Lambert-Eaton syndrome

Neurology

Clinicals - History

Fact Explanation
Introduction Lambert Eaton Myasthaenia syndrome is a disorder of neuromuscular junction which is auto immune in aetiology. In contrast to myasthaenia gravis Lambert Eaton Myasthaenia Syndrome (LEMS) cause pre synaptic pathology. The pathophysiology is due to auto antibody mediated inhibition of voltage gated calcium channels in pre synaptic membrane of the neuromuscular junction, which interrupts the release of acetyl choline neurotransmitters in a calcium flux depended manner. Mostly the LEMS is associated with an underlying malignancy, this fact has been discussed below separately. Usually LEMS is an adult disease though rarely seen in paediatric population as well. Usually it is commoner among males. Introduction
Lambert Eaton Myasthaenia syndrome is a disorder of neuromuscular junction which is auto immune in aetiology. In contrast to myasthaenia gravis Lambert Eaton Myasthaenia Syndrome (LEMS) cause pre synaptic pathology. The pathophysiology is due to auto antibody mediated inhibition of voltage gated calcium channels in pre synaptic membrane of the neuromuscular junction, which interrupts the release of acetyl choline neurotransmitters in a calcium flux depended manner. Mostly the LEMS is associated with an underlying malignancy, this fact has been discussed below separately. Usually LEMS is an adult disease though rarely seen in paediatric population as well. Usually it is commoner among males.
Muscular weakness of limbs The onset of the symptoms and the time of diagnosis may have a significant time interval. The disease is usually slowly progressive. Lower limb muscles mainly the proximal muscles are affected greatly and patient may complain difficulty in standing from chair, climbing and walking. The diseased limbs may be paining. Upper limb weakness may manifest with difficulty in reaching objects, combing and clothing. The weakness may worsen by exposing to hot temperature or generalized fever. Again in contrast to myasthaenia gravis in LEMS short term hyper activation of the muscle causes transient improvement of the weakness and symptoms, due to transiently adequate release of acetyl choline. Muscular weakness of limbs
The onset of the symptoms and the time of diagnosis may have a significant time interval. The disease is usually slowly progressive. Lower limb muscles mainly the proximal muscles are affected greatly and patient may complain difficulty in standing from chair, climbing and walking. The diseased limbs may be paining. Upper limb weakness may manifest with difficulty in reaching objects, combing and clothing. The weakness may worsen by exposing to hot temperature or generalized fever. Again in contrast to myasthaenia gravis in LEMS short term hyper activation of the muscle causes transient improvement of the weakness and symptoms, due to transiently adequate release of acetyl choline.
Drooping of eye lids and double vision. Ptosis and diplopia occur due to the involvement of extraoccular nervous system. This could occur but in to a less severe extent in compared to the limb weakness and less common in compared to myasthaenia gravis (MG). So if the ptosis is the initial or only complain the diagnosis is more towards myasthaenia gravis rather than LEMS. Again in contrast to MG in LEMS short term hyper activation of the muscle causes transient improvement of the weakness and symptoms, due to transiently adequate release of acetyl choline. When the LEMS and MG is coexistent those features would be obvious and causes diagnostic dilemmas. Drooping of eye lids and double vision.
Ptosis and diplopia occur due to the involvement of extraoccular nervous system. This could occur but in to a less severe extent in compared to the limb weakness and less common in compared to myasthaenia gravis (MG). So if the ptosis is the initial or only complain the diagnosis is more towards myasthaenia gravis rather than LEMS. Again in contrast to MG in LEMS short term hyper activation of the muscle causes transient improvement of the weakness and symptoms, due to transiently adequate release of acetyl choline. When the LEMS and MG is coexistent those features would be obvious and causes diagnostic dilemmas.
Difficulty in swallowing Dysphagia could occur due to the involvement of muscles of deglutination. Again if this symptom is usually seen in MG rather than in LEMS. Difficulty in swallowing
