Plasma Exchange For Myasthenia Gravis

Posted by Christopher Orr,  Drexel University College of Medicine 2014

Ms. AB presented last week in the Neurology office with shortness of breath and weakness, and she knew it was from her myasthenia gravis.

She was already on an anticholinesterase inhibitor, but it was very apparent that she was suffering from a severe exacerbation of myasthenia gravis.

We sent her to the Emergency Room in order to be admitted so she could receive plasmapheresis in order to minimize the antibodies that were blocking the acetylcholine receptors at her neuromuscular junctions.

To give a brief history of Ms. AB’s myasthenia gravis, she was diagnosed in the Fall of 2013 when she presented with muscle weakness and difficulty breathing.  She was treated with plasmapheresis during that initial episode, and improved.

In the interim, she had also been given steroids to reduce the immune response of her autoantibodies towards her acetylcholine receptors, but this actually caused increased leg weakness, more likely from steroid myopathy than myasthenia gravis.

Unfortunately she experienced another exacerbation in December, and she was treated with intravenous immunoglobulin (IVIG).  What is interesting is that when she was treated with IVIG, her symptoms did not improve as they had done plasmapheresis.

There is limited research on the efficacy of IVIG in comparison to plasmapheresis in the literature.  A comparison study of IVIG vs. plasmapheresis waspublished by Mandaway et. al. in the Annals of Neurology in 2010 and included 1,606 patients – both therapies showed similar clinical outcomes in terms of both mortality and complications.  From a purely financial perspective, IVIG was more cost effective because of lowered length of stay and total inpatient charges.

However, a smaller study published by Stricker et. al. in JAMA in 1993 reported 4 patients who did not respond to initial IVIG treatment but later responded to plasmapheresis.  There were no definite prognostic factors mentioned that might explain why plasma exchange may be better than IVIG in certain patients.  The article stated further research was needed.

Ms. AB did present with myasthenia gravis at a later age of onset than is typically observed.  For future studies that compare IVIG to plasmapheresis, I would be highly interested in a subgroup analysis on a patient’s age and the efficacy of the 2 treatment modalities of IVIG and plasmapheresis.

When we saw Ms. AB in the hospital, she was already doing much better with plasmapheresis.  In addition, we were For the future, Ms. AB would likely be discharged to a rehabilitation facility and there are considerations to start her on CellCept (mycophenolate mofetil).  It would be preferential to start the patient on CellCept as an immunomodulatory drug to decrease the autoantibodies against her acetylcholine receptors and reduce her need for plasmapheresis.

I chose to write a reflection on Ms. AB for 2 reasons.  First, she and her husband are both very kind people, and it is a pleasure to see her improve.  Second, I love technology in medicine and healthcare.  When we saw Ms. AB’s plasmapheresis treatment, it was fascinating to see the apparatus that was using centrifugal force to spin her blood and separate her plasma from the WBCs, RBCs, and platelets.  The mechanism behind performing the plasmapheresis was to take off her plasma, which had the autoantibodies, and replace new plasma with albumin.  Please look below to see a picture of a plasmaphresis apparatus and an explanation of how it works.  After my experience seeing Ms. AB, it was a pleasure to treat her and learn from her condition.

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Pictured above is an apparatus that is used for the plasmapheresis treatments.  Although this machine may seem very intimidating, it operates on the basis of how spinning blood can separate the blood into different components, such as the plasma, RBCs, WBCs, and platelets. To explain in a simple manner, a central venous line is obtained from the patient so blood can be brought to the machine and spun.  After the plasma is removed by the centrifugal force, the remaining components (RBCs, WBCs, and platelets) is added with albumin and saline (a protein found in plasma) then reintroduced into the patient.

In many instances, diseases can be complicated to comprehend.  I wanted to give a better understanding of myasthenia gravis.  I hope this picture and caption that I included make the disease easier to digest.

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The above image shows the synapse of a neuromuscular junction.  In a healthy patient, the acetylcholine can bind the acetylcholine receptor and produce a response in the muscle.  In a patient with myasthenia gravis, the antibody (shown in green) is blocking the acetylcholine receptor and preventing the acetylcholine in the synapse from reaching the muscle.  This picture is a good educational tool because it also shows how the treatment of pyridostigmine (Mestinon) can improve a patient’s symptoms.  The acetylcholinesterase (AChE, the red pac-man figure) is what degrades the acetylcholine in the synapase.  Pyridostigmine is an anticholinesterase inhibitor and impedes the red pac-man figure in the picture from working.  Therefore, pyridostigmine increases the amount of acetylcholine in the synapse that can reach the receptor and will improve the symptoms in an episode of myasthenia gravis.

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Diagnosis of Myasthenia Gravis Confirmed with Tensilon Test

Post prepared by Dr Mrugesh Panchani, PGYIII Medicine Resident, Monmouth Medical Center.

For patients with clinical features and signs suggestive of myasthenia gravis, the Tensilon test can serve as an easy bedside confirmatory test.

