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Myasthenia Gravis (Part 2): Diagnostic Evaluation & Differential Diagnosis | Harrison Simplified — Transcript

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0:00Your patient presents with fluctuating
0:02double vision and a drooping eyelid that
0:04miraculously improves after a few
0:06minutes of rest with an ice pack. Is it
0:08a transient ischemic attack, Horner's
0:11syndrome, or a classic sign of a disease
0:13that could quietly progress to
0:14respiratory failure?
0:16Diagnosing myasthenia gravis and knowing
0:19exactly what to rule out, such as
0:21Lambert-Eaton syndrome, congenital
0:23myasthenic syndromes, or drug or
0:25toxin-induced weakness, is one of the
0:27most critical skills on the wards.
0:29Today, we will master that differential.
0:32Welcome to Harrison Simplified.
0:35When we talk about the diagnosis of
0:37myasthenia gravis or MG, our suspicion
0:39is fundamentally clinical. We are
0:42looking to identify weakness and
0:43fatigability in a characteristic
0:45distribution, such as the proximal
0:47limbs, the neck extensors, or in a
0:49generalized pattern.
0:51Crucially, this weakness occurs without
0:53any loss of deep tendon reflexes,
0:55without sensory signs or symptoms, and
0:58without abnormalities of other
1:00neurologic functions.
1:01Let's break down the diagnostic
1:03evaluation, starting with the patient's
1:05history and physical examination.
1:07In the history, we listen for reports of
1:10diplopia, ptosis, dysarthria, dysphagia,
1:13and dyspnea. The absolute hallmark of
1:16this disease is fluctuation and fatigue,
1:19meaning the symptoms are worse with
1:20repeated activity and improved by rest.
1:23During the physical examination, we
1:25evaluate for ptosis at rest and
1:27following 1 minute of exercise. We check
1:30the extraocular muscles and ask about
1:32subjective diplopia. We also test
1:34orbicularis oculi and oris strength,
1:37along with jaw opening and closure. To
1:39assess the extremities and neck, we
1:41measure muscle strength and specifically
1:43look for weakness following repeated
1:45shoulder abduction. Vital capacity
1:47measurement is also performed, and we
1:49verify the absence of other neurologic
1:51signs.
1:52At the bedside or in the clinic, a quick
1:55and easy test for a patient presenting
1:57with ptosis is the ice pack test. If we
2:00apply a pack of ice over a ptotic eye
2:02for 2 minutes, it often results in
2:04improvement if the ptosis is due to a
2:06neuromuscular junction defect. A
2:08positive result is considered a lid rise
2:10of 2 mm following this cooling. The
2:13underlying hypothesis is that the cold
2:15temperature leads to less depletion of
2:17quanta of the acetylcholine receptor and
2:20reduced activity of acetylcholinesterase
2:22at the neuromuscular junction.
2:24Historically, the anticholinesterase
2:26test was commonly used for diagnosis.
2:29Drugs that inhibit the enzyme
2:30acetylcholinesterase allow acetylcholine
2:33to interact repeatedly with a limited
2:35number of acetylcholine receptors in MG,
2:38improving muscle strength.
2:40Edrophonium chloride at a dose of 2 mg
2:42plus 8 mg intravenously was the most
2:45common agent used because of its rapid
2:4830-second onset and short 5-minute
2:50duration of effect with an objective
2:52endpoint like ptosis typically measured.
2:55A highly probable diagnosis was made if
2:57unequivocally positive. However,
2:59edrophonium is no longer used today due
3:02to the potential for side effects and a
3:03lack of availability. Moving to
3:05laboratory testing, serology for
3:08autoantibodies is a cornerstone of
3:10diagnosis. Anti-acetylcholine receptor
3:13or anti-AChR antibodies are detectable
3:16by radioimmunoassay in the serum of
3:19about 85% of all patients with
3:21generalized MG and in about 50% of
3:24patients with weakness confined to the
3:26ocular muscles.
3:27The presence of anti-AChR antibodies
3:30provides a definite diagnosis, but a
3:32negative result does not exclude the
3:34disease. It's also important to note
3:36that the measured level of this antibody
3:38does not correspond well with the
3:39severity of MG in different patients.
3:42For patients with generalized MG who are
3:44AChR antibody negative, roughly 40% will
3:48have antibodies to muscle-specific
3:50tyrosine kinase or MuSK. MuSK antibodies
3:54are rarely present in patients who are
3:56AChR antibody positive or in those whose
3:59MG is limited to the ocular muscles.
