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 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.
This topic will review the pathophysiology, clinical features, and diagnosis of LEMS. Treatment and prognosis of LEMS are discussed separately. (See "Lambert-Eaton myasthenic syndrome: Treatment and prognosis".)
PATHOPHYSIOLOGY — LEMS is a disorder of reduced acetylcholine (ACh) release from the presynaptic nerve terminals, despite normal ACh vesicle number, normal ACh presynaptic concentration, and normal postsynaptic ACh receptors. Lambert and Elmqvist, through a series of elegant intracellular muscle recordings, found that patients with what is now called LEMS had the following unique features [1,2]:
●Normal miniature endplate potential amplitude, demonstrating normal postsynaptic sensitivity to ACh
●Markedly reduced evoked endplate potential amplitude, suggesting a significant reduction in ACh release
ACh release was increased by increasing calcium concentrations but not by potassium-induced membrane depolarization. The identification of normal presynaptic ACh content further supported the concept that LEMS is a disorder of reduced ACh release from the presynaptic nerve terminals .
The mechanism of LEMS is autoimmunity, with the development of antibodies directed against the voltage-gated calcium channel (VGCC).
Autoimmunity — Several lines of evidence support a humoral mechanism of disease in LEMS:
●Passive transfer experiments successfully induced calcium channel dysfunction in mice exposed to plasma or immunoglobulin G (IgG) from patients with LEMS. This calcium channel blockade could be overcome with high-frequency repetitive nerve stimulation (RNS) [4-7].
●Such antibody exposure in mice induced presynaptic neuromuscular junction morphologic changes similar to those seen in patients with LEMS.
●Removal of antibodies utilizing therapeutic plasma exchange and immunosuppressant agents in patients with LEMS has consistently improved both the clinical deficits and the electrophysiologic disease markers [4,8-10].
Voltage-gated calcium channel — Antibodies directed against the VGCC, a large transmembrane protein with multiple subunits, play a central role in the pathophysiology of LEMS. These antibodies interfere with the normal calcium flux required for the release of ACh .
The alpha-1 subunit of the VGCC contains a central calcium-conducting channel, a voltage sensor, and ligand binding sites. There are many subtypes of mammalian VGCCs, each characterized by the ligand binding characteristics of the alpha-1 subunit. Among these, the L-type, N-type, and P/Q-type VGCC are the most important.
P/Q-type VGCCs make up more than 95 percent of the functioning receptors at the neuromuscular junction and probably represent the main immunologic target in LEMS [12,13].
Paraneoplastic LEMS — The expression of functional VGCCs in the surface membrane of small cell lung cancer (SCLC) cells (among numerous other neural antigens) is probably responsible for most if not all cases of paraneoplastic LEMS . Antibodies from patients with LEMS inhibit the function of the VGCCs in the surface of SCLC cells in a dose-dependent fashion, further supporting the relationship . (See "Pathobiology and staging of small cell carcinoma of the lung".)
Nonparaneoplastic LEMS — The specific trigger inducing the development of VGCC antibodies in nonparaneoplastic LEMS is unknown . However, nonparaneoplastic LEMS is associated with underlying immune-mediated diseases [17,18]. One study found that autoimmune disorders, such as type 1 diabetes mellitus or thyroid disorders, occurred in 27 percent of LEMS patients without cancer and 11 percent of those with LEMS and SCLC . Families of patients with nonparaneoplastic LEMS had an increased frequency of autoimmune diseases, with affected family members linked through the maternal line; by contrast, families of patients with paraneoplastic LEMS had no increased frequency of autoimmune diseases. In another study, patients with nonparaneoplastic LEMS had an increased incidence of organ-specific autoantibodies to thyroid, gastric, and/or skeletal muscle compared with controls .
Toxic LEMS — The use of immune checkpoint inhibitor (ICI) therapy for malignancies has led to the recognition of immune-related adverse events (irAEs) affecting many different organs. Several neuromuscular irAEs have been reported, including myositis, myasthenia gravis, and neuropathies . In addition, case studies have identified an association between ICI therapy and LEMS , but it is not yet known if there is a causal relationship . If LEMS develops during ICI therapy, the medication is typically discontinued, and other treatment considerations are pursued. (See "Toxicities associated with immune checkpoint inhibitors".)
