Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome
Global view of a neuromuscular junction: 1. Axon 2. Motor end-plate 3. Muscle fiber 4. Myofibril
ICD-10	G73.1
ICD-9	358.1
DiseasesDB	4030
MedlinePlus	000710
MeSH	D015624

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Indhumathi Balaraman M.B.B.S[[3]]

Synonyms and keywords: Eaton-Lambert syndrome; Lambert-Eaton syndrome; LEMS

Overview

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder which affects the nerve-muscle (neuromuscular) junction.

The disease is usually observed in middle aged and older people but children and young people can be affected, as well. Due to the infrequency of the condition, the exact incidence is unknown.

Historical Perspective

• Anderson was the first person to mention a case with possible clinical findings of LEMS in 1953, but Lambert, Eaton and Rooke were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1966.
• Auto-immune self antibodies to the pre-synaptic voltage gated calcium channels leads to neuromuscular block.

Classification

Lambert Eaton syndrome may be classified as : [[4]]

• Paraneoplastic: Associated with malginancies like Lung cancer - Small cell Lung cancer more than non small cell lung cancer or mixed cell carcinomas, prostate cancer, Lymphoproliferative disorder and Thymomas.

• Non-paraneoplastic or Non tumor Lambert Eaton Syndrome: 65% association with HLA-B8-DR3 Haplotype Gene and idiopathic orgin.

PATHOPHYSIOLOGY

Understanding the concept of Neuromuscular junction,Presynaptic Acetylecholine (ACh) concentration,end plate potential, post-synpatic ACh receptors, role of Calcium and Voltage gated Calcium channel(VGCC) and role of potassium is essential to understand the pathophysiology of Lambert Eaton Myasthenic syndrome.

Briefly, The disease is of autoimmune origin, that is, it is caused by antibodies that are directed against the antigens of the neuromuscular junction. In 1989, the previously anticipated antibodies were demonstrated to be directed against presynaptic calcium channels, which are located in neuromuscular junction (see synapse) and are responsible for the efficient release of acetylcholine

In cases with both LEMS and lung cancer (usually small cell type), the antibodies are suggested to be aimed at cancer cells and to bind and affect the antigens in neuromuscular junction accidentally.

===Voltage Gated Calcium Channel=== [[5]]

• Potassium channels and the concentration of potassium ions does not contribute to the ACh release.

The mechanism by which the ACh is released is by increasing the concentration of calcium ions and their influx into the nerve terminal viz Voltage gated calcium channel (VGCC)

VGCC is a transmembrane protein with many subunits that is the main target in LEMS.

The commonly associated subtypes are L-type,N-type,P/Q-Type of alpha-1 subunit of VGCC, of which the P/Q subtype is the most important target in the disorder. N-Type is usually associated with the paraneoplastic LEMS.

VGCC is responsible for releasing the accumulated ACh in nerve terminal. Thereafter ACh binds to its receptor that depolarizes the muscle fibre end plate leading to a muscle contraction by generating a action potential. IgG antibodies of LEMS acts on the VGCC leading to the disorder of the above mechanism resulting in muscle weakness.

In paraneoplastic LEMS, Small cell lung cancer expresses the VGCC on the sufrace of the tumor cells that acts as the antigen to trigger the antibody production causing profound clinical symptoms.No genetic predisposition seen.

In Non-paraneoplastic syndrome,the autoimmunity against the P/Q type VGCC are seen usually in HLA-B8(HLA-Class I) and HLA- DR3 & HLA- DQ2 (HLA -class II) genes.

There are also some patients who do not carry these antibodies in their serum samples and the exact cause of disease in these cases still remains to be determined.

Causes

LEMS is usually a solitary diagnosis but lung cancer (small-cell lung cancer) may accompany the disease in some cases. It may also be associated with cancers such as lymphoma, non-Hodgkin's lymphoma, T-cell leukemia, non-small cell lung cancer, prostate cancer, and thymoma.