4:01A small proportion, about 2% of MG
4:04patients without antibodies to AChR or
4:07MuSK, have antibodies to lipoprotein
4:09receptor-related protein 4 or LRP4.
4:13However, sending LRP4 antibodies has low
4:16specificity. Because of this, we only
4:18check them in patients with clear MG by
4:20phenotype and electrodiagnostic testing,
4:23but who have absent AChR and MuSK
4:26antibodies.
4:27There are other antibodies associated
4:29with MG, but their clinical utility is
4:31limited. Antibodies against agrin have
4:34been found in rare patients, but it is
4:36unclear if they are pathogenic, and they
4:38are not currently tested in clinical
4:39practice. Anti-striated muscle
4:42antibodies, which are directed against
4:43titin and other skeletal muscle
4:45components, have also been identified in
4:47some patients. However, these are not
4:49pathogenic, and their presence does not
4:51confirm an MG diagnosis or the presence
4:54of a thymoma. Given this limited utility
4:57and the potential for misinterpretation,
4:59we do not order them. Additionally,
5:01antibodies directed against Caspr2 or
5:04contactin-associated
5:05protein-like 2 may coexist primarily in
5:09patients with thymoma who have MG and
5:11neuromyotonia or Morvan's syndrome. The
5:14presence of Caspr2 antibodies can help
5:16confirm the diagnosis of a second
5:18paraneoplastic syndrome in these
5:20clinical situations.
5:22Beyond blood tests, electrodiagnostic
5:24testing is highly probable for
5:26diagnosis. Repetitive nerve stimulation
5:29provides very helpful diagnostic
5:31evidence. For this test, medications
5:33that inhibit acetylcholinesterase should
5:35be stopped 12 to 24 hours or for as long
5:38as possible before testing. It is best
5:41to test weak muscles or proximal muscle
5:43groups. Electrical stimulation is
5:45delivered at a rate of two or three per
5:47second to the appropriate nerves, and
5:49action potentials are recorded from the
5:51muscles. While normal individuals see no
5:54change greater than 10% in the amplitude
5:56of their evoked muscle action potentials
5:58at these rates, myasthenic patients show
6:00a rapid reduction or decrement of
6:03greater than 10% at 3 Hz.
6:06If repetitive nerve stimulation is
6:07normal or if symptoms are exclusively
6:10ocular, we perform single-fiber
6:12electromyography or SFEMG.
6:15This is a more sensitive, specialized
6:17test typically done at MG referral
6:19centers. It looks for blocking and
6:21jitter with a normal fiber density. This
6:24test is confirmatory, but importantly,
6:26it is not specific to MG. As part of the
6:29evaluation, measurements of ventilatory
6:32function through pulmonary function
6:33tests are highly valuable. This is
6:35because of the frequency and seriousness
6:38of respiratory impairment in myasthenic
6:40patients. Given the wide range of
6:42neurological symptoms, we must always
6:44consider the differential diagnosis.
6:47Other conditions that cause weakness of
6:49the cranial or somatic musculature
6:51include non-autoimmune congenital
6:53myasthenia, drug-induced myasthenia,
6:56Lambert-Eaton myasthenic syndrome,
6:58hyperthyroidism, botulism, intracranial
7:02mass lesions, oculopharyngeal dystrophy,
7:05and mitochondrial myopathy.
7:07Let's discuss drug-induced mimics first.
7:11Treatment with immune checkpoint
7:12inhibitors or ICIs for cancer may result
7:15in autoimmune MG. Symptoms typically
7:18begin after the first or second cycle of
7:20treatment, presenting with ptosis,
7:23diplopia, bulbar, neck, extremity
7:25weakness, and respiratory weakness.
7:28Notably, myositis and myocarditis are
7:30often found in combination with MG as a
7:33complication of ICIs. ICI-related
7:36myositis without disordered
7:38neuromuscular transmission can also
7:40mimic MG, causing a similar pattern of
7:42weakness, including ocular and bulbar
7:44weakness, which is an uncommon finding
7:47in other autoimmune myopathies. These
7:49patients usually improve when the ICI is
7:52discontinued and a short course of
7:54glucocorticoids is given, along with
7:56intravenous immunoglobulin or IVIG, or
7:59plasma exchange depending on severity.
8:02However, with fulminant disease, the
8:04fatality rate remains high, mainly due
8:06to concurrent myocarditis.
8:09Other medications can also cause issues.
8:11Treatment with penicillamine, used for
8:13scleroderma or rheumatoid arthritis, has
8:16been associated with MG. Aminoglycoside,
8:19quinolone, and macrolide antibiotics,
8:22intravenous magnesium, or procainamide
8:24can cause an exacerbation of weakness in
8:26myasthenic patients. In very large
8:29doses, they can even cause neuromuscular
8:31weakness in normal individuals.
