myathenia gravis; diagnosis and treatment

1. MG
Efgartigimod
By
Dr Mohammud Ibraheem

2. INTRODUCTION

4. MG is an autoimmune disease affecting the NMJ
causing fatigable ocular, limb,and bulbar muscle
weakness.
The prevalence is 1 in 5000.
MG affects patients of all ages with a peak in younger
women and older men.
Antibodies against the AChR or the MuSK are found
in the majority of patients, but seronegative cases
occur in 50% of purely ocular cases and 20% of
generalized cases.
Severity varies from mild weakness limited to the
ocular muscles (purely ocular MG) to generalized limb
and bulbar weakness (generalized MG).
In 15%; severe weakness of respiratory muscles
causes respiratory failure (ie, myasthenic crisis).

5. MG is treatable with immunomodulation with
corticosteroid, long-term immunosuppressive
drugs as azathioprine and mycophenolate
mofetil, IV immunoglobulin (IVIg), and plasma
exchange. Thymectomy improve clinical
outcome.
Pharmacologic remission is common, and the
prognosis is good with a mortality of less than
5%.
Treatment should be tailored to the individual
patient, and special consideration should be
given to women of childbearing age, pregnant
women, children, and the elderly when
choosing the most suitable
immunosuppressant medication.

6. Congenital myasthenic syndromes are very
rare genetic diseases and causing ocular,
bulbar, and limb muscle weakness of varying
severity and usually with an onset early in life.
The diagnosis is based on clinical signs and
symptoms, a lack of serum antibodies, an
abnormal repetitive nerve stimulation test
with compound muscle action potential
(CMAP) decrement, and no response to
immunosuppressive therapy.
Multiple genes encoding proteins expressed
at the neuromuscular junction are associated
with different subtypes of congenital
myasthenic syndromes.

7. EPIDEMIOLOGY
the prevalence of MG has been steadily increasing for
the past 50 years because of better diagnosis.
MG is uncommon disease with approximately 60,000
estimated cases in the US.
Prevalence is 20 in 100,000 and varies in different
countries. In patients younger than 40, women are
more commonly affected with aratio of 7:3, whereas
men are more commonly affected among patients
older than 50,with aratio of 3:2.
More men are now affected than are women, and the
majority of MG patients in the US are over age 50.
Pediatric MG is very rare.

8. ETIOLOGY
MG is immune disease affecting epitopes in the postsynaptic
membrane of the neuromuscular junction. The antibody-
mediated, T cell dependent immunologic attack on the
postsynaptic membrane results in damage of the post
synaptic muscle membran causing simplification of the highly
folded surface and a reduced number and density of AChRs.
Antibodies against the AChR bind alpha subunit of the
AChR.
Thymic pathology includ:
 thymoma in 15% of MG
 thymichyperplasia with lymphofollicularhyperplasia in 65%.
antibodies to MuSK are in 1/3 of patients with MG who are
AChR seronegativ. MuSK plays a role in the clustering of
AChR and in endplate formation and maintenance

10. CLINICAL PICTURE

11. The core clinical feature of MG is fluctuating and
fatigable weakness of muscle groups that worsens
with exercise and improves with rest.
1. Ptosis, frequently asymmetric and varies during
sustained activity. Chronic contraction of the
frontalis muscle produces a worried or surprised
look. Patients may tilt their head back. Eyelid
closure is usually weak
2. Diplopia are the most common presenting
symptoms and appear in most cases early in the
disease course. the medial rectus is frequently
and more severely involved. Ptosis and/or
diplopia are the initial symptoms of MG in 85%.

13. OMG is 10%–15% of MG. The diagnosis of
OMG may be a challenge as RNS studies and
anti-AChR antibodies are often negative, and
SFEMG testing may be required.
3. Bulbar weakness resulting in flaccid
dysarthria, dysphagia, jaw closure
weakness, and facial weakness (weak
smile or a “myasthenic snarl”). Patients
report nasal speech, liquids escaping
through the nose; an inability to drink
through a straw or to whistle; food getting
stuck in the throat.

