By Ashraf Elsayegh, MD, FCCP, Pulmonary/Critical Care, Cedars-Sinai Medical Center –

Overview:

Charcot Marie Tooth Disease (CMT) is a spectrum of disorders (CMT-1A, CMT-1B, CMT-2, X-Linked CMT, CMT-3, CMT-4, and CMT 5-7) that affect peripheral nerves that carry motor and sensory information to and from the brain. These include the phrenic nerves as well as other peripheral nerves controlling the function of breathing. This produces symptoms of peripheral nerve dysfunction which can result in difficulty breathing. Although respiratory dysfunction is not a very common hallmark of CMT patients, it can occur.

Ashraf Elsayegh, MD, FCCP

Ashraf Elsayegh, MD, is a distinguished physician and researcher based in Los Angeles, California. With fifteen years of experience, Dr. Elsayegh is a foremost expert in the field of pulmonary medicine. He currently practices at Cedars-Sinai where his interest and research centers around neuromuscular disorders, specifically amyotrophic lateral sclerosis (ALS), as well as diaphragm dysfunction and disorders.

Clinical Manifestations:

Diaphragm Dysfunction:

Although breathing is controlled by multiple muscles, it appears that the diaphragm plays the most significant role. The diaphragm is a muscle at the bottom of your chest cavity controlled on each side by the right and left phrenic nerves. If the phrenic nerve becomes affected (damaged), the diaphragm will not be able to contract properly resulting in shortness of breath (dyspnea). An early sign of this problem is dyspnea while lying flat. Patients will have obvious shortness of breath or difficulty catching their breath when in a supine position usually relieved by sitting upright or sleeping at an angled position.

Spirometry Testing

Spirometry Testing

Diaphragm dysfunction may be diagnosed using multiple testing. The simplest test is pulmonary function which tests the strength and efficiency of breathing. A full pulmonary function test (PFT) is not typically recommended in CMT patients but could be performed if there are any symptoms of breathing problems. If abnormalities are detected on initial testing, then this can be followed by just the spirometry portion at least twice a year. Many clinics have this available in the office. Given that respiratory decline is rare and slow to occur in CMT, spirometry more frequently is usually not indicated. The major components of the PFT that are helpful in patients with neuromuscular weakness are the Forced Vital Capacity (FVC) which tests the total volume of air one can breathe out, and the Negative Inspiratory Force (NIF) which measures the force with which one can take a deep breath in. Data is not available to prove superiority of FVC vs NIF in monitoring respiratory decline, therefore, I recommend monitoring both for a more accurate gauge of respiratory dysfunction.

Another relatively easy test to evaluate diaphragm dysfunction is a SNIFF test. This test requires the patient to sniff while undergoing fluoroscopic imaging. This will measure the movement of the diaphragm. In general, this does not need to be performed unless surgical intervention on the diaphragm is required (discussed below).

Finally, phrenic nerve conduction and/or Diaphragm EMG may also be performed to evaluate diaphragm function. The phrenic nerve study is similar to the nerve conduction study done for the diagnosis of CMT except the phrenic nerve is stimulated in the neck and the recording is done with sticky pads on the chest wall and lateral rib. It is safe and no more uncomfortable than routine nerve tests. The diaphragm EMG requires a needle in the area of the diaphragm and carries some small risks. More recently ultrasound to evaluate the diaphragm has been utilized in some centers. Again, these are usually not necessary to perform unless surgical intervention is needed.

When respiratory decline is discovered, early management is warranted. The mainstay of therapy is noninvasive ventilation (NIV). Continuous Positive Airway Pressure (CPAP) therapy is not recommended in neuromuscular disease. Although Bilevel Positive Airway Pressure (BiPAP) therapy is better than CPAP, there are now more sophisticated forms of NIV that are much more comfortable for and much better tolerated by patients. Also, as the respiratory function declines further, the newer forms of NIV are far superior in managing the respiratory complications. They are superior in maintaining the respiratory system as well as maintaining a proper carbon dioxide (CO2) level. If the patient has reached the point of retaining CO2, they should already have been placed on noninvasive ventilation. Therefore, monitoring blood gases to follow the CO2 level is usually not indicated. It is a painful invasive test that will not add much information or contribute to changes in management. The exception is if the patient has signs of hypercapnia (high CO2) such as altered mental status, headaches, or difficulty to arouse. At that point measuring CO2 levels with a blood gas will help in adjusting the NIV settings. My recommendation is to wear the NIV at night while sleeping to start. If needed, NIV may be used during the day if dyspnea occurs.[1]

In CMT, as with other neuromuscular disorders, the weakness in breathing usually does not affect oxygen (O2) levels but, as mentioned above, may increases CO2 levels because of the inability to blow CO2 out of the body. Therefore, supplemental oxygen is rarely needed in CMT and may actually be harmful in some patients.[2]

If the respiratory decline has reached a point that the patient is requiring NIV 24 hours a day or NIV is no longer benefiting the patient, a tracheostomy may be considered at that point. The patient would then be attached to a portable ventilator through the tracheostomy. I would like to emphasize that this situation is exceedingly rare in CMT.

Diaphragm pacing always comes up when discussing respiratory dysfunction in neuromuscular patients. Diaphragm pacing has equivocal results at best in neuromuscular patients and has never been tested specifically in CMT patients. I recommend discussing with a center that performs this procedure if interested and if diaphragm dysfunction becomes a significant problem. If diaphragm pacing is a consideration, at that point, SNIFF testing and Diaphragm/Phrenic EMG are required.

