Setting: office
CC: “I feel so weak at the end of the day.”
VS: BP: 112/72 mm Hg; P: 90 beats/minute; T: 99.8°F (37.7°C); R: 18 breaths/minute
HPI: A 54-year-old woman comes to the office with increasing muscle weakness and tiredness over the past few months. She feels “totally spent” at the end of the day and her “arms and legs feel like lead.” She feels so tired that she has a hard time finishing meals.
ROS:
Double vision
No fever, no headache, no weight loss
PMHX: none
Medications: none
PE:
General appearance: tired, but fully alert
Neurological: decreased muscle strength in all four extremities equally; normal deep tendon reflexes (DTRs); normal pupillary response
Head, ears, eyes, nose, throat (HEENT): bilateral ptosis
Initial Orders:
Anti-ACh receptor antibodies
Anti-muscle specific kinase (MuSK) antibodies
Chest x-ray
Edrophonium (Tensilon) test is neither as sensitive or specific as antiacetylcholine receptor antibodies.
Myasthenia gravis (MG) is not a disease you start to treat empirically unless the patient experienced an acute, overwhelming presentation of weakness threatening breathing. MG is generally a disease that progresses over months.
Report:
Anti-ACh receptor (AChR) antibodies positive
Anti-MuSK antibodies present
Chest x-ray: normal
Anti-AChR antibodies are positive in 90% of those with MG. If patients present with MG limited to the eyes with diplopia, the sensitivity falls to 50%. Anti-MuSK antibodies are generally used in patients whose anti-AChR antibodies are negative.
Anti-MuSK is for those with false negative AChR antibodies.
What is usually the most common presentation of MG?
a. Proximal muscle weakness
b. Diaphragm and respiratory muscle weakness
c. Difficulty chewing and diplopia
d. Upper extremity and hip girdle weakness
e. Four-limb paralysis
Answer c. Difficulty chewing and diplopia
MG usually presents with diplopia and decreased ability to chew because they are the only two muscles used regularly. Because MG is a decremental decrease in strength on repetitive use, the patient must be using the muscles in order for it to be noticed.
What is the difference between pyridostigmine, neostigmine, and edrophonium?
a. Dosing and duration of effect
b. Mechanism of action
c. Adverse effects
d. Site of action
Answer a. Dosing and duration of effect
Acetylcholinesterase inhibitors are all essentially identical except for how long they last and therefore how frequently they are dosed. Acetylcholinesterase inhibitors all block the metabolism or breakdown of ACh at the neuromuscular junction. This increases the level and the clinical effect.
ACh receptors on muscle are nicotinic.
ACh receptors in the lung, bladder, bowel, saliva, and eye are muscarinic.
The patient is started on pyridostigmine. Move the clock forward 2 days. Do an “Interval History” to confirm the effectiveness of the medication. The patient reports a moderate improvement with pyridostigmine. You decide to confirm the diagnosis with additional testing before just increasing the dose.
What is the most accurate test for MG?
a. Biopsy
b. Single-fiber electromyography (EMG)
c. Creatine phosphokinase (CPK) and aldolase
d. ACh level
Answer b. Single-fiber electromyography (EMG)
EMG involves the placement of a needle into the muscle, and repetitive stimulation is sent through it. In MG, there is a clear decrease in muscle strength and frequency of contraction in response to nerve stimulation. More electrical jolts produce fewer muscular contractions.
Single-fiber EMG confirms the diagnosis as MG. You increase the dose of pyridostigmine. Do a chest CT as soon as the diagnosis of MG is confirmed. This is to exclude thymic hyperplasia and thymoma associated with MG. If it is found, it will need to be removed.
In children, the thymus gland “programs” T lymphocytes for action.
The thymus gland has little residual function in adults and can be removed without major adverse effect.
Move the clock forward and see the patient every month. Perform a neurological examination at each visit to assess the effectiveness of your medications. The patient is lost to follow-up for a few months and runs out of medications. When she returns, the patient has an overwhelming weakness and respiratory distress.