14. 4. Neck flexion is usually more affected than
neck extension, but dropped head syndrome
can occur
5. Weakness of limb muscles is usually
proximal more than distal and symmetric,
but fingers and wrist extension and foot
dorsiflexion are also commonly affected.
There is difficulty in::
Performing tasks that require the arms to be
above the head
Getting up from low seats or toilets, walking
for prolonged distances, and climbing stairs
Selective or predominant weakness of triceps
muscles has been described especially in
African American patients

15. 6. Patients with anti-MuSK antibody can
have atypical clinical presentations,
including either:
Neck extensor, shoulder, and respiratory
muscle weakness
Severe oculobulbar weakness, fixed facial
muscle weakness, and weakness of the
tongue and pharyngeal muscles that
respond poorly to treatment.
Many MuSK MG patients do not improve
with cholinesterase inhibitors, some
become worse, and many have profuse
fasciculations with these medications

16. 7. MG with anti-ryanodine receptor
antibodies positive is associated with
more severe, generalized, or
predominantly oropharyngeal weakness,
and frequent myasthenic crises
8. Focal distal predominant weakness
affecting finger flexors or extensors,
sometimes asymmetric, and foot drop
have also been described

17. 9. Myasthenic crisis occurs in about 15%
and is caused by severe weakness of the
diaphragm and accessory breathing
muscles, causing respiratory failure. It
needs to be managed in ICU with
ventilatory support and treatment with
corticosteroids with IVIg or plasma
exchange.
10.Refractory MG is defined by unchanged
or worsened symptoms after corticosteroid
treatment and at least 2 other
immunosuppressants used at adequate
doses for an adequate duration or until
intolerable side effects occurred.

18. Factors That Worsen MG
1) Surgery
2) Pregnancy and Postpartum
Period
3) Heat
4) Stress
5) Viral Infections
6) Bone Marrow Transplantation
7) Medications
 Antibiotics
A. Aminoglycosides
B. Fluoroquinolones
C. Tetracyclines
D. Sulfonamides
E. Penicillins
F. Nitrofurantoin
G. Telithromycin
 Magnesium and magnesium-
containing medications (eg,
laxatives, antacids)
 Botulinum toxin
 Interferon alfa
 D-Penicillamine
 Cardiovascular medications
a) Quinidine, quinine
b) Beta-blockers
c) Calcium channel blockers
 Anesthetics (eg, methoxyflurane)
 Neuromuscular blockers (eg,
succinylcholine)
 Checkpoint inhibitors (eg,
pembrolizumab)

19. DIAGNOSTIC TESTS

20. A. Serologic testing:
Positive AChR-binding antibodies are very
specific for autoimmune MG and are found
in 80% generalized MG, 50% of ocular
MG, and in 50% of children with MG.
False-positive results are extremely rare
and have been found in some patients
such as GBS and in patients with
thymoma without signs of MG.

21. Istriational antibodies are in 30% of MG and in
80% of patients with thymoma without MG.
they are more commonly found in older
patients.
MuSK antibodies are tested if AChR
antibodies are negative; MuSK antibodies are
found in 13 of seronegative patients with
generalized MG, usually female patients
(85%).
In 20% of patients who are double
seronegative (negative AChR and MuSK
antibodies), autoantibodies against the low-
density lipoprotein receptor related protein
4 (LRP4) is identified.

23. B. Electrodiagnostic testing
2-Hz to 5-Hz repetitive nerve stimulation
studies are more sensitive in generalized
than ocular MG. A CMAP decrement
greater than 10% is indicative of a
neuromuscular transmission defect.
Submaximal stimulation, and limb
temperature less than 35°C (95°F) during
repetitive nerve stimulation testing can
affect the validity of the results.

24. Single-fiber EMG, when performed in a
weak muscle, is the most sensitive
diagnostic test to confirm a neuromuscular
transmission disorder (positive in 97% of
affected patients). Usually, the extensor
digitorum communis muscle is studied
first, and if it is normal, a facial muscle
(frontalis or orbicularis oculi) should be
tested next. If single-fiber EMG is
normal in clinically affected muscles,
the diagnosis of MG is excluded.

