Muscle Disease and Myasthenia Gravis

Question 1

Definition - Myasthenia Gravis.

Answer 1

Autoimmune condition that causes muscle weakness that gets progressively worse with activity and improves with rest.

Question 2

Association - Thymomas and Myasthenia Gravis

Answer 2

10-20% of patients with Myasthenia Gravis have a Thymoma (or 50-70% - thymic hyperplasia).
20-40% of patients with a Thymoma develop Myasthenia Gravis.

Question 3

Myasthenia Gravis vs. Lambert-Eaton Myasthenic Syndrome (5).

Answer 3

1. Definition : MG & LEMS - Progressive muscle weakness as a result of damage at the NMJ.
2. Course : MG - More insidious and less pronounced symptoms.
3. Association : MG - Thymoma. LEMS - SCLC.
4. Antibodies : MG - Anti-ChR, Anti-MuSK, Anti-LPR4. LEMS - Anti-VGCC (in presynaptic terminals of NMJ).
5. Muscle Weakness : MG - Facial and Ocular Muscles. LEMS - Proximal Limb Weakness (Legs > Arms).

Question 4

What is Post-Tetanic Potentiation?

Answer 4

Reflexes become temporarily normal for a short period following a period of strong muscle contraction but are otherwise reduced.

This is a feature of LEMS.

Question 5

Epidemiology of Myasthenia Gravis (3).

Answer 5

1. Men : >60.
2. Women : <40.
3. 2x Women : Men.

Question 6

Clinical Features of Myasthenia Gravis (5).

Answer 6

1. Weakness worsens with activity and improves with rest (minimal in morning and worse at the end of the day).
2. Proximal Muscles and Small Muscles of Head and Neck.
3. Diplopia (Extraocular - Double Vision).
4. Ptosis (Eyelid - Drooping).
5. Weakness in Facial Movements, Swallowing, Chewing, Slurred Speech.

Question 7

Pathophysiology of Myasthenia Gravis.

Answer 7

85% : Anti-AChR antibodies bind to post-synaptic receptors at NMJ to prevent ACh functioning. As the receptors are used more during muscle activity, most of them will become blocked up, leading to less effective stimulation of the muscle with increased activity. Antibodies also activate the Complement at the NMJ to damage post-synaptic membrane cells.
15% : Anti-MuSK (Muscle Specific Kinase) or Anti-LRP4 (Low-Density Lipoprotein Receptor-Related Protein 4).
MuSK and LRP4 are responsible for the creation and organisation of the AChR.

Question 8

Examination of Myasthenia Gravis (3C).

Answer 8

1. Thymectomy Scar.
2. FVC.
3. Fatiguability
   A. Repeated Blinking - Ptosis Exacerbation.
   B. Prolonged Upward Gazing - Diplopia Exacerbation.
   C. Repeated Abduction of One Arm 20x - Weakness Exacerbation.

Question 9

Investigations of Myasthenia Gravis.

Answer 9

1. Bloods - CK is not raised (no muscle damage).
2. CT Thorax - exclude Thymoma.
3. Single Fibre Electromyography (high sensitivity).
4. Bloods - Measure Antibodies (Anti-AChR; Anti-MuSK; Anti-LRP4).

Question 10

Single Fibre Electromyography.

Answer 10

Needles are inserted into the muscles to measure electrical activity - typically around the eyes, forehead, arms. Electrical recordings can show whether signals sent to muscles from nerves are being disrupted.

Question 11

Tensilon/Edrophonium Test.

Answer 11

Patients are given an IV dose of Edrophonium Chloride/Neostigmine. Usually, AChEs in the NMJ break down Ach. Edrophonium blocks AchEs at the NMJ so ACh levels rise, giving a brief and temporary relief of muscle weakness.

This is no longer use due to the risk of cardiac arrhythmias.

Question 12

Treatment Options in Myasthenia Gravis (4).

Answer 12

1. Reversible AChE Inhibitors e.g. Pyridostigmine, Neostigmine.
2. Immunosuppression e.g. Prednisolone, Azathioprine, Cyclosporine, Mycophenolate Mofetil.
3. Thymectomy.
4. Monoclonal Antibodies.

Question 13

Reversible Acetylcholinesterase Inhibitors - Adverse Effects (7).

