Myasthenia Gravis

1. Usmanu Danfodiyo University Teaching
Hospital, Sokoto
Department of Medicine
Neurology /Rheumatology Team
LITERATURE REVIEW ON MYASTHENIA GRAVIS
18/02/2022

2. OUTLINE
• INTRODUCTION

3. • Myasthenia gravis (MG) is an autoimmune disease affecting the
neuromuscular junction

4. Historic background
• The first reasonably complete account of MG were those of Erb (1878) and
Goldman (1893)
• They characterized the disease as a bulbar palsy without an anatomic
lesion
• Many years thereafter was referred to as Erb-Goldman syndrome
• Jolly (1885) was the first to use the name myasthenia gravis to which he
added the name pseudoparalytica
• The relationship between MG and Thymic tumours was first noted by
Laquer and Weigert in 1901
• The immunologic nature of the disease was established through a series of
investigations by Patrick and Lindstrom, Fambrough, Lennon and A.G Engel
(1977)

5. Epidemiology
• The prevalence of MG has been steadily increasing for the past 50
years
• This is due to better diagnosis, improved treatment modalities, and
increased life expectancy
• MG remains an uncommon disease with approximately 60,000
estimated cases in the United States
• Prevalence is reported at about 20 in 100,000
• Varies in different countries

6. Epidemiology
• In patients younger than 40 years, women are more commonly
affected with a ratio of 7:3 with peak age of first symptoms between
20 – 30years
• Men older than 50 years are more commonly affected with a ratio of
3:2 with peak of first symptoms between 50 and 60 years
• In patients in their forties, cases are evenly distributed
• Paediatric MG is very rare
• Familial occurrence of MG is known but rare
• Ocular MG is more common in patients with prepubertal juvenile MG,
especially in people of Asian descent and in men with late-onset MG

7. Brief physiology of the Neuromuscular
junction and Transmission
• The neuromuscular junction includes;
-the presynaptic nerve terminal
-basal lamina containing synaptic cleft
-the postsynaptic muscle fiber endplate
• Nerve depolarization allows calcium influx through nerve terminal
voltage gated calcium channels (VGCCs)
• This results in release of Acetylcholine into the synaptic cleft which
binds to its receptor (acetylcholine receptor [AChR])

8. Brief physiology of the Neuromuscular
junction and Transmission
• This binding results in opening AChR channels producing an influx of
cations, mostly sodium at the endplate
• Depolarization of the muscle membrane produces an endplate
potential, which if of sufficient amplitude, results in an all or none
muscle fiber action potential and eventually muscle movement
• An excess of released acetylcholine and AChRs at the muscle
endplate provides a safety factor of neuromuscular transmission

9. Classification
• MG can be classified in several ways
• Each of which is useful when considering diagnostic tests, therapeutic
options and prognosis.

10. Classification
• Age of onset:
• Congenital myasthenic syndromes:
-genetic disorders with a mutation in a presynaptic, synaptic or
postsynaptic protein involved in neuromuscular transmission.
• Neonatal MG:
-Occurs after the transplacental transmission of AChR or MuSK
antibodies
-Previously said to occur in about 10% to 15% of babies of mothers
with MG but it may be less frequent now
-It is a self-limited disorder because the antibody producing cells are
not transmitted

11. Classification
• Juvenile myasthenia:
-Comprise about 10% to 15% of most series of patients with MG
-Arbitrarily defined as an age of onset of less than 18, excluding
congenital myasthenic syndromes and neonatal MG
-Cases of prepubertal onset are more likely to be seronegative,
have a benign clinical course, a higher prevalence of ocular and mild
generalized disease and are more common in Asians
-Postpubertal juvenile MG has similar rates of seropositivity and
thymic hyperplasia compared to early-onset adult MG.

12. Classification
• Early-onset MG
-Variably defined as age at onset after 18 years but before 40 to 60
years of age, with 50 being the most common age cutoff
-Women outnumber men
-The likelihood of thymic hyperplasia and of response to
thymectomy in nonthymomatous MG is greater
-Patients with MuSK MG are also more likely to have an early onset

13. Classification
• Late onset MG:
-includes patients with onset after 50 years of age
-more often men and have ocular MG
-a thymoma is more common than thymic hyperplasia

14. Classification
• Thymic pathology.
• The likelihood and type of thymic pathology is associated with age at
onset, clinical manifestations, and serologic status.
• Thymic hyperplasia is present in 50% to 80% of patients with AChR-
positive early-onset MG, less common in late-onset MG and is rare in MuSK
MG
• A thymoma, found in 10% to 20% of all cases of MG, more common with
onset after 40 years of age where it occurs in 25% to 35% of cases
• Thymomatous MG is usually more severe and less likely to be ocular
• The vast majority of thymomatous MG cases have positive AChR
antibodies, so AChR negativity essentially rules out a thymoma
• A thymoma is almost never found in MuSK MG.