What is the treatment that will have the fastest effect for this acute myasthenic crisis?
a. Start intravenous immunoglobulin (IVIG).
b. Give steroids.
c. Remove the thymus gland.
d. Give anti-tumor necrosis factor drugs (e.g., etanercept).
e. Give cyclosporine.
Answer a. Start intravenous immunoglobulin (IVIG).
Acute myasthenic crisis is treated with IVIG or plasmapheresis. IVIG is much easier to use. Plasmapheresis has the same difficulty as setting up dialysis. The presumed mechanism of IVIG is that the Fc portions of the immunoglobulins will “stuff up” or fully saturate the Fc receptors on the macrophage. The macrophage then can no longer remove ACh receptors at the neuromuscular junction (Figure 4-1). Anti-tumor necrosis factor (TNF) medications have no benefit in MG. Steroids, cyclosporine, azathioprine, and cyclophosphamide take weeks or months to work.
Figure 4-1. Pathogenesis of myasthenia gravis. Acetylcholine released at the nerve ending by the nerve impulse normally binds with acetylcholine receptors. This evokes the action potential in the muscle. In myasthenia gravis, antiacetylcholine receptor antibody binds to the acetylcholine receptor and inhibits the action of acetylcholine. Bound antibody evokes immune-mediated destruction of the endplate. (Reproduced with permission from Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed., New York: McGraw-Hill; 1998.)
MG will impair the patient’s ability to inhale.
Acute myasthenic crisis = IVIG or plasmapheresis
Plasmapheresis removes antibody that attacks ACh receptors.
IVIG blocks macrophages that attack ACh receptors.
IVIG and pyridostigmine are started. The patient is moved to the ICU. After 24 hours, she starts to improve. After 2 days, she is breathing normally and able to walk. Move the patient to the ward and advance the clock. After another day, send the patient home.
Never send the patient home directly from ICU.
After the patient is discharged, she does well for a few months, and then the disease starts to progress. See the patient on CCS at 1-month intervals and do an “Interval History” and neurological examination each time. The patient’s symptoms worsen on maximal pyridostigmine.
What is the next step?
a. Give IVIG.
b. Perform a thymectomy.
c. Add neostigmine.
Answer b. Perform a thymectomy.
The thymus gland programs the T cells that attack the neuromuscular ACh receptor. Removing the thymus gland in MG is like removing the spleen in a person with idiopathic thrombocytopenic purpura (ITP). Thymectomy markedly improves neuromuscular function in the majority of patients. It will not have much effect in those who are older than 60 to 70 years of age in whom T-cell function is already set and thymus removal will alter little.
You cannot move to a place called “Operating Room.”
Order the procedure you need. CCS will tell you if a consultation is required.
The patient undergoes thymectomy. Over the next few weeks symptoms have mild improvement, but the patient cannot function normally. There is additional drug therapy to consider in patients with MG:
Cyclosporine
Azathioprine
Tacrolimus or sirolimus
What is the mechanism of these medications?
a. Neutrophil inhibition
b. Interleukin-1
c. Leukotriene inhibition
d. Decrease of T-cell activation
e. Prostaglandin activation
Answer d. Decrease of T-cell activation
Cyclosporine is a calcineurin inhibitor. Azathioprine, its metabolite 6-mercaptopurine (6MP), and tacrolimus all inhibit activation of T cells. The major defect in MG is abnormal T-cell activation directed against the ACh receptor. Sometimes glucocorticoids can be used in the short term for control of MG over a few weeks. These other medications are then used to get the patient off steroids.
Make sure you exclude thymic hyperplasia and thymoma in MG.
MG is always progressive on acetylcholinesterase inhibitors. They do not interrupt the disease process.
Order each of the immunosuppressive drugs and advance the clock 1 month. It takes 2 to 3 months to see a maximal effect of these medications. They are slow in action. It is impossible to be sure which one will work in advance.
Check the renal function of patients on cyclosporine.