Myathenia Gravis

A neuromuscular disorder that leads to weakness of skeletal muscles.
Symptoms

Causes
Prevention
Complications
Common tests & procedures
Neurological examination:
Repetitive nerve stimulation test:

Antibody test:
Pulmonary function tests (PFTs): To check any breathing difficulty.

CT scan: To rule out a presence of tumor in thymus.

Magnetic resonance imaging (MRI): MRI of the chest is performed to rule out a presence of tumor in thymus.

Edrophonium (Tensilon) test:

Medication
Procedures
Nutrition

1. Amr Hassan MD,FEBN
Professor of Neurology
Cairo University
Myasthenia Gravis

2. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

3. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

4. •An autoimmune disorder affecting post synaptic nicotinic
Ach receptors inskeletal muscles interfering with
neuromuscular transmission , leading to generalized or
localized weakness characterized by fatigabilityand
diurnal variation.
Introduction:

5. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

6. Chemical Cascade:

7. Etiology

8. Let’s Start The Story from The Beginning:
Clonal deletion

9. Prison Break to Start A Revolution !
Fostieri, Efrosini& Kostelidou, Kalliopi& Poulas, Konstantinos & Tzartos, Socrates. (2006). Recent advances in the understanding and therapy of myasthenia gravis. Future Neurology. 1
799-817. 10.2217/14796708.1.6.799.

10. Formation of auto antibodies against postsynaptic nicotinic
acetyl choline receptors (AchR): Binding / Blocking/ Modulating
Etiology & Pathogenesis:

11. Most commonautoantibody: anti AChRantibody ( 85% of
patients with generalized MG and 50% of patients with
ocular MG)
Is it The Only Antibody in MG?

12. Is it The Only Antibody in MG?
Gilhus, N.E., Tzartos, S., Evoli, A. et al. Myasthenia gravis. Nat Rev Dis Primers 5, 30 (2019). https://doi.org/10.1038/s41572-019-0079-y

13. Largest subgroup of seronegativeMG
50% of SNMG
10% of MG
What is Anti MuSKMG?

14. Surface membrane enzyme
Expressed in skeletal muscle cells
On the inner surface of post synaptic Motor End Plate ( MEP)
Low-density lipoprotein receptor-related protein 4 ( LRP)
What is MuSK?

17. Thymus Pathology:
70% of patients é MG :thymus weight > NL

18. Thymoma
•Benign thymoma:may replace the gland é residual
glandular tissue at periphery.
•Lymphoepithelial type (Lymphoid cell are T cell the
neoplastic element are epithelial cells.
•Tumortend to occur in older patients.
•May invadecontagious pleura, pericardium or bl. Vessel or
distant thoracic structures including diaphragm nerve to
other organs.

19. Thymic Hyperplasia
•Lymphoid hyperplasia
•Thymic germinal centers contain (B-cells, Plasma cells, HLA
class II DR+T.cell)
•Normal & myasthenic thymus contain thymosin(thymic
hormone that →T cell maturation).

20. Thymic Hyperplasia
•Lymphorrage:
-in 50% of cases.
-present in muscles as focal duster of lymphocytes near
small necrotic foci é out perivascular predilection.
-Sometimes may be diffuse muscle fibers necrosis é
infiltrations of inflammatory cells.
-Rarely similar lesions Myocardium.

21. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

22. Types of Myasthenia Gravis
Sanders, D. B., & Guptill, J. T. (2014). Myasthenia gravis and Lambert-Eaton myasthenic syndrome. CONTINUUM: Lifelong Learning in Neurology, 20(5), 1413-1425.

23. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

24. Associated Autoimmune Disorders:
-Young women é MG tend to have HLBA8 DR3 implying
linked immune response gene that code for a protein
involved in autoimmune response.
-1st degree relative show unusual incidence of other
autoimmune disease (SLE,RA, thyroid disease).
-Thyroid disorders

25. Clinical Picture
•Any young female with ptosis: Myasthenia Gravis until
proved otherwise

26. Clinical Picture

27. Clinical Picture

28. Clinical Picture
Symptoms:
EASYFATIGUABILITY
-Weaknessoffluctuatingnature
(varieséinthedayevenéin
minutes,worstatnight)

29. Why Does MG Start with the eye?
•High firing frequencies of EOM motor units +++ their susceptibility
to fatigue
•Slight EOM weakness will sufficiently misalign the visual axis
to produce symptoms
•1: Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990 Nov;40(11):1663-9. Review. PubMed PMID: 1700335

30. Why Does MG Start with the eye?
•Physiological properties of EOM fibers which make them
uniquely susceptible to NMJ blockage
•Theories suggest that antibodies of ocular myasthenicsmay
preferentially bind to EOM epitopes
•1: Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990 Nov;40(11):1663-9. Review. PubMed PMID: 1700335

31. -Extraocular muscles show several
anatomical & physiological differences
from limb muscles.
-Extrocular muscles are more sensitive to
loss of functional Ach receptors.
-Antigenic properties of EOM make them
different from limb muscles.
Why Does MG Start with the eye?

32. •1: Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990 Nov;40(11):1663-9. Review. PubMed PMID: 1700335
Why Does MG Start with the eye?

33. Clinical Picture
Distributionofweakness:
-Ocularaffection(ptosis,diplopia):1sttooccurin40%ofpatients
&affects85%ofpatients
Clinicalresponsetocholinergicdrugs
-Apartofdefinitionofthedisease
-Maybedifficulttodemonstratespeciallyinthoseé
purelyocularmyasthenia.

34. Ocular Myasthenia Gravis
Incidence of ocular affection:
-70% as the presenting symptoms.
-90% during course of disease.
-20% remain é only ocular
Risk of developing generalized myasthenia after presentation
é ocular myasthenia ↓ to 15% after 2y.

35. Ocular Myasthenia Gravis
Clinical picture:
-Symptoms and signs fluctuate over hours and weeks.
Most common sign :
-Lid ptosis
-Unilateral or bilat lid retraction may occur in thyroid eye
disease
-Asymmetrical
-↑on sustained
-Contracted lid may be elevated due to ↑ innervation ↓ on
cover NL lid return to NL
-Rapid shift from one eye to the other = lid twitch sign of
Cogan (pathogenic)

36. Ocular Myasthenia Gravis
Pupils = NL
Prolonged ocular →Chronic or fixed ophthalmoplegia.

37. https://vimeo.com/262092100

40. Clinical Picture
-General examination including vital signs :é in NL except
if patient is in crisis.
-Neurological exam.
-Speech: Nasal tonationif oropharyngeal weakness
-Cr. N.:
-Ptosis, diplopia :
-Paralysis of weakness of EOM.
-Gaze plasy.
-INO.
-Complete unilateral or bilateral ophthalmoplagia.

41. Clinical Picture
-If. Facial muscles affected →expression less facies.
-Resp muscle weakness →pulmonary function test for
VC, Inspiratory & Expiratory Pressures.
-Motor system exam:
-Weakness?
-Wasting 10% only if malnutrition due to dysphagia.
-Fasiculation: absent but may be present if ptreceive
excessive amount of cholinergic drugs.
-Reflexes: present even in weak muscles.
-Sensory system exam: free

46. Severity Scale -Osserman’s:
Heldal, Anne & Eide, Geir& Romi, Fredrik & Owe, Jone& Gilhus, Nils. (2014). Repeated Acetylcholine Receptor Antibody-Concentrations and Association to Clinical Myasthenia Gravis Development. PloSone. 9. e114060.
10.1371/journal.pone.0114060.

47. When to Suspect Anti MuSK?

48. Female striking preponderance (7.5:1)
Ocular Sparing
Early / Severe Bulbar,
Facial, Mastication
muscle affection (82.4%)
Rarely generalized MG
Limb weakness is far less common
Severe atrophy of facial and lingual muscles,
, masticatory (may mimic ALS)
Neck weakness is common
Hints from Clinical Picture

49. HIGH RISK FOR RESPIRATOTY INSUFFICENCY : EARLY,
SEVERE (35.3%)
Myastheniccrisis is also more common
50 –70% of patients presenting at 18 -40 years
of age (early onset MG)
African-American & nonwhite population

