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Pathophysiology: Myasthenia Gravis & Restless Leg Syndrome

This presentation was given to first year pharmacy students as a part of course on medical physiology and pathophysiology.

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Pathophysiology: Myasthenia Gravis & Restless Leg Syndrome

  1. 1. Myasthenia Gravis &Restless Leg Syndrome Brian J. Piper, Ph.D., M.S. October 22, 2012
  2. 2. Learning objectivesPharmacy students should be able to:1. Explain the involvement of antibodies against the neuromuscular junction to Myasthenia Gravis (MG) symptoms.2. Describe the symptoms of Restless Leg Syndrome (RLS) and abnormalities in the dopamine system.
  3. 3. MG Overview • myasthenia: muscle weakness (skeletal) • gravis: lethal (historically) • chronic autoimmuneSir Thomas Willis 1621-1675
  4. 4. MG Symptoms • ptosis • diplopia • slurred speech, difficulty chewing and swallowing • weakness in the arms and legs • chronic muscle fatigue and difficulty breathingSymptoms & Onset (0:07 to 1:07): http://www.youtube.com/watch?v=6W-mC_Lg4WUMyasthenia Gravis Foundation of America: ww.myasthenia.org/
  5. 5. Epidemiology of MG • incidence: 20/100K (State: 266, City: 7) • onset: women: 20s, men 60s • sex ratio of 3:2 ------------------------------------------------------Phillips, L. H. (2003). Annals of the New York Academy of Sciences, 998, 407-412.
  6. 6. MS Characteristics• Antibodies for: – nicotinic acetylcholine receptor – muscle specific kinase (MuSK)• ice-pack diagnostic test
  7. 7. Neuromuscular JunctionNeuromuscular Junction 0 to 1 min: http://www.youtube.com/watch?v=9FF6UKvDgeE
  8. 8. Antibodies Against nACh • Rabbits (N=7) received injections of acetylcholine receptor from electric eel • Paralysis (top) is reversed by increasing ACh (bottom) Electrophorus electricusPatrick & Lindstrom (1973). Science, 180(4088 ), 871-872.
  9. 9. Nicotinic Acetylcholine (nACh) Receptor of MuscleDrachman DB (1998). New England Journal of Medicine, 330, 1797-1810.
  10. 10. Measurement of nACh• Deltoid biopsies from MG or non-MG (N=33/group)• 125I α bungarotoxinPestronck et al. (1985). Muscle & Nerve, 8, 245-251.
  11. 11. Drachman DB (1998). New England Journal of Medicine, 330, 1797-1810.
  12. 12. Types of MG• nACh receptor antibody + : 80% – ocular only MG• MuSK antibody +• antibody -
  13. 13. Lambert-Eaton Myasthenic Syndrome• symptoms: ptosis & diplopia• cranial nerve reflexes: absent• antibodies against calcium channels, ↓ACh• lung-cancer
  14. 14. Pattern & Spreading of WeaknessVerschuuren et al. (2010). Autoimmunity, 43(5-6), 344-352.
  15. 15. Non-Pharmacological Treatments• plasmapheresis• thymectomy
  16. 16. Plasmapheresis: An Evidence Based Treatment?• developed in 1976• widely used and generally accepted by clinicians & patients• “No adequate RCTs have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis” Cochrane Reviews, 2002/2011 Methodological rating summary.Gajdos P. et al. (2011). Cochrane Review 2011 Issue 3.Cortese et al. (2009). Neurology, 76, 294–300.
  17. 17. Plasmapheresis: An Evidence Based Treatment?• widely used and generally accepted by clinicians & patients• “No adequate RCTs have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis” Cochrane Reviews, 2002/2011• “Because of the lack of randomized controlled studies with masked outcomes, there is insufficient evidence to support or refute the efficacy of plasmapheresis” American Academy of Neurology, 2009Gajdos P. et al. (2011). Cochrane Review 2011 Issue 3.Cortese et al. (2009). Neurology, 76, 294–300.
  18. 18. Thymectomy • 15% of MG have thymomas • 70% of MG have thymus hyperplasia • Controversial (non-thymoma) & varied results – younger > older – delayed response – unchanged (25%), improved (50%), remits (25%)Raica et al. (2008). Clinical Experimental Medicine, 8, 61-64.
  19. 19. What causes MG?• unknown (majority)• penicillamine• maternal/neonatal• Candidates – virus: ? – genetics
  20. 20. Restless Leg Syndrome Sir Thomas Willis 1621-1675Allen et al. (2003). Sleep Medicine, 4, 101-119.
  21. 21. Epidemiology • 10% (2.7%) • females > males • Caucasians > African-Americans • increases with age • risk factors – Parkinson’s Disease – pregnancy (20%) – ADHDExample symptoms (0 to 30 sec): http://www.youtube.com/watch?v=k2eGoHk9AAc
  22. 22. Dopaminergic Abnormalities (Subtle) & RLS • RLS or controls (N=13/group, age matched) • PET scanning for dopamine integrity (DOPA uptake) or D2 receptors (raclopride)Positron Emission Tomography1 positron + 1 electron = 2 gamma rays
  23. 23. Scatter diagram of individual caudate and putamen 18F- DOPA uptake in patients with RLS treated (□) and not treated (▪) with L-DOPA and in control subjects (•). * Controls RLS Controls RLS * p < .05Turjanski N et al. (1999). Neurology, 52, 932-932.
  24. 24. Scatter diagram of individual caudate and putamen D2 binding in patients with RLS treated (□) and not treated (▪) with L-DOPA and in control subjects (•). * * Controls RLS Controls RLS * p < .05Turjanski N et al. (1999). Neurology , 52, 932-932.
  25. 25. Iron & RLS • Ferritin: iron storage protein • Spinal taps in controls, RLS FH+, or RLS FH- (N = 8/group) -> • Transferrin Receptor: protein needed for import of Fe into cell • Postmortem substantia nigra tissue stained for transferrin in: controls RLSEarly et al. (2000). Neurology, 54, 1698 – 1700; Conner et al. (2003). Neurology, 61, 304-309.
  26. 26. RLS & Catecholamine Biosynthesis • Tyrosine: non-essential amino acid found in eggs, peanuts, liver, turkey, salm on • Iron cofactorTH: tyrosine hydroxylase, DOPA: dihydroxyphenylalanine
  27. 27. Limited Efficacy of Iron Supplementation • “There is insufficient evidence to determine whether iron therapy is beneficial for the treatment of RLS.” • Benefit identified in 1 study with patients that were iron deficient.Trotti et al. (2012). Cochrane Database Systemic Reviews, 5:CD007834.
  28. 28. More Info• MG Quick Overview: 0:50 to 4:20 at: http://www.youtube.com/watch?v=j7ISC4OU--o• RLS Pathophysiology at: http://www.youtube.com/watch?v=p7G803oDx-c

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