BY: SAI MANOGNA (MSIWM014)
It is a rare autoimmune disorder acquired by an antibody-mediated neuromuscular transmission blockade that results in weakness in the skeletal muscle.
1. The autoimmune attack occurs when autoantibodies form at the neuromuscular junction of skeletal muscles against the nicotinic acetylcholine post-synaptic receptors.
2. Although the skeletal muscle nicotinic acetylcholine receptor (nAChR) is the main focus of autoimmune attack in most cases, other antigenic targets that are components of the neuromuscular junction (NMJ) have also been implicated.
3. With regular use and regeneration of muscle strength after a period of rest, the decrease in the amount of AChRs results in a characteristic trend of gradually reduced muscle strength. Most often and most remarkably, the ocular and bulbar muscles are impaired, but most patients still experience some degree of fluctuating generalized weakness.
4. Acute aggravation of fatigue, leading to neuromuscular respiratory failure is the most critical feature of MG in emergencies.
Pathophysiology:
In neuromuscular transmission, the following physiologic events occur:
1. A potential for nerve activity propagates down the axon and depolarises the terminal of the presynaptic nerve.
2. In response to depolarization, voltage-gage calcium channels open and there is calcium influx into the nerve terminal through these channels.
3. With the presynaptic membrane, synaptic vesicles fuse, releasing ACh into the synaptic room.
4. On the post-synaptic membrane, ACh molecules bind to AChR, allowing the receptors to undergo a conformational change, opening the ion channel.
5. Increases membrane conductance to Na+ ions (Na+ goes in, K+ goes out) resulting in endplate area depolarization, causing endplate potential (EPP).
6. An action potential is produced in the muscle fibre if the EPP is sufficient to depolarize the adjacent muscle membrane to the threshold. Conversely, it will not cause the muscle membrane to cross the threshold if it is of inadequate magnitude and thus fails to produce a potential for muscle fibre action.
7. There is an occasional release of ACh molecules in the resting state around the primary synaptic cleft.
8. On the post-synaptic membrane, the ACh molecules act as ligands and bind to the AChR. Two ACh molecules bind to and fuse with, the alpha subunits of the AChR. The bound AChR then undergoes a 3D conformational shift to open the funnel-shaped cation channel (whose inner wall is negatively charged) in the central ion channel portion of the AChR (M2, alpha-helical).
9. This opening is small, about 1 ms, resulting in sodium ion influx while allowing potassium efflux along the opposite gradient of concentration at the same time.
10. As a result, the muscle membrane will be shortly depolarized only in the junctional region, creating miniature endplate potential, known as post-synaptic non-propagative depolarization.
11. The standard membrane resting muscle fibre potential is -80 mV (inside negative). The threshold in the muscle fibre for activating an action potential is -50mV to -65mV. 12. As a nerve action potential depolarizes the terminal axons, sodium ion conductance is increased, and voltage-gated calcium channels (VGCCs) are triggered at the same time, facilitating calcium ion inflow to the terminal portion of the axon.
13. In the process of neuromuscular transmission, the entry of calcium ions is crucial (if Ca++ is withdrawn from extracellular space, the transmission of NMJ ceases).
14. The introduction of Ca++ initiates a complex interaction with the presynaptic membrane of several proteins, including the SNARE protein complex at the nerve terminal, which enables the fusion of ACh-containing vesicles.
15. Consequently, the discharge of ACh into the synaptic cleft occurs by exocytosis. The higher the concentration of calcium within the presynaptic terminal, the greater the amount of ACh released into the synaptic cleft.
16. ACh molecules bind to AChRs, which results in more significant post-synaptic membrane depolarization, resulting in endplate potential (EPP).
17. The EPP amplitude is typically high enough to activate the potential for action on the post-synaptic membrane. In the depths of secondary synaptic cleft, voltage-gated sodium channels promote the potential for action that is propagated through the muscle membrane of the NMJ.
18. As the transverse tubule system of the muscle is infringed by this action potential, another voltage-gated calcium channel (VGCC) is activated, triggering calcium ion influx and triggering mechanical contraction of the contractile muscle fibre apparatus.
19. ACh’s activity on the post-synaptic membrane is short-lived and is terminated by hydrolysis by the enzyme acetylcholinesterase into acetic acid and choline within a few milliseconds of its release from the nerve terminal. The presynaptic membrane picks up the latter and is repackaged into new ACh molecules.
The calcium ions are usually pumped within 100 ms from the terminal part of the axon, so they remain for a while and retain the axon terminal in a hyperexcitable state, enhancing the release of ACh should the axon be depolarized within this time frame by a second action potential.
