Okay, this is a absolutely bread and butter USMLE question, and it also happens to be one of my favorite topics.
A 32-year-old female presents to the clinic with the complaint of excessive fatigue for the past few weeks.
After returning home from the office, she feels too tired to climb up the stairs or even comb her hair or even chew food.
She has occasionally experienced double vision.
She denies having any fever, cough, weight loss, night sweats, or snoring.
Past medical history is unremarkable.
Physical examination reveals a blood pressure of 124/86, a heart rate of 85,
a respiratory rate of 14 and a temperature of 37°Celsius and a body mass index of 22.6.
On physical examination, the patient’s right upper eyelid is slightly drooping compared to the left side.
Her eye movements are normal. Flexion of the neck is mildly weak.
Muscle strength is 5/5 on all four limbs.
When she is asked to alternate flexion and extension of her arm continuously for five minutes,
power in the proximal upper limb becomes 4 out of 5.
Muscle tone and deep tendon reflexes are normal.
What is the most appropriate test to diagnosis this condition?
Answer choice A: A CT scan of the chest;
Answer choice B: Plasmapheresis;
Answer choice C: Presynaptic calcium channel antibodies;
Answer choice D: Single-fiber electromyography; or -
Answer choice E: Tensilon Test.
Now take a moment to come to your own answer before we go through it together.
Okay, this is a great question.
The topic here you're going to be asked about it on USMLE in one way or another.
Now, this is a Neurology question so that falls under Internal Medicine
and really here we're dealing with a person who has some type of hopefully you get the sense neuromuscular junction
or musculoskeletal some kind of problem.
So that falls under the category of Neuro.
Now this is a two step question.
First thing we got to do is figure out what's the diagnosis
and then second thing we got to do is figure out the most appropriate test to diagnose the condition
and I really want you to pay attention to the fact that they used the word most appropriate test.
When you glance at the answer choices, many ones are reasonable I mean there's not one glowing answer.
This is actually a pretty tough question, but what they're asking for is the ,most appropriate test,
so what is it really -- you got to pay attention to the most appropriate not just any old answer, so that’s USMLE,
it really narrows down to the small details.
And of course, in this case the stem is required because you have to be able to diagnose
and base that diagnosis to figure out the best test to use. Now, let’s do step one.
First thing, let’s determine the diagnosis.
Now, the patient comes in with the chief complaint of fatigue.
She has generalized muscle fatigue and exertion seems to make it worse.
Now, fatigue has a really broad differential
and it includes but not limited to even things like endocrine disorder such as hypothyroidism.
Viral infection such as infectious mononucleosis also called mono, or sleeping disorder such as obstructive sleep apnea -
that can make you have fatigue, or even cardiovascular or even respiratory pathologies or even malignancy can make you tired;
so fatigue has a really broad differential so we got to look past that,
look into at the details of the question stem to come to the diagnosis.
Now, very important in your thinking -- think like this.
She has no systemic complaints.
We’re told -- there’s no fever, there's no weight loss, there's no night sweats.
Her blood pressure’s normal, her heart rate’s normal, her respiratory rate’s normal,
there's no cough, there's no snoring, so really nothing systematically going on
but really what it sounds like is she wants to climb stairs, she wants to comb her hair,
she wants to chew food; double vision -- these all are muscle things.
Of not being able to chew your food for example, the muscles of mastication;
or tired or comb your hair -- that’s proximal muscle weakness; climbing stairs,
that’s proximal leg weakness so really here we're thinking musculoskeletal problem not systemic.
Now, the key here is though is that she actually has worse muscle weakness after exertion.
Early on in the question stem we're told that the fatigue is at the end of the day
so coming home after the office and during examination when they make her flex
and extend her hand continuously for five minutes strength in that limb went down
from a perfect five out of five down to a four out of five so she got weak with repetitive use.
Now, they also mentioned that in one of her eyes, she has drooping of her eyelid, this is also called ptosis.
Now, ptosis really is unique that you don’t see that very commonly.
Ptosis is very likely seen on USMLE at least in a condition called Myasthenia Gravis.
Now you can support that diagnosis a few different ways.
First thing they tell you is that the reflexes are normal, and in Myasthenia we expect it to be normal.
Also, they give you a few specialized exams that are really more specific to Myasthenia Gravis,
for example, repetitive muscle movement that’s getting weak -- that’s extremely likely to be Myasthenia Gravis,
and they also tell you a few more things, that flexion of the neck is mildly weak.
Now the neck is part of the axial structure so if a fraction of the neck is weak that is some axial weakness
and what we actually do in Neurology is use the weakness of neck flexion as an indicator of how much strength the diaphragm has
cuz if you imagine the diaphragm is also a muscle so with Myasthenia patients
can become too short of breath and may even require intubation
so they're actually giving you another big hint by telling you about neck flexion strength.