Answer 13

1. Hypersalivation.
2. Lacrimation.
3. Sweats.
4. Vomiting.
5. Miosis.
6. Diarrhoea.
7. Colic.

Question 14

Monoclonal Antibodies - Mechanism of Action (2).

Answer 14

1. Rituximab - targets B cells to reduce the production of antibodies (NHS if standard treatment is not effective).
2. Eculizumab - targets C5 Complement Protein to prevent Complement activation and destruction of AChR (NICE do not currently recommend it).

Question 15

Definition of Myasthenic Crisis.

Answer 15

A severe life-threatening complication : acute worsening of symptoms triggered by another illness e.g. RTI - leads to respiratory failure.

Question 16

Management of MyastheniC Crisis.

Answer 16

1. Immunomodulatory Therapy e.g. IVIG, Plasma Exchange.

2. NIV - BiPAP, Full Intubation and Ventilation.

Question 17

Exacerbating Factors of Myasthenia Gravis (5).

Answer 17

1. Exertion.
2. Drugs (10) - Penicillamine, Quinidine, Procainamide, B-Blockers, Lithium, Phenytoin, Antibiotics : Gentamicin, Macrolidies, Quinolones, Tetracyclines.
3. Pregnancy.
4. Hypokalaemia.
5. Emotion - Stress.

Question 18

Definition of Muscular Dystrophy and Types (7).

Answer 18

An umbrella term for genetic conditions that cause gradual weakening and wasting of muscles.

1. Duchennes’.
2. Beckers’.
3. Myotonic.
4. Facioscapulohumeral.
5. Oculopharyngeal.
6. Limb-Girdle.
7. Emery-Dreifuss.

Question 19

Genetics of Muscular Dystrophy.

Answer 19

Boys have a single copy of the X chromosome and girls have two copies (a spare). Female carries don’t usually notice any symptoms.

Question 20

Aetiology of Duchennes Muscular Dystrophy (4).

Answer 20

1. X-Linked Recessive (Xp21).
2. Defective Gene for Dystrophin (a protein that helps hold muscles together at the cellular level).
3. Frameshift mutation resulting in one or both of the binding sites being lost.
4. Dystrophin is part of a large membrane-associated protein that connects the muscle membrane to actin.

Question 21

Aetiology of Beckers Muscular Dystrophy (2).

Answer 21

1. Dystrophin gene is less severely affected so some function is maintained.
2. Non-Frameshift insertion in the Dystrophin gene, resulting in both binding sites being preserved.

Question 22

Aetiology of Myotonic Dystrophy (3B).

Answer 22

1. Autosomal Dominant.
2. Trinucleotide Repeat Disorder.
   3A. DM1 - CTG repeat at the end of DMPK (Dystrophia Myotonica Protein Kinase) gene on Chromosome 19.
   3B. DM2 - Repeat expansion of ZNF9 on Chromosome 3.

Question 23

Gower’s Sign.

Answer 23

1. Kid gets onto his/her hands and push his/her hips up and backwards to shift their weight backwards and transfer their hands to their knees.
2. Whilst keeping their legs mostly straight, they walk their hands up their legs to get their upper body erect.
   * It is a compensatory movement against the muscles around the weak pelvic girdle used by kids with proximal muscle weakness to stand up from a lying position.

Question 24

Clinical Presentation of Duchennes Muscular Dystrophy.

• Epidemiology (1).
• Clinical Features (3).

Answer 24

Epidemiology : Boys - 3-5.
Clinical Features :
1. Weakness in Pelvic Muscles - progressive, affecting all muscles (wheelchair bound by teenages).
2. Calf-Pseudohypertrophy (Gower’s Sign).
3. Associated : Dilated Cardiomyopathy and Intellectual Impairment.

Question 25

Clinical Presentation of Beckers Muscular Dystrophy.

• Epidemiology (1).
• Clinical Features (3).

Answer 25

Epidemiology : Boys - 8-12.
Clinical Features :
1. Some patients require wheelchairs in late 20s/30s.
2. Others can walk with assistance into late adulthood.
3. Intellectual impairment is less common than in Duchennes.

Question 26

Clinical Presentation of Myotonic Dystrophy.

• Clinical Features (9).
• Types (2).

Answer 26

Clinical Features :

1. Progressive Muscle Weakness.
2. Prolonged Muscle Contractions (e.g. unable to let go, myotonic facies - haggard face).
3. Cataracts and Bilateral Ptosis.
4. Cardiac Arrhythmias.
5. Frontal Balding.
6. Dysarthria.
7. Myotonia (Tonic Spasm of Muscle).
8. Diabetes Mellitus.
9. Testicular Atrophy.

