Neuro Emerg 24: Myasthenia Gravis Flashcards
What are the three forms of acquired Myasthenia Gravis?
- focal AMG: localized weakness of esophageal, pharyngeal, laryngeal and/or facial muscles - no evidence of appendicular weakness
- generalized AMG: obvious appendicular weakness +/- megaesophagus and facial/pharyngeal/laryngeal weakness
- acute fulminant AMG: profound appendicular weakness with acute onset, +/- facial, pharyngeal, esophageal, laryngeal weakness - rapidly fatal due to tetraparesis and respiratory muscle failure (diaphragm and intercostal!)
Fill the green gaps
Motor neuron axon
Motor neuron terminal or Axonal terminal
Motor end plate
Describe the steps of neuromuscular action potential as shown in this picture
- Action potential of motor neuron increases permeability of Ca++ channels –> increased IC [Ca++]
- Increase [Ca++] triggers exocytosis of Ach-containing vesicles
- Ach reaches synaptic cleft –> reaches nicotonic Ach receptors
- Two Ach molecules bind to each receptor –> 5. increases ligand-gated Na and K channels –> Na influx into cell –> threshold potential
- when threshold potential is reached –> voltage-gates Na+ channels open –> propagation of the action potential
- Acetylcholineesterase hydrolizes Ach –> hydrolyzed to choline and acetate
- Choline is taken up into the cholinergic axon terminal
- Acetylcholine synthesized from choline and acetyl-coenzyme A (acetyl-CoA) (enzyme: choline acetyl-transferase)
- Acetyl-CoA synthesized in the mitochondria
Which type of congenital myasthenia gravis is more common in dogs?
- post-synatpic - i.e., defect is related to the amount Acetylcholine-Receptors expressed on the postsynaptic region
- other forms: presynaptic or synaptic (observed in humans)
What 2 breeds have shown an absolute ACh-R deficiency leading to congenital MG?
Jack Russel Terrier, Springer Spaniel
What type of antibody is mostly implicated in acquired myasthenia gravis?
IgG
What subunit of the ACh-R do autoantibodies bind to in MG?
alpha subunit - separate region from the ACh binding site - called MIR (main immunogenic region)
Name the breeds with the highest risk of acquired myasthenia gravis
- Akitas
- Terrier breeds
- scottish terriers
- GSP
- Chihuahuas
What proportion of dogs with acquired MG present with megaesophagus?
84%
Why can dogs with myasthenia gravis develop urinary incontinence?
external urethral sphincter is made of a skeletal muscle
How does myasthenia gravis affect spinal reflexes and proprioceptic testing?
should remail normal - can have poor knuckling or hopping if profound weakness present
What do you expect to see from a facial nerve exam on a dog with myasthenia gravis?
Normal facial nerves, except decreased palpebral reflexes if facial muscle fatigue present
List autoimmune disorders reported to occur with acquired myasthenia gravis
- Hypothyroidism
- Hypoadrenocorticism
- Thrombocytopenia
- IMHA
- Polymyositis
- IBD
What types of neoplasia have been shown to be associated with paraneoplastic syndromes with acquired myasthenia gravis?
- Thyomoma
- Osteosarcoma
- Cholangiocellular carcinoma
- AGASACA
- Cutaneous lymphoma
How is thymoma proposed to contribute to the development of myasthenia gravis?
thyomoma can express antigenic epitopes similar to those of nicotinic ACh-R
What is the most common form of acquired myasthenia gravis in cats?
generalized AMG
What is the most common cardiac disease detected in dogs with acquired myasthenia gravis?
Third degree AV block
Name 4 examples for neuromuscular disorders mimicking myasthenia gravis
- botulism
- polyradiculoneuritis
- tick paralysis
- infectious neuropathies/myopathies
What 2 medications can you administer for presumptive diagnostic tests for myasthenia gravis?
Edrophonium challenge test
alternatively: neostigmine methyl sulphate
Explain how the Edrophonium challenge test works
ultra-short acting anticholineesterase agent –> decreases breakdown of ACh –> more ACh available for AChR -
Exercise dog until weakness occurs –> then give Edrophonium IV –> assess for transiet improvement
What adverse effects should be expected from Edrophonium administration in MG patients?
- Overstimulation of the AChR can produce depolarizing blockade –> worsens muscle weakness = cholinergic crisis –> respiratory paralysis
- SLUDGE + bradycardia from muscarinic overstimulation
Why do some patients with myasthenia gravis not respond to edrophonium?
may not have enough function AChR left - more common in acute fulminant MG
What is the gold standard diagnostic test for myasthenia gravis?
Serum AChR antibody assay
List your diagnostic plan for a dog suspected to have myasthenia gravis
- CBC/Chem/UA
- thyroid panel
- Thoracic radiographs –> assess for megaesophagus, if aspiration pneumonia suspected –> BAL or tracheal wash
- edrophonium challenge test (neostigmine alternatively
- Electrodiagnostic tests
- Immunocytochemical staining of muscle end plates (needs biopsy)
- Serum AChR antibody assay
What are the three components of treating a patient for myasthenia gravis?
- Anticholinesterase therapy
- Immunomodulatory therapy
- Supportive Care
List the treatment options for Anticholinesterase therapy in MG
- pyridostigmine bromide PO versus IV as CRI
- neostigmine bromide IV q6h IM
How can you monitor treatment of dogs with MG with pyridostigmine/ differentiate over or under-treatment?
- edrophonium chlordie challenge test –> if treatment with pyridostigmine is indadequate –> challenge will improve signs; if overtreated –> edrophonium makes signs worse
List indications for immunomodulatory therapy in dogs with myasthenia gravis
- dogs with persistently elevated AChR antibody titres
- seropositve dogs with negative edrophonium challenge test
- dogs with inadequate response to anticholinesterase therapy
- dogs with unacceptable side effects from anticholinesterase therapy
- cats
- only acquired MG - congenital is not immune-mediated
What is the main cause of death in dogs with myasthenia gravis?
aspiration pneumonia - associated with megaesophagus
How can corticosteroids worsen myasthenia gravis in dogs?
- glucocorticoids have negative effects on excitation-coupling of the contractile elements within myofibres
- cause altered function of the ion channel of the AChR
What is the mechanism of action of Mycophenolate?
active compound - mycophenolic acid –> selectively inhibits inosine monophosphate dehydrogenase - necessary for GTP synthesis –> impairs cells ability to synthesize DNA, RNA, proteins, glycoproteins –> targets preferentially lymphocytes
What are the main side effects of Mycophenolate?
- gastrointestinal signs
- bone marrow suppression
What is the mechanism of action of Azathioprine?
cytotoxic antimetabolite, purine antagonist –> incorperates into nucleid acid and terminates proliferation process
active metabolite: 6-mercaptopurine –> decreased lymphocyte proliferation
targets mostly T lymphocytes
What are the adverse effects of Azathioprine?
- bone marrow suppression
- hepatotoxicity
- GI signs
- pancreatitis
What is the mechanism of action of Cyclosporine?
- calcineurin inhibitor –> inhibits T-cell activation
- reduces IL-2 synthesis –> further inhibits T cell proliferation
What are the adverse effects of cyclosporine?
- gingival hyperplasia
- GI upset
Which antibiotics are contraindicated in myesthenia gravis and why?
- erythromycin
- imipenem
- aminoglycosides
- ampicillin
- ciprofloxacin
can potentially have adverse effects on the neuromuscular junction