50. Kirmani, Jawad & Yahia, Abutaher& Qureshi, Adnan. (2004). Myasthenic Crisis. Current Treatment Options in Neurology. 6. 3-15. 10.1007/s11940-004-0034-3.
DD of Acute LMNL weakness:

51. Ha, J. C., & Richman, D. P. (2015). Myasthenia gravis and related disorders: Pathology and molecular pathogenesis. Biochimicaet BiophysicaActa (BBA)-Molecular Basis of
Disease, 1852(4), 651-657.
DD of Acute LMNL weakness:

52. Differential Diagnosis of MG:
Ahmad, Omar & Hafner, Jessica. (2014). MYASTHENIA | Australian Doctor | 23 How to Treat.

53. Nicolle, Michael W.. “Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome.”
Continuum 22 6, Muscle and Neuromuscular Junction Disorders (2016): 1978-2005
Differential Diagnosis of MG:

54. Its Greatest Mimicker: LEMS
Oh, Shin & Dwyer, D & Bradley, R. (1987). Overlap myasthenic syndrome: Combined myasthenia gravis and Eaton-Lambert syndrome. Neurology. 37. 1411-4.
10.1212/WNL.37.8.1411.

55. Its Greatest Mimicker: LEMS

56. •The Canadian Journal of Neurological Sciences Inc. 2016DOI: https://doi.org/10.1017/cjn.2016.268

57. Chepurny, Z., & Macias, A. (2015). Myasthenia gravis. In L. Aglio, R. Lekowski, & R. Urman(Eds.), Essential Clinical Anesthesia Review: Keywords,
Questions and Answers for the Boards (pp. 354-356). Cambridge: Cambridge University Press. doi:10.1017/CBO9781139584005.112

58. Acute Worsening?

59. Chepurny, Z., & Macias, A. (2015). Myasthenia gravis. In L. Aglio, R. Lekowski, & R. Urman(Eds.), Essential Clinical Anesthesia Review: Keywords, Questions and
Answers for the Boards (pp. 354-356). Cambridge: Cambridge University Press. doi:10.1017/CBO9781139584005.112

62. Crisis Precipitants
Flavin, K., Morkane, C., & Marsh, S. (2018). Myasthenia Gravis. In Questions for the Final FFICM Structured Oral Examination
(pp. 295-299). Cambridge: Cambridge University Press. doi:10.1017/9781108233712.058

63. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture
•Treatment
•Diagnosis & Investigations
Agenda

64. Diagnosis & Diagnostic Tests:
Clinically: by history and examination
Neostigmine test
1.5-2mg
→2h

65. Neostigmine Test : Hospital Setting

66. 1-10mg I.V.
Improvementwithin
30sec&lastafew
minutes
Edrophonium Test : Hospital Setting

67. Take Care!
General notes about anti-choline esterase test:
-Positive response is diagnostic of MG.
-Return of strength to weak muscles occurs uniformly after
injection of neostigmine or edrophonium.
-Demonstration of clinical response to pharmacologic test
may be difficult to demonstrate thus if clinical features are
suggestive →
-Test should be repeated perhaps é different dosage or rate of
administration.

68. Take Care!
-Edrophonium test is better for evaluation of limb
weakness and respiratory muscle affection as it may
require more time.
-False +vetest may occur é structural lesions e.g. brain
stem tumor (MG can also coexist é other diseases e.g.
Graves ophthalmopathy or LES.
-Placebo injection may be needed in limb weakness
rather than cranial weakness as it cannot be simulated.

69. The diagnostic value of neostigmine or edrophonium test is
low in antiMUSKMG ( False –ve)
What About Anti MuSK?

70. Icepack Test: Outpatient Clinic Setting

71. Laboratory Investigations
Routine labs →NL
-Hyperthyroidism in 5% of patients é MG free T3, T4, TSH.
-HigherTitreof AChR Abs
-Specificity99.9%
-Foundin85%
-Nofalse+veexcept:-LES
-Inremission
-Thymoma é out clinical or provocableMG
-Titerdoesnotcorrelateéseverityofdisease.

72. Laboratory Investigations
Maybeabsentin:
-Ocular myasthenia.
-Some patients in remission
-Afterthymectomy
-Evenin patients ésevere symptom.

