Lambert-Eaton myasthenic syndrome
Encyclopedia
Lambert–Eaton myasthenic syndrome (LEMS, sometimes Lambert–Eaton syndrome or Eaton–Lambert syndrome) is a rare autoimmune disorder that is characterised by muscle weakness
of the limbs. It is the result of an autoimmune reaction
, where antibodies
are formed against voltage-gated calcium channels
in the neuromuscular junction
(the connection between nerve
s and the muscle
that they supply). Around 60% of those with LEMS have an underlying malignancy
, most commonly small cell lung cancer
; it is therefore regarded as a paraneoplastic syndrome
(a condition that arises as a result of cancer elsewhere in the body).
People who develop LEMS are usually over 40, although it may occur at any age. The diagnosis is usually confirmed with electromyography
and blood test
s; these also distinguish it from myasthenia gravis
, a related autoimmune neuromuscular disease.
If the disease is associated with cancer, direct treatment of the cancer often relieves the symptoms of LEMS. Other treatments often used are steroids
, azathioprine
and intravenous immunoglobulin
, which suppress the immune system, and pyridostigmine
and 3,4-diaminopyridine
, which enhance the neuromuscular transmission. Occasionally, plasma exchange
is required to remove the antibodies.
. The proximal muscles (those closest to the trunk) are predominantly affected; this leads to difficulties climbing stairs and rising from a sitting position. Physical exercise
and high temperatures can worsen the symptoms. Weakness of the bulbar muscles
(supplying the mouth and throat) is occasionally encountered. Weakness of the eye muscles
is uncommon. Some may have double vision
, drooping of the eyelids
and difficulty swallowing
, but generally only together with leg weakness; this distinguishes LEMS from myasthenia gravis, in which eye signs are much more prominent. In the advanced stages of the disease, weakness of the respiratory muscles
may occur. Some may also experience problems with coordination
(ataxia
).
Three quarters of people with LEMS also have disruption of the autonomic nervous system
. This may be experienced as a dry mouth
, constipation
, blurred vision
, impaired sweating, and orthostatic hypotension
(falls in blood pressure on standing, potentially leading to blackouts
). Some report a metallic taste in the mouth.
On neurological examination
, the weakness demonstrated with normal testing of power is often less severe than would be expected on the basis of the symptoms. 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.
In LEMS associated with lung cancer, most have no suggestive symptoms of cancer at the time, such as cough
, coughing blood
and unintentional weight loss. It has been suggested that LEMS associated with lung cancer is more severe.
. Of the people with small cell lung cancer, 1–3% have LEMS. In most of these cases, LEMS is the first symptom of the lung cancer, and it is otherwise asymptomatic
.
LEMS may be associated with autoimmune disease
s, such as hypothyroidism
(an underactive thyroid gland) or diabetes mellitus type 1
. 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. HLA-DR3
-B8
(an HLA
subtype), in particular, seems to predispose to LEMS.
is carried down the axon
(the long projection of a 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 transfer of vesicles
with the neurotransmitter
acetylcholine
to "active zones" in the presynaptic membrane, where it is released into the synaptic cleft and stimulates the acetylcholine receptor
on the muscle. The muscle then contracts. For the acetylcholine-containing vesicles to be mobilized, an influx of calcium
is required. This influx occurs through voltage-gated calcium channels (VGCC) in the presynaptic membrane.
In LEMS, antibodies against VGCC, particularly the P
/Q-type
VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be mobilized to the neuromuscular junction. Apart from skeletal muscle
, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS. P/Q voltage-gated calcium channels are also found in the cerebellum
, explaining why some experience problems with coordination. The antibodies bind particularly to the part of the receptor known as the "domain III S5–S6 linker peptide". Antibodies may also bind other VGCCs. Some have antibodies that bind synaptotagmin
, a protein involved in calcium-regulated vesicle transport, rather than against VGCC. Many people with LEMS, both with and without VGCC antibodies, have detectable antibodies against the M1 subtype of the acetylcholine receptor
; it is thought that their presence participates in a lack of compensation for the slow calcium influx.
Apart from the decreased calcium influx, there is also a decrease in the number of active zones, which is also thought to be antibody-dependent. 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 on electromyography by increasing amplitude of repeated compound muscle action potential
s.
It has been shown that 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. It has been suggested that the immune reaction to the cancer cells suppresses their growth and improves the prognosis from the cancer.