Dysphagia could occur due to the involvement of muscles of deglutination. Again if this symptom is usually seen in MG rather than in LEMS.
Difficulty in speak Dysarthria also could occur due to involvement of muscles used for speech. Again if this symptom is usually seen in MG rather than in LEMS. Difficulty in speak
Dysarthria also could occur due to involvement of muscles used for speech. Again if this symptom is usually seen in MG rather than in LEMS.
Respiratory difficulty The respiratory muscle weakness and consequent respiratory paralysis may occur later in the cause, but initial presentation with respiratory paralysis is less common. Respiratory difficulty
The respiratory muscle weakness and consequent respiratory paralysis may occur later in the cause, but initial presentation with respiratory paralysis is less common.
Autonomic features The commonest autonomic feature is dry mouth which may precede the onset of other symptoms. Therefore most patients may forget this symptom and it has to asked specifically. Other autonomic symptoms will be constipation, dry eyes, constricted pupils, impotence and postural hypo tension. Autonomic features
The commonest autonomic feature is dry mouth which may precede the onset of other symptoms. Therefore most patients may forget this symptom and it has to asked specifically. Other autonomic symptoms will be constipation, dry eyes, constricted pupils, impotence and postural hypo tension.
Associated symptoms of malignancies LEMS is a rare entity and usually associated with a concurrent malignancy, mostly small cell carcinoma of lungs. It also can be found in patients with lymphoma, sarcoma, thymoma, malignancies of the breast, colon, stomach, gall badder, thyroid, prostate or bladder. The diseases is usually presents in adult population and more prevalent in males. The prognosis depends on several factors such as the behavior of underlying malignancy, severity of the muscle weakness and so on.
The occurrence of LEMS in malignancies have been explained by the expression of similar voltage gated calcium channels in malignant cells and generation of antibody against them which also could react with the inert calcium channels. Other than with the malignancies it also could be associated with other autoimmune conditions such as thyroiditis and pancreatitis. Around 50-70% patients with LEMS will be found to have an underlying malignancy during the disease course. If presented earlier the patients may not have any symptoms of a malignancy even though with extensive LEMS. History about smoking, chonic cough, haemoptysis, anorexia and pleuritic type chest pain should be asked. In relation to other malignancies history of low grade fever, recurrent infections, lymph node enlargement, haematuria, dysphagia, per rectal bleeding, altered bowel habits etc. should be asked. Any malignancy which are associated with LEMS can be preceded, coexistent or followed the occurrence of LEMS, there fore the follow up screening is essential.
Associated symptoms of malignancies
LEMS is a rare entity and usually associated with a concurrent malignancy, mostly small cell carcinoma of lungs. It also can be found in patients with lymphoma, sarcoma, thymoma, malignancies of the breast, colon, stomach, gall badder, thyroid, prostate or bladder. The diseases is usually presents in adult population and more prevalent in males. The prognosis depends on several factors such as the behavior of underlying malignancy, severity of the muscle weakness and so on.
The occurrence of LEMS in malignancies have been explained by the expression of similar voltage gated calcium channels in malignant cells and generation of antibody against them which also could react with the inert calcium channels. Other than with the malignancies it also could be associated with other autoimmune conditions such as thyroiditis and pancreatitis. Around 50-70% patients with LEMS will be found to have an underlying malignancy during the disease course. If presented earlier the patients may not have any symptoms of a malignancy even though with extensive LEMS. History about smoking, chonic cough, haemoptysis, anorexia and pleuritic type chest pain should be asked. In relation to other malignancies history of low grade fever, recurrent infections, lymph node enlargement, haematuria, dysphagia, per rectal bleeding, altered bowel habits etc. should be asked. Any malignancy which are associated with LEMS can be preceded, coexistent or followed the occurrence of LEMS, there fore the follow up screening is essential.

