3. Anatomy and physiology of NMJ
• Chemical synapse between a motor neuron and a muscle fiber.
• It allows the motor neuron to transmit a signal to the muscle fiber,
causing muscle contraction.
• The neuromuscular junction is composed of three parts:
Presynaptic motor nerve terminal
Synaptic cleft or junctional cleft
Postsynaptic muscle fiber
4.
5.
6. cont.…
• Motor Unit-All the muscle fibers innervated by a single nerve fiber
It is the final common pathway for all motor activity, both
voluntary and involuntary
Small muscles that react rapidly and whose control must be
exact have more nerve fibers for fewer muscle fibers
Large muscles that do not require fine control may have several
hundred muscle fibers in a motor unit
7.
8.
9. cont.
• Alpha motor neurons reside in the anterior horn of the spinal cord and
the CN motor nuclei.
• The peripheral nerve enters the muscle at the motor point and divides
into intramuscular branches.
• These branches within a muscle fascicle and terminate as axon
boutons.
10. cont.
Functionally motor units are classified into:
Fast twitch or fast fatigable (FF)- rich in glycogen but poor in oxidative
enzymes
Slow twitch or fatigue resistant (S)- low in glycolytic but rich in oxidative
enzymes, desired for sustained tonic activity
Intermediate or fast fatigue resistant(FR)- fast twitch but more fatigue
resistant than type FF, high in glycolytic and intermediate in oxidative enzyme
12. Approach to NMJ Disorders
• The main feature that distinguishes neuromuscular junction defects
from myopathies is the fluctuation in symptoms and signs.
• Extraocular muscles are more commonly involved
• Associated with proximal muscle weakness
13. Medical History
• Onset and course
• Temporal pattern, age at onset
• Distribution of the weakness
• Triggering events
• Family history
• Past medical history and review of systems
14. Examination
• More affect proximal muscles than distal muscles
• Have a predilection for the ocular muscles
• Observing the patient while taking the history
• The presence of a characteristic rash
• Adequate exposure of patients
• Muscle testing
16. Myasthenia Gravis (MG)
• Autoimmune neuromuscular disease that causes fluctuating weakness
in ocular, bulbar, and limb muscles
• Acquired MG is the most common primary disorder of NMT
• The binding of autoantibodies to proteins, the acetylcholine receptor
(AChR), disrupts normal NMT.
• It causes destruction of the endplate region through complement
activation
• Autoantibody production is a T-cell–dependent process, and the
thymus is thought to play an important role
17. Epidemiology
• May begin at any age from infancy to very old age
• The estimated prevalence is approximately 20 cases per 100,000
population
• 3X more common F>M, in age < 40yrs
• M>F, in age > 50yrs
• M=F during adolescence
18. Immunopathology of Myasthenia Gravis
• In about 80%–85% of MG patients, weakness results from the effects
of circulating anti-AChR antibodies
• Antibodies bind to AChR on the terminal expansions of the junctional
folds:-
Accelerated turnover of AChRs
Complement-mediated destruction of the folds causing AchR
functional loss
They block ACh-AChR binding
19. cont.
• Destruction of the junctional folds results in distortion and
simplification of the postsynaptic region and loss of functional AChR
• This leads to NMT failure and muscle weakness.
• Approximately 10% of MG patients have circulating antibodies to
MuSK
• Approximately up to 50% of anti-AChR negative, generalized
myasthenia gravis [GMG] patients have circulating antibodies to
MuSK
20. cont.
• Thymoma- about 15% of patients with MG
• Lymphoid follicular hyperplasia- about 65% of patients with MG
• Seronegative cases occur in approximately 50% of purely ocular cases
and 20% of generalized cases.
21. Myasthenia Gravis Subtypes
• Based on clinical manifestations, age at onset, autoantibody profile,
and thymic pathology
Ocular Myasthenia Gravis- Ptosis and/or diplopia are the initial
symptoms of MG in up to 85% of patients
within 2 years of disease onset, almost all patients have
both symptoms
10%–15% of all MG
After 2 years, around 90% likelihood that the disease will
not generalize
single-fiber electromyography (SFEMG) testing
22. cont.
Generalized Myasthenia Gravis-
either early-onset (EOMG) or late-onset disease (LOMG)
cutoff age usually defined as age 50
Thymomatous Myasthenia Gravis-
About 10%–15% of MG patients have a thymic epithelial
tumor, or thymoma.
M=F
may occur at any age, with peak onset at age 50.
23. cont.
MuSK-Antibody Myasthenia Gravis
Up to 50% of patients with GMG who lack AChR-abs
Predominantly affects females
Patients have predominant weakness in cranial and bulbar
muscles, frequently with marked atrophy of these muscles
Thymic changes are absent or minimal
25. Clinical Presentation of MG
• Fluctuating and fatigable weakness of muscle groups that worsens
with exercise and improves with rest
• Approximately two-thirds of patients presented with drooping eyelids
or double vision as initial symptom
• one-sixth of patients presented with difficulty chewing, swallowing, or
talking as initial symptom
• The course of disease is variable but usually progressive.
26. cont.
