Most patients with myasthenia gravis (MG) have a silent onset, with only a few progressing rapidly. The disease may be triggered by prolonged stress, infection, pregnancy, or the use of certain medications.
Overview of Myasthenia Gravis
Myasthenia gravis is a chronic autoimmune neuromuscular disease caused by the blockade of antibodies through ACh receptors, leading to skeletal muscle weakness. It most commonly affects the muscles controlling the eyes and eyelids, facial expression, chewing, swallowing, and speaking. However, it can also affect almost any part of the body.
This is a type II hypersensitivity immune response. The underlying pathology is a decrease in the number of ACh receptors (AChR) at the postsynaptic muscle membrane due to a self-immune reaction generating AChR blocking antibodies.
MG can occur at any age, with the highest incidence in females at the age of 30, while in males it is around 60-70 years old. The average onset age is 28 years in females and 42 years in males. Transient neonatal myasthenia gravis occurs in newborns of myasthenic mothers with AChR blocking antibodies transmitted through transplacental IgG. Some newborns may have transient neonatal myasthenia gravis due to the effect of these antibodies. Most newborns of myasthenic mothers have AChR blocking antibodies at birth, but only 10-20% develop neonatal myasthenia gravis.
Signs of myasthenia gravis.
How is Myasthenia Gravis diagnosed?
The clinical symptoms used to diagnose Myasthenia Gravis include
The hallmark feature of myasthenia gravis is muscle weakness that occurs after a period of activity and improves partially or completely after rest.
Most patients have a gradual onset of symptoms, while only a few progress rapidly. The disease can be triggered by prolonged stress, infection, pregnancy, or certain medications.
Initially, patients usually experience weakness in the muscles of the eyes, face, chewing, throat, and neck. It is very rare for patients to present with weakness in the limb muscles. If the disease progresses severely, the patient may have muscle damage throughout the body.
Up to 85% of patients have ocular muscle involvement with symptoms such as:
- The typical drooping of the eyelid, sometimes on one side only, while the other eye opens wider due to compensatory effort. Along with this drooping, patients may experience double vision.
- The Cogan sign can be used to test patients: By having the patient look down and then quickly up, the upper eyelid will jerk up, then down.
- The Gorelick maneuver can be used to test for ocular muscle weakness: By having the patient look steadily at a fixed point above, the upper eyelid on one side will gradually droop, and the examiner can pull and hold it up. After a brief period, the upper eyelid on the other side will also begin to droop.
A patient with facial muscle weakness may have a droopy and expressionless face, with a crooked or absent smile. When at rest, the corners of the mouth may droop, making the patient appear sad. When attempting to smile, the middle part of the upper lip may be pulled back, but the tightness across the mouth and the lack of natural upward curve may make the smile appear unnatural.
About 40% of patients with muscle weakness in the abdomen may have difficulty with their speech, resulting in a nasal or muffled voice. Some may also experience nasal regurgitation. In some cases, patients may be unable to purse their lips or whistle.
Patients with weakness of the jaw muscles may have difficulty with chewing, and difficulty swallowing may increase over time. Patients may also experience weakness of the neck muscles, resulting in a drooping neck.
As the disease progresses, most muscles will become weak, including respiratory muscles such as the diaphragm, intercostal muscles, and abdominal wall muscles. Even the sphincter muscles of the bladder and rectum may become weak. At this point, patients may experience difficulty breathing and respiratory failure. If the patient has weakness in the proximal muscles of the limbs, it is usually more severe than weakness in the distal muscles.
Typically, the patient only experiences mild muscle weakness in the morning, but it worsens as the day progresses. Muscle atrophy is rare, and smooth muscles are not affected, and reflexes and eye movements remain normal.
The patient’s life may be in danger if they experience two almost opposite conditions: myasthenic crisis and cholinergic crisis.
Myasthenia gravis needs to be detected early.