15. Classification
• Serologic status.
• Arguably the most important classification with high specificity
• If either AChR or MUSK antibodies are positive, a diagnosis of MG is
certain.
• The specificity of antibodies against agrin, LRP4, or cortactin is less
well defined
• When AChR antibodies are negative, an underlying thymoma is very
rare, and thymic hyperplasia is less frequent.
• In MuSK MG the thymus is usually normal, the disease may be more
severe, and patients are less responsive to pyridostigmine or IV
immunoglobulin (IVIg)

16. Clinical presentation
• The core clinical feature of MG is fluctuating and fatigable weakness
of muscle groups that worsens with exercise and improves with rest.
• The weakness can involve any striated muscle but characteristically
affects some muscles more than others.
• Common and early presenting symptoms are;
• Ptosis: - which can be unilateral or bilateral
- If bilateral is frequently asymmetric
-may alternate side over time and

17. Clinical presentation
• Diplopia usually binocular
-milder involvement may produce blurring of vision or a halo
around objects
• Bulbar weakness resulting in flaccid dysarthria, dysphagia, jaw closure
weakness
• Facial weakness (weak smile or a “myasthenic snarl”)
• Inability to smile, which is noticed by other people and sometimes
wrongly interpreted as a flat mood or depression
• Nasal speech after prolonged speaking

18. Clinical presentation
• Liquids escaping through the nose when drinking
• Inability to drink through a straw or to whistle
• Food getting stuck in the throat when eating
• Jaw fatigue when chewing
• Neck flexion is usually more affected than neck extension, but
dropped head syndrome can occur
• Weakness of limb muscles is usually proximal (more than distal) and
symmetric

19. Clinical presentation
• Resulting in difficulty performing tasks that require the arms to be
above the head, getting up from low seats, walking for prolonged
distances and climbing stairs
• Fingers and wrist extension and foot dorsiflexion are also commonly
affected
• Selective or predominant weakness of triceps muscles has been
described especially in African American patients
• Focal distal predominant weakness affecting finger flexors or
extensors, sometimes asymmetric, and foot drop have also been
described.

20. Diagnosis
• Made based on clinical suspicion
• History, neurologic examination and supported by electrophysiologic
and serologic studies

21. Diagnosis: Neurologic/Clinical examination
• Fatigable ptosis
• Cogan eyelid twitch sign
• Single breath count
• Assessing for fatigable limb weakness
• Ice pack test
• Edrophonium test

22. Diagnosis: Electrophysiology
• Routine nerve conduction studies and needle EMG are usually normal
in patients with MG
• but should almost always be done first as myopathic or neurogenic
conditions may confuse the interpretation of repetitive nerve
stimulation and single fiber EMG
• When a diagnosis of MG is serologically proven, electrophysiologic
testing may not be necessary.

23. Diagnosis: Serological tests

24. Other ancillary tests
• Chest CT
• CT/MRI of the brain
• Vitamin B12 assay
• TFT

25. Factors That Can Trigger or Worsen
Myasthenia Gravis
• Surgery
• Pregnancy and Postpartum Period
• Heat
• Stress
• Viral Infections
• Bone Marrow Transplantation
• Medications

26. Medications
◆ Antibiotics
◇ Aminoglycosides
◇ Fluoroquinolones
◇ Tetracyclines
◇ Sulfonamides
◇ Penicillins
◇ Nitrofurantoin
◇ Telithromycin
◆ Cardiovascular medications
◇ Quinidine, quinine
◇ Beta-blockers
◇ Calcium channel blockers
◆ Anesthetics (eg, methoxyflurane)
◆ Neuromuscular blockers (eg, succinylcholine)
◆ Checkpoint inhibitors (eg, pembrolizumab)
◆ D-Penicillamine
◆ Magnesium and magnesium-containing
medications (eg, laxatives, antacids)
◆ Botulinum toxin
◆ Interferon alfa

27. Class Description
I Any ocular muscle weakness
May have weakness of eye closure
All other muscle strength is normal
II Mild weakness affecting other than ocular muscles
May also have ocular muscle weakness of any variety
IIa Predominantly affecting limb or axial muscles or both
May also have lesser involvement of oropharyngeal muscles
IIb Predominantly affecting oropharyngeal or respiratory muscles or both
May also have lesser or equal involvement of limb or axial muscles or both
III Moderate weakness affecting other than ocular muscles
May also have ocular muscle weakness of any severity
IIIa Predominantly affecting limb or axial muscles or both
May also have lesser involvement of oropharyngeal muscles
IIIb Predominantly affecting oropharyngeal or respiratory muscles or both
May also have lesser or equal involvement of limb or axial muscles or both

28. Class Description
IV Severe weakness affecting other than ocular muscles
May also have ocular muscle weakness of any severity
IVa Predominantly affecting limb or axial muscles or both
May also have lesser involvement of oropharyngeal muscles
IVb Predominantly affecting oropharyngeal or respiratory muscles or both
May also have lesser or equal involvement of limb or axial muscles or both
V Defined by intubation, with or without mechanical ventilation, except when
employed during routine postoperative management; the use of a feeding tube
without intubation places the patient in class IVb

29. Differential diagnosis

30. Treatment
• 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).
• This should be achieved with the minimal possible side effects from
medications.