8:33Botulinum toxin injections should be
8:35strictly avoided in MG patients.
8:39Next, let's explore the congenital
8:41myasthenic syndromes or CMS.
8:44This is a rare, heterogeneous group of
8:46disorders of the neuromuscular junction
8:49with an estimated prevalence of roughly
8:513.8 per 100,000.
8:53Unlike MG, they are not autoimmune, but
8:56are due to mutations in more than 30
8:58identified genes. These disorders can
9:01affect virtually any component of the
9:03neuromuscular junction, including the
9:05presynaptic nerve terminal, various AChR
9:08subunits, acetylcholinesterase,
9:11or other molecules involved in end plate
9:13development or maintenance. CMS shares
9:16many clinical features with MG, such as
9:19weakness and fatigability of proximal or
9:21distal extremity muscles, and often
9:23extraocular and eyelid muscle
9:25involvement in a similar distribution.
9:28We mostly suspect CMS when symptoms
9:30began in infancy or childhood, though
9:33some patients initially present in
9:34adulthood. Just like autoimmune MG,
9:37repetitive nerve stimulation is often
9:39associated with a decremental response.
9:42A key clue for CMS is the absence of
9:45AChR and MuSK antibodies. However,
9:48remember that these antibodies are also
9:50absent in roughly 10% of generalized MG
9:53patients, known as double seronegative.
9:56Another clue is that some forms of CMS,
9:59like acetylcholinesterase deficiency and
10:02prolonged open channel syndrome, have a
10:04feature of after discharges that are not
10:06seen in MG.
10:08The most common genetic defects in CMS
10:10occur in the epsilon subunit of the
10:12AChR, accounting for roughly 50% of
10:15cases.
10:17Mutations in genes encoding for rapsyn,
10:19COLQ, DOK7, agrin, and GFPT together
10:24account for another 40%. In most
10:27recessively inherited forms, the
10:29mutations are heteroallelic, meaning
10:31different mutations affect each of the
10:33two alleles. Let's look at the subtypes
10:36of CMS closely, as molecular analysis is
10:39required to elucidate the exact defect
10:42leading to helpful treatment and genetic
10:44counseling.
10:45For presynaptic disorders, mutations in
10:48CHAT and CHT genes cause early-onset
10:53episodic apnea and respiratory failure
10:55at birth, which improves with age. These
10:58show a decremental response to
11:00repetitive nerve stimulation and improve
11:03with acetylcholinesterase inhibitors and
11:053,4-diaminopyridine,
11:07or 3,4-DAP.
11:09For synaptic disorders, COLQ mutations
11:13cause acetylcholinesterase deficiency.
11:16Patients present with early-onset axial
11:18weakness with scoliosis, apnea, slow or
11:22absent pupillary responses, and variable
11:25extraocular muscle involvement.
11:27Electrophysiologically, they show after
11:29discharges on nerve stimulation and a
11:32decrement on repetitive nerve
11:33stimulation. Importantly, these patients
11:36worsen with acetylcholinesterase
11:38inhibitors and are treated with
11:40albuterol, ephedrine, and 3,4-DAP
11:43instead.
11:44For postsynaptic disorders involving
11:47AChR deficiency or kinetics, we see
11:50mutations in AChR subunit genes. Primary
11:54AChR deficiency presents with typical MG
11:58features and fatigue and improves with
12:00acetylcholinesterase inhibitors and
12:023,4-DAP.
12:04The fast channel syndrome presents with
12:06ptosis, weakness, and extraocular muscle
12:09involvement, improving with
12:11acetylcholinesterase inhibitors, but
12:13requiring caution with 3,4-DAP.
12:15Conversely, the slow channel syndrome
12:18presents with weak forearm extensors and
12:20neck and respiratory weakness, featuring
12:23after discharges on nerve stimulation.
12:25These patients worsen with
12:27acetylcholinesterase inhibitors and
12:29fluoxetine and quinidine can be useful
12:32treatments.
12:33For postsynaptic disorders involving
12:35abnormal clustering or function of AChR,
12:39DOK7 mutations cause limb girdle
12:42weakness with ptosis, but no extraocular
12:45muscle involvement. They have a variable
12:47response, may worsen with
12:49acetylcholinesterase inhibitors, and are
12:51treated with albuterol or ephedrine.
12:54Rapsyn mutations can resemble MG, but
12:57also present with early hypotonia and
12:59arthrogryposis, treating with albuterol.
