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Myasthenia Gravis & Other NMJ Disorders

Notes

Myasthenia Gravis & Other NMJ Disorders

Sections







Sections

Myasthenia gravis
Lambert-Eaton Myasthenic Syndrome
Botulism (neuromuscle complications)
See Board Review Highlights at the end.

Overview

Neuromuscle Junction Overview

The neuromuscle junction is the electrical-chemical-electrical link between nerve and muscle: this statement will help us remember key steps in neuromuscle transmission.

Key Neuromuscle Junction Pathophysiology

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.

Myasthenia Gravis

Epidemiology

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).

Myasthenia Gravis Variants

  • 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)

Clinical Features

Fatigable Weakness

Historical and exam clues to the diagnosis are fatigue that is worsened with activity and diminished with rest (so-called fatigable weakness).

Ocular Weakness

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.
  • Diplopia and ptosis are is worsened with such activities as reading and driving.
  • Cogan's twitch sign demonstrates subtle weakness of the superior rectus and inferior oblique muscles.

Bulbar Weakness

Bulbar weakness, which manifests with dysarthria and dysphagia, trouble swallowing with choking or regurgitating food when eating, and fatigable weakness with chewing.

  • Patients may have nasal speech ("mushy" speech). When asked to smile, patients may exhibit a "myasthenic snarl".

Respiratory Failure

Bulbar weakness can lead to respiratory failure. We follow breath count, forced vital capacity, and negative inspiratory force to determine need for endotracheal intubation, which can be life-saving.

Limb/Girdle Weakness

MG often presents in the majority of MG patients (even ~50% of the patients who present with isolate ocular involvement will still progress to limb weakness).

  • There is typically proximal muscle weakness (shoulders and hips) rather than distal (forearm and hand) weakness.
  • Proximal leg weakness typically presents with trouble getting up (ilopsoas) and down stairs (quadriceps), and getting out of a low chair (however, wrist drop or foot drop would not be expected in MG).

Deep tendon reflexes

Deep tendon reflexes will not be affected, which helps distinguish MG from neuropathy (decreased reflexes), myopathies (decreased reflexes) and, notably, Lambert-Eaton myasthenic syndrome (decreased reflexes).

Thymoma/Thymic Hyperplasia

In MG 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.

Family history

There is a strong association with family history of MG and also other autoimmune disorders (rheumatoid arthritis, autoimmune thyroid disease, systemic lupus erythematosus, etc…).

Exacerbating Medications

Numerous medications that can worsen MG but pay attention for aminoglycosides (eg, gentamicin), fluroquinolones (eg, ciprofloxacin), macrolides (eg, azithromycin), beta-blockers (eg, metoprolol), magnesium, succinylcholine.

Laboratory Testing

Edrophonium & Ice-pack

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.

EMG/NCS

Repetitive nerve conduction studies demonstrate decreased compound muscle action potential (CMAP) response following low frequency (3 Hz) repetitive nerve stimulation and following prolonged exercise.

Single fiber EMG can be used to evaluate for increased jitter but this is a technically difficult study to perform.

Acetylcholine receptor antibodies

Indicate that the acetylcholine receptor antibodies (binding (most frequently), and also blocking and modulating (less frequently)) 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.

See Neuromuscular Junction Pathophysiology for more details on MG pathophysiology.

Other Serologies

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.

Treatments

Pyridostigmine

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.

Immune Suppression

For chronic management via immune suppression, steroids and other immune suppressants (eg, azathioprine) are used.

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.

We can group the steroid-sparing immune suppressant medications as follows:

Rescue Therapy

For rescue therapy, plasmapheresis and IVIG are used.

Lambert-Eaton Myasthenic Syndrome

Clinical Features

Proximal lower extremity weakness

Draw a pair of legs and indicate that 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.

Reflex Facilitation

Also, draw a reflex hammer and indicate that there are typically reduced reflexes, which increase with muscle facilitation. This is unlike in MG where the reflexes are typically normal.

Autonomic Dysfunction

LEMS is associated with autonomic dysfunction, often dry mouth, constipation, or erectile dysfunction.

Pathophysiology & Treatment

Pathology

Draw lungs with a small cell lung cancer (SCLC) and indicate that LEMS is autoimmune in ~ 50% of cases and paraneoplastic due to small cell lung cancer (SCLC) in the other ~ 50%.

P/Q type voltage-gated calcium channel antibodies

From a laboratory standpoint, indicate that antibodies to the P/Q type voltage-gated calcium channel are ~ 95% sensitive in LEMS (90% in autoimmune, 100% in paraneoplastic).

  • VGCC antibodies help differentiate LEMS from MG, in which they are only rarely positive.

SOX1 antibody

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.

Treatment: 3,4-diaminopyridine (3,4-DAP)

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.

Botulinum Toxicity

Overview

Botulinum toxicity, which stems from toxins produced from Clostridium botulinum, of which there are seven types (A – G).

To encapsulate key presenting symptoms, draw a human figure with considerable ptosis and flattened facies and draw downward arrow to indicate the characteristic descending flaccid paralysis that occurs.

Clinical Features

Oculobulbar Weakness

Write out that 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.

Indicate that 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

Next, indicate that respiratory arrest can occur from diaphragm (and accessory muscle) failure in combination with the pharyngeal weakness.

Autonomic Dysfunction

From an autonomic standpoint, the blocking of cholinergic transmission results in constipation and mydriasis (pupillary widening) from parasympathetic inhibition and hypohidrosis from inhibition of post-ganglionic cholinergic sympathetic fibers.

For comparison, 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.

Causes

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 Testing

Indicate that laboratory confirmation requires demonstration of toxin in serum or stool (or gastric secretions).

And to reiterate the role of postganglionic sympathetic sweat fiber inhibition, indicate that an absent sweat reflex can also be identified.

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

Let's learn the 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).

Draw a series of CMAPs that progressively decrement (drop in amplitude) over a train of 5 action potentials but then recover and rise in amplitude, again.

With an arrow, show that this 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

Next, we can address the findings in LEMS and botulism, together, because they are essentially indistinguishable, due to their shared reduction in Ach release.

Show that 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).

Then, show that the post-exercise CMAP is normal because with exercise there is facilitation of Ach release.

Similarly, show that repetitive stimulation at fast frequency (40—50 Hz), which is the correlative to exercise, demonstrates a progressive increment in CMAP amplitude with each firing.

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.

Board Review

Clinical Presentation

Diagnostics

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USMLE & COMLEX-USA

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Neurology (ABPN)

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References

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