Edrophonium (Tensilon) is an acetylcholinesterase inhibitor and we have already blogged about how these drugs can improve conduction across the neuromuscular junction in myasthenics.

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Tensilon is preferable for diagnostic testing because of the rapid onset (30 s) and short duration (5 min) of its effect.

However, an objective end-point must be selected to evaluate the therapeutic effect, such as improvement in eye movements, ptosis, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction.

Here’s a real life example (we have a signed consent form on file):

The first video shows our patient at her baseline with R>L ptosis and facial weakness:

Then the patient is given a low dose (2mg) of iv Tensilon (with telemetry monitoring and bedside atropine at the ready) is given and we see a definite improvement in ptosis and a more expressionful face:

This test was considered positive and hence terminated.

Had there been no change, the patient would have been given an additional 8 mg of iv Tensilon.

We typically start with a low dose at first because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculation, and (rarely) bradycardia. Atropine (0.6 mg) should be drawn up in a syringe, ready for IV administration if these symptoms occur.

Neuromuscular respiratory failure

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Each lung is composed of >300 million tiny membrane bound sacs of air sacs (alveoli) which if spread out would cover a piece of ground roughly the size of a tennis court.  The purpose of this giant membrane is to exchange oxygen from the air for carbon dioxide from the blood stream.

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If the lungs become congested (or filled with fluid) from infection (pneumonia) or heart failure, it becomes harder to extract oxygen from the air:

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Treatment includes adding extra oxygen to the air to make this process more efficient.

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However, gas exchange across the alveoli can only occur if fresh air is brought into the lungs, and stale air is moved out, a process known as ventilation.  The diaphragm and muscles of the chest wall act like a giant bellows to make this happen:

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These muscles can become weak in nerve or muscle diseases such as Guillain-Barré syndrome, polio, amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy and myasthenia gravis.

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These patients are evaluated by pulmonary function testing, which will usually show a low forced vital capacity, low cough flow, and in advanced cases, elevated end-tidal carbon dioxide level.

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Patients with this type of ventilatory failure do not need extra oxygen, their lungs can extract oxygen from air normally, they need mechanical assistance moving air across their lungs:

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Early neuromuscular respiratory muscle weakness causes nocturnal hypoventilation.  This is because the weakened diaphragm is even more inefficient when laying supine in bed with the stomach contents pressing up on it.

Nocturnal hypoventilation presents with daytime sleepiness, early morning headaches, fatigue, and impaired cognition.

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Click here to take an on-line test, and find out how sleepy you are during the day.  If you score 10 or higher, you might have a problem!

Nocturnal hypoventilation is best treated using a non-invasive respirator at night, either with a face or nose mask:

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Other patients use a negative pressure respirator vest, or cuirass, which requires the patient to wear an upper body shell  attached to a pump which actively controls the respiratory cycle:

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Neuromuscular respiratory failure also leads to an ineffective cough, which in turn predisposes patients to aspiration, retention of secretions, or pneumonia.  Affected patients need to learn to use the cough assist machine when they get a minor respiratory tract infection to help them clear their secretions and prevent pneumonia:

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More severe neuromuscular ventilatory failure leads to rapid shallow breathing, accessory respiratory muscle use, thoracoabdominal paradox (inward motion of the abdomen during inspiration), and ultimately high blood levels of carbon dioxide.

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Thoracoabdominal paradox – Normal (upper) abdomen moves outward with inspiration (diaphragm contraction). NM weakness (lower) abdomen moves in when patient inspires using accessory muscles.

In these cases, respiratory support is needed day and night.

Some patients can continue to use non invasive respiratory support, sleeping with a face or nose mask, and using a mouth piece intermittently during the day:

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Others cannot tolerate noninvasive ventilation or have anatomic abnormalities that preclude fitting of noninvasive ventilators.  Some disease, such as advanced ALS and Duchenne muscular dystrophy, affect the upper airway muscles as well as the diaphragm, impairing swallowing and compromising airway protection from aspiration.  These patients can chose to be managed with invasive respiratory support using a tracheotomy and conventional ventilator.

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Click here and and here to find out more about the management of neuromuscular respiratory failure.

Acetylcholine and Myasthenia Gravis

How does the neuromuscular junction work?

The neuromuscular junction is the connection between a motor nerve and muscle fiber.

The activated motor nerve triggers the release of acetylcholine (ACh), which then diffuses across the neuromuscular junction to the muscle (post-synaptic) membrane, binds to any available acetylcholine receptor (AChR), which then in turn  activates the muscle fiber, ultimately leading to a motor contractions and a volitional movement.

What happens in myasthenia?

Autoimmune (acquired) myasthenia gravis (MG) is caused by antibodies circulating in the blood stream which bind to AChRs and disrupt neuromuscular transmission in a variety of ways:

Some of these antibodies simply block the receptor’s binding sites so that ACh cannot activate the muscle membrane:

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Other antibodies link the receptors together:

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Which then leads to internalization of the receptors (endocytosis) and simplification of the post-synaptic membrane:

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The end result is that the post synaptic membrane becomes simplified and devoid of working AChr, so there are little or no available binding sites for the released ACh to bind to:

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Excess ACh is removed from the synaptic cleft by the enzyme acetylcholinesterase (AChE), which breaks it down into inactive constituents.

