Neuromuscular Junction Disorders (Myasthenia Gravis, Lambert-Eat
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Neuromuscular Junction Disorders
Myasthenia Gravis (MG)
- Bimodal age of onset:
- Females predominate at younger age (peak incidence at ~ 25 y.o.); males predominate at older ages (peak incidence at ~ 65 y.o).
- Note that there are several key variants of MG as follows:
- Neonatal MG: maternal to neonatal transmission of Ach antibodies
- Juvenile MG: < 18 y.o.
- Early-onset MG: 18- 50 y.o. (higher likelihood of thymic hyperplasia)
- Late-onset MG: > 50 y.o. (higher likelihood of thymoma)
Key clinical features.
- MG most often presents with ocular symptoms (~ 75%), most often asymmetric ptosis, which manifests with diplopia or blurred vision; fatigable ptosis can be brought-out on physical exam with prolonged upgaze.
- We use the term ocular myasthenia for the ~ 20% of patients who never develop additional symptoms.
- Bulbar weakness manifests with dysarthria and dysphagia; specifically trouble keeping water out of the eyes, trouble swallowing with choking or regurgitating food when eating, and fatigable weakness with chewing.
- We follow breath count, forced vital capacity, and negative inspiratory force to determine need for endotracheal intubation, which can be life-saving.
- Limb/girdle pattern of weakness that is fatigable (worsens with activity); it manifests in the majority of MG patients (even ~50% of the patients who present with isolate ocular involvement will still progress to limb weakness).
- It's critical that we include the pathological finding of thymoma: enlarged thymus.
- There can sometimes be either a thymoma or thymic hyperplasia.
- Early-onset MG patients have a higher likelihood of demonstrating thymic hyperplasia, thus in these patients, thymectomy is often performed as a potential management strategy for the disorder, although response to thymectomy is variable.
- Late-onset MG patients have a higher likelihood of having thymoma, thus it is critical to get a chest CT to look for an associated thymoma.
Laboratory testing in MG:
- Improvement of ptosis with the application of edrophonium or an ice-pack are helpful diagnostic tools in the evaluation for MG but serologies and electrophysiologic studies (EMG/NCS) are more often relied upon.
- The acetylcholine receptor antibodies (binding, blocking, and modulating) are positive in ~ 85% of patients with generalized MG (~ 50% of those with ocular myasthenia).
- Note that they do not correspond to disease severity but the presence of AchR antibodies increases the likelihood of thymic hyperplasia or thymoma.
- Other serologies can be performed in AchR antibody negative patients to prove the diagnosis of MG. Of the potential tests, indicate that MuSK (muscle-specific tyrosine kinase) antibody has the highest sensitivity; it will be positive in ~ 40% of the AchR antibody negative MG patients.
- Additional potential serologic tests include striational antibodies (antibodies to titin and ryanodine) and, more recently discovered, LPR4 antibody testing.
Key treatments in MG.
- Pyridostigmine, an acetylcholinesterase inhibitor, is a symptomatic treatment in MG.
- Although it improves the symptoms of MG, it doesn't inhibit the underlying immune-pathology.
- Gastrointestinal upset is a key side effect because of its pro-cholinergic effect.
- For chronic management via immune suppression, steroids and other immune suppressants (eg, azathioprine) are used.
- For rescue therapy plasmapheresis and IVIG are used.
- However, IVIG is also used as regular infusions (typically every 3 weeks) in the chronic management of MG and plasmapheresis is sometimes scheduled at regular intervals, as well, to prevent worsening.
Lambert-Eaton Myasthenic Syndrome
- LEMS begins proximally, symmetrically in the lower extremities: patients present with trouble standing or climbing stairs. Oculobulbar in involvement in LEMS is milder than in MG.
- There are typically reduced reflexes, which increase with muscle facilitation. This is unlike in MG where the reflexes are typically normal.
- LEMS is associated with autonomic dysfunction, often dry mouth, constipation, or erectile dysfunction.
- LEMS is autoimmune in ~ 50% of cases and paraneoplastic due to small cell lung cancer (SCLC) in the other ~ 50%.
- From a laboratory standpoint, antibodies to the P/Q type voltage-gated calcium channel are ~ 95% sensitive in LEMS (90% in autoimmune, 100% in paraneoplastic).
- VGCC antibodies helps differentiate LEMS from MG, in which they are only rarely positive.
- SOX1 antibody carries a high specificity (but low sensitivity) for SCLC; thus LEMS patients with positive SOX1 antibody have a high risk of an associated SCLC (note that these antibodies are present in non-LEMS patients with SCLC, as well).