Now, this is a classic case of Myasthenia Gravis.
So now that we know the diagnosis -- the patient has repetitive weakness upon repetitive muscle use,
she has diplopia, some episodes of double vision that’s very common in patients with Myasthenia
because the extraocular muscles get fatigued and she also has ptosis in one of her eyes which is again very common in Myasthenia.
So here the diagnosis rather clearly is Myasthenia Gravis.
Now let’s figure out what the answer is now based on how we can diagnose
this patient most appropriately now that we know the diagnosis.
Well, if you think about Myasthenia itself it’s a disease that affects the neuromuscular junction.
Now, looking at the image you can see on the left a normal neuromuscular junction in which you have a myelin sheath, an axon.
You actually have the acetylcholine being released from the neuron
going into the neuromuscular junction and then going on to the nicotinic acetylcholine receptors
-- and then you’ll have the muscle contract.
Now look at the right side of that image you have what's going on in the condition of myasthenia gravis
in which antibodies are actually directed at those same nicotinic acetylcholine receptors.
Now, imagine those antibodies are getting in the way in the receptors and the acetylcholine can’t touch them.
So if you can't get the acetylcholine touching the receptor the muscle doesn’t know to move
and then you actually have prevention of binding and it gives you the weakness of Myasthenia Gravis.
Now why does repetitive movement make it worse?
Because you're just building up more fatigue from not being able to move your muscle.
Now, what ends up happening here if you think about it electrically,
you will have slow or a blocked electrical impulse between the neuron and the muscle at the neuromuscular junction,
so really the choice for testing Myasthenia Gravis is really to look at the interplay
between acetylcholine at the neuromuscular junction so we really have two choices here;
we can do single-fiber electromyography or EMG to measure the nerve conduction in the actual neuromuscular junction
or we can do what's called a Tensilon test. Now the Tensilon test,
Tensilon is just a substance that is actually called edrophonium.
Now edrophonium is an acetylcholinesterase inhibitor so it blocks the breakdown of acetylcholine.
Now, calcium channel antibodies will also affect the acetylcholine neuromuscular junction function
in a condition that is called Lambert-Eaton syndrome.
So really the Tensilon test is not the test we use for Myasthenia, it’s what we use for Lambert-Eaton
so that then narrows down the answer to single-fiber electromyography and that’s answer choice D as being the correct test.
Now, just so you know, no one uses the Tensilon test anymore,
it causes bradycardia and it has other side effects, we've gotten around that.
The reason why we use single-fiber electromyography
is because we’re actually stimulating repetitive use to see if the diagnosis is correct.
Now if you asked a patient with Myasthenia to repetitively move a limb, they're going to get tired.
That’s how the disease works.
Well, what we do in single-fiber electromyography is we take a needle,
we actually put it in the thenar eminence of the hand and repetitively stem the muscle with varied light electricity,
and we will see graphs on a computer as to the actual movement of the electricity
and what we will see is as we repetitively stimulating it, the actual amplitude of the electricity will go down
because of all those antibodies blocking the way and that’s how we diagnose it electrographically.
Now, when you looked at these answer choices, now that you know the answer is Myasthenia diagnosis
and the best test is single-fiber electromyography,
let’s look at the other answer choices to see how could you have eliminated the other ones
to help increase your odds of picking the right answer.
Now, obviously answer choice D, this patient’s coming in fluctuating proximal muscle weakness
that increases the fatigue with exertion and repetitive movements make it worse,
this is definitely is supposed to make you think Myasthenia,
it’s an autoimmune condition, we talked about how it’s antibodies against the nicotinic acetylcholine receptors.
Now, since it’s an autoimmune condition, just remember,
this disease is more common in young women than men as with most autoimmune conditions.
Now, with Myasthenia, it commonly affects the muscles that move a lot and that’s going to be the eyes,
the muscles of the face, bulbar muscles.
Bulbar muscles is just really a fancy way of saying muscles that are controlled by cranial nerves in your head,
that’s all that means and of course proximal limb muscles -
and that will give you the symptoms of ptosis, which is eyelid droop; diplopia,
that’s double vision from extraocular muscle fatigue; dysarthria,
that’s the muscles of swallowing that are controlled by the cranial nerves in talking; dysphagia,
also swallowing; difficulty in chewing, muscles of mastication are gonna be fatigued;
and of course proximal muscles of climbing stairs and combing your hair.
Now, since the disease is due to the antibodies against the acetylcholine receptor,
you need to memorize that you are going to be having antibodies against the acetylcholine receptor.
But USMLE is really, really, really clever, so it goes usually one-step beyond that basic fact that’s in most books.
