Editing Lambert–Eaton myasthenic syndrome

{{Short description|Autoimmune disorder causing muscular weakness}}
{{good article}}
{{Infobox medical condition (new)
| name = Lambert–Eaton myasthenic syndrome
| synonyms = Lambert–Eaton syndrome, Eaton–Lambert syndrome, myasthenic syndrome, carcinomatous myopathy, cancer LEMS
| image = Synapse diag4.png
| caption = Neuromuscular junction. Lambert–Eaton myasthenic syndrome is caused by autoantibodies to the presynaptic membrane. Myasthenia gravis is caused by autoantibodies to the postsynaptic acetylcholine receptors. {{ordered list |style=text-align: left;
    |1=[[Presynaptic]] terminal
    |2=[[Sarcolemma]]
    |3=[[Synaptic vesicle]]
    |4=[[Nicotinic acetylcholine receptor]]
    |5=[[Mitochondrion]]
    }}
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| onset = 
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| frequency = 3.4 per million people<ref name=Titulaer/>
| deaths = 
}}
<!-- Definition and symptoms -->

'''Lambert–Eaton myasthenic syndrome''' ('''LEMS''') is a rare [[autoimmune]] disorder characterized by [[weakness|muscle weakness]] of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy.<ref>{{Cite web |title=vocabulary.com - myasthenic syndrome |url=https://www.vocabulary.com/dictionary/myasthenic%20syndrome}}</ref> 

<!-- Cause and diagnosis -->
Around 60% of those with LEMS have an underlying [[cancer|malignancy]], most commonly [[small cell carcinoma|small-cell lung cancer]] (SCLC); it is therefore regarded as a [[paraneoplastic syndrome]] (a condition that arises as a result of cancer elsewhere in the body).<ref name=Verschuuren/> It is the result of [[antibody|antibodies]] against presynaptic [[Voltage-dependent calcium channel|voltage-gated calcium channels]], and likely other nerve terminal proteins, in the [[neuromuscular junction]] (the connection between [[nerve]]s and the [[muscle]] that they supply).<ref name=Mareska/> The diagnosis is usually confirmed with [[electromyography]] and [[blood test]]s; these also distinguish it from [[myasthenia gravis]], a related autoimmune neuromuscular disease.<ref name=Mareska/>

<!-- Treatment -->
If the disease is associated with cancer, direct treatment of the cancer often relieves the symptoms of LEMS. Other treatments often used are [[glucocorticoid|steroids]], [[azathioprine]], which suppress the immune system, [[intravenous immunoglobulin]], which outcompetes autoreactive antibody for Fc receptors, and [[pyridostigmine]] and [[3,4-Diaminopyridine|3,4-diaminopyridine]], which enhance the neuromuscular transmission. Occasionally, [[Plasmapheresis|plasma exchange]] is required to remove the antibodies.<ref name=Mareska/>

<!-- Epidemiology and history -->
The condition affects about 3.4 per million people.<ref name=Titulaer>{{cite journal |vauthors=Titulaer MJ, Lang B, Verschuuren JJ |title=Lambert–Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies |journal=Lancet Neurol |volume=10 |issue=12 |pages=1098–107 |date=December 2011 |pmid=22094130 |doi=10.1016/S1474-4422(11)70245-9|s2cid=27421424 }}</ref> LEMS usually occurs in people over 40 years of age, but may occur at any age.