73. Is it The Only Antibody in MG?
Gilhus, N.E., Tzartos, S., Evoli, A. et al. Myasthenia gravis. Nat Rev Dis Primers 5, 30 (2019). https://doi.org/10.1038/s41572-019-0079-y

74. Other Antibodies?
ANA, RF, thyroid antibodies are
encountered more often than in
control population
Antibodies to myofibrillar proteins
(titin, myosin, actin, actomyosin)
are found in 85% of pté thymoma
and may be 1st evidence of
thymoma in some cases.

75. Neurophysiological Testing:
•Characteristically, progressive decrement in
amplitudeof muscle action potential evoked by
repetitive nerve stimulation at 3 or 5Hz.
•Causes:↓NumberofAChRavailablefor
agonist.

76. Repetitive Supramaximal Nerve Stimulation

77. Repetitive Supramaximal Nerve Stimulation

78. Neurophysiological Testing:
Decrementalresponsecanbe
demonstratedinabout90%ofpt
ifatleast3nervemuscle
systemsareused:
-median-thenar.
-ulnar-hypothenar.
-accessosy-trapezius.

79. Neurophysiological Testing: Single fiber EMG
Smallelectrodemeasuretheintervalbetweenevoked
potentialofmusclefibersofthesamemotorunit.

80. NeurophysiolocalTesting: EMG
Usually normal
Occasionally →myopathic pattern
Absent signs of denervation unless other
conditions supervene

81. The diagnostic value of repetitive stimulation
is low ( false –ve)
(physiological abnormality is not as
widespread throughout the body)
(more often abnormal in facial/ bulbar/
proximal upper extremity muscles)
Routine repetitive nerve stimulation test has
a low sensitivity, while single fibreEMG has
very high sensitivity
What About Anti MuSK?

82. Unusual EMG findings may be
found e.g.: fibrillation potentials,
positive sharp waves,
and ‘‘myopathic’’ motor unit
potentials
What About Anti MuSK?

83. Justin Morgenstern, "Myasthenic crisis", First10EM blog, December 3, 2018.

84. Imaging: CT Chest
CT chest: -é contrast (may →crisis).
-Normal / Thymoma / Thymic hyperplasia
-CT has +vepredictive value :
-91% in detecting thymoma
-80% in detecting thymic hyperplasia

85. Diagnostic Tests
Thymoma
Thymic Hyperplasia

86. •Introduction
•Etiology and Pathogenesis
•Types
•Clinical Picture & DD
•Treatment
•Diagnosis & Investigations
Agenda

88. Treatment Strategy
Hake, Austin & Kaminski, Henry. (2011). Ocular Myasthenia Analysis of Diagnostic and Treatment Options. 10.5772/20861.

89. Treatment Strategy
Mantegazza, Renato & Bonanno, Silvia & Camera, Giorgia& Antozzi, Carlo. (2011). Current and emerging therapies for treatment of myasthenia gravis.
Neuropsychiatric disease and treatment. 7. 151-60. 10.2147/NDT.S8915.

91. Treatment Strategy
Dalakas, M.C. Immunotherapy in myasthenia gravis in the era of biologics. Nat Rev Neurol 15, 113–124 (2019). https://doi.org/10.1038/s41582-018-
0110-z

92. Mantegazza, Renato & Antozzi, Carlo. (2018). When myasthenia gravis is deemed refractory: Clinical signposts and treatment strategies. Therapeutic Advances
in Neurological Disorders. 11. 175628561774913. 10.1177/1756285617749134.

94. .
Jacob, Saiju. (2018). Myasthenia Gravis –A Review of Current Therapeutic Options. European Neurological Review. 13. 86. 10.17925/ENR.2018.13.2.86.

95. Treatment Outline
I-Lines of treatment:
1-Anticholine-estrases.
2-Steroids.
3-PE.
4-IVIg.
5-Immunosuppressants.
6-Thymectomy.
II-Management of myasthenic crisis.
III-Refractory

100. Cholinergic Receptors

101. Preliminary Approach:

102. Treatment Strategy
Mantegazza, Renato & Bonanno, Silvia & Camera, Giorgia& Antozzi, Carlo. (2011). Current and emerging therapies for treatment of myasthenia gravis.
Neuropsychiatric disease and treatment. 7. 151-60. 10.2147/NDT.S8915.