Now, in a small number of patients that have Myasthenia,
they actually have another type of muscle specific, tyrosine kinase antibody called MuSK, M-u-S-K.
So, in your head, I want you to memorize antiacetylcholine receptor antibody or antiMuSK,
as the two antibodies from Myasthenia Gravis and given how USMLE’s been performing lately antiMuSK
is more likely to be tested sometimes because it’s more rare and not as broadly taught but you're hearing it here from me.
Now, again the repetitive nerve conduction study is how we diagnosed it and it’s the best test for Myasthenia
and say for example, you get some serum from a patient and their serum negative there's no antibodies
to the acetylcholine receptor or antiMuSK but that repetitive stem show decrease,
well, wow, they still have Myasthenia Gravis, they just happen to have what's called seronegative Myasthenia Gravis,
and that’s why it’s the most appropriate test for this patient not just any old test
so that’s again the key I was mentioning earlier, answer the question being asked,
what's the most appropriate best test and it’s the nerve conduction study
because even when you can’t find antibodies in the serum, the nerve conduction study confirms the diagnosis.
Now, let’s look at the other answer choices.
Answer choice A, CT scan of the chest. Now, this is relevant to Myasthenia Gravis.
You do a CT of the chest in patients with Myasthenia to look for a thymoma
and if you see it, you take it out and usually the symptoms of the patient significantly improve
but this is a way to look for thymoma, it’s not how you diagnose the condition.
Now look at Answer choice B, plasmapheresis.
Now plasmapheresis is a machine that takes blood from your body, cleans out the antibodies and put’s the blood back.
Now this is an option we use for therapies, this is not a diagnostic, this is a therapeutic modality.
So, what happens here is when patient’s are in what’s called Myasthenic crisis meaning their Myasthenia
is so severe they can’t safely swallow or breathe,
we may have to intubate them and will usually give them something like plasmapheresis
to try to clean up those bad antibodies to improve their symptoms.
So, Answer choice C is presynaptic calcium channel antibodies.
Now these antibodies are specific for a Lambert-Eaton syndrome not Myasthenia Gravis
and if you were thinking, well, could this be Lambert-Eaton?
Well, no, because repetitive stem of repetitive muscle use will actually improve muscle strength not make it worse
and these patients actually have absent or depressed deep tendon reflexes, not normal,
and they also have autonomic dysfunction but very high-yield to know for Lambert-Eaton,
it’s a paraneoplastic condition most highly associated with small-cell lung carcinoma.
And Answer choice E which is the Tensilon test or the edrophonium test
and again, that’s an acetylcholinesterase enzyme inhibitor, but then and again,
that’s not the best test, it is the actual muscle test with the nerve conduction
and given all the side effects no one uses a Tensilon test anymore.
Okay, now let’s review some high-yield facts for this case.
Now Myasthenia Gravis, this is an autoimmune neuromuscular disease
in which you actually have antibodies directed at the nicotinic acetylcholine receptors.
Now it’s not enough to just know it’s acetylcholine receptors, also memorize nicotinic,
classically love the board question.
Now the onset of Myasthenia Gravis can be sudden or gradual, and the main symptom here
that you really need to memorize this is increase muscle weakness on exertion or repeated use.
So at the end of the day, the patient feels tired after repetitive movements, you know, repetitive use they feel tired,
and the ocular region is actually the first place where patients are gonna feel tired
because if you imagine you’re always moving your eyes nonstop so your extra-ocular muscles becomes fatigue.
Now we diagnosis Myasthenia Gravis most accurately with electromyography
and then this condition of course, is more common in women than men as is most autoimmune conditions
and really treatment here starts with acetylcholinesterase inhibitors that is giving inhibitors
that inhibit acetylcholinesterase to allow for more acetylcholine to be at the neuromuscular junction.
Now, we also have more advanced therapies such as amino suppressants
you can give people to decrease their immune system given this is an autoimmune condition.
We can also remove the thymus for people who have a thymoma
because it’s been associated that thymus removal
and that’s where we think the antibodies come from, the thymus,
actually leads us to an improved outcome and in some patients cured Myasthenia.
You can also do plasmapheresis which is a technique
in which you place a central line in the patient, remove blood, run it through a machine,
take out the antibodies and then give the blood back and this can be used in move severe conditions.
Now electromyography is something that we said is a tool we use to diagnose Myasthenia.
Now that’s a diagnostic test and we use it for neuromuscular diseases.
Now what we are actually doing with this test is detecting electrical potentials generated by muscle cells
in response to us using the stimulator giving an electrical stimulus to the muscle.
Now, we can also use needle electrodes that we insert into the muscle,
so a slightly invasive procedure to check the actual activity of the muscle with their electrical stimulus.