Neuromuscular Junction Disorders Flashcards
What kind of clinical signs are (UMN vs LMN) or seen with neuromuscular junction disease?
LMN
What happens at a neuromuscular junction?
Action potential –> via ventral horn motor neuron –> pre-synaptic terminal –> release of Acetylcholine (with help of Ca2+) –> into synaptic clef –> Acetylcholine receptors on the post-synaptic muscle membrane –> muscle contraction
- there is usually excess ACh and AChR to as “safety factor”
- ACh in the synaptic cleft is degraded by acetylcholinesterase
What are some clinical signs of NMJ dissease?
- Symmetrical flaccid paresis
- in more severe cases can have decreased segmental spinal reflexes, CN deficits, and autonomic signs
- usually have normal mentation and sensory
What are some pre-synaptic diseases of NMJ?
- Tick paralysis
- Botulism
- Elapid snake envenomation
How dose tick paralysis cause NMJ?
- Dermacentor sp or Ixodes sp
- neurotoxin released from female tick salivary gland
- inability to release Ach from pre-synaptic terminal due to mechanisms associated with Ca2+
- tx = remove tick
What are some clinical signs associated with tick paralysis?
In North America, Dermacentor more common.
- c/s noted 5-9 days after tick attachment
- acute, rapidly progressive ascending flaccid paresis
tetraplegia can happen in 12-72h
- segmental spinal reflexes severely diminished, decreased muscle tone
- hypoventilation can occur in severe cases
- autonomic, sensory, and sphincter function = normal
- tick removal = dramatic improvement within hours
What are some c/s with Ixodes paralysis in Australia?
- in addition to the rapid flaccid paresis, can also have autonomic, sensory, and sphincter abnormalities
- congestive heart failure (diastolic dysfunction)
- pupillary dilation
- can get pulmonary edema, aspiration pneumonia
- may continue to decline several days after tick removal
What’s the most common botulism neurotoxin in dogs?
neurotoxin type-C (BoNT-C)
How does botulism cause NMJ disease?
Botulism toxin irreversibly binds to SNARE protein, which is essential in docking of Ach in the pre-synaptic terminal –> therefore, there is no release of ACh
- it’s at pre-synaptic terminal of skeletal muscle and cholinergic autonomic synapsis
What are some clinical signs of botulism?
acute, progressive, tetra paresis
- also has autonomic signs (mydriasis, changes in heart rate)
- CN deficits (palpebral, megaesophagus, PLR) also common
- can be seen within hours or up to 6d
What are the treatment for botulism?
- supportive therapy
- anti-toxins don’t work (most are not against BoNT-C), watch for anaphylaxis
- don’t use aminoglycosides or ampicillin –> may potentiate NM blockade
How does snake venom cause NMJ disease?
It can block pre-synaptic release of ACh
Where are some clinical signs of envenomation?
- flaccid tetraparesis/ tetrplegia
- hypotonia
- reduced/ absenet segmental spinal reflexes
- hypoventilation
- CN deficits: drooling, dhysphagia, dysphonia, facial paresis/ paralysis
- discolored urine (esp in dogs): not a feature in other pre-synaptic NMJ disease
What are some causes of post-synaptic NMJ disease?
acquired or congenital myasthenia gravis
How does acquired myasthenia gravis cause NMJ disease?
- autoimmune
- produces antibodies against muscarinic AChR in skeletal muscles
- therefore, post-synaptic terminal less responsive to ACh
- skeletal muscle weakness, often exacerbated by activity
What’s the typical signalment for acquired myasthenia gravis?
- <4y or >9y
- Golden, German Short-hair pointers, Akita, Chihuahua, GSH, Newfoundlanders
- less common in cats (Abyssinians, Somali, other purebreds)
What are the 3 forms of myasthenia gravis? Which one is the most common one?
- Generalized (most common)
- focal
- fulminant
What are the c/s related to generalized myasthenia gravis?
- neurological normal at rest
- has a choppy, tilted gait, first seen in hind limbs
- with increased activity, will see it in the front limbs
- segmental spinal reflexes typically normal
- can have fatigable palpebral reflex
- megaesophagus/ regurgitation common
- ptyalism, dysphonia possible
- ventroflexion of neck is more common in cats
What are some signs associated with fulminant myasthenia gravis?
- rapidly progressive severe diffuse weakness –> nonambulatory tetraparesis, lateral recumbency
- doesn’t get better with rest
- lots of regurgitation and aspiration pneumonia = common
- respiration muscle weakness and urine retention
- thymoma
- seen in 16% of dogs, and 15% of cats with MG
What are some signs of focal myasthenia gravis?
disorder isolated to a single muscle group: ocular, facial, esophageal, pharyngeal, or laryngeal muscles
What are some conditions associated with acquired myasthenia graivs?
- thymoma
- hypothyroidism
- hypoadrenocorticism
- polymyositis
- masticatory myositis
- hyperthyroid cats on methimazole
How is acquired myasthenia gravis diagnosed?
- no change with CBC or chemistry panel
- Gold standard = demonstration of anti-AChR antibodies
- a decrease in CAMP can be noted from repeated nerve stimulation
- edrophonium test (short acting anti-acetylcholinesterase) – not 100% specific to MG
- watch for cholinergic crisis with edrophonium (weakness, hypersalivation, tremors, vomiting, bradycardia, bronchoconstriction, respiratory distress)
What are some treatment options for acquired myasthenia gravis?
- acetylcholinesterase inhibitors: neostigmine, pyridostigmine bromide (oral). Both have narrow therapeutic window
- immunosuppressive drugs: cyclosporin, mycophenoalte, azathioprine (targets adaptive and spares the innate immunity)
- corticosteroids
- spontaneous recovery possible
Which breeds have congenital myasthenia gravis been reported in?
- Jack Russel Terriers
- Min Dachshund
- Smooth Fox Terriers
- Gammel Dansk Honsehund
- others
What are the clinical signs of congenital myasthenia gravis?
- usually evident by 6-9 weeks, multiple puppies affected in one litter
- generalized limb and cervical muscle weakness, worse with activity
- +/- megaesophagus
- in Gammel Dansk Honsehund, it’s seen around 4m
What’s the treatment for congenital myasthenia gravis?
- neostigmine or pyridostigmine
- euthanasia
- in Min Dachshund, spontaneous resolve by 6m
- Gammel Dansk Honsehund, c/s mild, so no tx necessary
What’s exercise induced collapse of Labrador Retrievers?
- fatigue and flaccid para or tetra paresis during or after strenuous exercise
- ataxia, pelvic limb weakness, collapse
- normal at rest
- recover within 30min of activity
- severe episode can lead to death
How is congenital myasthenia gravis diagnosed?
Muscle biopsy = definitive diagnosis
What’s the etiology of exercise induced collapse in Labrador Retrievers?
- heritable mutation
- autosomal recessive Arg256Leu, for protein dyamin 1
- this protein encodes a family of proteins that maintain synaptic vesicle function during sustained neurotransmission
- important in recycling or synaptic vesicles
- usually seen before 2yo