- SOX1 is an intracellular protein (specifically a transcription factor); it's alternate name: anti-glial nuclear-antibody (AGNA) helps us remember this.
- 3,4-diaminopyridine (3,4-DAP) is the most effective management in LEMS. It blocks voltage-gated potassium channels, which lengthens depolarization and, thus, augments acetylcholine release. Although pyridostigmine should be beneficial in this disorder, in practice it's rarely actually effective.
Botulinum Toxicity
Botulinum toxicity stems from toxins produced from Clostridium botulinum, of which there are seven types (A – G).
- Considerable ptosis with flattened facies; descending flaccid paralysis occurs.
- From a neuromuscle junction standpoint, botulinum toxicity causes oculbulbar and facial weakness, specifically there is ptosis, facial and extraocular movement weakness, and dysarthria/dysphagia.
- This manifests with eyelid drooping, diplopia, limitation of extraocular mobility, expressionless (flat) facies, and choking and regurgitation.
- Flaccid paralysis follows the oculobulbar weakness and that the weakness begins proximally in the neck and shoulders before it extends distally along the upper extremities and that it subsequently develops in the pelvis and thighs before it descends down the lower extremities.
- Respiratory arrest can occur from diaphragm (and accessory muscle) failure in combination with the pharyngeal weakness.
- From an autonomic standpoint, the blocking of cholinergic transmission results in:
Many causes of botulinum toxicity exist, including:
- Foodborne botulism.
- Contaminated foods produce toxin in an anaerobic milieu.
- Wound botulism.
- Environmental spores germinate and produce toxin in an anaerobic abscess.
- Infant botulism.
- Intestinal colonization can occur in infants because they lack the normal bowel florae necessary to compete with C. botulinum. Note that this can occur in adults with excessive antimicrobial use or functional bowel abnormalities, as well.
- Inhalational botulism.
- Deliberate aerosolization of botulism toxin (which is not a naturally occurrence) is a potential bioterrorism weapon.
- Iatrogenic botulism.
- Rarely, intramuscular botulism injection can result in systemic botulism.
Laboratory
- Laboratory confirmation requires demonstration of toxin in serum or stool (or gastric secretions).
Treatment
- Botulism anti-toxin and supportive care are the key treatment modalities.
- Consider that botulism toxin binding is noncompetitive and irreversible, however, and that the anti-toxin must be delivered early to be effective.
- Fortunately, however, with good intensive care support, patients can survive and within weeks to months, with ample time for nerve terminal regeneration, ~ 95% of patients will recover.
Electrodiagnostics: EMG/NCS
EMG/NCS findings in these neuromuscle junction disorders, which will reinforce our understanding of neuromuscle transmission.
Myasthenia Gravis
- First, for MG, we'll focus on repetitive stimulation at slow frequency (2 – 3 Hz), which simulates muscle fatigue with repetitive use (a characteristic finding in MG).
- CMAPs progressively decrement (drop in amplitude) over a train of 5 action potentials but, then, ultimately recover and rise in amplitude, again.
- his is the characteristic "U" shaped response to slow repetitive stimulation in MG.
- Thus, in MG, the routine CMAPs are normal but there is fatigable reduction in muscle response to stimulation because there are too few Ach receptors to continually reproduce maximal muscle cell firing when repeated at close intervals.
Note that decrement to repetitive stimulation is also found in neuropathies, motor neuron disorders, myopathies, and LEMS, but these disorders typically will have reduced baseline CMAPs.
LEMS and Botulism
We can address the findings in LEMS and botulism, together, because they are essentially indistinguishable, due to their shared reduction in Ach release.
- The baseline CMAP amplitude is abnormally low, because in both of these disorders there is failure of Ach release (in contrast, in MG the baseline amplitude is normal).
- The post-exercise CMAP is normal because with exercise there is facilitation of Ach release.
- In LEMS, the muscle facilitation effect is due to calcium accumulation in the presynaptic terminal, which triggers greater Ach release.
- In botulism, muscle facilitation is directly due to increased Ach release with fast frequency repetitive stimulation.
In myasthenia gravis there is minimal autonomic nervous system dysfunction, in LEMS there is a fair amount of dysfunction, and botulinum toxicity there is considerable autonomic disturbance.
The Neuromuscle Junction & these Disorders
- The neuromuscle junction is the electrical-chemical-electrical link between nerve and muscle: this statement will help us remember key steps in neuromuscle transmission.
