DISORDERS OF THE NMJ

• Nerve Transmission – nerve action potential moves along a terminal; voltage-gated Ca channels open; vesicles exoctyose at specific active release zones; Ach is released and binds to the post-synaptic membrane to make an action potential => if large enough, muscle fiber AP; Ach hydrolyzed by AchE with choline reuptake.

• 300 000 main store of Ach; 10 000 mobilization Ach; 1000 releasable Ach.

• Small depolaraizations are called MEPPs (mini end plate potentials)

• EPP must reach the AP threshold to generate an AP (safety factor guarantees muscle activation).

• Disorders may be divided into pre-synaptic, post-synaptic based on the compound muscle action potential (CMAP):

There are two mechanisms for the slow rate decrementation seen in both pre and post-synaptic disorders (see Syllabus for individual description and variability). For fast rate, build-up of Ca helps presynaptic but does not affect the post-synaptic because too few receptors.

MG – clinical picture characterized by intermittency of weakness and ocular changes, overt progressive weakness that is alleviated by rest (eyes closed shut for a while are better, but may progressively worsen). Symptoms may be worse in the evening, worse in cold weather situations. The differential often includes MS which can be separated by CNS involvement.

• MG tested by edrophonium, treated with neostigmine or pyridostigmine (AChE inhibitors)

• The post-synaptic muscle membrane is altered by anti-Ach receptor antibodies, making the membrane less sensitive to applied Ach. There are reduced numbers of quanta released as a result => small EPP, below threshold. Reduced probability that a nerve potential will be followed by a muscle action potential.

• Electromyography of MG patients reveals that the CMAP of nerve stimulation is normal. The amplitude of the 4th or 5th nerve stimuli falls to 10% of the initial value. Unfortunately, repetitive nerve stimulation is not a sensitive test for MG dx.

• Single fiber EMG shows jitter in some muscles in almost all patients with MG. Jitter is not specific, but a general sign of disturbed neuromuscular transmission. Jitter is useful in excluding abnormal neuromuscular transmission (ie jitter in a weak muscle puts NM transmission problems low on the differential). Jitter is the most sensitive in vivo test of NM transmission.

Botulism – clinical picture characterized by rapid onset with descending weakness (cf to G-B which is an ascending disorder), blurred vision, dysphagia, dysarthria, dry mouth & other reverse SLUDS. Think food (not properly cooked, nearly endemic in some Alaskan villages), wounds, cocaine use, colostomy bag contamination. Presentation among children is a hypotonic kid with a poor suck who recently ate some honey from PA, CA (clostridium botulinum). Kids have a better chance of isolating bug in poo.

• Botulinum toxin is one of the most deadly known to man, and destroys the neurotransmitter pre-synaptically.

• Botulinum toxin used to treat achalasia (remember from GI?), cervical dystonia, and blink spasms.

Category: Neurology notes