Clinicals - Examination

Fact Explanation
Features of muscle weakness The patient may be specially having weakness of proximal muscle groups. The gait may be unsteady, waddling. Patient may have difficulty in reaching objects due to the upper limb weakness. The muscle power of the proximal muscle may usually be reduced. The power of the muscle can be transiently increased by little hyper activation or over exercise of the muscle for a short period. Following transient improvement of the muscle power the weakness worsen if the activity is sustaained. This transient improvement of the muscle power can be used to differentiate LEMS from MG. Features of muscle weakness
The patient may be specially having weakness of proximal muscle groups. The gait may be unsteady, waddling. Patient may have difficulty in reaching objects due to the upper limb weakness. The muscle power of the proximal muscle may usually be reduced. The power of the muscle can be transiently increased by little hyper activation or over exercise of the muscle for a short period. Following transient improvement of the muscle power the weakness worsen if the activity is sustaained. This transient improvement of the muscle power can be used to differentiate LEMS from MG.
Deep tendon reflexes Usually the deep tendon reflexes are absent or diminished. In the same way as transient muscle power improvement with transient hyperactivity tendon reflexes also can be elicited. Deep tendon reflexes
Usually the deep tendon reflexes are absent or diminished. In the same way as transient muscle power improvement with transient hyperactivity tendon reflexes also can be elicited.
Sensory examination The sensory examination has to be normal.But associated peripheral neuropathy may be present in patients with malignancies. Sensory examination
The sensory examination has to be normal.But associated peripheral neuropathy may be present in patients with malignancies.
Occular and oropharyngeal examination Mild degree of ptosis, diplopia, dysphagia and dysarthria may be observed less commonly. Similar transient improvement can be seen with short lasting over activation of the muscles which again diminish with sustained activation. Occular and oropharyngeal examination
Mild degree of ptosis, diplopia, dysphagia and dysarthria may be observed less commonly. Similar transient improvement can be seen with short lasting over activation of the muscles which again diminish with sustained activation.
Respiratory distress and respiratory weakness Though not common in initial phases of the illness difficulty in breathing and respiratory distress may be seen in later part of the illness. Respiratory distress and respiratory weakness
Though not common in initial phases of the illness difficulty in breathing and respiratory distress may be seen in later part of the illness.
Autonomic manifestations The commonest would be the dry mouth and erectile dysfunction in males. Others would be postural hypotension, pupillary constriction, urinary retention and constipation. Autonomic manifestations
The commonest would be the dry mouth and erectile dysfunction in males. Others would be postural hypotension, pupillary constriction, urinary retention and constipation.
Features of underlying malignancy As mentioned above the manifestations of malignancies may not be obvious in initial phase of the illness. The possible signs of small cell carcinoma are clubbing, cachexia and evidence of focal lesions on respiratory examination and lymphadenopathy. Other than for small cell carcinoma of lungs physical signs should be elicited in other possible malignancies such as generalized lymphadenopathy, hepatosplenomegaly, abdomina or loin masses, pelvic masses and goiters. Breast examination also have to be performed. Features of underlying malignancy
As mentioned above the manifestations of malignancies may not be obvious in initial phase of the illness. The possible signs of small cell carcinoma are clubbing, cachexia and evidence of focal lesions on respiratory examination and lymphadenopathy. Other than for small cell carcinoma of lungs physical signs should be elicited in other possible malignancies such as generalized lymphadenopathy, hepatosplenomegaly, abdomina or loin masses, pelvic masses and goiters. Breast examination also have to be performed.