Diaphragm dysfunction also plays a role in coughing. Again, although coughing is controlled by multiple aspects, having a weakened diaphragm can diminish the ability to cough. This may lead to secretion build up in the chest cavity. The increased secretions can also contribute to dyspnea.

As of right now there is no good test to measure cough function aside from clinically watching the patient cough. If coughing is affected there are two main forms of airway clearance devices that may be tried. First there is a high frequency chest wall oscillator. This helps break down secretions making them easier for the patient to expectorate. Second there is a cough assist that can actually help expectorate the secretions for the patient.

In my opinion, the most important key to proper pulmonary care is a DME company and respiratory therapist who specializes in neuromuscular patients. They will help in day to day management and adjustment of the noninvasive ventilator and will be an excellent resource for the patient on simple questions involving the equipment.

Vocal Cord Paralysis:

Although relatively rare, some patients with CMT can have vocal cord paralysis. In general, it is usually more problematic in children than in adult patients. This may present with unilateral or bilateral vocal cord involvement. Unilateral vocal cord paralysis rarely presents with symptoms. Chronic aspiration of gastric content may occur with vocal cord paralysis resulting in repeated pneumonias. Bilateral vocal cord paralysis can result in stridor and difficulty breathing.

If patients develop chronic multiple pneumonias secondary to aspiration, vocal cord paralysis should be considered. This may be evaluated easily with a laryngoscopy. If paralysis is discovered, no significant intervention is usually warranted. Aspiration precautions should be taken. If vocal cord paralysis becomes problematic with hoarseness and difficulty breathing, a tracheostomy is indicated. These situations are rare but again tend to be more common in children than in adults.

Sleep Disorders:

As with any neuromuscular disease, sleep apnea may occur in CMT patients. Both obstructive (OSA) and central (CSA) sleep apnea may present in these patients. Also, restless leg syndrome (RLS) and periodic limb movements (PLMs) may occur.

Sleep apnea is cessation of breathing (or reduction of respiratory effort) during sleep. Obstructive sleep apnea is secondary to obstruction of the upper airway, whereas central sleep apnea is caused by receptors in the brain. Symptoms of sleep apnea include poor sleep, frequent night time awakenings, daytime fatigue, and morning headaches. Snoring may or may not occur. Witnessed apneas may also be a seen by the patients’ sleep partner.

Restless leg syndrome is pain or discomfort in the legs (may be unilateral or bilateral) occurring during periods of inactivity usually at night. The pain is relieved by movement of the leg.

Periodic limb movements consist of the jerking of limbs during sleep resulting in sleep disturbance.

OSA, CSA, and PLMs may all be diagnosed with an overnight sleep study. A screening sleep study is not indicated. However, if patients have any of the above symptoms, an overnight sleep study (Polysomnogram/PSG) would be indicated. Treatment is warranted if the PSG is positive for sleep apnea. Again, the newer forms of NIV are recommended rather than CPAP for neuromuscular patients. Also, CPAP is generally not appropriate for central sleep apnea. Therefore, I usually recommend NIV for all patients with neuromuscular disease and sleep apnea.

The only caveat to the above recommendation is for patients who may have already received an NIV for respiratory dysfunction. If the patient has NIV already ordered, they generally do not also need a sleep study since the NIV will treat the sleep apnea automatically. In addition, most PLMs improve with treatment of the sleep apnea and NIV is usually all that is needed.

Restless leg syndrome is a diagnosis that is made clinically and no testing is needed. Multiple pharmacological treatments are available when the diagnosis is made.

Summary

I would like to again emphasize that pulmonary complaints are very rare in CMT patients. When problems occur, they are usually slow in onset and slow in progression. However, if they do occur it is a good idea to have a plan. Hopefully, this article provides a good starting point for that plan. I recommend seeing a pulmonologist who specializes in neuromuscular patients as well as being followed by a center that specializes in CMT patients. In addition, if equipment is ever needed, I recommend using a DME/respiratory therapist that specializes in neuromuscular patients.

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[1] NIV is a portable noninvasive ventilator. Trilogy and Astral are two common brand names. CPAP and BiPAP are extremely uncomfortable for neuromuscular patients with respiratory problems. When working with an NIV, the physician can program many more variables (rather than just a simple pressure), so it becomes much better tolerated by the patient. When treating sleep apnea, neuromuscular patients have a higher percentage of central sleep apnea (rather than obstructive). A CPAP would worsen central apnea, so NIV is again the device of choice.

[2] Patients with neuromuscular disease have a problem with respiratory muscles not with the lungs (usually … unless they have a different underlying lung problem … asthma, COPD, etc.). Since the problem is muscular in nature (and not lungs) oxygen would not help. Positive pressure ventilation helps. Usually oxygen is not beneficial.  Patients that have severe respiratory muscle weakness (again rare in CMT) and are not treated properly with positive ventilation may have decreased air movement (ventilation) which results in hypercapnia (high CO2). Oxygen may worsen the hypercapnia in some patients. However if the patient is treated properly with noninvasive pressure ventilation … adding or not adding oxygen will not make a huge difference. This is more likely in other neuromuscular diseases and less likely in CMT.