440 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Flashcards
Normal events in the neuromuscular junction
Action potential down the motor nerve and to the nerve terminal
Ach is released and combines with AChRs at the postsynaptic folds
Ach combines with alpha subunit of AChR –> channel opens and permits rapid entry of cations, chiefly sodium
Depolarization at the end-plate region of the muscle fiber
If depolarization is sufficiently large –> action potential along the muscle fiber –> muscle contraction
Hydrolysis of ACh by AChE or diffusion of ACh away from the receptor
Fundamental defect in myasthenia gravis
Decrease in the number of available AChRs at the postsynapic muscle membrane (postsynaptic folds are also flattened or simplified)
Cause of “myasthenic fatigue” (increasing weakness/decremental response)
Decreased efficiency of neuromuscular transmission (due to decreased AChRs) combined with the normal presynaptic rundown (amount of ACh released per impulse normally declines on repeated activity)
Most common cause of MG
Anti-AChR antibodies (autoimmune disorder)
1) accelerated turnover of AChRs by a mechanism involving the cross-linking and rapid endocytosis of the receptors
2) damage to postsynaptic muscle membrane m=by the antibody in collaboration with complement
3) blockage of the active site of the AChR
Other antibodies involved in MG
Anti-MuSK (muscle-specific kinase)
Anti-LRP4 (low-density lipoprotein receptor-related protein 4)
TRUE OR FALSE: The thymus is abnormal in ~75% of patients with AChR antibody-positive MG.
TRUE
Most common abnormality of the thymus in MG (~65%)
Hyperplasia (with presence of active germinal centers detected histologically)
Others: Thymomas (thymic tumors), myoid cells (muscle-like cells within the thymys)
Who is more often affected in MG, women or men?
Women ~3:2
Cardinal features of MG
Weakness and fatigability of muscles
Muscles that are typically involved early in the course of MG
Lids and extraocular muscles (presenting as diplopia and ptosis)
Which manifestation is especially prominent in MuSK antibody-positive MG?
Bulbar weakness (i.e. difficulty in chewing and swallowing)
If weakness remains restricted to the EOMS in this span of time, it is likely that it will not become generalized, and these patients are said to have ocular MG.
3 years
Characteristic limb weakness in MG
Often proximal and may be asymmetric
TRUE OR FALSE: Deep tendon reflexes are preserved in MG.
TRUE
The patient is said to be in crisis when the ventilatory weakness leads to….
Requirement of respiratory assistance
TRUE OR FALSE: If a patient has ptosis, application of a pack of ice over a ptotic eye often results in improvement if the ptosis is due to an NMJ defect.
TRUE
Why will the ptosis improve during an ice-pack test?
Less depletion of quanta of AChR in the cold
Reduced activity of AChE at the NMJ
The finding of these is virtually diagnostic of MG.
Anti-AChR antibodies
TRUE OR FALSE: The absence of anti-AChR antibodies exclude MG.
FALSE (~85% of all myasthenic patients; ~50% of patients with weakness confined to the ocular muscles)
Which medication should be stopped prior to repetitive nerve stimulation in MG?
Anti-AChE medication should be stopped 6-12 h before testing.
How is repetitive nerve stimulation performed?
Electrical stimulation is delivered at a rate of 2-3 per second to the appropriate nerves (weak muscles or proximal muscle groups), and action potentials are recorded from the muscles.
Result of repetitive nerve stimulation that is “highly probable” for MG
Rapid reduction/decrement of >10% at 3 Hz in the amplitude of evoked responses
Drug most commonly used in the anticholinesterase test
Edrophonium (due to rapid onset of 30 s and short duration of ~5 mins)
A positive test in anticholinesterase test means that..
highly probable diagnosis if unequivocally positive
There was definite improvement after a dose of edrophonium (usually given in 2 parts, 2mg + 8 mg IV)
What should be on standby during the anticholinesterase test
Atropine
What is a confirmatory, but not specific, result on single-fiber electromyography
Blocking and jitter, with normal fiber density
Percent of AChR antibody-negative patients with generalized MG that have anti-MuSK antibodies
~40%
What can distinguish congenital myasthenic syndromes (CMS) from MG?
1) Not autoimmune but rather due to genetic mutations in which virtually any component of the NMJ may be affected
2) Symptoms of myasthenia have begun in infancy or childhood
3) Absence of AChR and MuSK antibodies (although also absent in ~10% of generalized MG patients - so called “double seronegative MG”)
The most common genetic defects in congenital myasthenic syndromes (CMS) occur in this subunit of the AChR
Epsilon (~50% of CMS cases)
What can distinguish Lambert-Eaton myasthenic syndrome (LEMS) from MG?
1) Depressed or absent reflexes
2) Presence of autonomic changes such as dry mouth and impotence
3) Nerve stimulation will also show decrement in low-amplitude but will show incremental responses at high rates
4) Caused by autoantibodies to the P/Q-type calcium channels at the motor nerve terminals, which will impair the release of ACh
In older adults, most LEMS is associated with malignancy, most commonly _____.
Small-cell lung cancer
Treatment of LEMS
Plasmapheresis and immunotherapy
3,4-Diaminopyridine (blocks potassium channels which results in prolonged depolarization of motor nerve terminals and thus enhances ACh release)
Pyridostigmine (prolongs the action of ACh, allowing repeated interactions with AChRs)
Characteristics of Botulism
Caused by potent bacterial toxins produced by any of 8 different strains of Clostridium botulinum, which enzymatically cleave specific proteins essential for the release of ACh from the motor nerve terminal
Most commonly caused by ingestion of improperly prepared food containing toxin
Myasthenia-like bulbar weakness (diplopia, dysarthria, dysphagia) and lack sensory symptoms and signs
Reflexes may diminish as disease progresses
Also with autonomic findings
Mentation is normal
Definitive dx: demonstration of toxin in serum (but may be negative)
Treatment: ventilatory support, aggressive inpatient supportive care, antitoxins ASAP
What is Neurasthenia?