Investigations - Diagnosis

Fact Explanation
Anti body assays Anti bodies against Voltage Gated Calcium channel can be seen in patients with LEMS. It is mostly (75-100%) present when it is associated with small cell lung cancer. It can also present (25%) even with out LEMS in patients with small cell lung cancers. Small number of patients with MG will show low titers of voltage gated calcium channel antibodies. In MG anti bodies against acetyl choline receptors are greatly present though low titers can be in in LEMS as well. Anti body assays
Anti bodies against Voltage Gated Calcium channel can be seen in patients with LEMS. It is mostly (75-100%) present when it is associated with small cell lung cancer. It can also present (25%) even with out LEMS in patients with small cell lung cancers. Small number of patients with MG will show low titers of voltage gated calcium channel antibodies. In MG anti bodies against acetyl choline receptors are greatly present though low titers can be in in LEMS as well.
Edrophonium (Tensilon) Test Edrophonium injection test can be used to differentiate LEMS from MG, where there will be a good response in MG. Edrophonium (Tensilon) Test
Edrophonium injection test can be used to differentiate LEMS from MG, where there will be a good response in MG.
Repetitive nerve stimulation test This is the diagnostic test when typical features are demonstrated. Initially the compound muscle action potential (CMAP) is less than the normal and CMAP increases to around twice normal when stimulated with 20-50 Hz or voluntary contraction. Repetitive nerve stimulation test
This is the diagnostic test when typical features are demonstrated. Initially the compound muscle action potential (CMAP) is less than the normal and CMAP increases to around twice normal when stimulated with 20-50 Hz or voluntary contraction.
Electromyography This will show the markedly unstable action potential at motor neuron unit with variability with the voluntary contraction of the muscle. Electromyography
This will show the markedly unstable action potential at motor neuron unit with variability with the voluntary contraction of the muscle.
Investigations to detect underlying small cell carcinoma of lungs and other malignacies. In all adult patients with LEMS thorough investigations must be carried out to exclude small cell lung cancers. Chest xray, CT scan and MRI scan of the chest have to be performed. The broncoscopy is essential if the imaging is normal. If the facilities are available positron emission tomography (PET) scanning should be considered. Even with negative investigations patient may be having early lung cancer therefore the further surveillance is must during follow up.
To exclude other malignancies ultra sound scan of the neck, abdomen, pelvis, breast and mammography, CT or MRI scan, endoscopies can be performed. Serology vise markers of malignancies such as LDH, CEA, CA-125, CA-19.9 can be tested.
Investigations to detect underlying small cell carcinoma of lungs and other malignacies.
In all adult patients with LEMS thorough investigations must be carried out to exclude small cell lung cancers. Chest xray, CT scan and MRI scan of the chest have to be performed. The broncoscopy is essential if the imaging is normal. If the facilities are available positron emission tomography (PET) scanning should be considered. Even with negative investigations patient may be having early lung cancer therefore the further surveillance is must during follow up.
To exclude other malignancies ultra sound scan of the neck, abdomen, pelvis, breast and mammography, CT or MRI scan, endoscopies can be performed. Serology vise markers of malignancies such as LDH, CEA, CA-125, CA-19.9 can be tested.
For other differential diagnoses As mentioned above for other differential diagnoses serum electrolytes including sodium , potassium, calcium and magnesium has to be checked. For patients suspected to have hypothyroidism TSH and free T4 to be checked. For other differential diagnoses
As mentioned above for other differential diagnoses serum electrolytes including sodium , potassium, calcium and magnesium has to be checked. For patients suspected to have hypothyroidism TSH and free T4 to be checked.

Investigations - Management

Fact Explanation
For the emergency management When the patients are presenting with acute respiratory distress acute management should be done at the emergency department. There full blood count, ECG, arterial blood gas analysis, serum electrolytes and saturation should be done. For the emergency management
When the patients are presenting with acute respiratory distress acute management should be done at the emergency department. There full blood count, ECG, arterial blood gas analysis, serum electrolytes and saturation should be done.
Spirometry To assess the status of respiratory function spirometry which is a bed side test can be carried out which shows the vital capacity of the patient. It denotes the indication for ventilation support as well. Spirometry
To assess the status of respiratory function spirometry which is a bed side test can be carried out which shows the vital capacity of the patient. It denotes the indication for ventilation support as well.
Seek for a malignancy During the followup visits investigations must be carried out to seek for hidden malignancies. These include CT scans, MRI scans, Broncoscopies and malignancy markers as discussed above. Seek for a malignancy
During the followup visits investigations must be carried out to seek for hidden malignancies. These include CT scans, MRI scans, Broncoscopies and malignancy markers as discussed above.
FBC, Serum Calcium levels, DEXA scan, Fasting blood sugar, Upper GI endoscopies During the management with long term steroids infections can cause such as infection, osteoporosis, Diabetes mellitus and gastritis. So those should be detected early and treated timely. FBC, Serum Calcium levels, DEXA scan, Fasting blood sugar, Upper GI endoscopies
During the management with long term steroids infections can cause such as infection, osteoporosis, Diabetes mellitus and gastritis. So those should be detected early and treated timely.

