pathophysiology: myasthenia gravis & restless leg syndrome
DESCRIPTION
This presentation was given to first year pharmacy students as a part of course on medical physiology and pathophysiology.TRANSCRIPT
Myasthenia Gravis & Restless Leg Syndrome
Brian J. Piper, Ph.D., M.S.
October 22, 2012
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.
MG Overview
• myasthenia: muscle weakness (skeletal)• gravis: lethal (historically)• chronic autoimmune
Sir Thomas Willis
1621-1675
MG Symptoms• ptosis• diplopia• slurred speech, difficulty chewing and
swallowing• weakness in the arms and legs• chronic muscle fatigue and difficulty breathing
Symptoms & Onset (0:07 to 1:07): http://www.youtube.com/watch?v=6W-mC_Lg4WUMyasthenia Gravis Foundation of America: ww.myasthenia.org/
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.
------------------------------------------------------
MS Characteristics• Antibodies for:
– nicotinic acetylcholine receptor– muscle specific kinase (MuSK)
• ice-pack diagnostic test
Neuromuscular Junction
Neuromuscular Junction 0 to 1 min: http://www.youtube.com/watch?v=9FF6UKvDgeE
Antibodies Against nACh• Rabbits (N=7) received
injections of acetylcholine receptor from electric eel
• Paralysis (top) is reversed by increasing ACh (bottom)
Electrophorus electricus
Patrick & Lindstrom (1973). Science, 180(4088 ), 871-872.
Nicotinic Acetylcholine (nACh) Receptor of Muscle
Drachman DB (1998). New England Journal of Medicine, 330, 1797-1810.
Measurement of nACh
• Deltoid biopsies from MG or non-MG (N=33/group)
• 125I α bungarotoxin
Pestronck et al. (1985). Muscle & Nerve, 8, 245-251.
Drachman DB (1998). New England Journal of Medicine, 330, 1797-1810.
Types of MG
• nACh receptor antibody + : 80%– ocular only MG
• MuSK antibody +• antibody -
Lambert-Eaton Myasthenic Syndrome
• symptoms: ptosis & diplopia• cranial nerve reflexes: absent• antibodies against calcium channels, ↓ACh• lung-cancer
Verschuuren et al. (2010). Autoimmunity, 43(5-6), 344-352.
Pattern & Spreading of Weakness
Non-Pharmacological Treatments
• plasmapheresis• thymectomy
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
Gajdos P. et al. (2011). Cochrane Review 2011 Issue 3.Cortese et al. (2009). Neurology, 76, 294–300.
Methodological rating summary.
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, 2009
Gajdos P. et al. (2011). Cochrane Review 2011 Issue 3.Cortese et al. (2009). Neurology, 76, 294–300.
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.
What causes MG?
• unknown (majority)• penicillamine• maternal/neonatal• Candidates
– virus: ?– genetics
Restless Leg Syndrome
1621-1675
Sir Thomas Willis
Allen et al. (2003). Sleep Medicine, 4, 101-119.
Epidemiology
• 10% (2.7%)• females > males• Caucasians > African-Americans• increases with age• risk factors
– Parkinson’s Disease– pregnancy (20%)– ADHD
Example symptoms (0 to 30 sec): http://www.youtube.com/watch?v=k2eGoHk9AAc
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
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 (•).
Turjanski N et al. (1999). Neurology, 52, 932-932.
Controls RLS Controls RLS
*
* p < .05
Scatter diagram of individual caudate and putamen D2
binding in patients with RLS treated (□) and not treated (▪) with L-DOPA and in control subjects (•).
Turjanski N et al. (1999). Neurology , 52, 932-932.
Controls RLS Controls RLS
**
* p < .05
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 RLS
Early et al. (2000). Neurology, 54, 1698 – 1700; Conner et al. (2003). Neurology, 61, 304-309.
RLS & Catecholamine Biosynthesis
• Tyrosine: non-essential amino acid found in eggs, peanuts, liver, turkey, salmon
• Iron cofactor
TH: tyrosine hydroxylase, DOPA: dihydroxyphenylalanine
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.
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