EPIDEMIOLOGY — The true incidence of LEMS is unknown, but the condition is uncommon and occurs much less frequently than myasthenia gravis, the other major disorder of neuromuscular junction transmission. In a population-based study from a region of Holland with 1.7 million inhabitants, 220 cases of myasthenia gravis and 10 of LEMS were identified over a nine-year period; the annual incidence and prevalence of LEMS were 0.5 and 2.3 per million population . A similar prevalence for confirmed cases of LEMS (2.6 per million) was reported in a later population-based study of 12.5 million patients in the United States Veterans Affairs health system .
Most cases of LEMS occur among middle-aged adults, but LEMS can affect younger and older adults, and rare cases have been reported in children . However, the age of LEMS onset is earlier in patients without cancer (nonparaneoplastic LEMS) compared with those with cancer (paraneoplastic LEMS) .
Approximately one-half of LEMS cases are associated with a malignancy, mainly small cell lung cancer (SCLC), and less often with lymphoproliferative disorders. (See "Lambert-Eaton myasthenic syndrome: Treatment and prognosis", section on 'Evaluation for malignancy'.)
The incidence and prevalence of LEMS in patients with SCLC are estimated to be approximately 3 percent [27,28].
CLINICAL FEATURES — Most patients with LEMS present with complaints of slowly progressive proximal muscle weakness, and this feature is present in almost all patients at some point in the illness [29,30]. Occasional patients have a subacute or acute presentation. The clinical signs of LEMS parallel the symptoms.
Most often, LEMS has a pattern more suggestive of a myopathy than a neuromuscular junction disorder, with slowly progressive proximal lower extremity weakness, distinctive autonomic findings, a smattering of oculobulbar findings, and recovery of lost deep tendon reflexes or improvement in muscle strength with vigorous, brief muscle activation.
The paraneoplastic and nonparaneoplastic forms of LEMS have similar signs and symptoms . However, those with an underlying malignancy may experience more rapid progression of neurologic symptoms than those without cancer [26,31].
Some patients have combined paraneoplastic cerebellar degeneration and LEMS . In a series of Japanese patients with LEMS, 9 of 65 patients (14 percent) with small cell lung cancer (SCLC) had appendicular ataxia, probably from associated paraneoplastic cerebellar degeneration . All nine patients had high titers of voltage-gated calcium channel (VGCC) antibodies compared with none of the 45 patients without cancer. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic cerebellar degeneration".)
Muscle weakness — Patients typically describe an alteration in gait or difficulty arising from a chair or managing stairs caused by proximal leg weakness. Upper extremity complaints are usually modest and typically involve proximal muscle function. Many describe aching or stiff muscles. Muscle fatigability or cramping is common, particularly after protracted exercise.
Proximal limb weakness without significant muscle atrophy is the most frequent finding. The degree of weakness is often less than the functional difficulty would lead one to expect, a discrepancy that sometimes leads to a misdiagnosis of functional neurological symptom disorder (conversion disorder). There tends to be relative preservation of distal muscle function. Deep tendon reflexes are almost always depressed or absent. Ptosis is the most common cranial nerve finding in LEMS; extraocular, pharyngeal, tongue, and neck muscles are less often affected. (See 'Ptosis and cranial nerve involvement' below.)
Compared with patients who have nonparaneoplastic LEMS, patients with paraneoplastic LEMS and SCLC typically have a more rapidly progressive course with a greater degree of weakness involving proximal and distal arm muscles and distal leg muscles .
Symmetric muscle involvement is the most common pattern in LEMS. However, there are observations of patients presenting with regional weakness (eg, weakness in one area only, such as the proximal legs alone, or weakness isolated to limb, ocular, oropharyngeal, or respiratory muscles) [34-36].