The diagnosis is usually made on electromyography
(EMG), which is one of the standard tests in the investigation of otherwise unexplained muscle weakness. This involves the insertion of small needles into the nerves supplying several muscles, administering small electrical impulses through these needles, and measuring the electrical response of the muscle in question. Two EMG investigations can be characteristic in LEMS: compound motor action potentials (CMAP) and single-fiber examination.
CMAP shows small amplitudes but normal latency and conduction velocities. If repeated impulses are administered (two per second or 2 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 ten seconds). This is attributed to the influx of calcium in response to these stimuli. On single-fiber examination, features may include increased jitter (seen in other diseases of neuromuscular transmission) and blocking.
Blood tests may be performed to exclude other causes of muscle disease (elevated creatine kinase
may indicate a myositis
, and abnormal thyroid function tests may indicate thyrotoxic myopathy
). Antibodies against voltage-gated calcium channels can be identified in 85% of people with EMG confirmed LEMS. Once LEMS is diagnosed, investigations such as a CT scan of the chest are usually performed to identify any possible underlying lung tumors. 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. As a result, scans are typically repeated every six months for the first two years after diagnosis.
, with radiation therapy
in those with limited disease.
The two treatment modalities aimed at improving LEMS symptoms directly are improving the neuromuscular conduction and suppression of the immune system. Two classes of medication are used to improve neuromuscular transmission. Pyridostigmine decreases the degradation of acetylcholine after release into the synaptic cleft, and thereby improves muscle contraction. In LEMS, the potassium channel
blocker 3,4-diaminopyridine (amifampridine) is also used. It delays the repolarization of nerve terminals after a discharge, thereby allowing more calcium to accumulate in the nerve terminal. 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.
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. Intravenous immunoglobulin
(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. Again, plasma exchange is less effective than in other related conditions such as myasthenia gravis, and additional immunosuppressive medication is often needed. According to a systematic review by the Cochrane Collaboration
, the best evidence in the treatment of LEMS exists for 3,4-aminopyridine and IVIG.
, London, were the first to mention a case with possible clinical findings of LEMS in 1953, but Lambert, Eaton and Rooke at the Mayo Clinic
were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1956. In 1972, the clustering of LEMS with other autoimmune diseases led to the hypothesis that it was caused by autoimmunity. Studies in the 1980s confirmed the autoimmune nature, and research in the 1990s demonstrated the link with antibodies against P/Q-type voltage-gated calcium channels.
Weakness
Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a...
of the limbs. It is the result of an autoimmune reaction
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
, where antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
are formed against voltage-gated calcium channels
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
in the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
(the connection between nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s and the muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
that they supply). Around 60% of those with LEMS have an underlying malignancy
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, most commonly small cell lung cancer
Small cell carcinoma
Small cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate....
; it is therefore regarded as a paraneoplastic syndrome
Paraneoplastic syndrome
A paraneoplastic syndrome is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors excreted by tumor cells or by an immune response against the tumor...
(a condition that arises as a result of cancer elsewhere in the body).
People who develop LEMS are usually over 40, although it may occur at any age. The diagnosis is usually confirmed with electromyography
Electromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
and blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s; these also distinguish it from myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, a related autoimmune neuromuscular disease.
If the disease is associated with cancer, direct treatment of the cancer often relieves the symptoms of LEMS. Other treatments often used are steroids
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
, azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
and intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
, which suppress the immune system, and pyridostigmine
Pyridostigmine
Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...
and 3,4-diaminopyridine
3,4-Diaminopyridine
3,4-Diaminopyridine is an organic compound with the formula C5H3N2. It is formally derived from pyridine by substitution of the 3 and 4 positions with an amino group....
, which enhance the neuromuscular transmission. Occasionally, plasma exchange
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
is required to remove the antibodies.
Signs and symptoms
The weakness of LEMS typically involves the legs and arms. Leg involvement is more striking than in myasthenia gravisMyasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
. The proximal muscles (those closest to the trunk) are predominantly affected; this leads to difficulties climbing stairs and rising from a sitting position. Physical exercise
Physical exercise
Physical exercise is any bodily activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons including strengthening muscles and the cardiovascular system, honing athletic skills, weight loss or maintenance, as well as for the purpose of...
and high temperatures can worsen the symptoms. Weakness of the bulbar muscles
Corticobulbar tract
The corticobulbar tract is a white matter pathway connecting the cerebral cortex to the brainstem. The 'bulb' is an archaic term for the medulla oblongata; in modern clinical usage, it sometimes includes the pons as well...