• Maximum weakness occurs during the first year in two-thirds of
patients
• Approximately one-third of patients improved spontaneously, one-
third became worse, and one-third died of the disease
• Weakness of limb muscles is usually proximal (more than distal) and
symmetric
• Clinical exacerbations can be induced by some medications, surgery,
and infections
27. Physical Findings in Myasthenia Gravis
Ocular Muscles- asymmetrical weakness
• Medial rectus being more frequently and severely involved.
• The pupillary responses are normal.
• Ptosis that shifts from one eye to the other is virtually
pathognomonic of MG
• After downgaze, upgaze produces lid overshoot (“lid twitch”)
• Enhanced ptosis or “curtain sign”
• peek sign
28.
29.
30.
31. cont.
Oropharyngeal Muscles- changes in the voice, difficulty chewing
and swallowing
• Inadequate maintenance of the upper airway
• Patients may have a characteristic facial appearance.
• weak smile or a myasthenic snarl
32. cot.
Limb Muscles- begins in limb or axial muscles in about 20% of MG
• Neck flexors are usually weaker than neck extensors
• Deltoids, triceps, and extensors of the wrist and fingers and
ankle dorsiflexors are frequently weaker
• “Dropped head syndrome”
• Muscle atrophy
33. Diagnosis
• Suspected based on clinical presentation
• Serologic testing is the first diagnostic step
• AChR-binding antibodies are very specific-
80% of patients with generalized MG
50% of patients with ocular MG
50% of children with autoimmune MG
• Some patients may be seronegative at the time of initial testing
• MuSK antibodies are tested if AChR antibodies are negative
• Antibody testing should not be used to follow clinical response to
treatment or disease severity over time.
34. cont.
Edrophonium Chloride Test- fast-acting acetylcholinesterase
inhibitor with a 30-second onset and about 5-minute duration
• Incremental doses starting at 2 mg and up to a total 10 mg
• Positive in 60%–95% of patients with OMG and in 72%–
95% with GMG
35.
36. cont.
Ice pack test-high diagnostic specificity and sensitivity
• Applied to the weak eyelid for 5 minutes
• Improvement of palpebral fissure of at least 2 mm is
considered a positive test
• Chest CT
• Thyroid function test
37.
38. cont.
• Repetitive nerve stimulation
Decrement of >10% at 3Hz – highly probable
• Single-fiber EMG, when performed in a weak muscle, is the most
sensitive diagnostic test to confirm NMJD
blocking and jitter
41. Symptom Management: Cholinesterase Inhibitors
Pyridostigmine bromide
• Initial dose- 30–60 mg every 4–8 hours ( 1 mg/kg in pediatrics)
• No fixed dosage schedule
• Effect starts in 30 to 60 minutes and lasts for 3 to 4 hours.
42. cont.
Plasma exchange-used for short term treatment of severe MG,
• Myasthenic crisis,
• In preparation for surgery (e.g., thymectomy), or
• To prevent corticosteroid-induced exacerbations
• Usually 5 to 6 exchanges of 2 to 3 liters on alternating days
43. cont.
• Intravenous immunoglobulin (IVIg)-
• rapid improvement in patients with severe disease or crisis
• reduces perioperative morbidity prior to surgery
• 2 g/kg, administered over 2–5 days
• Improvements seen with in 1 week and lasts weeks to
months
44. cont.
• Prednisone-used in all MG patients who have not met treatment goals
after an adequate trial of pyridostigmine
• marked improvement or complete relief of symptoms in more
than 75%
• Initial dose- 50 mg/d to 80 mg/d
• Outpatient 10 mg/d to 20 mg/d and increased by 5 mg/d every
week until the target dose is achieved
• Continued untis Sustained improvement occurs, which is
usually within 2–4 weeks.
47. cont.
Mycophenolate mofetil (MMF)-
• blocks purine synthesis, thereby suppressing both T- and B-
cell proliferation.
• Used as monotherapy or as a steroid-sparing agent
• 1000 mg twice daily
48. cont.
Thymectomy
• Improved strength and function
• Less prednisone and addition of second line requirement
• Fewer hospitalization for exacerbations
• Not an emergency procedure
• If possible after IVIg or plasmapheresis
49. Myasthenic Crisis
• It is respiratory failure from myasthenic weakness
• occurs in about 15% of patients
• True neurologic emergency
• Infection, aspiration, surgery, or medication change are precipitating
factors
• ICU care
• Corticosteroids along with IVIg or plasma exchange
• Management of medical complication
50. Myasthenia in Pregnancy
• Myasthenia may improve, worsen, or remain unchanged during
pregnancy
• 20% to 30% of women can experience an exacerbation, most
commonly in the first trimester or in the postpartum period
• Goals- to minimize the mother’s MG symptoms and risk of
exacerbation and to avoid the potentially harmful exposure of the fetus
to the immunosuppressants
• Safe- pyridostigmine, IVIg, plasma exchange, prednisone
51. cont.
• Avoid MgS04 for preeclampsia treatment
• During delivery:
MG not an indication for C/S
Second stage of delivery fatigue, protracted labor, fetal distress can
occur
Assist delivery if needed
Neostigmine 1.5mg IM or 0.5mg IV ( equivalent to pyridostigmine
60mg) can be given
epidural analgesia is the anesthetic intervention of choice for
delivery
• Breast feeding is not contraindicated
52. References
• Continuum NMJD 2019
• Bradley and Daroff neurology in clinical practice 8th edition
• Merritt's Neurology 14th edition