Postexercise facilitation — Recovery of lost deep tendon reflexes or improvement in muscle strength with vigorous, brief muscle activation is a unique aspect of LEMS. Maximal isometric contraction of the relevant muscle for 10 to 15 seconds can sometimes lead to temporary reappearance of previously depressed or absent deep tendon reflexes, and to temporary improvement of muscle weakness. This phenomenon, referred to as postexercise or postactivation facilitation, is often the defining bedside clinical observation and should be part of the routine examination of a patient with proximal muscle weakness or even complaints of weakness, especially when hyporeflexia or areflexia are conjoined. Postexercise or postactivation facilitation are also applied to an increase in compound muscle action potential (CMAP) amplitude that may be seen with repetitive nerve stimulation (RNS) or brief exercise in patients with LEMS. (See 'Electrodiagnostic studies' below.)
Because of possible facilitation after exercise, reflexes and muscle power testing are best performed after a period of rest. More sustained physical activity can often induce muscle weakness (fatigable weakness). At times, this pattern can appear to represent an inconsistent effort on the part of the patient.
Ptosis and cranial nerve involvement — Cranial nerve involvement is present in some patients with LEMS but is typically less severe and less striking than that seen in myasthenia gravis. Ocular symptoms, particularly ptosis and diplopia, are the most common cranial nerve manifestation with LEMS . Excessive or paradoxical eyelid elevation may occur after sustained upgaze in patients with LEMS .
Initial eye muscle weakness is uncommon in LEMS [39,40], but patients with LEMS can develop prominent ocular or oropharyngeal manifestations during the course of their illness. One retrospective report found initial extraocular muscle weakness occurred in none of the 38 patients with LEMS . In another retrospective series of 23 patients with LEMS, the presenting symptoms were ptosis, diplopia, dysarthria, or dysphagia in seven (30 percent) . During the course of LEMS, ptosis and/or diplopia were noted in 15 patients (65 percent), and dysphagia and/or dysarthria in 12 (52 percent).
Autonomic dysfunction — Autonomic dysfunction is often present in patients with LEMS and can be an important clue to the diagnosis, though it is rarely a defining feature. Dry mouth from reduced salivation is the most common autonomic symptom and is occasionally the presenting complaint . Symmetric, sluggish pupillary light responses are also common, as is erectile dysfunction in men with LEMS. In a study of autonomic dysfunction in LEMS involving 30 patients, dry mouth was identified in 77 percent of patients, and impotence was present in 45 percent of men . Abnormalities were found in tests of sudomotor function (83 percent), cardiovagal reflexes (75 percent), salivation (44 percent), and adrenergic function (37 percent). Other autonomic symptoms may include blurred vision and constipation.
Respiratory failure — Although most patients with LEMS do not have significant diaphragmatic involvement, particularly in the early stages of the illness, respiratory failure can occur late in the course [44-47]. Thus, LEMS must be considered in the differential diagnosis of patients presenting with neuromuscular respiratory failure.
Even in patients without respiratory symptoms, detailed investigations into respiratory muscle function with transdiaphragmatic pressure recording, sustained inspiratory force measurements, and phrenic nerve stimulation may reveal mild to moderate respiratory weakness .
EVALUATION AND DIAGNOSIS — The diagnosis of LEMS deserves careful consideration for any patient who presents with proximal muscle weakness. The collection of limb weakness, dry mouth, hyporeflexia, and any combination of oropharyngeal muscle weakness or ptosis should strongly suggest the diagnosis. A significant degree of clinical suspicion is necessary to recognize the atypical patient with LEMS, such as those who present with isolated respiratory insufficiency or regional weakness isolated to limb, ocular, or oropharyngeal muscles.
Confirming the diagnosis — Patients with suspected LEMS should have electrodiagnostic studies, including repetitive nerve stimulation (RNS), and anti-P/Q-type voltage-gated calcium channel (VGCC) antibody testing to confirm the diagnosis.