Diagnostic tests in clinical practice for diagnosing myasthenia gravis
The Edrophonium (Tensilon) test is a useful method for differentiating between a myasthenic crisis and cholinergic crisis caused by medication based on the recovery of muscle strength after Edrophonium injection. Before performing the test, 0.8 mg of Atropine is injected subcutaneously to the patient. Then, the patient is instructed to look upward until the ptosis appears or gaze steadily in one direction to induce diplopia. When symptoms appear, Tensilon is administered intravenously at a total dose of 10 mg, corresponding to 1 ml. Initially, 1 mg is injected, and if the patient responds well and muscle strength gradually recovers after 45 seconds, 3 to 6 mg is injected further. If there is still no response after 45 seconds, the remaining amount can be administered within 1 minute. Most patients respond to 5 mg of Tensilon, and the effect lasts for 4 to 5 minutes. If the patient is given the maximum dose but there is no improvement in ptosis or diplopia, cholinergic crisis or muscle weakness may not be due to myasthenia gravis.
The Neostigmine test is also used in myasthenia gravis, and 0.8 mg of Atropine is injected subcutaneously before the test. Next, the patient is injected with Neostigmine intramuscularly at a dose of 1.5 mg. After 10 to 15 minutes, the symptoms of muscle weakness will gradually diminish, which may last for 2 to 3 hours. Most negative cases will not be due to myasthenia gravis, but this risk cannot be completely ruled out.
The ice pack test is performed if ptosis is suspected to be due to myasthenia gravis. A rubber glove filled with ice water is wrapped in a cloth and placed on the patient’s eye for 2 minutes. If the ptosis resolves, the diagnosis of myasthenia gravis is confirmed.
In addition, the patient may undergo further diagnostic tests such as electromyography, chest X-ray, arterial blood gas analysis, and respiratory function tests.
How is myasthenia gravis treated?
Treatment of muscle weakness with Cholinesterase inhibitors
Inhibitors of Acetylcholine esterase (AChE) are considered the basic treatment method for myasthenia gravis. The drugs help improve muscle weakness in patients and usually decrease after several weeks to months of treatment.
Pyridostigmine in immediate-release form is taken at a dose of 60 to 1500 mg per day, usually 600 mg/day divided into 5 or 6 doses. For extended-release formulations, a dose of 180 to 540 mg once or twice daily, with at least a 6-hour interval between doses, is used.
Neostigmine orally: the initial dose is 15 mg per dose, 3 times per day. The usual daily dose is 150 mg divided into two doses, used within 24 hours.
Neostigmine IM, IV: the dose used per administration is 0.5 to 2.5 mg, depending on the patient’s response and appropriate dosage.
Cholinesterase inhibitors can cause adverse effects, including muscarinic syndrome with symptoms such as nausea, vomiting, pallor, sweating, salivation, slow heart rate, abdominal pain, and diarrhea. To minimize the side effects of Cholinesterase inhibitors, patients are often treated in combination with Atropine.
Using Corticosteroids for Myasthenia Gravis Patients
Using Corticosteroids for Myasthenia Gravis Patients
Corticosteroids are anti-inflammatory and immunomodulatory drugs used to treat autoimmune and idiopathic disorders. They are one of the first immunomodulatory agents used to treat myasthenia gravis and are still commonly used with effectiveness. These drugs are typically used in cases where patients have only partial response or are severe and unresponsive to AChE inhibitors and thymectomy.
Patients with myasthenia gravis usually take corticosteroids orally, starting with a dose of 10-15mg of prednisone per day and gradually increasing to 1-2mg/kg depending on response. If patients are started at too high a dose or have a rapid increase in dose, their symptoms may worsen.
If patients cannot take oral medication, intravenous methylprednisolone can be given. A commonly used brand is Solu-Medrol, with doses ranging from 40-60mg per injection, administered 3-4 times a day. Special caution and adjustment is needed for pediatric patients.
How are immunosuppressive drugs used for patients with Myasthenia Gravis?
Immunosuppressive drugs for patients with Myasthenia Gravis are used in combination with Corticosteroids or as monotherapy when patients do not respond to Corticosteroids. Liver function, kidney function, and white blood cell counts must be monitored during treatment with this approach.
Azathioprine is an Imidazolyl derivative of 6-Mercilaurine (6-MP) and is the second most commonly used immunosuppressive drug for Myasthenia Gravis. Patients are initially started on a dose of 50mg/day for 5 days. If well-tolerated, the dose is increased by 50mg every 5 days until a maximum dose of 150mg/day is reached. The maintenance dose of Azathioprine is typically between 100-200 mg/day, corresponding to 2-3 mg/kg per day.