==Signs and symptoms==
The weakness from LEMS typically involves the muscles of the proximal arms and legs (the muscles closer to the trunk). In contrast to [[myasthenia gravis]], the weakness affects the legs more than the arms. This leads to difficulties climbing stairs and rising from a sitting position. Weakness is often relieved temporarily after exertion or [[physical exercise]]. High temperatures can worsen the symptoms. Weakness of the [[Corticobulbar tract|bulbar muscles]] (muscles of the mouth and throat) is occasionally encountered.<ref name=Mareska/> Weakness of the [[Muscles of orbit|eye muscles]] is uncommon. Some may have [[diplopia|double vision]], [[Ptosis (eyelid)|drooping of the eyelids]] and [[dysphagia|difficulty swallowing]],<ref name=Mareska/> but generally only together with leg weakness; this too distinguishes LEMS from myasthenia gravis, in which eye signs are much more common.<ref name=Verschuuren>{{cite journal |vauthors=Verschuuren JJ, Wirtz PW, Titulaer MJ, Willems LN, van Gerven J |title=Available treatment options for the management of Lambert–Eaton myasthenic syndrome |journal=Expert Opin. Pharmacother. |volume=7 |issue=10 |pages=1323–36 |date=July 2006 |pmid=16805718 |doi=10.1517/14656566.7.10.1323|s2cid=31331519 }}</ref> In the advanced stages of the disease, weakness of the [[Muscles of respiration|respiratory muscles]] may occur.<ref name=Mareska>{{cite journal |vauthors=Mareska M, Gutmann L |title=Lambert–Eaton myasthenic syndrome |journal=Semin. Neurol. |volume=24 |issue=2 |pages=149–53 |date=June 2004 |pmid=15257511 |doi=10.1055/s-2004-830900|s2cid=19329757 }}</ref> Some may also experience problems with [[motor coordination|coordination]] ([[ataxia]]).<ref name=Rees>{{cite journal |author=Rees JH |title=Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage |journal=J. Neurol. Neurosurg. Psychiatry |volume=75 |issue= Suppl 2|pages=ii43–50 |date=June 2004 |pmid=15146039 |pmc=1765657 |doi=10.1136/jnnp.2004.040378}}</ref>

Three-quarters of people with LEMS also have disruption of the [[autonomic nervous system]]. This may be experienced as a [[xerostomia|dry mouth]], [[constipation]], [[blurred vision]], impaired [[perspiration|sweating]], and [[orthostatic hypotension]] (falls in blood pressure on standing, potentially leading to [[Syncope (medicine)|blackouts]]). Some report a metallic taste in the mouth.<ref name=Mareska/>

Along with a medical history and physical examination by a neuromuscular physician, a Voltage-gated calcium channels (VGCCs) antibody test and Electromyography (EMG) test can obtain a diagnosis of LEMs. However, positive VGCC antibody tests may indicate other diseases. Strength improves further with repeated testing, e.g. improvement of power on repeated hand grip (a phenomenon known as "[[Lambert's sign]]"). At rest, [[reflex]]es are typically reduced; with muscle use, reflex strength increases. This is a characteristic feature of LEMS. The [[pupillary light reflex]] may be sluggish.<ref name=Mareska/>

In LEMS associated with small cell lung cancer, most have no suggestive symptoms of cancer at the time, such as [[cough]], [[hemoptysis|coughing blood]], and [[Weight loss#Unintentional weight loss|unintentional weight loss]]. However, LEMS symptoms can occur up to 5 years prior to cancer diagnosis and also after cancer diagnosis.<ref name=Verschuuren/>  LEMS associated with lung cancer may be more severe.<ref name=Rees/>

==Causes==
LEMS is often associated with lung cancer (50–70%), specifically [[small-cell carcinoma]],<ref name=Mareska/> making LEMS a paraneoplastic syndrome.<ref name=Rees/> Of the people with small-cell lung cancer, 1–3% have LEMS.<ref name=Verschuuren/> In most of these cases, LEMS is the first symptom of the lung cancer, and it is otherwise [[asymptomatic]].<ref name=Verschuuren/>

LEMS may also be associated with [[endocrine disease]]s, such as [[hypothyroidism]] (an underactive [[thyroid gland]]) or [[diabetes mellitus type 1]].<ref name=Mareska/><ref name=Takamori/> [[Myasthenia gravis]], too, may happen in the presence of tumors ([[thymoma]], a tumor of the [[thymus]] in the chest); people with MG without a tumor and people with LEMS without a tumor have similar genetic variations that seem to predispose them to these diseases.<ref name=Verschuuren/> [[HLA-DR3]]-[[HLA-B8|B8]] (an [[human leukocyte antigen|HLA]] subtype), in particular, seems to predispose to LEMS.<ref name=Takamori/>

