Pathophysiology: Myasthenia Gravis & Restless Leg Syndrome

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.

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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