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So, you can think of MG like a game of musical chairs, when some of the chairs have been taken away, and there some of the acetylcholine can’t find a place to sit down before it is gobbled up by the AChE.

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You can tip the odds more in favor of facilitating neuromusucular transmission by inhibiting AChE, allowing ACh to stick around longer, making it more likely to find an available AChR to bond to, rather like waiting longer to remove the chairs in musical chairs.

Dr Mary Walker first uses physostigmine in MG

mg mwDr Walker was first to discover the benefits of using a acetylcholinesterase inhibitor (AChEI) in MG in 1934.  While still a house physician at St Alfege’s Hospital, Greenwich, she found herself taking care of a 56-year-old woman with severe MG.  She happened to review the case with visiting neurologist, Dr Denny Brown, who explained to Dr Walker that MG resembled the effect of curare poisoning. Dr Walker, reading that the effect of curare could be reversed by injecting physostigmine, tried this drug on her patient, with remarkable improvement. She then treated a second case, a 40-year-old woman, using prostigmine, marketed by Roche. This case was presented to the Royal Society of Medicine in December 1934, and became known as ‘The Miracle of St Alfege’s’.

The Tensilon Test

We do still (rarely) use injectable AChEIs  like prostigmine (neostigmine) for managing MG.

However, we now more often use them for diagnosing MG, and in particular the short acting drug edrophonium or Tensilon has become synonymous with the diagnosis of MG, the so-called Tensilon test.

Mestinon

The oral AChEI pyridostigmine or Mestinon is now widely prescribed for symptomatic treatment of MG

Drooping eyelids (ptosis)

Ptosis can affect one or both eyes and results from weakness affecting the muscles that raise the eyelid.

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Left sided ptosis

Ptosis can be congenital (you are born with it), or acquired (it develops during life).

Acquired ptosis can result from a variety of problems affecting the nerves, muscles, neuromuscular junction or tendons involved in elevating the eye lids.

Neurogenic ptosis is usually unilateral, and can be caused by a lesion affecting either the oculomotor nerve or the sympathetic nerve fibers to the eye (Horner’s syndrome).

When ptosis is caused by an oculomotor nerve lesion, there is  generally also some degree of eye movement abnormality (ophthalmoparesis).  Oculomotor nerve palsy can be caused by something as simple as diabetes, but if the nerve fibers to the pupil are involved (causing a dilated pupil in addition to the ptosis and ophthalmoparesis), that is very suggestive of a compressive lesion such as an aneurysm (see below) and warrants immediate evaluation.

R ptosis, occulomotor palsy (eye is deviated down and outwards), with a dilated pupil, caused by nerve compression from aneurysm (red arrow)

R ptosis, oculomotor palsy (eye is deviated down and outwards), with a dilated unreactive pupil, caused by nerve compression from aneurysm (red arrow)

Horner’s syndrome causes mild ptosis associated with a small pupil (miosis) sometimes associated with lack of sweating (anhidrosis) on the face, and can be caused by trauma to the carotid artery, lung tumors, or strokes.

L Horner's syndrome with mild ptosis and miosis

L Horner’s syndrome with mild ptosis and miosis

Myasthenia gravis is an autoimmune disease that affects the neuromuscular junction, and frequently presents with fatiguable ptosis often associated with double vision and limb weakness.   The ptosis will usually get worse when the patients is tired at the end of the day (diurnal variation):

Fatiguable ptosis in myasthenia gravis

Fatiguable ptosis in myasthenia gravis

The ptosis of myasthenia can be temporarily improved with an acetylcholinesterase inhibitor medication, such as an injection of edrophonium (Tensilon), and this can used a diagnostic test.

Ptosis can also be seen in certain muscle diseases, including oculopharyngeal muscular dystrophy, mitochondrial myopathy and myotonic dystrophy.

Bilateral ptosis in a patient with myotonic muscular dystrophy

Bilateral ptosis in a patient with myotonic muscular dystrophy

However, acquired ptosis is most commonly caused by dehiscence or disinsertion of the levator aponeurosis, causing a disconnection between the eye lid and the elevating muscles.

This usually occurs in elderly patients, but can sometimes affect younger contact lens users.

L ptosis from levator dehiscence - Note that when the eye is closed, the lid crease is fainter and further away from the lid margin in the left eye, compared to the right eye

L ptosis from levator dehiscence – Note that when the eye is closed, the lid crease is fainter and further away from the lid margin in the left eye, compared to the right eye

Patients who notice a drooping eyelid, unequal pupils, or double vision should consult with a neurologist in order to establish the correct diagnosis.

After that, treatment might include medical therapy for an underlying disorder (such as diabetes or myasthenia), surgery or even eye lid crutches:

Myasthenic patient with isolated L ptosis, demonstrating improvement with the eye lid "crutch"

Myasthenic patient with isolated L ptosis, demonstrating improvement with the eye lid “crutch”