The diagnosis of LEMS is confirmed on high-frequency RNS by a reproducible postexercise increase in compound muscle action potential (CMAP) amplitude of at least 100 percent compared with pre-exercise baseline value (see 'Repetitive nerve stimulation and exercise testing' below). A high titer P/Q-type VGCC antibody result is strongly suggestive of LEMS in the appropriate clinical setting (see 'VGCC antibody testing' below). However, P/Q-type VGCC antibodies are present in a variety of clinical situations where LEMS is not present. If these studies are not definitive, single-fiber electromyography (SFEMG) can be diagnostic for a neuromuscular junction disorder but is less specific for LEMS than the above studies. (See 'Single-fiber electromyography' below.)
Electrodiagnostic studies — The electrodiagnostic evaluation of suspected LEMS typically involves the following elements :
●Routine motor and sensory nerve conduction studies (NCS)
●High-frequency RNS and/or exercise testing
●Needle electromyography (EMG)
●SFEMG for selected patients only
All patients suspected of LEMS require a routine set of NCS and a conventional EMG in addition to either a postexercise motor nerve test or a high-frequency RNS test. SFEMG is reserved for the occasional patient where the diagnosis remains in doubt following these more conventional procedures. SFEMG is very sensitive for a neuromuscular junction disorder but not as specific for a presynaptic localization.
Motor and sensory nerve conduction studies — The CMAP of resting muscle in patients with LEMS usually has a significantly reduced baseline amplitude . In fact, the presence of unexpectedly low motor amplitudes, especially with normal sensory amplitudes, should suggest the possibility of a presynaptic neuromuscular junction disorder. At times, excessive variability in maximum CMAP amplitude from stimulus to stimulus should be a hint to consider LEMS as well. In patients with LEMS, distal latencies and conduction velocities are normal.
Occasionally, an electrophysiologist makes the diagnosis of LEMS when it was not suspected clinically on the basis of isolated low CMAP amplitudes. For patients with low or borderline-low CMAP amplitudes at rest, repeating the motor nerve conduction distal motor stimulation after 10 seconds of maximal exercise is recommended to look for postexercise facilitation of the CMAP amplitude, which is a characteristic finding in LEMS .
Repetitive nerve stimulation and exercise testing — During high-frequency (10 to 50 Hz) RNS (waveform 1) or after brief (eg, 10 seconds) maximal isometric muscle activation (waveform 2), patients with LEMS typically have a significant increment with a marked increase in the CMAP amplitude. The increase in the CMAP amplitude with high-frequency stimulation is referred to as postactivation facilitation, and the increase in CMAP amplitude after brief isometric exercise (compared with the baseline pre-exercise CMAP amplitude) is called postexercise facilitation.
An increase in the CMAP amplitude >100 percent after exercise or with high-frequency RNS is considered diagnostic of a presynaptic neuromuscular junction disorder [50,51], and the increase is frequently even greater. However, some studies have found that a significant number of patients have increments with RNS below 100 percent [52-54]; thus, increments of 60 to 99 percent are strongly supportive of a presynaptic neuromuscular junction disorder. One study of 156 patients undergoing evaluation for LEMS showed an increased electrodiagnostic sensitivity of 78 percent compared with 59 percent without loss of specificity when using an incremental threshold of 60 percent .
The high-frequency RNS test may be more sensitive than the postexercise facilitation test for the diagnosis of LEMS, but evidence is equivocal, and the high-frequency RNS test is painful [54,56,57]. Most experts favor using the 10 second exercise test first because it is simple and better tolerated . However, when there is a strong level of clinical suspicion for LEMS, the high-frequency RNS test is indicated for patients who do not show a diagnostic incremental increase in CMAP amplitude after the exercise test. It is also indicated for those unable to cooperate with intense voluntary muscle activation.
Needle electromyography — Needle EMG is usually normal in LEMS . However, in some cases the motor unit action potentials are unstable, and uncommonly they can be small (low amplitude), polyphasic, and short in duration, mimicking a myopathy .