26. Edrophonium test; IV edrophonium chloride is
a acetylcholinesterase inhibitor with a 30sec
onset and 5minute duration. Incremental
doses starting at 2mg and up to a total 10mg
are administered with intervals of 1-2 minutes
to observe for improvement or muscarinic SE
(sweating, lacrimation, salivation, nausea,
vomiting, diarrhea, bradycardia and
bronchospasm) atropine should be available.

27. The ice pack test has a high specificity
and sensitivity for distinguishing
myasthenic ptosis from other causes of
ptosis. An ice pack is applied to the eyelid
for 5minutes, an improvement of palpebral
fissure of 2 mm is considered a positive
test.
Chest CT to rule out thymoma or thymoma
recurrence.
Thyroid function testing

29. DIFFERENTIAL
DIAGNOSIS

30. MG needs to be differentiated from other neuromuscular
junction disorders, such as:
1) Lambert-Eaton myasthenic syndrome
2) Congenitalmyasthenic syndromes
3) Botulism
4) Lyme disease
5) Bulbar ALS
6) Brainstem ischemia
7) Acute inflammatory demyelinating
polyradiculoneuropathy (AIDP), such as Miller Fisher
syndrome and pharyngeal-cervical-brachial variants.

31. Purely ocular MG needs to be differentiated
from mitochondrial disorders, such as
chronic progressive external ophthalmoplegia
and oculopharyngeal muscular dystrophy.
The ptosis in these disorders is usually
symmetric, chronically progressive, and non-
fatigable or fluctuating.

32. Ophthalmoplegia in chronic progressive
external ophthalmoplegia and
oculopharyngeal muscular dystrophy,
rarely causes significant diplopia because
of the slow progression and uniform
involvement of intrinsic ocular muscles.
Muscle biopsy and DNA testing confirm
the diagnosis of chronic progressive
external ophthalmoplegia or
oculopharyngeal muscular dystrophy.

33. In cases with predominantly bulbar
weakness and minimal ocular symptoms,
bulbar ALS is the alternative diagnosis:
UMN signs and atrophy and fasciculations
in the tongue and other muscles
distinguish ALS from MG. The dysarthria
in MG is flaccid and nasal, while in bulbar
ALS is frequently a spastic. One
confusing feature is the presence of
fasciculations and atrophy of the tongue in
some MuSK-positive MG patients.

34. Patients with a primary symptom of
generalized fatigue without weakness in
specific muscle groups, especially if pain
is also present, are usually not affected by
MG. Electrodiagnostic evaluation that
includes EMG, repetitive nerve stimulation,
and single-fiber EMG of affected muscles
is very helpful in differentiating the above
disorders.

35. TREATMENT

36. The goal in the management of MG is to
achieve remission (no signs or symptoms of
myasthenic weakness) or minimal
manifestations (no subjective symptoms and
only mild weakness found on objective
neurologic examination that does not interfere
with normal function).
Plasma exchange and IVIg are used in
generalized MG as rapid-onset short-term
immunotherapy,

37. Plasma exchange and IVIg are used in generalized MG,
for severe acute exacerbations, and preoperatively to
optimize the patient’s strength prior to surgery.
In refractory patients and in patients who do not respond
to or cannot tolerate oral immunosuppressants, IVIg and
plasma exchange are used more chronically.
1) Plasma exchange
5 to 6 exchanges of 2 to 3 liters on alternating days, is
effective in improving strength in majority of patients with
MG and is the treatment of choice in true myasthenic
crisis because of its fast onset (usually after the 2nd or 3rd
exchange).
.

38. 2) IVIg
Dose of 1 g/kg to 2 g/kg divided over 2 to 5 days is
used to treat moderate to severe exacerbations and
for patients who do not respond to or cannot tolerate
any immunosuppressant.
Improvement occurs between a few days and 2weeks
and usually lasts weeks to months.
SE include idiosyncratic reactions (chills, fever,
headaches) and aseptic meningitis.
Premedication with acetaminophen, diphenhydramine,
and hydrocortisone help in preventing or mitigating the
side effects.
Caution is taken in patients with cardiomyopathy or
valve disease and renal impairment due to the risk of
volume overload.