Differentiating Lambert-Eaton myasthenic syndrome from other Diseases

Both the etiology and the clinical findings of Lambert-Eaton myasthenic syndrome may resemble myasthenia gravis, but there are many substantial differences between clinical presentations and pathogenetic features of two disorders. In patients with affected ocular and respiratory muscles, the involvement is not as severe as myasthenia gravis.

Diseases	History and Physical								Diagnostic tests		Other Findings
	Motor Deficit	Sensory deficit	Cranial nerve Involvement	Autonomic dysfunction	Proximal/Distal/Generalized	Ascending/Descending/Systemic	Unilateral (UL) or Bilateral (BL) or No Lateralization (NL)	Onset	Lab or Imaging Findings	Specific test
Adult Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis
Infant Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis
Guillian-Barre syndrome	+	-	-	-	Generalized	Ascending	BL	Insidious	CSF: ↑Protein ↓Cells	Clinical & Lumbar Puncture	Progressive ascending paralysis following infection, possible respiratory paralysis
Eaton Lambert syndrome	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, repetitive nerve stimulation test (RNS)	Voltage gated calcium channel (VGCC) antibody	Diplopia, ptosis, improves with movement (as the day progresses)
Myasthenia gravis	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, Edrophonium test	Ach receptor antibody	Diplopia, ptosis, worsening with movement (as the day progresses)
Electrolyte disturbance	+	+	-	-	Generalized	Systemic	BL	Insidious	Electrolyte panel	↓Ca++, ↓Mg++, ↓K+	Possible arrhythmia
Organophosphate toxicity	+	+	-	+	Generalized	Ascending	BL	Sudden	Clinical diagnosis: physical exam & history	Clinical suspicion confirmed with RBC AchE activity	History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating
Tick paralysis (Dermacentor tick)	+	-	-	-	Generalized	Ascending	BL	Insidious	Clinical diagnosis: physical exam & history	-	History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)
Tetrodotoxin poisoning	+	-	+	+	Generalized	Systemic	BL	Sudden	Clinical diagnosis: physical exam & dietary history	-	History of consumption of puffer fish species.
Stroke	+/-	+/-	+/-	+/-	Generalized	Systemic	UL	Sudden	MRI +ve for ischemia or hemorrhage	MRI	Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.
Poliomyelitis	+	+	+	+/-	Proximal > Distal	Systemic	BL or UL	Sudden		PCR of CSF	Asymmetric paralysis following a flu-like syndrome.
Transverse myelitis	+	+	+	+	Proximal > Distal	Systemic	BL or UL	Sudden	MRI & Lumbar puncture	MRI	History of chronic viral or autoimmune disease (e.g. HIV)
Neurosyphilis	+	+	-	+/-	Generalized	Systemic	BL	Insidious	MRI & Lumbar puncture	CSF VDRL-specifc CSF FTA-Ab -sensitive	History of unprotected sex or multiple sexual partners. History of genital ulcer (chancre), diffuse maculopapular rash.
Muscular dystrophy	+	-	-	-	Proximal > Distal	Systemic	BL	Insidious	Genetic testing	Muscle biopsy	Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.
Multiple sclerosis exacerbation	+	+	+	+	Generalized	Systemic	NL	Sudden	↑CSF IgG levels (monoclonal)	Clinical assessment and MRI	Blurry vision, urinary incontinence, fatigue
Amyotrophic lateral sclerosis	+	-	-	-	Generalized	Systemic	BL	Insidious	Normal LP (to rule out DDx)	MRI & LP	Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).
Inflammatory myopathy	+	-	-	-	Proximal > Distal	Systemic	UL or BL	Insidious	Elevated CK & Aldolase	Muscle biopsy	Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.

Epidemiology and Demographics

'''PARANEOPLASTTIC (LEMS)'''[[6]]

• Age of presentation is found to be around 58 years.
• More common in male than female. ( May be explained by the association with the small cell lung cancer )
• Lambert Eaton Myasthenic Syndrome(LEMS) is a rare disorder which has a very low prevalence than Myasthenia Gravis(MG). It is about 40 times less prevalent than MG, perhaps the incidence is only 10 times lesser than the MG per year.
• Association with the malignancy and its lower prevalence may explain the poor prognosis of the disorder.

