Myasthenia Gravis and Other Disorders of the NMJ 2 Flashcards
Lambert - Eaton pathogenesis
Autoimmune or paraneoplastic syndrome caused by autoantibodies against P/Q type voltage gated calcium channels (presynaptic) and reduced neurotransmitter release at the NMJ AND AUTONOMIC terminals
Lambert - Eaton clinical symptoms
Generalized fatigable weakness is the major symptom.
Patients often complain of myalgia, muscle tenderness, and stiffness.
There may be improvement in strength with exercise.
Oculobulbar and respiratory symptoms are much less common than with MG, but patients with LEMS can present with respiratory compromise.
Patients may complain of a metallic taste, and often have autonomic dysfunction causing dry mouth, orthostasis, constipation, and impotence.
Lambert - Eaton clinical examination
Proximal limb weakness without significant muscle atrophy is the most frequent finding
The elicited weakness is often mild compared with the patient’s complaints
Deep tendon reflexes are almost always depressed or absent but may be potentiated by brief contraction
Pupils may be dilated and weakly responsive to light secondary to autonomic dysfunction
Lambert - Eaton diagnosis
1) Antibodies:
- Antibodies against P/Q-type VGCCs can be detected in more than 90% of patients with LEMS.
- Antibodies to N-type VGCCs can be found in up to 50% of patients (this percentage is higher in malignancy-associated LEMS)
- Organ-specific autoantibodies (to thyroid, gastric parietal cells, or skeletal muscle) and non–organ-specific autoantibodies (antinuclear, antimitochondrial) are also found in patients with LEMS.
2) Electrodiagnostic studies
- The CMAP is low in most muscles tested and CMAP amplitude at rest is the best marker of disease severity.
As in MG, most patients have a decrementing response to slow rates of repetitive stimulation; however, the decrement progresses during the course of the stimulation.
The diagnosis of LEMS is confirmed on high-frequency RNS by a reproducible postexercise increase in compound muscle action potential (CMAP) amplitude of at least 100 percent compared with pre-exercise baseline value
(increments of 60 to 99 percent are strongly supportive of a presynaptic neuromuscular junction disorder)
- Needle electromyography demonstrates unstable motor unit action potentials that change configuration from impulse to impulse due to blocking of individual muscle fibers. When many muscle fibers are blocked, the motor units can be small, polyphasic, and of short duration.
- As with MG, increased jitter and impulse blocking are seen on single-fiber electromyography
Percentage of Lambert Eaton with small cell lung cancer
60%
Characteristic of younger patients with LE compared to older patients
Younger patients are more likely to have underlying autoimmune disease as opposed to malignancy
Lambert - Eaton differential diagnosis
- MG
- Motor neuron disorder
- Inflammatory myopathy
- Limb-girdle muscular dystrophy
- Peripheral nerve disorder
LEMS association with cancer
- Small cell lung carcinoma
- lymphoproliferative disorders, including Hodgkin lymphoma
Rarely:
- atypical carcinoid
- Merkel cell carcinoma
- thymic neuroendocrine carcinoma
- malignant thymoma
- thymic small cell carcinoma
- neuroblastoma
LEMS initial cancer evaluation
- CT of the chest, abdomen, and pelvis.
- MRI of the brain and/or spinal cord should also be obtained if there are focal neurologic symptoms or signs suggesting involvement of the CNS
- FDG-PET imaging for all high-risk patients, such as those with a Dutch-English LEMS Tumor Association Prediction (DELTA-P) score ≥3, who have negative CT imaging.
- testing for SOX antibodies for any patient with suspected LEMS without a known SCLC and suggest FDG-PET imaging for patients of any age or smoking history who have elevated SOX antibodies and nondiagnostic CT imaging
If the initial malignancy evaluation is negative in patients with LEMS, repeating the chest CT scan at three months for high-risk patients (eg, a DELTA-P score ≥3) and patients with elevated SOX antibody titers and at six months for low-risk patients is recommended. This is followed by screening at least every six months up until at least two years if testing remains unrevealing
LEMS treatment
For patients with LEMS with or without a malignancy who have weakness that interferes with function, initial symptomatic therapy with amifampridine is suggested.
(Amifampridine is the phosphate salt of 3,4-diaminopyridine (3,4-DAP))
Search and treat malignancy!
● Immunotherapy for refractory weakness
*IVIG – For patients with LEMS without malignancy or with a treated malignancy who have moderate or severe weakness that interferes with function and does not improve sufficiently with symptomatic therapy, initial use of intravenous immune globulin (IVIG) at a dose of 2 g/kg total over two to five days is suggested, rather than oral immunosuppressive drugs or plasma exchange
*Alternative and adjunctive options – Our preferred alternative regimen to IVIG is to simultaneously start oral prednisone, 1 mg/kg per day or 1 to 1.5 mg/kg every other day, and azathioprine 2 to 3 mg/kg per day, followed later by an attempt to taper or discontinue prednisone
Other reasonable choices would be oral prednisone (1 mg/kg per day or 1 to 1.5 mg/kg every other day) alone, azathioprine alone at 2 to 3 mg/kg per day, other oral immunosuppressives (cyclosporine and mycophenolate), or plasma exchange given as five or more exchanges (3 to 5 L of plasma each) over 7 to 14 days.
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Botulism pathogenesis
Botulism is caused by ingesting the neurotoxin of the bacterium Clostridium botulinum (found in soil)
After absorption into the bloodstream, botulinum toxin binds irreversibly to the presynaptic nerve endings of the peripheral nervous system and cranial nerves.
Once internalized, the toxin inhibits the release of acetylcholine through the cleavage of polypeptides essential for the docking of synaptic vesicles to the presynaptic membrane of the nerve terminal.
Botulism clinical findings
The initial symptoms of food-borne botulism (but not the wound-acquired form) may be gastrointestinal—nausea, vomiting, and diarrhea—and generally appear within 2–36 hours of ingestion. Constipation is more common once
neurologic symptoms are present.
The earliest neurologic symptoms are oculobulbar and include dry mouth, blurred vision, diplopia, dysarthria, dysphagia, and dysphonia.
In contrast to most cases of Guillain-Barré syndrome, botulism is characterized by a descending paralysis.
Weakness begins in the cranial nerves, followed by the upper extremities, respiratory muscles, and finally lower extremities. The weakness progresses from proximal to distal muscles.
Botulism also affects autonomic synaptic transmission, resulting in constipation, postural hypotension, and urinary retention.
On examination, pupils are unreactive and tendon reflexes are absent.
Botulism types
- Food-borne botulism
- Infant form of botulism (C botulinum spores enter and colonize the immature gastrointestinal tract and produce toxin. This is most often
associated with the ingestion of honey) - Wound botulism (eg intravenous drug users)
- Patients treated with intramuscular injections of botulinum toxin
Difference in presentation between botulism and Guillain Barre
In contrast to most cases of Guillain-Barré syndrome, botulism is characterized by a descending paralysis.
Weakness begins in the cranial nerves, followed by the upper extremities, respiratory muscles, and finally lower extremities.
The weakness progresses from proximal to distal muscles.
Botulism has no sensory symptoms
Botulism diagnosis
Blood and stool can be sent for detection of the botulinum toxin.
C botulinum itself can be detected in stool
Electrodiagnostic studies:
The most consistent finding is a small CMAP in response to a supramaximal stimulus.
As with LEMS, repetitive stimulation testing may show a decrement of the CMAP to low rates of stimulation and postexercise facilitation of the CMAP amplitude.