We'll use key disorders to reinforce the underlying physiology:
- Myasthenia gravis (MG) is due to postsynaptic nicotinic acetylcholine receptor antibodies.
- Lambert Eaton myasthenic syndrome (LEMS) is due to pre-synaptic voltage-gated calcium channel antibodies.
- Botulinum toxin blocks presynaptic release of acetylcholine (via SNARE complex attack).
- Neuromyotonia results from presynaptic voltage-gated potassium channel antibodies.
Neuromuscle Junction Anatomy
- Presynaptic nerve terminal: the knob-like terminal end of an motor axon.
- Postsynaptic muscle cell membrane (the end-plate); include its junctional folds (which increase the surface area of the postsynaptic membrane).
- The space between the two cells is the synaptic cleft.
- Then, along the crest of the one of the junctional folds, is the nicotinic acetylcholine receptor, which is a ligand-gated ion channel.
- The synaptic vesicle is a spherical, membrane-bound organelle.
- Each vesicle contains ~ 10,000 molecules of acetylcholine Ach (which is synthesized within the nerve terminal from acetyl-CoA and choline).
- For reference, the 10,000 molecules of Ach contained the vesicle are referred to as a quantum.
- Voltage-gated calcium channel along the presynaptic membrane.
Depolarization
- Depolarization along the nerve (this is the first "electrical") triggers an influx of calcium, which will ultimately trigger the release (the exocytosis) of acetylcholine (which is the "chemical").
- Consider that the greater the influx of calcium, the greater the release of Ach.
- In LEMS there are antibodies directed against the presynaptic P/Q-type voltage-gated calcium channels.
- Thus, in this disorder, there is a failure of sufficient calcium influx and a weak release of Ach.
- The SNARE (soluble NSF attachment protein receptor) complex helps the synaptic vesicles dock and fuse to the presynaptic cell membrane.
- We can remember that this complex is necessary when we consider that vesicle to presynaptic membrane fusion involves the fusion of two negatively-charge membranes.
- Botulinum toxin attacks various SNARE proteins, which prevents docking and fusion of the synaptic vesicle.
- Thus, in botulinum toxin, there is reduction/failure of release of acetylcholine.
- For reference: Botulinum A & E attack SNAP-25. Botulinum B, D, F, and G attack VAMP.
- Release of acetylcholine; the acetylcholine traverses the synapse and binds to the post-synaptic nicotinic acetylcholine receptor, which, again, are ligand-gated sodium channels.
- For reference, with each depolarization, ~ 100 vesicles are released.
- Acetylcholine binding at two receptor sites produces a conformational change in the receptor that allows sodium influx.
- With enough depolarization, an end-plate potential (EPP) occurs that exceeds the threshold for an action potential (the second "electrical"), and thus an action potential is produced, which progresses along the muscle membrane and ultimately initiates intracellular excitation-contraction coupling, which produces a muscle contraction.
- Consider that miniature end plate potentials (MEPPs) occur when vesicles spontaneously leak into the synaptic cleft and induce small depolarizations that fail to exceed the action potential threshold. In EMG, we record these MEPPs as end plate spikes.
- Sin MG, antibodies attack the postsynaptic acetylcholine receptors (or various other related proteins (eg, muscle-specific tyrosine kinase (MuSK)).
- In this disorder, there is normal acetylcholine release but failure of postsynaptic muscle cell depolarization because of a lack of acetylcholine receptors.
- In the presynaptic cell, draw a voltage-gated potassium channel and show that potassium eflux from the cell repolarizes the presynaptic terminal.
- In neuromyotonia (Isaac's syndrome), there is autoantibody attack against these voltage-gated potassium channels, thus there is failure of repolarization of the presynaptic cell and prolongation of the presynaptic action potential.
- This results in stiffness and delayed relaxation of muscle with symptoms of muscle twitching and rippling (myokymia), as well as muscle cramps and functional weakness.
- Acetylcholinesterase, which is bound to the muscle cell membrane, catalyzes the hydrolysis of acetylcholine.
- Choline is then taken back up into the presynaptic terminal.
Pharmacological Correlates
- Pyridostigmine is used as an acetylcholinesterase inhibitor for the symptomatic management of myasthenia gravis: it prevents the hydrolysis of Ach.
- 3,4-diaminopyridine (3,4-DAP), which is used in the management of LEMS, blocks voltage-gated potassium channels, which lengthens depolarization and, thus, augments calcium influx and acetylcholine release.
- As a potential side effect, we may be able to predict that 3,4-DAP has the risk of inducing seizures because it prolongs nerve depolarization.