103. Anti Choline Esterases : Elixir of Life!
Mechanism of action: motor end plate →destruction of
acetyl choline →allows its accumulation in the synapse.
Cholinergic synapse →effects
–Cholinergic autonomic synapse →side effects.
_ Cannot pass B.B.B

104. Anti Choline Esterases
Indications:
Drug of choice once myasthenia is diagnosed
Dosage & administration:
Depend on severity of disease , patient sensitivity to the
drug
Parenteral dose : = 1/30 oral dose.
é food →delay absorption →↑ side effects.
parenteral administration is indicated.
-During acute attack.
-After surgery.
-Dysphagia: S.C. 1h before meal.

105. Anti Choline Esterases

107. Poor response
May even worsen!
Have more adverse effects than in MG
Hypersensitive reaction to average doses
What About Anti MuSK?

108. Corticosteroids:
First and most commonly used immunosuppressant medications
in MG
-Indications:
1-Anticholine esterases: excessive SE / insufficient alone to
control MG symptoms
2-Before thymectomy: to improve strength.
3-After thymectomy: if failure of remission.
4-Ocular myasthenia.
5-if rapid effect is desired.

109. Hoffmann, S., Kohler, S., Ziegler, A., & Meisel, A. (2014). Glucocorticoids in myasthenia
gravis–if, when, how, and how much?. Acta NeurologicaScandinavica, 130(4), 211-221.
Corticosteroids:

110. Corticosteroids:
Good response can be achieved with initial high doses
and then taperingit to the lowest dose to maintain the response.
Temporary exacerbation can occur after starting high doses of
prednisone within the first 7–10 days which can last for several
days ( STEROID DIP)→alternate day therapy
In mildcases, cholinesterase inhibitors are usually used to manage
this worsening.
In cases known to have severeexacerbations: plasma exchange or
IVIgcan be given before high dose prednisone therapy
Oral prednisonemight be more effective than anticholinesterase
drugs in oMGand should therefore be considered in all patients
with Omg نووزيتروكلانووويعلل

111. -Side Effects:
-Steroids general side effects: e.g2ry DM , HTN,
gastritis
-Proximal weakness
-High dose →initial worsening
-Withdrawal →worsening
Corticosteroids:

112. Dose High low
60-100mg 25mg on alternate day ↑
gradually 12.5mg every 3
rd
da
→100mg
Advantages Induction of remission Avoidance of worsening
Disadvantages Initial worsening (5days) Relapseon↓dose
Improvement Starts 12d after onset 6-7weeks
Duration Till max improvement
↓
Then 2weeks after: start
withdrawal
3m then withdraw

113. (47%) responded to
corticosteroid
immunosuppression,
Better response to
corticosteroid treatment
in thymectomised
patients.
What About Anti MuSK?

114. N EnglJ Med 2016; 375:2570-2581 DOI: 10.1056/NEJMra1602678.
Immunosuppressants?

115. Azathioprine
Azathioprine tablets (Azasan) product package insert.Salix Pharmaceuticals, Inc., Wilmington, NC. 2003.

116. Azathioprine
It has been utilized as an immunosuppressant agent in MG
since the 1970s
Effective in 70%–90% of patients with MG
Usually takes up to 15 months to detect clinical response
When used in combination with prednisone, it might be
more effective and better tolerated than prednisone alone

117. Azathioprine
Start at doses of 25 mg/ day
Increase every 2 weeks to 50 mg/ day →100 mg/ day →150
mg/ day (AAN 2016)
May be administered in a single dose or twice-daily doses.

118. Azathioprine Side Effects:
Leukopenia (28-50%)
Infection (20%)
Hepatotoxicity
Macrocytic anemia
Thrombocytopenia
Myalgia
Nausea or vomiting
Rash

119. Less likely to respond to
azathioprine
What About Anti MuSK?

120. Colombo, Delia & Pietro, Antonino. (2012). Systemic Cyclosporin in the Treatment of
Psoriasis. 10.5772/27484.
Cyclosporine

121. Cyclosporine
Mechanismofaction:
-inhibitproductionofIL2byThelpercellscriticaltothe
functionofCD4Tcells
-Onsetofaction:éin1-2months.
-Dose:6mg/kgintwodivideddosesdaily→satisfactory
response→withdraw.

