly normal, but a significant minority are disabled. (See 'Prognosis' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