(supplying the mouth and throat) is occasionally encountered. Weakness of the eye muscles
Muscles of orbit
The muscles of the orbit are a group of six muscles that control movement of the eye. Four of the muscles control the movement of the eye in the four cardinal directions: up, down, left and right...
is uncommon. Some may have double vision
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
, drooping of the eyelids
Ptosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
and difficulty swallowing
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
, but generally only together with leg weakness; this distinguishes LEMS from myasthenia gravis, in which eye signs are much more prominent. In the advanced stages of the disease, weakness of the respiratory muscles
Muscles of respiration
The various muscles of respiration aid in both inspiration and expiration, which require changes in the pressure within the thoracic cavity. The respiratory muscles work to achieve this by changing the dimensions of the thoracic cavity....
may occur. Some may also experience problems with coordination
Motor coordination
thumb|right|Motor coordination is shown in this animated sequence by [[Eadweard Muybridge]] of himself throwing a diskMotor coordination is the combination of body movements created with the kinematic and kinetic parameters that result in intended actions. Such movements usually smoothly and...
(ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
).
Three quarters of people with LEMS also have disruption of the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
. This may be experienced as a dry mouth
Xerostomia
Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, blurred vision
Blurred vision
-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....
, impaired sweating, and orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
(falls in blood pressure on standing, potentially leading to blackouts
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
). Some report a metallic taste in the mouth.
On neurological examination
Neurological examination
A neurological examination is the assessment of sensory neuron and motor responses, especially reflexes, to determine whether the nervous system is impaired...
, the weakness demonstrated with normal testing of power is often less severe than would be expected on the basis of the symptoms. 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
Reflex
A reflex action, also known as a reflex, is an involuntary and nearly instantaneous movement in response to a stimulus. A true reflex is a behavior which is mediated via the reflex arc; this does not apply to casual uses of the term 'reflex'.-See also:...
es are typically reduced; with muscle use, reflex strength increases. This is a characteristic feature of LEMS. The pupillary light reflex may be sluggish.
In LEMS associated with lung cancer, most have no suggestive symptoms of cancer at the time, such as cough
Cough
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
, coughing blood
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
and unintentional weight loss. It has been suggested that LEMS associated with lung cancer is more severe.
Causes
LEMS is often associated with lung cancer (50–70%), making LEMS a paraneoplastic syndromeParaneoplastic syndrome
A paraneoplastic syndrome is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors excreted by tumor cells or by an immune response against the tumor...
. Of the people with small cell lung cancer, 1–3% have LEMS. In most of these cases, LEMS is the first symptom of the lung cancer, and it is otherwise asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
.
LEMS may be associated with autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s, such as hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
(an underactive thyroid gland) or diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
. Myasthenia gravis, too, may happen in the presence of tumors (thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
, a tumor of the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
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. HLA-DR3
HLA-DR3
HLA-DR3 is composed to the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease....
-B8
HLA-B8
HLA-B8 is an HLA-B serotype. The serotype identifies the HLA-B*08 gene products. HLA-B8, previously known as HL-A8 was one of the first identified of the HLA antigens. It coined the "Super B8" haplotype, also called the ancestral European haplotype because of its common occurrence in Europe,...
(an HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
subtype), in particular, seems to predispose to LEMS.
Mechanism
In normal neuromuscular function, a nerve impulseAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
is carried down the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
(the long projection of a nerve cell
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
) from the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. At the nerve ending in the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
, where the impulse is transferred to the muscle cell, the nerve impulse leads to the transfer of vesicles
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
with the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
to "active zones" in the presynaptic membrane, where it is released into the synaptic cleft and stimulates the acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
on the muscle. The muscle then contracts. For the acetylcholine-containing vesicles to be mobilized, an influx of calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
is required. This influx occurs through voltage-gated calcium channels (VGCC) in the presynaptic membrane.
In LEMS, antibodies against VGCC, particularly the P
P-type calcium channel
The p-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
/Q-type
Q-type calcium channel
The Q-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be mobilized to the neuromuscular junction. Apart from skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS. P/Q voltage-gated calcium channels are also found in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, explaining why some experience problems with coordination. The antibodies bind particularly to the part of the receptor known as the "domain III S5–S6 linker peptide". Antibodies may also bind other VGCCs. Some have antibodies that bind synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
, a protein involved in calcium-regulated vesicle transport, rather than against VGCC. Many people with LEMS, both with and without VGCC antibodies, have detectable antibodies against the M1 subtype of the acetylcholine receptor
Muscarinic acetylcholine receptor M1
The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor.This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.It is predominantly found bound to G proteins...