==Mechanism==

=== Normal physiology ===
In normal neuromuscular function, a [[Action potential|nerve impulse]] is carried down the [[axon]] (the long projection of a [[neuron|nerve cell]]) from the [[spinal cord]]. At the nerve ending in the [[neuromuscular junction]], where the impulse is transferred to the muscle cell, the nerve impulse leads to the opening of [[voltage-gated calcium channels]] (VGCC), the influx of calcium ions into the nerve terminal, and the calcium-dependent triggering of synaptic vesicle fusion with plasma membrane. These synaptic vesicles contain [[acetylcholine]], which is released into the synaptic cleft and stimulates the [[acetylcholine receptor]]s on the muscle. The muscle then contracts.<ref name=Mareska/>

=== Pathology of LEMS ===
In LEMS, antibodies against VGCC, particularly the [[P-type calcium channel|P]]/[[Q-type calcium channel|Q-type]] VGCC and possibly the N-type VGCC antibody, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be released from the neuromuscular junction. Apart from [[skeletal muscle]], the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS.<ref name=Mareska/><ref name=Verschuuren/> P/Q voltage-gated calcium channels are also found in the [[cerebellum]], explaining why some experience problems with coordination.<ref name=Rees/><ref name=Takamori/> The antibodies bind particularly to the part of the receptor known as the "domain III S5–S6 linker peptide".<ref name=Takamori/> Antibodies may also bind other VGCCs.<ref name=Takamori/> Some have antibodies that bind [[synaptotagmin]], the protein sensor for calcium-regulated vesicle fusion.<ref name=Takamori/> Many people with LEMS, both with and without VGCC antibodies, have detectable antibodies against the [[Muscarinic acetylcholine receptor M1|M1 subtype of the acetylcholine receptor]];  their presence may participate in a lack of compensation for the weak calcium influx.<ref name=Takamori/> N-type VGCCs are found on autonomic nerve terminals.

Apart from the decreased calcium influx,  a disruption of active zone vesicle release sites also occurs, which may also be antibody-dependent, since people with LEMS have antibodies to components of these active zones (including voltage-dependent calcium channels). Together, these abnormalities lead to the decrease in muscle contractility. Repeated stimuli over a period of about 10 seconds eventually lead to sufficient delivery of calcium, and an increase in muscle contraction to normal levels, which can be demonstrated using an [[electrodiagnostic medicine]] study called needle electromyography by increasing amplitude of repeated [[compound muscle action potential]]s.<ref name=Mareska/>

The antibodies found in LEMS associated with lung cancer also bind to calcium channels in the cancer cells, and it is presumed that the antibodies originally develop as a reaction to these cells.<ref name=Mareska/> It has been suggested that the immune reaction to the cancer cells suppresses their growth and improves the prognosis from the cancer.<ref name=Verschuuren/><ref name=Takamori>{{cite journal |author=Takamori M |title=Lambert–Eaton myasthenic syndrome: search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis |journal=J. Neuroimmunol. |volume=201–202 |pages=145–52 |date=September 2008 |pmid=18653248 |doi=10.1016/j.jneuroim.2008.04.040|s2cid=23814568 }}</ref>

==Diagnosis==
[[Image:Thorax pa peripheres Bronchialcarcinom li OF markiert.jpg|thumb|right|Chest X-ray showing a tumor in the left lung (right side of the image)]]

The diagnosis is usually made with nerve conduction study (NCS) and [[electromyography]] (EMG), which is one of the standard tests in the investigation of otherwise unexplained muscle weakness. EMG involves the insertion of small needles into the muscles.  NCS involves administering small electrical impulses to the nerves, on the surface of the skin, and measuring the electrical response of the muscle in question. NCS investigation in LEMS primarily involves evaluation of compound motor action potentials (CMAPs) of effected muscles and sometimes EMG single-fiber examination can be used.<ref name=Mareska/>

CMAPs show small amplitudes but normal latency and conduction velocities. If repeated impulses are administered (2 per second or 2&nbsp;Hz), it is normal for CMAP amplitudes to become smaller as the acetylcholine in the motor end plate is depleted. In LEMS, this decrease is larger than observed normally. Eventually, stored acetylcholine is made available, and the amplitudes increase again. In LEMS, this remains insufficient to reach a level sufficient for transmission of an impulse from nerve to muscle; all can be attributed to insufficient calcium in the nerve terminal. A similar pattern is witnessed in myasthenia gravis. In LEMS, in response to exercising the muscle, the CMAP amplitude increases greatly (over 200%, often much more). This also occurs on the administration of a rapid burst of electrical stimuli (20 impulses per second for 10 seconds). This is attributed to the influx of calcium in response to these stimuli.<ref name=Mareska/><ref name=Verschuuren/> On single-fiber examination, features may include increased jitter (seen in other diseases of neuromuscular transmission) and blocking.<ref name=Mareska/>