Types :
DM1 - Distal Weakness is more prominent.
DM2 - Proximal Weakness is more prominent.

Question 27

Clinical Presentation of Facioscapulohumeral Dystrophy.

- Clinical Features (2).

Answer 27

1. Weakness around face, progressing to shoulders and arms.
2. Classic Initial Symptom : Sleeping with eyes slightly open and weakness in pursing lips and unable to blow cheeks out without air leaking.

Question 28

Clinical Presentation of Oculopharyngeal Dystrophy.

- Clinical Features (3).

Answer 28

1. Weakness of Ocular Muscles and Pharyngeal Muscles.
2. Bilateral Ptosis, Restricted Movement, Swallowing Problems.
3. Late Adulthood Onset.

Question 29

Clinical Presentation of Emery-Dreifuss Muscular Dystrophy.

Answer 29

1. Contractures in childhood, elbows and ankles.

These are shortenings of muscles and tendons which restrict the range of movement in limbs.

Question 30

Management of Muscular Dystrophy (3).

Answer 30

1. No curative treatment.
2. Aim : Highest Quality of Life.
3. Oral Steroids - slow progression of muscle weakness by 2 years.

Question 31

Differential Diagnoses of Myopathy.

Answer 31

Inherited - Early age of onset, with relatively longer duration of disease.
Acquired - Sudden/Sub-Acute, with a later age of onset.

Question 32

Clinical Features of Myopathy (4).

Answer 32

1. Symmetrical Muscle Weakness (Proximal > Distal).
2. Common Problems rising from a chair/bath.
3. Normal Sensation and Reflexes.
4. No Fasciculation.

Question 33

Pathophysiology of Polymyositis.

Answer 33

Inflammatory disorder causing symmetrical proximal muscle weakness - T-Cell mediated cytotoxic process directed against muscle fibres; it can be idiopathic, related to connective tissue disorders or malignancy.

Question 34

Clinical Features of Polymyositis (5).

Answer 34

1. Proximal Muscle Weakness and Tenderness.
2. Raynaud’s.
3. Respiratory Muscle Weakness.
4. Interstitial Lung Disease.
5. Dysphagia and Dysphonia.

Question 35

Epidemiology of Polymyositis.

Answer 35

Middle-Aged. Women 3:1 Men.

Question 36

Investigations of Polymyositis (3).

Answer 36

1. 85-95% of Patients : Elevated CK levels and other muscle enzymes e.g. LDH, Aldolase, AST, ALT.
2. Anti-Synthetase Antibodies.
3. Anti-Jo-1 in a specific pattern with lung involvement, Raynaud’s and Fever.

Question 37

Pathophysiology of Dermatomyositis.

Answer 37

Variant of Polymyositis where skin manifestations are prominent e.g. Purple (Heliotrope) rash on cheeks and eyelids. Malignancies associated include Ovarian, Breast and Lung Cancer (20-25%).

Question 38

Clinical Features of Dermatomyositis (6).

Answer 38

In addition to Polymyositis :

1. Photosensitive Skin.
2. Macular Rash over Back and Shoulder.
3. Heliotrope (Purple) Rash in Periorbital Region.
4. Gottron’s Papules - Roughened Red Papules on Extensor Surface of Fingers.
5. Mechanic’s Hands - extremely dry and scaly hands with linear cracks on palmar and lateral aspects of fingers.
6. Nail Fold Capillary Dilation.

Question 39

Investigations of Dermatomyositis.

Answer 39

1. 80% - ANA-positive.
2. 30% - Anti-Synthetase Antibodies (Antibodies against Aminoacyl-tRNA-Synthetases) e.g. Anti-Jo-1 (Histidine-tRNA-Ligase), Anti-SRP (Signal Recognition Particles), Anti-Mi2.

Question 40

Management of Polymyositis and Dermatomyositis (2).

Answer 40

1. Steroids (reduce swelling and ease muscle pain).

2. DMARDs - flare-up.

Question 41

Pharmacological Risk Factor for Myopathy.

Answer 41

Statins - especially lipophilic ones e.g. Simvastatin and Atorvastatin.

Question 42

Gold-Standard Investigation of Muscular Dystrophy.

Answer 42

Muscle Biopsy.