Single-fiber electromyography — SFEMG in LEMS often shows significant jitter and transmission blocking that is characteristically improved at higher firing rates [60-62]. SFEMG is more sensitive than RNS for the diagnosis of neuromuscular junction disorders but is less specific and cannot definitively distinguish between LEMS and myasthenia gravis. SFEMG is also less widely available than RNS, which is therefore the preferred initial test [50,51]. However, when RNS is normal in patients with a high suspicion of a neuromuscular junction disorder, SFEMG of at least one symptomatic muscle should be performed and, if one muscle is normal, a second muscle can be studied. (See "Electrodiagnostic evaluation of the neuromuscular junction", section on 'Single-fiber electromyography'.)
VGCC antibody testing — Antibodies against the P/Q-type VGCC are present in approximately 85 to 95 percent of patients with LEMS [11,33,63], and radioimmunoassay for these antibodies is the preferred serologic test. While the anti-P/Q-type VGCC antibody test is confirmatory in patients who otherwise have clinical and electrophysiologic features of LEMS, the antibody test alone is not diagnostic, especially in the presence of a malignancy or amyotrophic lateral sclerosis.
There is a low frequency of P/Q-type VGCC antibodies in healthy control patients, in patients with myasthenia gravis, and in patients with other autoimmune diseases, confirming the high specificity of the test when there is a high pretest probability of LEMS . However, low titer VGCC antibodies have been detected in several groups of patients, including those with other neurologic paraneoplastic disorders, those who have cancer without neurologic signs or symptoms, and those with amyotrophic lateral sclerosis.
Test performance was evaluated in a series of 65 patients with LEMS . High titer anti-P/Q-type VGCC antibodies were present in 62 patients (95 percent), including all 32 with a diagnosis of cancer. Lower titer anti-P/Q-type and anti-N-type VGCC antibodies were also present in 38 of 70 patients (54 percent) who had lung, ovarian, or breast carcinoma and paraneoplastic complications other than LEMS; in 22 of 90 patients (24 percent) who had cancer without overt neurologic complications; in 18 of 78 patients (23 percent) who had sporadic amyotrophic lateral sclerosis; and in 2 of 69 patients (3 percent) who had myasthenia gravis, epilepsy, or scleroderma.
While P/Q-type VGCC antibodies are specific for LEMS, there is no established clinical utility for other VGCC antibodies that are sometimes associated with LEMS. Antibodies to the N-type VGCC are found in approximately 30 to 40 percent of patients with LEMS, and there is some evidence to suggest that the presence of these antibodies increases the likelihood of small cell lung cancer (SCLC). Furthermore, one study raised the possibility that antibodies directed against domain IV of the alpha-1 subunit of P/Q-type VGCC are more common in the nontumor LEMS cases . More data are needed to determine if this will be a clinically useful observation.
Evaluation for malignancy — The aggressive search for a primary underlying malignancy is central to the management of patients with LEMS; SCLC is the most common associated tumor in patients with LEMS. This issue is discussed in detail separately. (See "Lambert-Eaton myasthenic syndrome: Treatment and prognosis", section on 'Evaluation for malignancy'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of LEMS varies by symptom presentation. Conditions that present with progressive muscle weakness are most commonly implicated, particularly myasthenia gravis, inflammatory muscle disease, limb-girdle muscular dystrophy (LGMD), and motor neuron disease. (See 'Progressive muscle weakness' below.)
Progressive muscle weakness
●Myasthenia gravis – LEMS has distinct differences from the symptoms and signs seen with myasthenia gravis, which is the most common clinical disorder of neuromuscular junction transmission. LEMS usually presents with slowly progressive proximal leg weakness and difficulty walking, while ocular and bulbar muscles are typically less prominently involved. Myasthenia gravis characteristically presents with fluctuating ocular or bulbar weakness and less often with constant and progressive skeletal muscle weakness. (See "Clinical manifestations of myasthenia gravis", section on 'Clinical features' and "Differential diagnosis of myasthenia gravis", section on 'Lambert-Eaton myasthenic syndrome'.)