Blood tests may be performed to exclude other causes of muscle disease (elevated [[creatine kinase]] may indicate a [[myositis]], and abnormal [[thyroid function test]]s may indicate [[thyrotoxic myopathy]]). Antibodies against voltage-gated calcium channels can be identified in 85% of people with EMG-confirmed LEMS.<ref name=Mareska/> Once LEMS is diagnosed, investigations such as a [[X-ray computed tomography|CT scan]] of the chest are usually performed to identify any possible underlying lung tumors. Around 50–60% of these are discovered immediately after the diagnosis of LEMS. The remainder is diagnosed later, but usually within two years and typically within four years.<ref name=Verschuuren/> As a result, scans are typically repeated every six months for the first two years after diagnosis.<ref name=Mareska/> While CT of the lungs is usually adequate, a [[positron emission tomography]] scan of the body may also be performed to search for an occult tumour, particularly of the lung.<ref>{{cite book |veditors=Ropper AH, Brown RH | title=Adams and Victor's Principles of Neurology | edition=8th |vauthors=Ropper AH, Brown RH | chapter=53. Myasthenia Gravis and Related Disorders of the Neuromuscular Junction | year=2005 | pages=1261  | publisher=McGraw-Hill Professional | location=New York | isbn=0-07-141620-X }}</ref>

==Treatment==
[[Image:Diaminopyridine.png|thumb|right|Molecular structure of 3,4-diaminopyridine, a commonly used drug treatment for LEMS]]
If LEMS is caused by an underlying cancer, treatment of the cancer could lead to resolution of the symptoms.<ref name=Mareska/> Treatment usually consists of [[chemotherapy]], with [[radiation therapy]] in those with limited disease.<ref name=Verschuuren/>

Firdapse is the only FDA-approved treatment for LEMS. Firdapse works in the presynaptic neuromuscular junction to increase the release of acetylcholine helping to improve muscle function and relieve/reduce the symptoms of LEMS.

===Immunosuppression===
Some evidence supports the use of [[intravenous immunoglobulin]] (IVIG).<ref name=Ke2011>{{cite journal|last1=Keogh|first1=M|last2=Sedehizadeh|first2=S|last3=Maddison|first3=P|title=Treatment for Lambert-Eaton myasthenic syndrome.|journal=The Cochrane Database of Systematic Reviews|date=16 February 2011|volume=2011|issue=2|pages=CD003279|pmid=21328260|doi=10.1002/14651858.CD003279.pub3|pmc=7003613}}</ref> Immune suppression tends to be less effective than in other autoimmune diseases. Prednisolone (a glucocorticoid or steroid) suppresses the immune response, and the steroid-sparing agent azathioprine may replace it once therapeutic effect has been achieved. IVIG may be used with a degree of effectiveness. Plasma exchange (or plasmapheresis), the removal of plasma proteins such as antibodies and replacement with normal plasma, may provide improvement in acute severe weakness. Plasma exchange is less effective than in other related conditions such as myasthenia gravis, and additional immunosuppressive medication is often needed.<ref name=Mareska/>

===Other===
Three other treatment modalities also aim at improving LEMS symptoms, namely [[pyridostigmine]], [[3,4-diaminopyridine]] (amifampridine), and [[guanidine]]. They work to improve neuromuscular transmission.  Intravenous immunoglobulin (IVIg) and Mestinon tablets (Pyridostigmine) are secondary treatments.<ref>{{cite web |last1=Illa |first1=Isabel |title=IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status |url=https://pubmed.ncbi.nlm.nih.gov/15959667/ |website=National Library of Medicine}}</ref>