13:03Agrin mutations cause limb girdle or
13:05distal weakness and apnea, may worsen
13:08with acetylcholinesterase inhibitors,
13:10and treat with albuterol. MuSK mutations
13:14cause congenital or childhood ptosis,
13:16extraocular and progressive limb girdle
13:19weakness. They have a variable response
13:21to acetylcholinesterase inhibitors and
13:243,4-DAP, but a positive response to
13:26albuterol. Lastly, LRP4 mutations cause
13:31hypotonia, mild ptosis, and ventilatory
13:34failure, and these patients worsen with
13:36acetylcholinesterase inhibitors.
13:38All of these subtypes show a decremental
13:41response to repetitive nerve
13:42stimulation.
13:44Other postsynaptic disorders include
13:46limb girdle CMS with tubular aggregates
13:49caused by GFPT1,
13:52DPAGT1,
13:54ALG2, and ALG14 mutations. This
13:59typically presents without ptosis or
14:01extraocular muscle weakness and treats
14:03with albuterol or ephedrine. Plectin
14:06mutations can resemble MG, but also
14:08present with early hypotonia and
14:11arthrogryposis, treating with albuterol.
14:14Ephedrine and 3,4-DAP may be of benefit
14:17in some forms of CMS. Now, let's
14:20contrast MG with Lambert-Eaton
14:22myasthenic syndrome, or LEMS.
14:25LEMS is a presynaptic disorder of the
14:27neuromuscular junction causing skeletal
14:30muscle weakness. However, the pattern of
14:32involvement differs greatly from MG.
14:35The proximal muscles of the lower limbs
14:37are most commonly affected, while
14:39cranial and bulbar weakness, like
14:41ptosis, diplopia, dysarthria, and
14:43dysphagia may occur, they are not
14:46typically the presenting or prominent
14:48symptoms. Furthermore, LEMS patients
14:50often have depressed or absent reflexes
14:53and experience autonomic symptoms such
14:55as dry mouth, orthostasis, and
14:57impotence, which helps distinguish it
14:59from MG.
15:00Electrophysiologically, nerve
15:02stimulation in LEMS produces an initial
15:05low-amplitude compound muscle action
15:07potential. At low rates of repetitive
15:09stimulation, between 2 and 3 Hz, it
15:12shows a decremental response, as seen in
15:14MG. However, at high rates of 20 to 50
15:17Hz or following brief exercise,
15:20incremental responses occur.
15:22LEMS is caused by autoantibodies
15:24directed against P/Q-type calcium
15:26channels at the presynaptic motor nerve
15:28terminals, which are detected in about
15:3185% of LEMS patients. These antibodies
15:34impair the release of acetylcholine. In
15:36young adults, particularly women, LEMS
15:39is less commonly associated with
15:41underlying cancer, but in older adults,
15:43it is associated with malignancy, most
15:45commonly small cell lung cancer, or
15:48SCLC.
15:49Virtually all of these older patients
15:51have P/Q-type calcium channel
15:53autoantibodies, as the tumor cells may
15:56express calcium channels that stimulate
15:58the autoimmune response.
16:00Initial management of LEMS requires a
16:02comprehensive evaluation for malignancy
16:04and reassessment if the initial
16:06evaluation is negative. Treatment
16:08involves symptomatic therapy first with
16:103,4-DAP,
16:12which blocks potassium channels to
16:14prolong depolarization and enhance
16:16acetylcholine release, along with
16:18pyridostigmine, which prolongs the
16:20action of acetylcholine. If symptoms are
16:23severe, life-threatening, or if
16:24symptomatic therapy is insufficient,
16:27immunomodulatory therapy, including IVIG
16:30or plasma exchange, can be used.
16:32Botulism is another condition that can
16:34mimic MG. It is due to potent bacterial
16:37toxins produced by eight different
16:39strains of Clostridium botulinum. These
16:42toxins enzymatically cleave specific
16:44proteins essential for the release of
16:46acetylcholine from the motor nerve
16:48terminal. Most commonly, it's caused by
16:50ingesting improperly prepared food
16:52containing the toxin. Rarely, ubiquitous
16:55spores may germinate in wounds, or in
16:57infants, the spores may germinate in the
16:59gastrointestinal tract and release
17:01toxin.
17:02Patients present with myasthenia-like
17:04bulbar weakness, such as diplopia,
17:06dysarthria, and dysphagia, and they lack
17:09sensory symptoms and signs. The weakness
17:12may generalize to the limbs and result
17:14in respiratory failure. Mentation
17:16remains normal and reflexes are present
17:18early, but may be diminished as the
17:20disease progresses.