A study comparing the clinical features of 38 patients with LEMS and 101 patients with myasthenia gravis confirmed the marked contrast in their presentations :
•Initial limb weakness occurred in 95 percent of patients with LEMS compared with 12 percent of patients with myasthenia gravis.
•Initial extraocular muscle weakness occurred in none of the patients with LEMS compared with 59 percent of patients with myasthenia gravis.
•Both groups infrequently presented with oropharyngeal muscle weakness (5 and 12 percent for LEMS and myasthenia gravis, respectively).
At the point of maximum severity, no patient with LEMS had weakness restricted to extraocular muscles, oropharyngeal muscles, or arms. All patients with LEMS had leg weakness. By contrast, weakness in patients with myasthenia gravis was purely ocular in 25 percent, purely ocular and oropharyngeal in 5 percent, and restricted to the arms as the only limb manifestation in 12 percent. These findings suggest that LEMS is unlikely in patients with limb weakness confined to the arms .
Of note, patients with LEMS usually have significant symptoms and abnormalities on electrodiagnostic studies that can be out of proportion to the less pronounced weakness found on examination, while patients with myasthenia gravis usually have rather significant weakness and fatigability in contrast to modest abnormalities on electrodiagnostic studies [65,66].
At the bedside, pronounced eyelid elevation may occur after sustained upgaze in patients with LEMS . This finding is in contradistinction to the fatigable ptosis commonly seen in patients with myasthenia gravis during the same maneuver. The ice pack test can also be useful to support the diagnosis of myasthenia gravis, but the diagnosis is typically confirmed by immunologic and/or electrodiagnostic studies. The diagnosis of myasthenia gravis is discussed in detail separately. (See "Clinical manifestations of myasthenia gravis" and "Diagnosis of myasthenia gravis".)
The coexistence of LEMS and myasthenia gravis was first reported in two patients who were seropositive for both voltage-gated calcium channel (VGCC) antibodies and acetylcholine receptor (AChR) antibodies . Subsequent data suggest that only rare patients have the clinical, immunologic, and electrophysiologic features of both disorders .
●Inflammatory muscle disease – The most common clinical presentation of LEMS, that of slowly progressive, symmetric proximal muscle weakness, can suggest inflammatory muscle disease, including polymyositis, dermatomyositis, or inclusion body myositis. However, deep tendon reflexes are preserved in myopathies, but absent in LEMS unless activated by exercise. Myalgias are common with myopathies, and patients with dermatomyositis may also have associated skin findings. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Clinical manifestations and diagnosis of inclusion body myositis".)
●Limb-girdle muscular dystrophy (LGMD) – Patients with LGMD typically present with proximal weakness. Weakness in LGMD may also be accompanied by muscle atrophy, an uncommon feature in LEMS. Electromyography shows myopathic changes in LGMD but is typically normal in LEMS. (See "Limb-girdle muscular dystrophy".)
●Motor neuron disease – Motor neuron disease (eg, amyotrophic lateral sclerosis), a motor neuropathy, myasthenia gravis, or a myelopathy are less likely alternatives. These conditions can be distinguished from LEMS on clinical and electrodiagnostic grounds:
•Amyotrophic lateral sclerosis typically presents with asymmetric limb weakness or bulbar weakness with dysarthria or dysphagia, usually with a combination of upper motor neuron and lower motor neuron symptoms and signs. The electrodiagnostic findings in amyotrophic lateral sclerosis combine features of acute and chronic denervation and reinnervation, which are not present in LEMS. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
•Multifocal motor neuropathy typically presents with the subacute onset of progressive asymmetric arm and hand weakness and lower motor neuron signs. There are no upper motor neuron signs, and no bulbar involvement or sensory loss. The neuronal involvement is most often patchy, with some nerves unaffected and others severely involved. Motor nerve conduction studies (NCS) usually show evidence of focal demyelination and conduction block. Sensory conduction through the same segment of nerve is normal. Elevated titers of anti-GM1 antibodies are present in 30 to 80 percent of patients. (See "Multifocal motor neuropathy".)