Cyclosporine A is an 11-amino acid peptide used for patients with myasthenia gravis. Patients are usually given a dose of 2.5 to 4 mg/kg twice daily with meals containing fat. The drug may increase the risk of developing malignancies, cutaneous malignancies, hypertension, renal failure, immunosuppression, hepatotoxicity, seizures, PRES…
Mycophenolate mofetil, marketed as Cellcept, is a derivative of Mycophenolic acid (MPA). It is initially started at a dose of 250mg twice daily for 5 days. Then the dose is increased to 500mg twice daily for the next 5 days and then increased to a dose of 1g twice daily. The drug’s drawbacks include an increased risk of lymphoma, immunosuppression, teratogenicity, renal failure, and other adverse effects like nausea, diarrhea, abdominal pain, fever, leukopenia, and edema.
Plasma exchange for patients with myasthenia gravis
Plasma exchange is a treatment method used for patients with severe and life-threatening myasthenia gravis who do not respond to other treatments. It can also be used for patients before and after thymectomy, or when initiating immunosuppressive therapy.
Immune globulin therapy for myasthenia gravis
Intravenous immunoglobulin (IVIG) infusion is a short-term treatment for life-threatening myasthenia gravis such as respiratory failure or dysphagia that does not respond to other treatments. The patient receives 2 or 5 days of treatment with a total dose of 2g/kg divided evenly, and if necessary, a dose can be repeated every month.
When should myasthenia gravis patients undergo thymectomy?
Abnormal thymus is common in patients with myasthenia gravis. Among all patients with myasthenia gravis, up to 85% have increased thymus production and 10-15% have thymic disease. Thymic disease in generalized myasthenia gravis begins with continuous thymus production. These patients always have the risk of anti-AChR antibodies.
Thymectomy is a standard care for all patients with thymic cancer. This method is also applied to patients aged 10-55 years old without thymic disease but with generalized myasthenia gravis. Patients with thymic tumors almost always use anti-AChR antibodies, so consider carefully those with late onset and positive AChR antibodies. Thymus removal is necessary to prevent local spread and systemic metastasis. Thymectomy may not alter the development of myasthenia gravis in patients with late-onset and generalized myasthenia gravis with thymic abnormalities.
Emergency situations in myasthenia gravis
Patients with myasthenia gravis experiencing a myasthenic crisis or cholinergic crisis can be life-threatening. It is important to differentiate between the two using the Tensilon test as outlined above.
Patients with a cholinergic crisis due to prolonged or high-dose use of cholinesterase inhibitors may exhibit symptoms similar to organophosphate poisoning. The patient may be overly stimulated, resulting in soft muscle paralysis, which can cause bronchospasm and can be difficult to distinguish from weakness due to myasthenia gravis.
If a patient experiences pupillary constriction and the SLUDGE syndrome, it is identified as a cholinergic crisis. However, the symptoms of this syndrome do not always appear. The patient needs to be assessed for arterial blood gas levels, and if the pCO2 level rises, prompt respiratory support is necessary.
In myasthenic crisis, weakness rapidly progresses to limb paralysis and respiratory failure. Patients may experience reduced vital capacity, restlessness, anxiety, diaphoresis, and tremors. If the diaphragm is paralyzed, the patient may exhibit shallow breathing or abdominal and chest movements in the opposite direction during respiration.
Once the patient is on mechanical ventilation, Cholinesterase inhibitors may be temporarily discontinued, and replacement therapy such as plasma exchange or IVIG initiated. Before weaning the patient off the ventilator, Cholinesterase inhibitors should be reintroduced in combination with corticosteroids.
Avoid Aminoglycoside, Polymyxin, Quinolone, and macrolide antibiotics for patients with underlying myasthenia gravis or myasthenic weakness. In addition, avoid antiarrhythmic drugs, corticosteroids, and intravenous magnesium, as they can exacerbate or induce myasthenic weakness.
It is hoped that this article will aid in the diagnosis and treatment of myasthenia gravis.
Johnny Jacks was born in 1985 in Texas, USA. He is the founder of Good Health Plan and is passionate about helping people improve their health and physical well-being. With over a decade of experience working in the healthcare industry, he currently works at Goodheathplan.com – a blog that shares knowledge on beauty and health.