39. 3) Pyridostigmine
It is acetylcholinesterase inhibitor used for the
symptomatic treatment of MG, alone in pure
ocular and mild generalized cases or in
combination with immunosuppressants in
severe cases.
The symptomatic effect starts in 30 to 60
minutes and lasts for 3 to 4 hours. The dose
should be administered 30 minutes before
meals.if dysphagia is the main symptom or
every 4 hours while the patient is awake if
diplopia is the main symptom.
Common side effects include abdominal
cramps, diarrhea, and excessive lacrimation

40. 4) Corticosteroids
They are the first choice for ocular and generalized
MG if require more than pyridostigmine.
The dose is 60 mg/d-80 mg/d until improvement
occur, but because of the possible risk of short-term
exacerbation especially in bulbar weakness, this
option is reserved for the inpatient setting whereas
in the outpatient setting taper up.
In the outpatient, prednisone is started at 10 mg/d-
20 mg/d and increased by 5 mg/d every week till
improvement. Once improvement is reached, a slow
taper should starte on an alternating day schedule
and a long term steroid-sparing immunosuppressant
added if symptoms recur.

41. 5) Mycophenolate mofetil and azathioprine
They are the commonest used
immunosuppressants in management of MG.
They are the first choice if corticosteroids are
contraindicated.
that
suppresses cell-mediated immune response
and antibody formation. The doses in adults
are 2 g/d-3 g/d divided in 2 doses. Side
effects include abdominal pain, diarrhea, and
nausea. Because of potential leukopenia and
anemia, periodic monitoring of complete blood
cell counts is performed. The therapeutic
effect takes few weeks to 2 months.

42. . The dose is 2
mg/kg/d-3 mg/kg/d, and side effects
include myelosuppression, toxic hepatitis,
idiosyncratic allergic flu-like reaction, and
pancreatitis. Monitoring of complete blood
cell count and liver enzymes is required.
The therapeutic effect takes 4 to 8 months.

43. 6) Rituximab
it is a synthetic CD20 antibody given IV. It induce
significant improvement and even remission in some
patients with severe and refractory generalized MG,
especially in MuSK-positive patients. Side effects include
hepatitis B virus reactivation, infusion reactions, skin and
mouth ulcers, and progressive multifocal
leukoencephalopathy.
Indications of rituximab
A. CD20 positive B-cell Non Hodgkin lymphoma
B. Chronic lymphocytic leukemia
C. Rheumatoid arthritis
D. Wagener granulomatosis and microscopic polyangitis
E. Pemphigus vulgaris
F. Rasmussen encephalitis

44. 7) Eculizumab
It is a complement inhibitor recently approved by the FDA
for the treatment of adult patients with AChR-antibody
positive generalized MG. Its use is indicated for patients
with severe or refractory disease who either have not
responded to or are unable to tolerate other
immunosuppressants. Because of the risk of
meningococcal and other serious bacterial infections,
vaccination recommendations should be followed prior to
use.
Indications of eculizumab
A. paroxysmal noctornal hemoglobinuria
B. hemolytic uremic syndrome
C. MG
D. NMOSD

45. 8) Efgartigimod
it is a first in class neonatal Fc receptor antagonist being
developed for treatment of autoimmune diseases including
MG.
The neonatal Fc receptor plays a key role in prolonging the
life-span of IgG as it protects them from lysosomal
degradation by recycling them back into the circulation
In December 2021, IV efgartigimod received the FDA
approval for the treatment of generalized MG in adults who
are anti AChR antibody positive.
The dose is 10 mg/kg ( MAX 1200mg), is administered as a
1h IV infusion once weekly for 4 weeks as one treatment
cycle; It is diluted with 0.9% NaCL injection to a total of 125
mL. Patient is monitored for signs and symptoms of
hypersensitivity reactions. Subsequent cycles are
administered based on clinical evaluation; not less than 50
days after previous cycle. It causes transient decrease in IgG
levels so immunization with live or live-attenuated vaccines is
not recommended during treatment