122. Colombo, Delia & Perego, Renata & Bellia, Gilberto. (2013). Drug Interaction and Potential Side Effects of Cyclosporine..
Cyclosporine

123. Mycophenolate mofetil

124. selectively blocks purinesynthesis →suppressing T-cell and
B-cell proliferation.
ونيفيفاص(مسمسلا عوزنم)
Mycophenolate mofetil

125. The standard dose ( in MG): 1000 mg b.i.d
Doses up to 3000 mg daily can be used
Higher doses are associated with myelosuppression
Complete blood counts :at least once monthly
Contraindicated in pregnancy
Used with caution in renal diseases, GI diseases, bone
marrow suppression, and elderly patients
Mycophenolate Mofetil

126. Chang, Peng-Yu & Giuliari, G & Shaikh, M & Thakuria, P & Makhoul, Dorine & Foster, C.. (2011). Mycophenolate mofetil monotherapy in the management of
pediatric uveitis. Eye (London, England). 25. 427-35. 10.1038/eye.2011.23.
Mycophenolate Mofetil

127. Sarder, A., Rabbani, M. G., Chowdhury, A. S. M. H. K., & Sobhani, M. (2015). Molecular Basis of Drug Interactions of Methotrexate,
Cyclophosphamide and 5-Fluorouracil as Chemotherapeutic Agents in Cancer. Biomedical Research and Therapy, 2(02), 196-206. Retrieved from
Cyclophosphamide

128. Cyclophosphamide
Elimination of T regulatory cells (CD4+CD25+ T cells) in
naive and tumor-bearing hosts
Induction of T cell growth factors, such as type I IFNs

129. Cyclophosphamide
Fernandes, NurimarC., & Zubaty, Vanessa M.. (2005). Cyclophosphamide pulse therapy for pemphigus: report of seven cases. Anais
Brasileirosde Dermatologia, 80(2), 165-168.

130. Rituximab Monarsen Eculizumab

131. Rituximab
Musette, P., & Bouaziz, J. D. (2018). B cell modulation strategies in autoimmune diseases: new concepts. Frontiers in immunology, 9, 622.

132. Rituximab
Indications:
Refractory MG
Anti MuSK+veMG
Advantages:
Efficacious , fast acting, rather safe

133. Rituximab
Rajagopalan M, VasaniR. Rituximab in the treatment of skin diseases. Indian J Drugs
Dermatol 2017;3:105-9

134. Eculizumab
C5monoclonal antibody →complement protein C5 →
prevent the formation of the terminal complement complex, C5b-9.

135. Eculizumab
Was previously approved by FDA for paroxysmal
nocturnal hemoglobinuria(PNH) & HUS.
In 2017, eculizumab was approved for MG (REGAIN
study).
Prevents complement-mediated damage at the NMJ
endplate in MG

136. Rozanolixizumab
Humanized anti-human neonatal Fc receptor (FcRn) monoclonal
antibody →--IgG in autoimmune diseases.
Currently in phase II trials for both MG and primary immune
thrombocytopenia.

137. Rozanolixizumab

138. Efgartigimod

139. Efgartigimod
An FcRnmonoclonal antibody,
recently completed its phase II trial

140. First Approach:

141. Monarsen
antisense oligonucleotide which
intermixes with the mRNA encoding
for acetylcholinesterase
A phase Ib(2007)

142. Tacrolimus:
--calcineurin involved in the production of interleukin-2,

143. Tacrolimus:

144. Etanercept:
Etanercept, a soluble and a
recombinant tumor necrosis factor
(TNF) receptor blocker, has also been
shown to have steroid-sparing effects
in studies on small groups of patients

145. Official reprint from UpToDate®
© 2020 UpToDate, Inc. and/or its affiliates.

146. Surgical treatment is strongly recommended for patients with
thymoma
Thymectomy is advised as soon as the patient's degree of
weakness is sufficiently controlled to permit surgery
Usually pretreated with low-dose glucocorticoids and IVIg
Most experts consider thymectomy to be a therapeutic option in
anti-AChRAb-positive MG with disease onset before the age of 50
years
Thymectomy:

147. Thymic hyperplasia is uncommon
in MuSKMG
Thymomais almost never found
in MuSKMG
Positive anti MusKantibodies
don’t point to underlying thymic
pathology
What About Anti MuSK?