Historic term for a myasthenia-like fatigue syndrome without an organic basis (muscle testing reveals the “give-away weakness:)
Which thyroid disorder causes MG-like symptoms?
Both hypo- and hyperthyroidism
TRUE OR FALSE: Some types of congenital myasthenic syndromes can have worsening when given AChE inhibitors.
TRUE
CT scan finding that is highly suspicious of thymoma
Enlargement of the thymus in a patient age >40 years (normally present in young adulthood)
Recommended laboratory tests or procedures in MG
CT or MRI of chest Tests for antinuclear antibodies, rheumatoid factor Thyroid function tests Testing for tuberculosis Fasting blood glucose, HbA1c Pulmonary function tests Bone densitometry
Medication that can produce partial improvement in most myasthenic patients, and usually the first line of treatment except in crisis
Anticholinesterase medications (but with less benefit in or may actually cause worsening in anti-MuSK MG)
Most widely used anticholinesterase drug
Pyridostigmine (action begins within 15-30 mins and lasts for 3-4 h)
Medications given for the treatment of GI side effects of pyridostigmine (diarrhea, abdominal cramps, salivation, nausea)
Atropine/diphenoxylate or loperamide
Recommendations on thymectomy
1) Surgical removal of thymoma
- Necessary because of the possibility of local tumor spread, although most thymomas are histologically benign
2) Thymectomy as a treatment for MG
- Conflicting evidence
- Should NEVER be carried out as an emergency procedure, but only when the patient is adequately prepared (may need to treat with IVIg or plasmapheresis to maximize strength in weak patients)
Types of immunosuppression that must be given depending on the urgency
If immediate improvement is essential
- IVIg or plasmapheresis
If intermediate effect is wanted
- Glucocorticoids and cyclosporine or tacrolimus (clinical improvement within 1-3 months)
For long-term treatment
- Azathioprine and mycophenolate mofetil (beneficial effects begin after many months, as long as a year)
Recommended dosing of glucocorticoids in MG
1) prednisone given in a single dose rather than in divided doses throughout the day (to minimize adverse effects)
2) initial dose should be relative low (to avoid early weakening that occurs in perhaps 10-15% of patients treated initially with a high-dose regimen), in patients with only mild or moderate weakness
3) maintain patient on the dose that seems to control their symptoms for about a month, and then slowly taper
3 most common errors in glucocorticoid treatment of myasthenic patients
1) insufficient persistence - improvement may be delayed or gradual
2) tapering the dosage too early, too rapidly, too excessively
3) lack of attention to prevention and treatment of side effects
Mycophenolate mofetil
MOA?
Advantage?
Why effects take long?
MOA: Inhibition of purine synthesis by the de novo pathway (inhibits proliferation of lymphocytes but not proliferation of other cells; does not kill or eliminate preexisting autoreactive lymphocytes)
Advantage: Relative lack of adverse side effects including very small risks of malignancy
Clinical improvement is delayed for many months to a year, until the preexisting autoreactive lymphocytes die spontaneously
Idiosyncratic reactions to azathioprine, which is why a low initial dose is given to test for side effects
Flulike symptoms of fever and malaise
Bone marrow suppression
Abnormalities of liver function
Drug that should never be used in combination with azathioprine, because the 2 drugs share a common degradation pathway, and may result in severe bone marrow suppression due to increased effects of azathioprine
Allopurinol
Drugs that are effective and work more rapidly but associated with more frequent side effects including hypertension and nephrotoxicity
Calcineurin inhibitors - cyclosporine and tacrolimus
Rituximab
- MOA
- Particularly effective in what type of MG?
MOA: Rituximab is a monoclonal antibody that binds to the CD20 molecule on B lymphocytes
Particularly effective in MuSK antibody-positive MG
MOA of eculizumab
Eculizumab is a monoclonal antibody that binds membrane attack complex.
Treatment that is reserved for refractory MG patients
High-dose cyclophosphamide
- “reboots” the immune system
- eliminates mature lymphocytes but spares hematopoietic precursors (stem cells) because they express the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophosphamide
Treatment that is useful as a temporary expedient in seriously affected patients or to improve the patient’s condition prior to surgery
Plasmapheresis
- plasma which contains the pathogenic antibodies is mechanically separated from the blood cells, which are returned to the patient
- 5 exchanges is generally administered over a 10- to 14-day period
- short-term reduction in anti-AChR antibodies
Definition of “myasthenic crisis”
Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually includes ventilatory failure caused by diaphragmatic and intercostal muscle weakness.
Most common cause of myasthenic crisis
Intercurrent infection
What cause of myasthenic crisis can be best excluded by temporarily stopping it?
“Cholinergic crisis” - deterioration that is caused by excessive anticholinesterase medication
Treatment of myasthenic crisis
ICU treatment
Early and effective antibiotic therapy, ventilatory assistance, and pulmonary physiotherapy
Plasmapheresis or IVIg is frequently helpful in hastening recovery
Drug that should be avoided when treating MG patients with azathioprine
Allopurinol (combination may result in myelosuppression)
Percentage of MG patients that can be tapered off all immunotherapies and achieve a sustained remission.
Approximately 20%
TRUE OR FALSE:
Anti-MuSK patients typically do not experience myasthenic crises, but are generally more difficult to treat than anti-AChR MG.
What should we screen for in an elderly patient diagnosed with LEMS?
An underlying tumor, because LEMS is most often paraneoplastic in older adults