; it is thought that their presence participates in a lack of compensation for the slow calcium influx.
Apart from the decreased calcium influx, there is also a decrease in the number of active zones, which is also thought to be antibody-dependent. 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 on electromyography by increasing amplitude of repeated compound muscle action potential
Compound muscle action potential
The compound muscle action potential or compound motor action potential is a electromyography investigation ....
s.
It has been shown that 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. It has been suggested that the immune reaction to the cancer cells suppresses their growth and improves the prognosis from the cancer.
Diagnosis
Electromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
(EMG), which is one of the standard tests in the investigation of otherwise unexplained muscle weakness. This involves the insertion of small needles into the nerves supplying several muscles, administering small electrical impulses through these needles, and measuring the electrical response of the muscle in question. Two EMG investigations can be characteristic in LEMS: compound motor action potentials (CMAP) and single-fiber examination.
CMAP shows small amplitudes but normal latency and conduction velocities. If repeated impulses are administered (two per second or 2 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 ten seconds). This is attributed to the influx of calcium in response to these stimuli. On single-fiber examination, features may include increased jitter (seen in other diseases of neuromuscular transmission) and blocking.
Blood tests may be performed to exclude other causes of muscle disease (elevated creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
may indicate a myositis
Myositis
Myositis is a general term for inflammation of the muscles. Many such conditions are considered likely to be caused by autoimmune conditions, rather than directly due to infection It is also a documented side effect of the lipid-lowering drugs statins and fibrates.Elevation of creatine kinase in...
, and abnormal thyroid function tests may indicate thyrotoxic myopathy
Thyrotoxic Myopathy
Thyrotoxic myopathy is a neuromuscular disorder that develops due to the overproduction of the thyroid hormone thyroxine. Also known as hyperthyroid myopathy, TM is one of many myopathies that lead to muscle weakness and muscle tissue breakdown. Evidence indicates the onset of TM may be caused by...
). Antibodies against voltage-gated calcium channels can be identified in 85% of people with EMG confirmed LEMS. Once LEMS is diagnosed, investigations such as a CT scan of the chest are usually performed to identify any possible underlying lung tumors. 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. As a result, scans are typically repeated every six months for the first two years after diagnosis.
Treatment
If LEMS is caused by an underlying cancer, treatment of the malignancy usually leads to resolution of the symptoms. Treatment usually consists of chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, with radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
in those with limited disease.
The two treatment modalities aimed at improving LEMS symptoms directly are improving the neuromuscular conduction and suppression of the immune system. Two classes of medication are used to improve neuromuscular transmission. Pyridostigmine decreases the degradation of acetylcholine after release into the synaptic cleft, and thereby improves muscle contraction. In LEMS, the potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
blocker 3,4-diaminopyridine (amifampridine) is also used. It delays the repolarization of nerve terminals after a discharge, thereby allowing more calcium to accumulate in the nerve terminal. An older agent, guanidine
Guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...
, causes many side-effects and is not recommended. 4-Aminopyridine
4-Aminopyridine
4-Aminopyridine is an organic compound with the chemical formula C5H4N–NH2. The molecule is one of the three isomeric amines of pyridine...
(dalfampridine), an agent related to 3,4-aminopyridine, causes more side-effects than 3,4-DAP and is also not recommended.
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. Intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
(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. Again, plasma exchange is less effective than in other related conditions such as myasthenia gravis, and additional immunosuppressive medication is often needed. According to a systematic review by the Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
, the best evidence in the treatment of LEMS exists for 3,4-aminopyridine and IVIG.
History
Anderson and colleagues from St Thomas' HospitalSt Thomas' Hospital
St Thomas' Hospital is a large NHS hospital in London, England. It is administratively a part of Guy's & St Thomas' NHS Foundation Trust. It has provided health care freely or under charitable auspices since the 12th century and was originally located in Southwark.St Thomas' Hospital is accessible...
, London, were the first to mention a case with possible clinical findings of LEMS in 1953, but Lambert, Eaton and Rooke at the Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1956. In 1972, the clustering of LEMS with other autoimmune diseases led to the hypothesis that it was caused by autoimmunity. Studies in the 1980s confirmed the autoimmune nature, and research in the 1990s demonstrated the link with antibodies against P/Q-type voltage-gated calcium channels.