Signs and Symptoms:
The most prevalent signs of myasthenia gravis are
Ptosis, diplopia, muscular atrophy
When the affected muscles are resting, fatigue resolves but returns when they are used again. In colder temperatures, fatigue due to myasthenia decreases.
In 40 per cent of patients and finally, in 85 per cent, ocular muscles are initially affected and are the only muscles affected by 15 per cent. When generalized myasthenia occurs after ocular signs, it occurs within one year in 78 per cent of patients and within the first three years is 94 per cent.
Handgrip (milkmaid’s grip) may alternate between low and regular. Muscles in the neck can become weak. It is normal to have proximal limb weakness. Some patients have signs of bulbar disease ( e.g. speech alteration, nasal regurgitation, choking, dysphagia). Deep tendon reflexes and sensations are common. In strength, manifestations fluctuate from minutes to hours to days.
Myasthenic crisis, a severe generalized quadriparesis or life-threatening weakening of the respiratory muscle, occurs at least once in their lives in around 15 to 20 per cent of patients. It is also due to an infection that overcomes the immune system and reactivates it. Respiratory failure can occur quickly once respiratory insufficiency begins.
Muscle fatigue that can occur when the dosage of anticholinesterase drugs (e.g., neostigmine, pyridostigmine) is too high is a cholinergic crisis. It can be challenging to distinguish a moderate crisis from a worsening of myasthenia. Typically, an extreme cholinergic crisis can be distinguished because it results in increased lacrimation and salivation, tachycardia, and diarrhoea, unlike myasthenia gravis.
Diagnosis:
- Checks are done by bedside
- Levels of AChR antibody, electromyography, or both
Symptoms and symptoms indicate the diagnosis of myasthenia gravis and are confirmed by tests.
a. Checking Bedside:
The standard bedside anticholinesterase test using the short-acting drug edrophonium (< 5 minutes) is not used in the US and many other countries, and edrophonium is no longer available in the USA.
Because weakness due to myasthenia decreases at cooler temperatures, the ice pack test can be used to test patients with ptosis. An icepack is applied to a patient’s closed eyes for 2 minutes for this examination, then removed. Complete or partial resolution of ptosis is a good outcome. The ice pack test typically does not work if ophthalmoparesis is present in patients. The rest of the procedure can be used to procedure patients with ophthalmoparesis. Patients are asked to lie passively in a dark room for 5 minutes with their eyes closed for this examination. After this rest, if ophthalmoparesis resolves, the outcome is positive.
b. Testing against antibodies and electromyography:
To validate the diagnosis, even if a bedside test is unambiguously positive, one or both of the following are required:
i. Levels of Serum AChR antibody
ii. EMG (Electromyography)
Treatment:
Drugs with anticholinesterase to alleviate symptoms
Corticosteroids, immunomodulating therapies (e.g., plasma exchange IV immune globulin [IVIG]), immunosuppressants, or thymectomy to minimize autoimmune reactions
Supportive Treatment
Anticholinesterase medications and immunomodulating therapies are not effective in patients with congenital myasthenia and should be avoided. Intubation and mechanical ventilation are required for respiratory failure patients.
Symptomatic therapy:
Anticholinesterase medications are the foundation of symptomatic therapy but do not change the mechanism of the underlying disorder. Besides, they rarely alleviate all symptoms, and these medications can become refractory to myasthenia.
Pyridostigmine is given orally and titrated on a symptom-based basis to a maximum of 120 mg/dose. Neostigmine can be substituted when parenteral therapy is required (for example, due to dysphagia). Anticholinesterase medications, which are treated with oral atropine or propantheline, can cause abdominal cramps and diarrhoea.
Respiratory treatment is needed for patients who have reacted well to therapy and then deteriorated because they may have a cholinergic crisis, and anticholinesterase drugs must be stopped for several days.
Immunomodulators:
The immunosuppressants disrupt the autoimmune response and slow down the progression of the disease, but do not quickly relieve the symptoms.
Corticosteroids are essential for many patients as maintenance therapy but have no immediate impact on the myasthenic crisis. After the start of high-dose corticosteroids, more than half of the patients worsen acutely. It can take several months to improve; the dosage should then be decreased to the minimum required to manage symptoms.
Azathioprine can be as effective as corticosteroids, but for several months there may be no substantial benefit. The usual precautions include these medications.
Methotrexate, cyclophosphamide, and mycophenolate mofetil are other medications that can be useful.
Monoclonal antibodies (e.g., rituximab, eculizumab) can be helpful but are expensive for patients with refractory disease.
Thymectomy can be recommended for patients with generalized myasthenia if they are older than 80 years of age and should be performed in all thymoma patients.
Plasma exchange or IVIG is useful before thymectomy for myasthenic crisis and for patients who are not drug-responsive.
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