17:22Autonomic findings are present,
17:24including paralytic ileus, constipation,
17:27urinary retention, dilated or poorly
17:29reactive pupils, and dry mouth.
17:32Definitive diagnosis requires the
17:34demonstration of toxin in serum by
17:36bioassay, though results take a
17:38relatively long time and may be
17:40negative. Nerve stimulation studies
17:42reveal reduced compound muscle action
17:44potential amplitudes that increase
17:46following high-frequency repetitive
17:48stimulation. Treatment includes
17:50ventilatory support and aggressive
17:52inpatient supportive care, like
17:54nutrition and deep vein thrombosis
17:56prophylaxis.
17:57Antitoxin should be given as early as
17:59possible, obtained through the Centers
18:01for Disease Control and Prevention. For
18:03laboratory workers or highly exposed
18:05individuals, a preventative vaccine is
18:07available. Other conditions to rule out
18:09include hyperthyroidism.
18:11Abnormalities, like hyper- or
18:13hypothyroidism, may increase myasthenic
18:16weakness and can be readily diagnosed or
18:18excluded by tests of thyroid function.
18:21Diplopia resembling MG may also
18:24occasionally be due to an intracranial
18:26mass lesion that compresses nerves to
18:28the extraocular muscles, such as a
18:31sphenoid ridge meningioma. To evaluate
18:34this, a CT or MRI of the head and orbits
18:36is used. Finally, progressive external
18:39ophthalmopathy, a rare condition causing
18:42symmetric ptosis and extraocular
18:44weakness accompanied by proximal limb
18:46weakness, is mostly caused by
18:48mitochondrial disorders, like
18:50Kearns-Sayre syndrome, detectable by
18:53genetic testing or muscle biopsy.
18:55Lastly, as part of our evaluation, we
18:58must search for associated conditions.
19:00Myasthenic patients have an increased
19:02incidence of several associated
19:04disorders. For example, thymic
19:06abnormalities occur in roughly 75% of
19:10AChR antibody-positive patients.
19:13Neoplastic change, or thymoma, may
19:15produce enlargement of the thymus. A
19:18thymic shadow on a CT scan may normally
19:20be present through young adulthood, but
19:22enlargement of the thymus in a patient
19:24over age 40 is highly suspicious for a
19:27thymoma. Because approximately 10 to 15%
19:30of patients with MG have a thymoma, a
19:33chest CT or MRI is performed at
19:35diagnosis to evaluate this possibility.
19:38Hyperthyroidism occurs in 3 to 8% of
19:41patients, so thyroid function tests
19:44should be obtained in all patients with
19:46suspected MG.
19:47We also check for other autoimmune
19:49disorders that can coexist with MG. Most
19:52commonly systemic lupus erythematosus
19:55and rheumatoid arthritis by testing for
19:57anti-nuclear antibodies and rheumatoid
20:00factor.
20:01Associations also occur with
20:03neuromyelitis optica, multiple
20:05sclerosis, neuromyotonia,
20:08Morvan syndrome, which includes
20:09encephalitis, insomnia, confusion,
20:12hallucinations, autonomic dysfunction,
20:14and neuromyotonia,
20:16rippling muscle disease, granulomatous
20:19myopathy or myocarditis, chronic
20:21inflammatory demyelinating
20:23polyneuropathy, Hashimoto's thyroiditis,
20:26Graves' disease, and skin disorders. We
20:29must also consider a family history of
20:31autoimmune disorders.
20:33Furthermore, an infection of any kind
20:35can exacerbate typical MG and should be
20:38sought carefully in patients with
20:40relapses. Because the glucocorticoids
20:42and other immunotherapies used in MG
20:45treatment have side effects, a thorough
20:47medical investigation is required to
20:49find disorders that may interfere with
20:51therapy.
20:52We specifically test for evidence of
20:54chronic or latent infections like
20:56tuberculosis or hepatitis and run tests
20:59like a fasting blood glucose and
21:01hemoglobin A1C for diabetes and bone
21:05densitometry for osteoporosis.
21:07We also evaluate for hypertension, renal
21:10disease, asthma, obesity, peptic ulcer,
21:13gastrointestinal bleeding, and glaucoma.
21:16And that's our comprehensive dive into
21:18the diagnosis and evaluation of
21:20myasthenia gravis. If you found this
21:23video valuable, please take a moment to
21:24hit the like button and subscribe for
21:26more high-yield content. Thanks for
21:29being part of our community and we'll
21:30see you in the next video.

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