MYASTHENIA GRAVIS

SARA SEALS AND RYAN PHILLIPS

IMMUNOLOGY

Picture taken from http://naturalcureproducts.wordpress.com/tag/myasthenia-gravis-cure

SYMPTOMS AND ANALYSISSymptoms

Ptosis

Diplopia1

Muscle weakness

Myasthenic crisis

Dysphonia2

Thymoma/thymic hyperplasia

Analysis

Electrodiagnostic testing

Presence of Anti-AChR Ab

Edrophonium challenge2

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EPIDEMIOLOGY

Most common NMJ disease3

Up to 150 per million

Prevalence has been increasing1

Mid- to late adulthood

Incidence increases with age3

Prevalence in women4

Rarely inheritable3

Picture from http://mgakc.org/newly-diagnosed/sample-page/ocular-mg

RISK FACTORS AND TRIGGERS

Risk Factors

Possible genetic factors

HLA B8, DRw3, and DQw22

Down-regulation of miR320a3

Triggers

Infections3

Stress

Sometimes drug-induced4

Ferrer

NEUROMUSCULAR JUNCTION

PATHOPHYSIOLOGYAntibodies against:

AChR – most common

Muscle-specific kinase (MuSK)

Seronegative types (LRP4, agrin, clustered AChR)5

Reduction of AChRs at the NMJ in anti-AChR2

Decreased AChR clustering in other types6

Pathophysiological mechanisms for anti-AChR:

AG presentation

T-cell recognition and activation of B cells

Ab activation of complement

PATHOPHYSIOLOGICAL MECHANISMS FOR ANTI-MUSK

Col Q

IgG4 block collagen Q binding to MuSK5

Less AChE leads to less clustering due to activation

Picture from http://www.jcsm.info/index.php/en/57-fullarticlesvolume2/v2number4december-20113/191-molecular-control-of-neuromuscular-junction-development44

ACHR CLUSTERING PATHWAY

Picture from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835321/

IMMUNOLOGICAL MECHANISMS

Polymorphisms in FOXP3

Reduces Treg cell number and function

Increased CD28 activity

Active proinflammation cytokines3

More Tfh cells in the peripheral blood

More circulating anti-AChR Ab

Picture from http://neuromuscular.wustl.edu/mtime/modulation.htm

MOST COMMON TREATMENTS

Immunosuppressive therapy—most common7

Prednisone2

Corticosteroids, azathioprine, cyclosporine

Reversible cholinesterase inhibitors2

Helps reduce muscle weakness

Counterproductive in MuSK-MG8

Thymectomy – beneficial in ~96% of patients9

Usually high remission rates

Pictures from http://info.agscientific.com/blog/bid/175925/4-IMPORTANT-USES-OF-IMMUNOSUPPRESSANTS and http://www.lkhtc.com/cms/features/surgery/minimal-access-surgery/thymectomy-for-myasthenia-grevis.html

LESS CONVENTIONAL TREATMENTS

Short-term immunomodulation

Plasmapheresis and intravenous immunoglobulin

Crisis intervention

Rituximab (monoclonal Ab therapy)

Possible use early on in drug-resistant cases

Controversial3

Targets CD208

Eculizaumab/complement inhibitors3

Still in the testing phase

Monoclonal Ab prevents enzymatic cleavage of C5

Picture from http://myrome.org/portal/plasmapheresis-multiple-sclerosis

OPTIMISTIC PROGNOSIS WITH TREATMENT

Long-term natural course is highly variable4

Death (20-30%)10

Current treatment lowers mortality to <4%10

Maximal weakness is usually achieved within the first 3 years4

Picture from http://southtees.nhs.uk/news/hospitals/surgeon-performs-regions-first-vats-thymectomy/

QUESTION 1

How do anti-AChR Ab arise?

A. Activation of B cells via mitogens

B. Polymorphisms in FOXP3 causing a reduction in Treg numbers and function

C. B cell activation via crosslinking

D. Similarities of the AG to bacterial AG cause memory cell activation

QUESTION 2

What role does MuSK play in the neuromuscular junction?

A. Triggers clustering of AChR

B. Signals opening of sodium channels

C. Breakdown of AChR

D. Increases AChE production

QUESTION 3

What treatment is used during myasthenic crisis?

A. Immunosupressants

B. Thymectomy

C. Complement inhibitors

D. Filtration/donation of plasma (plasmapheresis)

QUESTION 4

Who is most likely to be diagnosed with MG?

A. 15-year-old male

B. 15-year-old female

C. 35-year-old male

D. 35-year-old female

ESSAY TIME!!!

A) Where does agrin usually fit in the pathway?

B) How would antibodies against agrin result in myasthenia gravis?

QUESTION ANSWERS

1: B

2: A

3: D

4: D

Essay: A) It’s a ligand for LRP4, which dimerizes MuSK so that AChR will cluster.

B) AChR has to cluster in order to function. Without AChR, the muscle will not receive the signal from the neuron

and will not contract.

REFERENCES1. Saeed S, Patel S. 2011. Use of non invasive ventilation to avoid re-intubation in myasthenia gravis; a case report and review of literature. J Pak Med Assoc. 61(3): 293-295.

2. Mackey JR, Desai S, Larratt L, Cwik V, Nabholz J-M. 1997. Myasthenia gravis in association with allogenic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplantation. 19: 939-942.

3. Querol L, Illa I. 2013. Myasthenia gravis and the neuromuscular junction. Wolters Kluwer Health. 26(5): 459-465.

4. Tormoehlen LM, Pascuzzi RM. 2008. Thymoma, myasthenia gravis, and other paraneoplastic syndromes. Hematology/oncology Clinics of North America. 22(2008): 509-526.

REFERENCES

5. Cavalcante P, Bernasconi P, Mantegazza R. 2012. Autoimmune mechanisms in myasthenia gravis. Wolters Kluwer Health. 25(5): 621-629.

6. Wu H, Xiong WC, Mei L. 2010. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 137(7): 1017-1033.

7. Auriel E, Regev K, Dori A, Karni A. 2011. Safety of influenza and H1N1 vaccinations in patients with myasthenia gravis, and patient compliance. Muscle & Nerve. 893-894.

8. Sieb JP. 2013. Myasthenia gravis: an update for the clinician. Clinical and Experimental Immunology. 175: 408-418.

REFERENCES

9. Barrons RW. 1997. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy. 17(6): 1220-1232.

10. Ferrer E, Moral A, Bozzo J. 2007. Myasthenia gravis. Drugs of the Future. 32(7): 615-624.