●Peripheral nerve disorders – Several peripheral nerve disorders such as polyneuropathy or polyradiculopathy may present with diffuse or multifocal weakness, similar to weakness in LEMS. However, these conditions do not feature postexercise facilitation. In addition, the sensory components seen with polyneuropathy or polyradiculopathy clearly distinguish those disorders from LEMS in most cases. (See "Overview of polyneuropathy" and "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes".)
Neurologic manifestations of Sjögren's disease are protean and may include muscle weakness. Dry mouth may suggest Sjögren's disease when it is a prominent symptom early in the course of LEMS. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)
Cranial nerve deficits — When cranial nerve abnormalities are present or prominent, the main consideration in the differential diagnosis of LEMS is myasthenia gravis (see 'Progressive muscle weakness' above). Multiple cranial mononeuropathies or at times a meningeal-based disease also need to be considered, but the pure motor nature of LEMS makes these distinctions fairly clear.
Respiratory failure — Isolated respiratory failure is an uncommon or late-appearing feature in LEMS, typically associated with other neurologic symptoms. For the unusual presentation of fairly isolated respiratory failure, the differential diagnosis includes:
●Motor neuron disease (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
●Myasthenia gravis (See "Clinical manifestations of myasthenia gravis".)
●Acid maltase deficiency (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)".)
●Polymyositis (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
SUMMARY AND RECOMMENDATIONS
●Definition and pathophysiology – Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon disorder of neuromuscular junction transmission in which the primary clinical manifestation is muscle weakness. (See 'Introduction' above and 'Pathophysiology' above.)
•Antibodies directed against the voltage-gated calcium channel (VGCC) interfere with the normal calcium flux and reduce acetylcholine release from the presynaptic nerve terminals.
•The autoimmunity in LEMS may be paraneoplastic, occurring mainly in patients with small cell lung cancer (SCLC), or nonparaneoplastic, occurring typically in those with underlying immune-mediated conditions or receiving immunosuppression therapies.
●Epidemiology – The incidence of LEMS is unknown, but the condition is rare. Most cases of LEMS occur among middle-aged adults, but LEMS can affect younger and older adults, and rare cases have been reported in children. (See 'Epidemiology' above.)
Approximately one-half of LEMS cases are associated with a malignancy, mainly SCLC. The age of LEMS onset is earlier in patients with nonparaneoplastic LEMS compared with those with cancer (paraneoplastic LEMS).
●Clinical features – Most patients with LEMS present with slowly progressive proximal muscle weakness, particularly involving the legs. Deep tendon reflexes are typically depressed or absent. Ocular symptoms, especially ptosis and diplopia, or bulbar muscle weakness may occur with LEMS but are rarely the presenting or dominant feature of the illness. Most patients do not have significant respiratory muscle weakness, but respiratory failure may occur late in the course. (See 'Clinical features' above.)
Recovery of lost deep tendon reflexes or improvement in muscle strength with vigorous, brief muscle activation is a unique aspect of LEMS.
●Diagnosis – The diagnosis of LEMS is usually made clinically. Confirmatory evidence on electrodiagnostic studies includes a reproducible postexercise increase in compound muscle action potential amplitude of at least 60 percent compared with pre-exercise baseline value or a similar increment on high-frequency repetitive nerve stimulation without exercise. A high titer P/Q-type VGCC antibody is also strongly suggestive of LEMS in the appropriate clinical setting. (See 'Evaluation and diagnosis' above.)
●Differential diagnosis – The differential diagnosis of LEMS typically includes conditions that present with progressive muscle weakness, particularly myasthenia gravis, inflammatory muscle disease, limb-girdle muscular dystrophy, and motor neuron disease. (See 'Differential diagnosis' above.)
For patients who present with prominent cranial nerve deficits, myasthenia gravis, multiple cranial mononeuropathies, and meningeal-based disease should be considered. Isolated respiratory failure may also be due to conditions such as motor neuron disease, myasthenia gravis, acid maltase deficiency, or polymyositis.
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