148. Thymectomy controversial???:
Because their thymilack the
germinal centers and infiltrates of
lymphocytes that characterize
thymiin patients who have anti-
AChRantibodies
What About Anti MuSK?

149. Rabinstein, A.A. (2015). Acute Neuromuscular Respiratory Failure. Continuum, 21 5
Neurocritical Care, 1324-45 .

150. 1-Plasma Exchange
2-Intravenous Immunoglobulin
Similar in efficacy
Rapid onset
Improvement within days,
Transient effect.
Emergency Salvage Treatment Procedures

151. Indications: myasthenic crisis and preoperatively before thymectomy
or other surgical procedures.
can be used intermittently to maintain remission in patients with MG
who are not well controlled despite the use of chronic
immunomodulating drugs.
Emergency Salvage Treatment Procedures

153. Plasma Exchange

154. Plasma Exchange
•Effect: striking temporary remission (2-8 weeks)
•Indications:
Life saving in myasthenic crisis →shorten duration of
associated ventilation.
-After thymectomy.
-Before thymectomy.
-At the start of steroid (or any other immune sup ttt).
-Resort measure if other lines failed.

155. •Adverse effects :
•Hypotension
•Paresthesias& Electrolyte disturbance (Ca)
•Infections
•Thrombotic complications related to venous access
•Bleeding tendencies due to decreased coagulation factors
•Allergic reaction: pruritis, urticaria
Plasma Exchange

156. Pooled immunoglobulin from thousands of donors
Effect is seen typically in less than a week, and the benefit can
last for three to six weeks
Indications: quickly reverse a severe and life-threatening
exacerbation of myasthenia
Refractory MG, as a preoperative treatment before thymectomy
"bridge" to slower-acting immunotherapies
The total dose of IVIG is 2 g/kg, usually over 2-5 days
Intravenous Immunoglobulin

157. Side effects:
Headache
Chills
Dizziness
Fluid retention
Other uncommon complications: include aseptic meningitis,
acute renal failure, thrombotic events, and anaphylaxis.
Anaphylaxis has been associated with immunoglobulin A (IgA)
deficiency
Intravenous Immunoglobulin

158. Negi, Vir-Singh & Elluru, Sri Ramulu& Siberil, Sophie & Graff-Dubois, Stéphanie& Mouthon, Luc & Kazatchkine, Michel & Lacroix-Desmazes, Sébastien & Bayry, Jagadeesh &
Kaveri, Srini. (2007). Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action. Journal of clinical immunology. 27. 233-45. 10.1007/s10875-
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Experience with IVIgin the treatment of patients with myasthenia gravis
MarinosC. Dalakas
Neurology Apr 1997, 48 (Suppl 5) 64S-69S; DOI: 10.1212/WNL.48.Suppl_5.64S

160. Refractory: defined by the international
consensus guidance for management of MG
as unchanged or worsening post-intervention
status after corticosteroids and at least two
other immunosuppressive agents used in
adequate doses for an adequate duration
Refractory Myasthenia Gravis?

161. Mantegazza, Renato & Antozzi, Carlo. (2018). When myasthenia gravis is deemed refractory: Clinical signposts and treatment strategies. Therapeutic Advances
in Neurological Disorders. 11. 175628561774913. 10.1177/1756285617749134.

162. European Neurological Review. 2018;13(2):86–92 DOI: https://doi.org/10.17925/ENR.2018.13.2.86

163. Concept: designed to selectively remove the
immunoglobulin fraction from the serum
Advantage: reduce albumin consumption
Minimize the volume of substitution fluid required
Usually used 0.5-1.0 L of an 8% albumin solution as the
replacement fluid.
Equivalent to 2.5-5.0 L of fresh plasma used in regular
plasma exchange.
Double Filtration Plasma Pharesis

164. THANK YOU
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