W2: Muscle Pathology Workshop Flashcards
What antibodies are often checked for in suspected myasthenia gravis?
Anti-acetylcholine receptor antibody
Anti-MuSK antibodies
Low density lipoprotein receptor related protein 4 (LRP4)
One or both may be positive.
What does rheumatoid factor identify?
Rheumatoid factors are proteins made by the immune system. (autoimmune)
Can indicate mainly rheumatoid arthiritis, also other autoimmune disease, infections and cancers.
Can also be found in healthy people.
Bind to Fc of IgG
What is the purpose of an anti-nuclear antibody test?
Are autoantibodies directed against material in the nucleus of the cell either DNA, histone, non-histone proteins bound to RNA or nucleolarl antigens.
Positive indicates an autoimmune disease, normally a connective tissue disease, such as SLE, RA, scleroderma, addisons disease etc.
What is the edrophonium test?
Also called a tensilon test
Symptoms assessed before test
Patient is given Tensilon (an AChesterase inhibitor)
If muscle strength improves and the test is considered positive this can indicate myasthenia gravis
Why might a chest x-ray be ordered in suspected myasthenia gravis patient?
To look for thymoma (malignant growth in thymus)
Accounts for cause of 15% of MG cases.
What is the pathophysiology of myasthenia gravis?
Autoantibodies directed against postsynaptic NMJ.
Minority: Anti-MuSK antibodies - MuSK anchors AChesterase to the synaotic basal lamina, promotes AChR clustering - create function AChR.
Mainly: anti acetylcholine receptor antibodies - large loss of number of functional ACh receptors - reduced muscle fibre depolarisation leading to reduced action potential leading to reduced muscle fibre contraction
This failure of neuromuscular transmission results in clinical weakness in functional muscles.
How do Anti-AChR auto-antibodies disrupt neuromuscular transmission?
1)Complement system activation that leads to membrane attack complex formation degrading of receptor antibodies and NMJ.
2)Endocytosis of the AChR
3) Direct blockage of the ACh binding site.
What is the clinical presentation of Myasthenia Gravis?
Intial: Diplopis or ptosis (extrocular muscle weakness)
1-2yrs: generalised weakness
Hallmark: fluctating or fatiguable weakness that is worse over the course of the day or after exercise and improves with rest.
Often affects the upper muscles more - typically face and upper limbs and bulbar muscles.
What helps distinguish Myasthenia gravis from other conditions?
Symptoms improve with rest - diff from motor neuron disease
Pupillary reflexes are normal - diff from botolinus toxin.
What is myasthenic crisis?
When respiratory muscles become fatigued - person has hypoventilation and struggles to breathe - leads to respiratory failure
Precursor tends to be bulbar symptoms
In patient with mysathenic gravis
What is the diagnostic approach to myasthenia gravis?
Women - present between 20-30yrs
Males - present between 50-60yrs
Clincal suspicion - ptosis and upper muscle weakness, worse in evening and better after rest
In clinic: ice pack test and assess for improvement in ptosis
Tests:
1) Serum AChR and MuSK antibodies (note some patient can be negative for these - only detectable an cell based assay)
2) Compound muscle action potential decrease on slow reptitive motr nerve stimulation.
3) Imaging for thymoma often x-ray or CT
What( lab) investigations should be performed on a suspected Myasthenia Gravis test?
- AChR antibody test
- MuSK antibody test
- Repetitive nerve stimulation test.
- EMG - muscle weakness reduced electrical activity
- Edrophonium test
- Ice pack test
- Pulmonary function test (complication precurosor)
What are the potential management strategies for myasthenia gravis?
- Anticholinesterases e.g pyridostigmine
- Oral corticosteroids for remission
- Immunosuppressants - reduce production of abnormal antibodies
- Thymectomy (younger patients for malignant thymic mass)
- Acute management therapies - intravenous immune globulin or plasmapheresis (remove antibodies from patient blood)
What is the NICE recommended treatment for myasthenia gravis?
Anticholinesterases first line in ocular MG
Alongside immunosuppresants in generalised
Corticosteroids are used when first line insufficient, give with a second line imunosuppresant to reduce dose.
Plasmapheresis, IVIg and thymectomy as needed in emergency.
What is Lambert-Eaton syndrome?
Pre-synaptic neuromuscular transmission disroder
Autoantibodies target voltaged gated calcium ion channels on the pre-synaptic membrane/nerve terminal - prevents opening so no calcium ion influx
Prevents the mobilisation and release of ACh into the synpatic cleft.
Most causes of paraenoplastic associated with small cell lung cancer (molecular mimicry) and other is sporadic autoimmune.
What is the clinical presentation of Lambert Eaton Syndrome?
Proximal Muscle weakness, autonomic dysfunction and areflexia
Often presents with leg weakness (standing or climbing stairs)then generalised weakness or pain, dry mouth.
Spread rostrally
Improves with exercise.
What tests can help diagnose Lambert Eaton Syndrome?
Creatine kinase - muscle damage
VGCC antibodies
CT for underlying small cell lung cancer
Electrophysiological testing - low CMAP at rest.
What treatment can be given for Lamber Eaton Syndrome?
Often malignancy is cause so chemotherapy and radiotherapy
Concern over giving Immunosuppressants as may encourage cancer growth
AntiAcyetylcholineesterase
Potassium channel blockers - prolong opening of VGCC.
What is the pathophysiology of botulism?
Presynaptic neuromuscular junction disorder.
Bacterium clostridium botulinum released neurotoxin (normally type A and B)
Heavy chain of toxin beinds to protein on synaptic terminal causing endocytosis.
Toxin is taken up into the synpatic terminal.
Light chain binds to and cleaves SNARE proteins, disrupts formation of the SNARE complex as unable to bind with SNAP-25 and VAMP
Unable to release ACh.
How does botulism present?
Exposure to contaminated soil, honey or home canned food.
Bulbar weakness - poor speach and swallowing, (weak cry and difficulty feeding in babies)
Constipation, bladder atony, tachy cardia and dry mouth - due to autonomic dysfunction.
Sluggish pupillar reflexes, ptosis, blurred vision, pupillary dilation.
Weakness of extermity muscle
Children - lose control of head, hyptonic and diminished spontaneous movements.
What differential diagnosis should be considered with a patient presents with a tingling sensation in toes?
Peripheraly neuropathy from diabetes or from pernicious anemia
Gullian Barre Syndrome
What is meant by peripheral neuropathy?
Damage or dysfunction of the peripheral nerves
Has many different causes
What is pathophysiology of multiple sclerosis?
Chronic autoimmune neurological disorder characterized by neuroinflammation, demyelination and formation of scar tissue in the central nervous system.
Results in lesions in the white matter.
Affects the CNS only as targets oligodendorocytes.
Exact cause in unknown: thought to be an environmental exposure such as Epstein-Barr virus, smoking etc combined with a genetic predisposition.
Risk factor in HLA allele
What is the pathophysiology of Guillain Barre syndrome?
Also known as acute inflammatory demyelinating polyneuropathy.
Acute rapidly progressive demyelinating autoimmune disorder of the peripheral nerve.
Molecular mimicry - similar antigens on a campylobacter, antibody cross reacts - note infection is an important indicator in the history.