Management - Supportive

Fact Explanation
Emergency management As an emergency patient may present to the emergency department with evidence of respiratory paralysis. In these situation the ABC should follow. The airway has to be maintained breathing has to be optimized. The patient may need intubation and ICU care for ventilation. Large bore cannula with adequate hydration should be ensured. With the achieve of the diagnosis plasma paresis or immunosupression may be needed who presents with acute weakness. Emergency management
As an emergency patient may present to the emergency department with evidence of respiratory paralysis. In these situation the ABC should follow. The airway has to be maintained breathing has to be optimized. The patient may need intubation and ICU care for ventilation. Large bore cannula with adequate hydration should be ensured. With the achieve of the diagnosis plasma paresis or immunosupression may be needed who presents with acute weakness.
Health education This should the rare occurrence of the disease, the brief pathophysiology, progression and the prognosis of the illness, importance of follow up, available treatment options and patient should be thoroughly emphasized about the high probability of having a malignancy underlying. He or she should be educated about the importance of followup with investigations in view of finding a hidden malignancy. Health education
This should the rare occurrence of the disease, the brief pathophysiology, progression and the prognosis of the illness, importance of follow up, available treatment options and patient should be thoroughly emphasized about the high probability of having a malignancy underlying. He or she should be educated about the importance of followup with investigations in view of finding a hidden malignancy.
Avoidance of exacerbating environmental factors The mostly identified aggravating environmental factor would be the hot ambient temperature, therefore the avoidance of such factors including hot shower baths may prevent the worsening of symptoms. Avoidance of exacerbating environmental factors
The mostly identified aggravating environmental factor would be the hot ambient temperature, therefore the avoidance of such factors including hot shower baths may prevent the worsening of symptoms.
Avoidance of exacerbating or worsening medications The drugs which may impede the transmission of neuro muscular junction will cause worsening symptoms. Therefore those medications are better avoided unless really indicated. Examples are antibiotics (aminoglycosides, fluoroquinolones and some macrolides), antiarrhythmics (quinine, quinidine, procainamide) and beta blockers. IV magnesium or Iodine containing contrast mediums also could cause worsening symptoms. Avoidance of exacerbating or worsening medications
The drugs which may impede the transmission of neuro muscular junction will cause worsening symptoms. Therefore those medications are better avoided unless really indicated. Examples are antibiotics (aminoglycosides, fluoroquinolones and some macrolides), antiarrhythmics (quinine, quinidine, procainamide) and beta blockers. IV magnesium or Iodine containing contrast mediums also could cause worsening symptoms.
Proper exercise and physiotherapy Properly arranged regular physiotherapy may help to maintain the muscle strength. Proper exercise and physiotherapy
Properly arranged regular physiotherapy may help to maintain the muscle strength.

Management - Specific

Fact Explanation
Treatment of underlying malignancy As mentioned previously the associated malignancy commonly the small cell carcinoma of lungs should be identified and managed promptly. The treatment of the cancer will improve the symptoms of LEMS. When the patient is having an underlying cancer the may be no or little improvement with immmunotherapy when administered prior to the treatment of cancer. When there is no underlying malignancy aggressive immunotherapy can be started. Treatment of underlying malignancy
As mentioned previously the associated malignancy commonly the small cell carcinoma of lungs should be identified and managed promptly. The treatment of the cancer will improve the symptoms of LEMS. When the patient is having an underlying cancer the may be no or little improvement with immmunotherapy when administered prior to the treatment of cancer. When there is no underlying malignancy aggressive immunotherapy can be started.
Medications which will improve the neurotranmittion via neuromuscular junction. These drugs improve the conduction through the neuromuscular junction either by improving the acetyl choline release at pre-synaptic membrane (3,4-diaminopyridine) or reducing the turn over of acetyl choline at post-synaptic membrane (pyridostigmine). Medications which will improve the neurotranmittion via neuromuscular junction.
These drugs improve the conduction through the neuromuscular junction either by improving the acetyl choline release at pre-synaptic membrane (3,4-diaminopyridine) or reducing the turn over of acetyl choline at post-synaptic membrane (pyridostigmine).
Immunotherapy When the improvement with above medication is not adequate aggressive immunotherapy is indicated. This can be achieved by plasma exchange or Intravenous Immunoglobulin (IVIG 2 g/kg over 2-5 days). But it has to be followed up by long term immuno suppression. Plasma exchange has to be done 4-6 cycles over 5-7 days. Complications should be monitored, such as hypercalcaemia, bleeding and autonomic instability. Immunotherapy
When the improvement with above medication is not adequate aggressive immunotherapy is indicated. This can be achieved by plasma exchange or Intravenous Immunoglobulin (IVIG 2 g/kg over 2-5 days). But it has to be followed up by long term immuno suppression. Plasma exchange has to be done 4-6 cycles over 5-7 days. Complications should be monitored, such as hypercalcaemia, bleeding and autonomic instability.
Immuno suppressants The commonly used immuno suppressants are prednisolone and azathioprine, which can be used alone or in combination. Another option would be cyclosporin.The side effects has to be monitored. Immuno suppressants
The commonly used immuno suppressants are prednisolone and azathioprine, which can be used alone or in combination. Another option would be cyclosporin.The side effects has to be monitored.

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