'''NON-PARANEOPLASTIC (LEMS)'''[[7]]

• Two peaks of incidence in ages around 35 years and a much larger peak at about 60 years.
• Female more than male like other auto immune diseases.
• good prognosis and survival rate is near normal.

Risk Factors

• Smoking may be considered as a risk factor.[[8]]

Natural History, Complications and Prognosis

Possible complications include:

• Difficulty breathing, including respiratory failure
• Difficulty swallowing
• Infections, such as pneumonia
• Injuries from falls and problems with coordination

The symptoms of Lambert-Eaton syndrome may improve by treating the underlying disease, suppressing the immune system, or removing the antibodies. However, not everyone responds well to treatment.

Symptoms

Symptoms may include:

• Weakness or loss of movement that can be more or less severe, including:
  • Difficulty chewing
  • Difficulty climbing stairs
  • Difficulty lifting objects
  • Difficulty talking
  • Drooping head
  • Need to use hands to get up from sitting or lying positions
• Swallowing difficulty, gagging, or choking
• Vision changes such as:
  • Blurry vision
  • Double vision
  • Problems keeping a steady gaze

Symptoms related to the autonomic nervous system usually occur, and include:

• Blood pressure changes
• Dizziness upon standing
• Dry mouth

Diagnosis

Red flag to investigate may be proximal muscle weakness with areflexia and autonomic dysfunction.

SEROLOGY :

• Antibodies against P/Q Voltage gated Calcium Channel(not a definitive test as it may be present in other autoimmune disease and neurological conditions) more frequently than antibodies against N type Calcium channels.
• LEMS with SCLC are found to have Antibodies against SOX1(immunogenic tumor antigen) - 95% specific.

ELECTRODIAGNOSITC TESTING:

• Repetitive Nerve Stimulation (RNS) testing and the Compound muscle action potential amplitude. ( much commonly used and the availability is more common than SFEMG)

Low rate of repetitive nerve stimulation - decrease in the amplitude and clinical response. High rate - increase in clinical response and amplitude recorded. Following exercise or RNS in high frequency shows a cent percent increase in amplitude and response is noted. perhaps to diagnose LEMS percentage equal to or higher than 60% increase in amplitude is required.

• Needle EMG: Action potentials that are unstable.

• Single Fiber Electromyography (SFEMG) has a better diagnostic power than RNS. On increased frequency of firing, the characteristic jitters and the blockade improves.

Physical Examination

Laboratory Findings

• Antibodies to calcium channels
• Incremental response in repetitive nerve stimulation - incremental response is an increased response of muscle fibers to very high frequencies of electrical stimulation. Observed increase in the response of muscle fibers proves that there is a difficulty with the release of acetylcholine and this difficulty can be overwhelmed by intensive stimulation.

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Chest X-ray

• Chest x-ray for a possible lung malignancy

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

The main goals of treatment are to:

• Identify and treat any underlying disorders, such as lung cancer
• Give treatment to help with the weakness

Corticosteroids, azathioprine and 3,4-diaminopyridine are used in treatment of LEMS with limited success. In some cases with a progressive and intractable course, plasma exchange or intravenous immunoglobulin can be tried.

A treatment called plasma exchange usually improves symptoms. Plasma exchange involves removing blood plasma from the body and replacing it with donated plasma. This helps to make sure that any harmful proteins (antibodies) that are interfering with nerve function are removed from the body.

Plasmapheresis may also be effective. During this treatment, the blood is removed from the body. The plasma is separated, the antibodies are removed, and the plasma is returned to the body.

Medications that suppress the immune response, such as prednisone, may improve symptoms in some cases. Medications may also include:

• Anticholinesterase medications such as neostigmine or pyridostigmine (although these are not very effective when given alone)
• 3,4 diaminopyridine works by blocking K+ channel efflux in nerve terminal so that action potential duration is increased. Ca2+ channels can then be open for longer time and allow greater acetylcholine release to stimulate muscle at end plate.

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].