Tentative evidence supports 3,4-diaminopyridine at least for a few weeks.<ref name=Ke2011/> The 3,4-diaminopyridine base or the water-soluble 3,4-diaminopyridine phosphate may be used.<ref>{{cite journal|last1=Lindquist|first1=S|last2=Stangel|first2=M|last3=Ullah|first3=I|title=Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine.|journal=Neuropsychiatric Disease and Treatment|date=2011|volume=7|pages=341–9|pmid=21822385|doi=10.2147/NDT.S10464|pmc=3148925|doi-access=free}}</ref> Both 3,4-diaminopyridine formulations delay the repolarization of nerve terminals after a discharge, thereby allowing more calcium to accumulate in the nerve terminal.<ref name=Mareska/><ref name=Verschuuren/>

Pyridostigmine decreases the degradation of acetylcholine after release into the synaptic cleft, and thereby improves muscle contraction. An older agent, guanidine, causes many side effects and is not recommended. [[4-Aminopyridine]] (dalfampridine), an agent related to 3,4-aminopyridine, causes more side effects than 3,4-DAP and is also not recommended.<ref name=Verschuuren/>

The FDA approved amifampridine for use in children 6 years and older with LEMS in addition to the prior approval for use in adults with LEMS on November 28, 2018.<ref>{{cite web|url=https://www.drugs.com/history/firdapse.html|title=Firdapse (amifampridine phosphate) FDA Approval History|website=Drugs.com|access-date=February 5, 2019}}</ref>

==History==
Anderson and colleagues from [[St Thomas' Hospital]], London, were the first to mention a case with possible clinical findings of LEMS in 1953,<ref>{{cite journal |vauthors=Anderson HJ, Churchill-Davidson HC, Richardson AT |title=Bronchial neoplasm with myasthenia; prolonged apnoea after administration of succinylcholine |journal=Lancet |volume=265 |issue=6799 |pages=1291–3 |date=December 1953 |pmid=13110148 |doi=10.1016/S0140-6736(53)91358-0}}</ref> but [[Edward H. Lambert]], Lee Eaton, and E.D. Rooke at the [[Mayo Clinic]] were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1956.<ref>{{WhoNamedIt|synd|2738|Lambert-Eaton-Rooke syndrome}}</ref><ref>{{cite journal |vauthors=Lambert EH, Eaton LM, Rooke ED | title=Defect of neuromuscular conduction associated with malignant neoplasms  | journal=Am. J. Physiol. | year=1956 | volume=187 | pages=612–613}}</ref> In 1972, the clustering of LEMS with other autoimmune diseases led to the hypothesis that it was caused by autoimmunity.<ref>{{cite journal |vauthors=Gutmann L, Crosby TW, Takamori M, Martin JD |title=The Eaton–Lambert syndrome and autoimmune disorders |journal=Am. J. Med. |volume=53 |issue=3 |pages=354–6 |date=September 1972 |pmid=4115499 |doi=10.1016/0002-9343(72)90179-9}}</ref> Studies in the 1980s confirmed the autoimmune nature,<ref name=Takamori/> and research in the 1990s demonstrated the link with antibodies against P/Q-type voltage-gated calcium channels.<ref name=Mareska/><ref>{{cite journal |vauthors=Motomura M, Hamasaki S, Nakane S, Fukuda T, Nakao YK |title=Apheresis treatment in Lambert–Eaton myasthenic syndrome |journal=Ther. Apher. |volume=4 |issue=4 |pages=287–90 |date=August 2000 |pmid=10975475 |doi=10.1046/j.1526-0968.2000.004004287.x}}</ref>

==References==
{{reflist}}

==External links==
* [https://www.lemsfamily.org/ LemsFamily.org]
{{Medical resources
| DiseasesDB     = 4030
| ICD11          = {{ICD11|8C62}}
| ICD10          = {{ICD10|G73.1}}
| ICD9           = {{ICD9|358.1}}
| MedlinePlus    = 000710
| eMedicineSubj  = neuro
| eMedicineTopic = 181
| eMedicine_mult = {{eMedicine2|emerg|292}}
| MeshID         = D015624
}}
{{Diseases of myoneural junction and muscle}}
{{Paraneoplastic syndromes}}

{{DEFAULTSORT:Lambert-Eaton myasthenic syndrome}}
[[Category:Myoneural junction and neuromuscular diseases]]
[[Category:Paraneoplastic syndromes]]
[[Category:Autoimmune diseases]]
[[Category:Syndromes affecting muscles]]
[[Category:Channelopathies]]